10-K

如果註冊人是《證券法》第405條所定義的知名經驗豐富的發行人，則通過勾選標記進行驗證。是 ☒ 沒有 ☐

如果註冊人無需根據該法案第13或15（d）條提交報告，則通過勾選標記進行驗證。是的不是 ☒

通過勾選標記確定登記人是否：（1）在過去12個月內（或在登記人被要求提交此類報告的較短期限內）提交了1934年證券交易法第13或15（d）條要求提交的所有報告，以及（2）在過去90天內是否遵守此類提交要求。是 ☒ 沒有預設

通過勾選標記檢查註冊人是否已在過去12個月內（或在註冊人被要求提交此類文件的較短期限內）以電子方式提交了根據S-t法規第405條（本章第232.405條）要求提交的所有交互數據文件。是 ☒ 沒有預設

通過複選標記來確定註冊人是大型加速申報人、加速申報人、非加速申報人、小型報告公司還是新興成長型公司。請參閱《交易法》第120億.2條規則中「大型加速備案人」、「加速備案人」、「小型報告公司」和「新興成長公司」的定義。

如果是新興成長型公司，請通過勾選標記表明註冊人是否選擇不利用延長的過渡期來遵守根據《交易法》第13（a）條規定的任何新的或修訂的財務會計準則。☐

通過勾選標記檢查註冊人是否已提交報告並證明其管理層根據《薩班斯-奧克斯利法案》（15 U.S.C.）第404（b）條對其財務報告內部控制有效性的評估7262（b））由編制或發佈審計報告的註冊會計師事務所執行。 ☒

如果證券是根據該法案第12（b）條登記的，請通過勾選標記表明文件中包含的登記人的財務報表是否反映了對先前發佈的財務報表錯誤的更正。 ☐

通過勾選標記來驗證這些錯誤更正是否是需要根據§240.10D-1（b）對註冊人的任何高管在相關恢復期內收到的激勵性補償進行恢復分析的重述。 ☐

通過勾選標記檢查註冊人是否是空殼公司（定義見《交易法》第120億.2條）。是的沒有 ☒

登記人的非關聯公司（不承認任何股份未被納入此類計算的人是關聯公司）持有的登記人有投票權和無投票權普通股的總市值，參考截至登記人最近完成的第二財政季度（2024年6月28日）的最後一個營業日普通股最後一次出售的價格計算）是美元488,707,919.

這份10-K表格年度報告包含符合1933年《證券法》(下稱《證券法》)第27A條和1934年《證券交易法》(下稱《交易法》)第21E條的前瞻性表述，這些表述與未來事件或我們未來的業務或財務表現有關。任何前瞻性陳述都涉及已知和未知的風險、不確定因素和其他因素，這些風險、不確定性和其他因素可能導致我們的實際結果、活動水平、業績或成就與此類前瞻性陳述明示或暗示的任何未來結果、活動水平、業績或成就大不相同。在一些情況下，前瞻性陳述由以下詞語來標識：「預期」、「相信」、「繼續」、「可能」、「估計」、「預期」、「未來」、「目標」、「打算」、「可能」、「正在進行」、「目標」、「計劃」、「潛在」、「預測」、「項目」、「尋求」、「應該」，「戰略」、「目標」、「將」和「將」或這些術語的否定或其他類似術語，旨在識別關於未來的陳述，儘管並不是所有前瞻性陳述都包含這些識別詞語。除歷史事實陳述外，前瞻性陳述包括但不限於：我們爲未來業務提供資金的能力；我們的財務狀況、收入、成本、支出、現金用途和資本需求；我們對額外融資的需求或我們現有現金資源足以滿足我們的運營需求的時期；我們研發活動、臨牀前研究和臨牀試驗的成功、進展、數量、範圍、成本、持續時間、時間或結果，包括啓動或完成任何臨牀前研究和臨牀試驗結果的時間，或提交、審查或批准任何監管申報的時間；我們獲得和維持任何候選產品的監管批准的時機和能力；我們的任何候選產品可能獲得的潛在利益；我們與第三方合作的成功；我們的合作伙伴可能向我們支付的任何款項；我們識別和開發新產品的能力；我們的知識產權地位；我們的商業化、營銷和製造能力和戰略；我們開發銷售和營銷能力的能力；我們對未來費用和額外融資需求的估計；我們識別、招聘和留住關鍵人員的能力；我們的財務業績；與我們行業競爭對手有關的發展和預測；我們的流動性和營運資本要求；新會計準則的預期影響；以及我們對任何本地和全球衛生流行病對我們業務的影響的預期，包括我們的研發活動、臨牀前研究和臨牀試驗、藥品供應和員工隊伍。

儘管我們相信本報告中包含的每個前瞻性陳述都有合理的基礎，但我們提醒您，這些陳述是基於我們對未來的估計或預測，這些估計或預測會受到已知和未知的風險和不確定性以及其他重要因素的影響，這些因素可能會導致任何前瞻性陳述明示或暗示的實際結果、活動水平、業績或成就有所不同。這些風險、不確定性和其他因素包括但不限於我們的關鍵會計政策；我們的臨牀前研究產生足以支持全球臨牀試驗申請的數據的能力及其時機；我們繼續建立和維護實現我們目標所需的公司基礎設施和人員的能力；我們的計劃的臨牀結果和時間安排，這些可能不支持我們的候選產品的進一步開發；監管機構的行動，這可能會影響臨牀試驗的啓動、時間和進度；我們在管理當前和未來的臨牀試驗和監管流程方面的有效性；我們的平台在成功確定可行的候選者方面的成功；核酸療法作爲一類藥物的持續開發和接受；我們在臨牀試驗中展示我們的立體候選藥物的治療益處的能力，包括我們在多種治療方式中開發候選藥物的能力；我們獲得、維護和保護知識產權的能力；我們針對侵權者強制執行我們的專利並針對第三方的挑戰捍衛我們的專利組合的能力；我們爲我們的運營提供資金和根據需要籌集額外資本的能力；來自其他開發類似用途療法的競爭；這些風險和不確定性包括但不限於本地和全球衛生流行病、俄羅斯和烏克蘭衝突、中東衝突、全球經濟不確定性、通脹波動、利率波動或市場中斷對我們業務的任何影響，以及本年度報告中「風險因素」一節以及我們提交給美國證券交易委員會(「美國證券交易委員會」)的其他文件中提到的其他風險和不確定性。

本報告中包含的每一項前瞻性陳述都基於我們目前已知的事實和因素以及我們對未來的預期的組合，而我們對此無法確定。

由於這些因素，我們無法向您保證本年度報告中的前瞻性陳述將被證明是準確的。此外，如果我們的前瞻性陳述被證明不準確，則不準確可能是重大的。鑑於這些前瞻性陳述中存在重大不確定性，這些陳述不應被視爲我們或任何其他人將在任何指定時間內或根本實現目標和計劃的陳述或保證。我們警告您不要過度依賴任何前瞻性陳述。

此外，本報告中的任何前瞻性陳述僅代表我們截至本報告日期的觀點，不應被視爲代表我們在任何後續日期的觀點。我們預計後續事件和事態發展可能會導致我們的觀點發生變化。儘管我們可能會選擇在未來的某個時候公開更新這些前瞻性陳述，但我們沒有義務公開更新任何前瞻性陳述，無論是由於新信息、未來事件還是其他原因，適用法律要求的除外。我們的前瞻性陳述並不反映我們未來可能進行的任何收購、合併、處置、合資企業或投資的潛在影響。

如本10-K表格年度報告中所用，除非另有說明或上下文另有說明，否則所提及的「Wave」、「公司」、「我們」、「我們的」、「我們」或類似術語是指Wave Life Sciences Ltd.和我們的全資子公司。

浪潮生命科學有限公司和浪潮生命科學有限公司。浪潮生命科學有限公司的名稱、浪潮生命科學標誌、PRISM以及浪潮生命科學有限公司的其他註冊和待定商標、商號和服務標誌均爲浪潮生命科學有限公司的財產。本年度報告中的10-K表格還包含其他屬於浪潮生命科學有限公司和其他公司的商標、商標和服務標誌。我們不打算使用或展示其他方的商標、商號或服務標誌，並且此類使用或展示不應被解釋爲暗示與這些其他方的關係、或對我們的背書或贊助。僅爲方便起見，本年度報告中提及的10-K表格中的商標和商號沒有使用®和™符號，但此類提及不應被解釋爲其各自所有者不會根據適用法律最大程度地主張其權利的任何指示。

我們在表格10-K中提供了本年度報告所載風險因素的以下摘要，以提高我們風險因素披露的可讀性和可訪問性。我們鼓勵您仔細審查本10-K表格年度報告中包含的全部風險因素，以獲取有關使我們的證券投資具有投機性或風險的重大因素的更多信息。該等風險及不確定性包括但不限於以下各項：

我們是一家臨牀階段的生物技術公司，專注於釋放核糖核酸（「RNA」）藥物（也稱爲寡核苷酸）或靶向RNA的藥物的廣泛潛力，以改變人類健康。我們的RNA藥物平台PRism®結合了多種治療方式、化學創新和對人類遺傳學的深入見解，實現治療罕見和常見疾病的科學突破。我們的RNA靶向模式工具包包括RNA編輯、拼接、使用RNA干擾（「siRNA」）的沉默和反序列沉默，爲我們提供了設計和可持續地提供最佳解決疾病生物學問題的候選物的獨特能力。我們多元化的管道包括肥胖症、阿爾法-1抗胰蛋白酶缺乏症（「AATD」）、杜氏肌營養不良症（「DMZ」）和亨廷頓病（「HD」）的臨牀項目，以及利用我們多功能RNA藥物平台的幾個臨牀前項目。

我們成立的基礎是認識到，利用化學創新來調節寡聚酸的藥理學性質存在一個重要的、尚未開發的機會。我們擁有十多年的經驗，在挑戰與寡聚酸設計相關的慣例和開創性的新型化學修飾以優化我們分子的藥理學性質。我們在臨牀試驗中看到，這些化學修飾增強了分子的效力、分佈和持久性。我們的新型化學反應還使我們避免使用複雜的遞送載體，例如脂質納米顆粒和病毒，而是使用臨牀驗證的結合物（例如， N- 乙基半乳糖胺或（「GalNAc」））或自由吸收以遞送至多種細胞和組織類型。我們擁有強大而廣泛的知識產權，包括我們的新型化學修飾。

我們一流的化學能力還打開了生物學的新領域，例如利用作用於RNA的腺苷脫氨酶（「ADAR」）進行信使RNA（「mRNA」）糾正和上調、選擇性沉默突變體等。通過開闢新的生物學領域，我們還開闢了減緩、阻止或逆轉疾病的新機會，並擴大了通過我們平台提供的可能性。

我們多模式平台的靈感基於對生物機械的認識 (即，解決人類疾病所需的酶）已經存在於我們的細胞中，並且可以通過正確的工具用於治療目的。我們相信，我們已經建立了行業中最通用的RNA靶向模式工具包，具有多種修復、恢復或減少蛋白質的方法，並根據特定疾病目標的獨特生物學設計最適合的解決方案。我們正在積極推進使用四種不同方式的項目，包括新型A-to-I RNA編輯寡聚核酸（「AIMers」）。

我們有意專注於使用寡聚酸而不是其他核酸模式（例如基因治療和DNA編輯）來靶向轉錄組。這一重點使我們能夠：

我們擁有強大且多樣化的潛在一流或最佳項目管道，可治療罕見和常見疾病：：

肥胖越來越被認爲是一種日益嚴重的全球流行病。在美國，估計有42%的成年人口患有肥胖症，美國和歐洲估計有17500萬成年人患有肥胖症。肥胖成年人患許多嚴重健康問題的風險更高，包括心臟病、2型糖尿病和某些形式的癌症;據估計，肥胖每年使美國醫療保健系統損失近1730億美元。

美國和歐盟（「歐盟」）批准了兩種用於治療肥胖症的GL-1受體激動劑：Saxenda（利拉肽，諾和諾德）和Wegovy（索馬魯肽，諾和諾德）。替西帕特胺（Eli Lilly）於2023年11月被美國食品藥品監督管理局（「FDA」）批准爲Zepbound，並被歐洲藥品管理局（「EMA」）批准爲Mounjaro，是一種GLP-1/GIP受體激動劑。FDA批准的其他肥胖療法包括Xenical（H2-Pharma，1999年在美國獲得批准）、Qsymia（Vivus，2012年在美國獲得批准）和Contrave（Currax Pharmaceuticals，2014年在美國獲得批准）。

儘管GLP-1受體激動劑可誘導體重減輕，但肥胖症的需求仍然沒有得到滿足，因爲GLP-1受體導致體重減輕，但以犧牲肌肉質量爲代價。例如，在索馬魯肽的3期研究中，總體重減輕的34%來自瘦體重減輕（King 2021），在替西帕特的3期研究中，治療導致脂肪量減輕約34%，瘦體重減輕約11%（Jastreboff 2022）。研究還表明，GLP-1可以抑制一般獎勵系統，並與耐受性差、頻繁（每週）給藥和高達68%的停藥率有關。

WVE-007是一種GalNAc-siRNA，旨在沉默INHBE基因以誘導脂肪分解（脂肪燃燒），同時保留肌肉質量以恢復和維持健康的代謝特徵。雜合INHBE功能喪失（「LOF」）人類攜帶者表現出健康的代謝特徵，包括腰臀比降低和患2型糖尿病或冠狀動脈疾病的幾率降低，並且INHBE減少50%或更多預計將恢復健康的代謝特徵。在2023年研發日之際，我們分享了體內飲食誘導肥胖（「DIO」）小鼠的概念驗證數據表明INHBE沉默遠遠超出了預期的50%治療閾值，這導致與對照組相比體重大幅降低和內臟脂肪減少。這些是第一個證明INHBE沉默的數據體內在動物模型中與雜合功能喪失攜帶者的表型一致。

WVE-007利用我們的下一代GalNAc-siRNA形式。在臨牀前飲食誘導的肥胖（「DIO」）小鼠模型中，我們的INHBE GalNAc-siRNA已經證明了高效的INHBE沉默（ED 50 < 1毫克/公斤），一次低個位數劑量後持續沉默，支持人體每六個月或每年皮下給藥，體重減輕，肌肉質量不損失，脂肪質量減少，對內臟脂肪有優先影響，與INHBE LOF在人類遺傳學中的概況一致。

統計數據：（左、中、右）線性混合效應ANOVA，每個時間點（左）或每個組織（中、右）的邊際治療效應與PBS的事後比較 * p < 0.05

在DIO小鼠的一項頭對頭研究中，我們觀察到單劑量的INHBE GalNAc-siRNA具有與索馬魯肽類似的減肥效果。此外，在停止索馬魯肽治療之前使用我們的INHBE GalNAc-siRNA治療可以減少預期的反彈體重增加。此外，在一項正在進行的DIO小鼠中的另一項研究中，當作爲索馬魯肽的添加劑給藥時，我們的INHBE GalNAc-siRNA單劑量使單用索馬魯肽觀察到的體重減輕增加了一倍，並且這種效果在整個研究期間持續存在。

左：小鼠中的10 nmo/kg相當於人體中的GLP-1的治療劑量。統計數據：線性混合效應方差分析，對每個時間點的Sempine與Sempine + INHBE GalNAc-RNA的邊際治療效應進行事後比較 * p < 0.05;右側統計：線性混合效應方差分析，對每個治療的第28天與第56天的邊際效應進行事後比較 * p < 0.05

2025年2月，我們宣佈啓動INLIGHT，這是WVE-007治療肥胖症的首個人體I期臨牀試驗。INLIGHT正在招募超重或肥胖的成年人，以評估安全性、耐受性、藥代動力學（「PK」）、目標參與的生物標誌物、體重和成分以及代謝健康。INLIGHT的給藥工作正在進行中，我們預計將於2025年下半年從INLIGHT提供臨牀數據。

我們正在利用我們的RNA編輯平台能力來開發一流的AATD治療方法。AATD是一種罕見的遺傳性疾病，通常由G-to-A點突變引起 SERPINA1 基因;這種突變的基因被稱爲 Z 基因。這種突變導致肝細胞中Z-AAT蛋白的錯誤摺疊和聚集，以及肺部缺乏功能性Alpha-1抗胰蛋白酶（「AAT」）。AATD患者通常會表現出進行性肺損傷、肝損傷或兩者兼而有之，導致頻繁住院並可能出現晚期肺病和/或肝臟疾病。每週一次的靜脈加強治療是患有肺部病理的AATD患者的唯一治療選擇;目前還沒有批准的治療方法來解決肝臟病理。在美國和歐洲，大約有20萬人是Z基因純合的，Z基因是最常見的嚴重疾病形式。

美國目前批准有五種治療方法，用於治療先天性缺乏Alpha 1-蛋白酶抑制劑（「Alpha 1-PI」）而患有肺氣腫的成年人的慢性增強和維持治療。根據FDA對每種藥物的標籤，任何Alpha 1-PI加強治療對Alpha 1-PI缺乏症的肺急性加重和肺氣腫進展的影響尚未在隨機對照臨牀試驗中得到證實。歐盟也批准了增強療法，但報銷和可及性因國家而異。AATD患者還可以接受用於其他肺部疾病的治療，包括支氣管擴張劑打開氣道和皮質類固醇以減少AATD患者肺部常見的慢性炎症。

目前還沒有批准的療法來防止錯誤摺疊的AAT蛋白在肝臟中積聚。治療方法可以幫助處理腸道出血、腹部液體、營養問題和肝臟疤痕造成的其他併發症，但最終許多患者將需要進行肝臟移植。

我們的AATD計劃使用我們新型的GalNAc結合的AIMers（RNA編輯寡聚核酸）和內源性ADAR酶來糾正突變型WRPINA 1 mRNA中的單個鹼基。通過糾正導致大多數Pi*ZZ基因型AATD病例（在美國和歐洲約有200，000個）的單一RNA鹼基突變，RNA編輯可能提供一種理想的方法來增加野生型AAT蛋白的循環水平並減少肝臟中的突變蛋白聚集，從而同時解決疾病的肺部和肝臟表現。

WVE-006是AATD領域的一流項目，也是目前臨牀開發中最先進的項目，該項目使用寡核酸利用內源性酶進行RNA編輯。我們研究WVE-006作爲AATD治療方法的RestorAATion臨牀項目由兩個部分組成：RestorAATion-1，一項針對健康志願者的研究;和RestorAATion-2，一項針對具有純合Pi*ZZ突變的AATD患者的研究。我們已經在RestorAATion-1頂級隊列的健康志願者中完成了多次給藥，劑量水平高於RestorAATion-2中任何隊列的計劃劑量。RestorAATion-2是一項1b/2a期開放標籤研究，旨在評估WVE-006在具有純合Pi*ZZ突變的AATD患者中的安全性、耐受性、藥效學（「PD」）和PK。該試驗包括單次給藥劑量增加（「SAD」）和多次給藥劑量增加（「MAD」）部分。

2024年10月，我們宣佈了正在進行的1b/2a期RestorAATion-2研究的積極機制證明數據：在該研究的前兩名患者中單次皮下注射200毫克WVE-006後，第15天血漿中循環野生型M-AAT蛋白達到平均6.9微摩爾，佔總AAT的60%以上。中性粒細胞彈性蛋白酶抑制較基線的增加與功能性M-AAT的產生一致。平均總AAT蛋白從基線時的定量水平以下增加到第15天的10.8微摩爾，達到了歷史上監管機構批准AAT增強療法的基礎水平。早在第3天至第57天就觀察到總AAT和M-AAT蛋白較基線增加。WVE-006耐受性良好，安全性良好。RestorAATion-2以及健康志願者的RestorAATion-1試驗中的所有不良事件均爲輕度至中度，未報告嚴重不良事件（「嚴重不良事件」）。這些數據是人類RNA編輯的首次臨牀演示。

於2025年第一季度，我們在第一個RestorAATion-2隊列中開始多次給藥，患者每兩週接受200 mg皮下給藥，並開始第二個RestorAATion-2單次給藥隊列，劑量爲400 mg。我們預計將在2025年分享來自RestoraAATion-2的多劑量數據。

葛蘭素史克擁有WVE-006的全球獨家許可，在我們完成RestorAATion試驗後，臨牀開發和商業職責將移交給葛蘭素史克。根據合作條款，我們有資格獲得高達52500萬美元的開發、發佈和商業里程碑付款，以及高達十幾歲的兩位數分層特許權使用費（佔WVE-006淨銷售額的百分比）。2023年12月，我們宣佈與葛蘭素史克合作實現了第一個WVE-006里程碑，支付了2000萬美元。

臨牀前數據顯示，在已建立的AATD小鼠模型（NSG-PiZ）中，用WVE-006治療導致血清AAT蛋白水平高達30微摩爾。WVE-006還導致血清中約50%野生型M-AAT蛋白恢復，中性粒細胞彈性蛋白酶抑制活性增加3倍，表明恢復的M-AAT蛋白具有功能。我們的AATD AIM對WRPINNA 1 RNA具有高度特異性體外和體內基於全轉錄組分析。

DMZ是一種罕見的遺傳性進行性神經肌肉疾病，由線粒體突變引起 dystrophin X染色體上的基因影響着全球約5，000名新生男孩（每年約20，000例新病例）。肌萎縮蛋白蛋白是稱爲肌萎縮蛋白相關蛋白複合物的蛋白複合物的一部分，該複合物充當錨，通過肌肉細胞膜將每個肌肉細胞的結構框架與細胞外的蛋白質和其他分子的網格連接起來。肌營養不良蛋白相關蛋白複合物在收縮和放鬆期間保護肌肉免受損傷。DMZ患者通常在早年出現肌肉無力，並在青少年時期被迫坐在輪椅上。隨着疾病進展，DMZ患者通常會出現呼吸道、骨科和心臟併發症。心肌病和呼吸困難通常從20歲開始，很少有DMZ患者能活到30多歲。

雖然有批准的DMD治療方法，但沒有治癒方法，並且仍然存在顯著的未滿足的醫療需求。在大多數國家，皮質類固醇是標準的藥物治療，它可以減緩肌無力的進展，並將肌無力的喪失延遲兩到三年。2017年，Emflaza（deflazacort）成爲FDA批准的第一種皮質類固醇，用於治療DMD患者。Santhera Pharmaceuticals的Agamree（vamorolone）是一種替代類固醇，於2023年在美國和歐盟獲得批准。 2024年，FDA批准了Italfarmaco/ITF Therapeutics的Duvyzat（吉維司他），一種組蛋白脫乙化酶抑制劑。

四種外顯子跳躍療法已在美國獲得批准，所有這些都是在加速批准途徑下。其中包括Sarepta Therapeutics的三種產品：Exondys 51 （eteplirsen）用於外顯子51跳躍，於2016年批准; Vyondys 53（golodirsen）用於外顯子53跳躍，於2019年批准; Amondys 45（casimersen）用於外顯子45跳躍，於2021年批准。 NS Pharma的Viltepso（viltolarsen）於2020年獲批用於53號外顯子跳讀。所有這些產品都需要每週靜脈輸注，迄今爲止，這些產品都沒有在驗證性試驗中證明其臨牀益處。

Sarepta Therapeutics的Elevidys是一種微肌營養不良蛋白基因療法，已在美國和部分前歐盟市場上市。目前，美國的標籤適應症是針對至少四歲且確診患有DMZ基因突變的非臥牀和非臥牀DMZ患者。包括非臥牀DMZ患者的適應症是根據傳統批准獲得的，包括非臥牀DMZ患者的適應症是根據Elevidys微肌營養不良蛋白的表達在加速批准下獲得的。對非臥牀DMZ患者的繼續批准可能取決於驗證性試驗中臨牀受益的驗證和描述。

2014年，PTC Therapeutics的Translarna（ataluren）是第一個獲得EMA有條件批准的疾病修飾治療，用於在DMD中有無義突變的DMD患者（佔DMD病例的12%）。 dystrophin基因然而，於2023年，EMA人用藥品委員會（「CHMP」）就有條件上市許可續期發出否定意見，而於2024年，CHMP再次確認此否定意見。一旦歐盟委員會通過，這一裁決將導致Translarna退出歐盟市場。

在DMZ方面，我們正在推進WVE-N531，該方法旨在跳過肌營養不良蛋白基因內的第53號WVE-N531的設計目的是在mRNA前加工過程中使細胞拼接機制跳過第53號exon，從而恢復肌營養不良蛋白mRNA閱讀框，並能夠產生截短但有功能的肌營養不良蛋白。Exon skipping在天然基因調節元件的控制下，從內源性肌營養不良蛋白基因（而不是從外來載體表達的微型或微型肌營養不良蛋白）產生肌營養不良蛋白，導致對其表達的生理控制。WVE-N531是我們第一個將在臨牀上評估的包含PN主幹（「PN」）化學的拼接候選物。2024年第三季度，FDA授予WVE-N531罕見兒科疾病認定和孤兒藥認定。

2022年12月，我們宣佈了WVE-N531 1b/2a期概念驗證、開放標籤試驗A部分的積極更新，該試驗在三名適合第53號突變的DMZ男孩中進行。開始每隔一週10毫克/公斤多次給藥後，六週觀察到肌肉中WVE-N531和exon跳，在試驗中實現了概念驗證。WVE-N531似乎也安全且耐受性良好。

2023年9月，我們分享了對A部分概念驗證試驗的肌肉活檢數據的分析，表明WVE-N531存在於肌源性幹細胞中，而肌源性幹細胞是肌肉再生不可或缺的組成部分。這是臨牀研究中首次證明肌源性幹細胞的吸收，並支持WVE-N531與其他治療方法（包括基因治療）的潛在差異。

2023年12月，我們開始在開放標籤試驗的2期部分FOWARD-53中給予WVE-N531。該研究旨在每兩週輸注10毫克/公斤的WVE-N531（「Q2 W」），並在給藥24周和48周後進行肌肉活檢。主要終點將是肌萎縮蛋白蛋白水平，該試驗還將評估PK、數字和功能終點以及安全性和耐受性。

2024年9月，我們宣佈了正在進行的2期FORWARD-53研究的積極中期數據。入組了11名適合進行第53號突變的男孩（5-11歲; 10名不臥牀，1名不臥牀）。中期分析在10毫克/公斤Q2 W給藥24周後進行。WVE-N531看起來安全且耐受性良好。在對流動參與者的預先指定的分析中，我們觀察到平均肌肉內容物調整的肌萎縮蛋白表達爲9.0%，未調整的肌萎縮蛋白表達爲5.5%，參與者之間具有高度一致性。

* 從門診患者的預定平均分析中排除;使用公式進行肌肉含量調整：MHC標準化肌萎縮蛋白/（總肌纖維面積/活檢切片總面積）;圖表顯示所有具有適當活檢樣本的患者（包括非門診）;通過Western Blot測量肌萎縮蛋白（AB 15277）

從兩種同工型中量化了肌萎縮素的表達，與在病情較輕的貝克爾肌營養不良症患者中觀察到的一致。此外，我們觀察到肌肉健康的血清生物標誌物有了有意義的改善，WVE-N531在肌源性幹細胞和肌纖維中定位。平均骨骼肌濃度約爲41，000納克/克，組織半衰期爲61天，支持未來每月給藥。

FORWARD-53試驗正在進行中，所有患者均選擇在研究的計劃擴展部分繼續治療，每月接受一劑WVE-N531。2025年第一季度，我們預計將提供爲期48周的FORWARD-53數據和監管機構關於加速批准途徑的反饋。在這項試驗取得積極結果之前，我們計劃使用PN修飾的拼接寡核酸來推進更廣泛的DMZ管道，旨在跳過其他exon，目標是爲更多患有DMZ的男孩群體提供新的治療選擇。

HD是一種罕見的遺傳性神經退行性疾病，會導致過早死亡，目前尚無治癒方法。在HD患者中，大腦中神經元逐漸喪失，導致認知、精神和運動障礙。HD是由亨廷頓蛋白（「亨廷頓蛋白」）中的突變（擴大的胞苷-腺苷-鳥苷（「MAG」）三重重複）引起的HTT”）基因，其導致mHTT蛋白的產生並降低表達的wtHTT蛋白的量。HD患者仍然表達一些wtHTT蛋白，這對神經元功能很重要，並且可能在成人大腦中具有神經保護作用。研究表明mHTT蛋白的獲得和wtHTT蛋白的同時丟失可能驅動HD的病理生理學的多方面機制。

因此，旨在降低mHTT但同時抑制wtHTT的HD治療方法可能會產生有害的長期後果。野生型HTT對於成人中樞神經系統的正常神經元功能和預防HD都很重要。它可以在多種模型系統中預防應激誘導的神經退行性病變：在培養的神經元中，wtHTT可以保護應激誘導的細胞死亡;在小鼠中，wtHTT的出生後缺失導致進行性神經表型、神經退行性病變和過早死亡，而wtHTT的過度表達在應激期間傳遞神經保護，包括缺血和其他類型的中樞神經損傷，以及NDA誘導的興奮性毒性。在YAC 128 HD小鼠模型中，wtHTT的過表達改善了紋狀體神經病理學，而野生型小鼠Htt的喪失則改善了運動性能、存活率和紋狀體神經元大小。

在HD患者中，調節元件的變體會影響相關HTT基因的表達。相對於G變體，A變體在該位置減少表達。因此，當A變體與mHTT關聯時，mHTT的表達會減少，疾病發作會延遲（平均10年）。相比之下，當A變體與wtHTT相關時，wtHTT的表達會減少，疾病發病時間會提前（平均四年），這表明wtHTT的表達增加可以保護患者免受HD的侵害。總而言之，這些研究提供了證據，表明wtHTT在壓力期間既具有神經保護作用，又具有針對HD的專門保護作用;因此，我們相信，一種可以減少mHTT產生同時保留wtHTT的基因選擇性治療方法可能是理想的。

在HD患者中，調節元件的變體會影響相關HTT基因的表達。因此，降低mHTT表達的變體與疾病發病延遲有關（與增加mHTT表達的變體相比，平均延遲10年）。相比之下，降低wtHTT表達的同一變體與發病早相關（與wtHTT表達增加相比，平均需要四年），這表明wtHTT表達增加可以保護患者免受HD的影響。總而言之，這些研究提供了證據，表明wtHTT在壓力期間既具有神經保護作用，又具有針對HD的專門保護作用;因此，我們相信，一種可以減少mHTT產生同時保留wtHTT的基因選擇性治療方法可能是理想的。

HD的症狀通常出現在30至50歲之間，並在未來10至20年內惡化。許多人將HD的症狀描述爲類似於同時患有肌萎縮性側索硬化症、帕金森病和阿爾茨海默病。患者的運動功能下降和心理障礙。症狀出現後的預期壽命約爲20年。在症狀最嚴重的階段，通常持續10年以上，受影響的人變得完全依賴他人來管理所有日常生活活動;他們失去了做出決定、養活自己和行走的能力，並且通常需要過早地安置在長期護理機構。據估計，在美國和歐洲，有超過200，000名患有HD的人處於所有疾病階段;約160，000人處於症狀前，約65，000人處於症狀狀態。我們的基因選擇方法可能使我們能夠解決有症狀和症狀前人群的問題。

大腦深層區域中的中等多刺神經元由尾狀核和殼核組成，對HD中的死亡特別敏感。通過磁共振成像（「MRI」）測量的尾狀體積是一種成像生物標誌物，在疾病的最早階段始終顯示萎縮，並且它是作爲疾病進展標誌的生物標誌物之一（Tabrizi等人，2022年柳葉刀神經元）。我們對TRACK-HD和PREDICT-HD的縱向自然史數據的評估表明，尾狀核萎縮率絕對降低1%與HD患者的殘疾發作延遲至少7.5年有關。

TRACK-HD（n=366）和PREDICT-HD（n= 1，078）是縱向HD自然史研究，包括MRI腦部成像、臨牀結局評估。保爾森等人，Neurosci.2014，Tabrizi等人，Lancet Neurol 2009，Tabrizi等人，Lancet Neurol 2012，Tabrizi等人，柳葉刀神經元。2013

目前還沒有批准的治療方法可以逆轉或減緩HD進展。目前的藥物療法僅針對HD症狀。抗精神病藥物用於治療抑鬱、易怒和舞蹈症（不自主運動）。Xenazine（四苯那嗪）、Austedo（deeterbenazine）和截至2023年8月，Thomzza（Valbenazine）是美國唯一批准用於治療與HD相關的舞蹈病的療法。在歐盟，Xenazine、Haldol（氟吡醇）和Tiapridal（硫必利）被批准用於治療與HD相關的舞蹈病。

在HD中，我們目前正在推進WVE-003，這是一種立體純的基因選擇性寡聚體，旨在選擇性地靶向rs 362273，rs 362273是單核苷酸多態性（「SNP」）的變體，「mHTT SNP 3」，與HTT基因內致病的mHTT mRNA轉錄物相關（Iwamoto等人，MTNA）。根據已發表的文獻（Carroll等人，分子療法，2011年），未來可能會使用其他SNP靶向候選藥物來治療高達80%的HD。

WVE-003結合了我們專有的PN化學。通過SNP 3靶向mRNA使我們能夠降低突變型基因轉錄物的表達，同時保持健康的轉錄物相對完整，從而保留野生型（健康）亨廷頓蛋白（「wtHTT」）蛋白，這對神經元功能很重要。只有降低mHTT的基因選擇性方法才有可能既保護wtHTT蛋白的庫，又降低神經元中mHTT與wtHTT的比例，從而可能將wtHTT從mHTT的抑制作用中釋放出來。在臨牀前研究中，WVE-003顯示mHTT mRNA的劑量依賴性和選擇性減少體外，以及有效且持久的mHTT mRNA和蛋白質的敲除體內在小鼠模型中。

2023年第三季度，我們與武田製藥有限公司（「武田」）的合作取得了里程碑，該合作涉及WVE-003在非人類靈長類動物中的非臨牀研究的積極結果，並向我們支付了700萬美元。這項研究顯示，包括紋狀體在內的大腦深層區域中WVE-003的組織暴露水平顯着，並增強了我們現有的數據集，證實了我們的寡聚酸能夠分佈到對HD重要的中樞神經系統區域。

SEN CT-HD是一項全球、多中心、隨機、雙盲、安慰劑對照的1b/2a期臨牀試驗，旨在評估WVE-003在確診爲HD的患者中的安全性和耐受性，這些患者處於疾病早期階段，並攜帶SNP 3與其MAG擴展相關。其他目標包括評估PK和探索性PD以及臨牀終點。

2024年6月，我們公佈了WVE-003的1b/2a期SELECT-HD研究的積極臨牀數據。來自該試驗的多劑量部分的結果（其評估了每八週施用三次劑量的30 mg WVE-003）顯示了靶向接合向臨牀的明確轉化，其中腦脊液（「CSF」）mHTT的統計學顯著、有效、持久和等位基因選擇性降低高達平均46%，同時保留了wtHTT蛋白。

多劑量隊列還揭示了mHTT減少與尾狀核萎縮減緩之間存在統計學顯着的相關性，表明了基因選擇性mHTT減少的潛在益處。通過MRI測量的尾狀核萎縮是HD疾病進展的良好特徵指標。

基線MRI單劑量第1-3天MRI;最終MRI多劑量第169天;在MNI空間標準化後通過雅可比積分推導出DTS。結果來自混合模型重複測量（MMRM）分析; CSF mHTT濃度：單次給藥基線，多次給藥第141天

在多劑量隊列中，WVE-003總體安全且耐受良好，出現輕至中度不良事件（「AE」），無嚴重不良事件。2024年11月，即一名患者完成最後一次安全訪視五個月後，報告了一起嚴重不良事件，我們評估該事件與WVE-003無關。

在取得積極的臨牀結果後，我們開始與FDA合作。2024年11月，我們收到了FDA的初步支持反饋，FDA認識到HD的嚴重性，並就加速批准的潛在途徑接受我們並與我們合作。FDA對我們評估生物標誌物（包括尾狀核萎縮）的計劃持開放態度，作爲評估HD進展並有可能預測臨牀結果的終點。同樣在2024年11月，FDA授予WVE-003孤兒藥稱號。

WVE-003的全球可能註冊的2/3期研究正在準備中，該研究將尾狀核萎縮作爲主要終點。我們預計將於2025年下半年提交WVE-003的研究性新藥（「IND」）申請。

我們正在多個疾病領域推進新的目標，以擴大我們全資擁有的項目渠道。我們令人信服的臨牀前數據表明，我們的寡核苷酸可以在不需要複雜輸送工具的情況下分佈到各種組織和細胞中，使我們能夠應對包括肺和腎臟疾病在內的各種疾病。在RNA編輯中，我們已經在臨牀前證明，我們可以通過恢復或糾正治療AATD的蛋白質功能來編輯以糾正單基因疾病。在AATD工作的基礎上，我們已經證明了我們有能力通過編輯RNA來上調或增加mRNA轉錄本的穩定性，從而增加內源蛋白質的產生，從而解決更普遍的疾病。利用我們專有的由基因數據集和深度學習模型提供支持的「編輯反面」，我們已經確定了幾個RNA編輯目標，這些跡象利用了易於獲得的生物標記物，提供了在人類身上進行概念驗證的有效途徑，並代表了有意義的商業機會。

我們全資擁有的發現階段管道包括肝臟和肝外靶點，包括肝臟中的三個RNA編輯程序，這些程序利用GalNAc結合物，並具有有效的臨牀概念驗證路徑。

通過與葛蘭素史克的合作，我們還利用葛蘭素史克的新穎基因見解來擴大我們的全資管道。此外，我們和葛蘭素史克正在積極開展多個目標驗證計劃，作爲葛蘭素史克合作計劃，我們的所有成本和費用均由葛蘭素史克預付。2024年4月，葛蘭素史克在實現目標驗證後選擇了前兩個項目來推進開發候選人，引發葛蘭素史克向我們支付了總計1200萬美元的初始付款。這些程序利用我們的下一代GalNAc-siRNA形式，用於肝臟病學。

我們計劃在2025年分享來自我們全資擁有的肝臟和肝外RNA編輯計劃的新臨牀前數據。2026年，我們預計將啓動其他RNA編輯程序的臨牀開發，包括PPLA 3、LDLR和APOB。

我們正在通過利用PRism來建設一家領先的RNA藥品公司，爲醫療需求高度未滿足的適應症設計、開發和商業化優化的疾病修飾藥物。我們擁有強大且多樣化的一流或一流的RNA藥物管道，使用我們的RNA編輯、拼接、使用SiRNA的沉默和安東尼沉默模式。我們的主導項目旨在解決罕見和常見疾病，包括肥胖、AATD、DMZ和HD，以及肝臟疾病和HeFH的臨牀前項目。除了推動臨牀和臨牀前項目外，我們還在不斷投資PRism，以充分釋放我們獨特且不斷擴展的平台能力的潛力。

我們的PRism平台展示了一流化學與人類遺傳學的強大融合。該平台建立在這樣一種認識之上：通過利用這些分子的三個關鍵特徵（鹼基修飾和序列、化學和立體化學）來調節寡聚酸的藥理學性質存在重大機會。我們獨特的控制立體化學的能力提供了優化藥理學特徵以及開發和生產立體純寡聚酸所需的分辨率。立體純寡聚酸由原子在每個連接處精確且有目的地以三維方向排列的分子組成。我們的立體純寡核苷酸與目前市場上或其他人開發的手性骨架修飾或「基於混合物」的寡核苷酸不同，我們認爲這些寡核苷酸在穩定性、催化活性、功效或毒性方面沒有優化。我們相信，PRISM有可能爲複雜寡核苷酸混合物的分子表徵建立一個新的行業標準。我們設計立體純寡核苷酸的合理過程使我們能夠選擇性地優化特定治療方式的化學修飾，以產生同類最佳的寡核苷酸。

我們相信PRism是寡聚酸開發方面的重大進步。我們方法的優點包括：

在我們的基礎上 Nature Biotechnology 論文（Iwamoto N等人. Nature Biotechnol. 2017年; 35（9）：845-851），我們描述了我們的研究，使用我們的專有化學設計和合成基於米波美生的立體純寡聚酸和寡聚酸混合物。Mipomersen是一種包含20個核苷和19個PS修飾的寡聚體，通過傳統的寡聚體化學合成;因此，它是超過500，000種不同立體同體的混合物（219 = 524，288）。我們合理地設計和合成了米波美生的各個立體同體，每種同體都具有位置特異性和不同的立體化學，並進行了比較這些定義的立體同體與米波美生立體混合物的研究。這些和其他臨牀前研究表明，立體化學會影響藥理學，通過控制立體化學，我們可以調節藥理學的多個方面，包括穩定性、催化活性和功效。

我們隨後發表了多篇額外的手稿，提供了證據，表明可以開發立體純寡聚酸，使其具有比立體無規寡聚酸更好的藥理學。

我們對骨架化學和立體化學對寡核酸藥理學的影響的初步研究集中在廣泛使用的磷酸二酯（「PO」）和硫代磷酸（「PS」）骨架上，因爲它們適合所有寡核酸模式。2020年，我們將PN化學引入到我們的骨架修飾中;這種骨架修飾用含氮部分取代了磷酸二酯鍵中的非橋連氧原子，如下所示。

We have incorporated these PN modifications – specifically phosphoryl guanidine – into oligonucleotide compounds. As with PS modifications, PN modifications are chiral, and we have the capacity to control PN backbone stereochemistry. Unlike PS modifications, PN modifications are neutral, meaning that the negative charge of the oligonucleotide is reduced with every PN modification added to the backbone. In preclinical experiments, we have demonstrated that judicious use of PN backbone chemistry modifications in stereopure oligonucleotides have generally increased potency, tissue exposure and durability of effect across our RNA editing, siRNA, splicing, and antisense modalities.

We have also investigated the impact of PN chemistry and performed experiments under gymnotic or free uptake conditions. In the graph labeled one below, the data demonstrate the contrast between AIMer uptake in cells, depending on whether it incorporates PN chemistry, shown in light blue, or not, shown in dark blue. To the right, in the graph labeled two, the data demonstrate the proportion of AIMer released from endosomes inside the cell. The addition of PN chemistry drove a greater than 2-fold increase in cellular uptake and an over 4-fold increase in endosomal release compared with PS chemistry.

Below, we also demonstrated the benefits of PN chemistry on cellular residency, with a higher percentage of PN-containing molecules persisting within the cell, a 5-fold benefit on nuclear uptake, and ultimately, evidence this modification leads to a dramatic 30-fold improvement in target engagement in a cell free lysate system.

2023年，我們引入了鹼基修飾（例如，N-3-尿苷，N3 U）加入到我們的化學修飾中，使我們能夠將寡聚核酸的活性調節到生物學模式。例如，我們已經表明，在RNA編輯寡核酸的「孤兒位置」（與轉錄物中的編輯位點相對）引入N3 U，可以增強臨牀前研究中多種序列的RNA編輯。

在2024年 Nucleic Acids Research 論文（Lu等人，2024年Nuc Acid Res; doi.org/10.1093/nar/gkae681 N），我們描述了具有鹼基修飾以及序列、糖和骨架修飾的新AIMer設計的開發，這些修飾比我們之前的設計提高了RNA編輯效率。結合了新型骨架和2 '糖修飾模式的AIM支持增強多個序列的編輯效率。通過在孤兒位置摻入N3 U代替胞苷（C），進一步提高效率。分子建模表明，N3 U可能會通過穩定AIMer-ADAR相互作用並可能減少將目標鹼基翻轉到活性位點所需的能量來增強ADAR催化活性。支持這一假設的是，在多個序列和多個最近鄰序列組合中，含有N3 U的AIM始終比含有C的AIM增強了RNA編輯。這些對AIM的修改改進了RNA編輯體外在.中體內.

我們不斷探索我們廣泛的陣容中的新修飾和新的修飾組合如何重新定義寡核酸療法的可能性。

使用PRism，我們設計和優化了不同的立體純寡聚酸組，這使我們能夠描述和比較各種化學修飾對影響特定形態的關鍵性質的影響。

在下一部分中，我們描述了不同的治療模式，我們使用PRISM來優化立體純寡聚酸並開發專爲目的構建的候選藥物以最佳地解決疾病生物學問題。

我們已將我們的PRism平台應用於生成短的、單鏈的、高度特異性的A-to-I（G）RNA編輯寡聚核酸（稱爲「AIMers」）。由於我們的AIM相對較短且穩定（完全化學修飾），因此我們可以通過皮下給藥利用臨牀證明的GalNAc介導的向肝細胞的遞送。我們正在開發具有和不具有GalNAc結合的完全化學修飾的AIM。在臨牀前研究中，我們評估了數千種AIMer，評估了各種糖和鹼基修飾、骨架化學和立體化學以及AIMer長度等其他參數，以深入了解AIMer的結構與其引發RNA編輯活動的能力之間的關係。

通過PRism，我們生成了針對化學和立體化學進行優化的立體純AIM，可以促進細胞模型中使用內源性ADAR酶進行RNA編輯。如下圖所示，我們顯示了具有和不具有PN連接的β-肌動蛋白編輯立體純AIMer的活性，與原代人肝細胞中匹配的立體無規AIMer（黑色顯示）進行了比較。這些AIMer與GalNAc結合，以增加肝細胞的吸收。PN化學的添加大大提高了效力和編輯效率。

在我們發表的基礎RNA編輯論文中 Nature Biotechnology （Monian P等人。阿爾。，2022; doi.org/10.1038/s41587-022-01225-1），我們展示了高效的RNA編輯體外與我們的AIMers在多種細胞系中進行研究，包括非人靈長類動物（「NHP」）和人原代肝細胞，如下圖所示。我們觀察到三種化學上不同的立體純AIM（ACTB 1、ACTB 2、ACTB 3）通過GalNAc介導的吸收進行有效的、劑量依賴性的RNA編輯。

接下來我們評估了這些相同的ACTB編輯AIM 體內在NHP中，結果如下圖所示。在這項研究中，我們每天皮下注射NHP一次，持續五天。我們在最後一次給藥後兩天和45天的基線時採集了肝臟活檢樣本來評估編輯。與0%編輯的基線相比，最後一劑疫苗兩天後，我們檢測到高達50%的編輯，如下圖中間所示。這些編輯結果是持久的：最後一劑疫苗接種後45天，我們繼續看到顯着的編輯。PK數據（如下圖左圖所示）證實，當時肝臟中仍然可以檢測到大量的AIMer。爲了評估整個轉錄組的脫靶編輯，使用突變調用軟體來調用編輯位點。從該分析中，我們觀察到轉錄組中的標稱脫靶編輯。發生潛在脫靶編輯的位點主要映射到轉錄組的非編碼區，並且在分析中具有低讀段覆蓋率或以低於10%的低百分比發生，表明這些是相對罕見的事件，如右圖所示。

我們已經證明UGP 2 mRNA的有效（高達65%）和持久（至少四個月）編輯體內在人ADAR小鼠模型中單次未結合的AIMer給藥後，在中樞神經系統的多個區域中出現，如下圖所示。

我們還證明，在小鼠中觀察到的RNA編輯在轉移到非人類靈長類動物時會轉化。如下圖左圖所示，我們觀察到UGP 2 mRNA的編輯體內在人ADAR小鼠模型中單次未結合的AIMer給藥後，在中樞神經系統的多個區域出現。如右圖所示，我們在非人靈長類動物中單次鞘內未結合AIMer給藥後觀察到ACTB mRNA在中樞神經系統多個區域的編輯。

We have also observed productive editing beyond liver and CNS with unconjugated AIMers in multiple tissue types including the retina in mice (below top right), kidney, liver, lung and heart of NHPs (below bottom left), and human PBMCs in vitro (below bottom right).

We also observed potent, durable, and specific editing across multiple additional tissues following systemic administration of a single dose of an unconjugated UGP2 AIMer in mice. These additional tissues in mice include heart, kidney, lung, pancreas and spleen, as well as liver cells beyond hepatocytes.

The application of PRISM to RNA editing opens the door to therapeutic applications extending beyond precise correction of genetic mutations, including upregulation of expression, modification of protein function, or alteration of protein stability. To date, we have achieved in vivo proof-of-concept modulating protein-protein interactions and upregulating protein expression.

To exemplify our ability to modulate protein-protein interactions using ADAR, we evaluated the well characterized KEAP1/NRF2 system. Through direct protein-protein interactions, KEAP1 negatively regulates the activity of NRF2 as an inducer of antioxidant gene expression. As a proof-of-concept experiment, we investigated if we could mimic the cellular stress response by using ADAR to edit individual amino acids at the protein-protein interaction interface between NRF2 and KEAP1 in vivo in mice. If these edits work as designed, we would expect to see downstream upregulation of the NRF2-dependent gene expression program even in the absence of cellular stressors. As shown below, treatment with AIMers resulted in increased expression of known downstream NRF2-dependent genes involved in the antioxidant response. Control treatment did not increase expression of any of the NRF2-dependent genes, indicating that AIMer treatment did not lead to NRF2-dependent gene expression changes through non-specific mechanisms such as increased cellular stress.

To exemplify our ability to upregulate protein expression levels using ADAR, we evaluated AIMers designed to modify regulatory elements in RNA that mediate protein-RNA or RNA-RNA interactions. Specific structural or sequence motifs that mediate these intermolecular interactions impact RNA processing and stability. In the figures below, we demonstrate in vivo proof-of-concept for this application of AIMers using an undisclosed target. Moving from left to right, we first demonstrate over 75% RNA editing of the target, which leads to >2-fold upregulation of that mRNA, and, ultimately, an increase in protein expression (as shown on the far right).

使用PRISM，我們可以生產立體純PN修飾的寡聚酸，其在臨牀前實驗中促進有效且特異性的RNA轉錄物沉默活性。

RNAi: 我們已經將我們的立體純PS和PN修飾應用於使用雙鏈siRNA的siRNA模式，並證明了有效和持久的沉默體內在轉基因小鼠中，利用GalNAc增強向肝細胞的遞送。

2023年4月，我們宣佈在《期刊》上發表了我們的新型SiriRNA形式的臨牀前數據 Nucleic Acids Research.臨牀前數據表明，單次皮下注射GalNAc-siRNA後，出現了前所未有的Argonaute 2（「Ago 2」）負載，從而提高了效力和耐久性體內在小鼠中與比較的RNA形式。

如下所示的數據說明了具有受控立體化學和PN骨架化學的GalNAc-siRNA，與接受基於最先進設計的SiriRNA處理的小鼠相比，單次給藥三個月後在小鼠中導致了顯着持久的轉錄沉默，其中表達水平已恢復到對照水平（左）。下面的數據（中間和右邊）還強調，用PRISM開發的siRNA顯示出改進的活性特徵，因爲它們比對照組支持更多的Ago 2負載。

左、中、右：用siRNA（3毫克/公斤）或PBS處理的表達人HUD 17 B13轉基因的小鼠、肝臟mRNA、引導鏈濃度、定量Ago 2載量。統計數據：雙向方差分析和事後檢驗 * P<0.05，*P<0.0001。Liu等人，2023年Nuc Acids Res doi：10.1093/nar/gkad

我們繼續改進我們的GalNAc-siRNA設計，我們的下一代siRNA形式具有同類最佳的潛力。如下圖所示，我們的下一代GalNAc-siRNA（以深藍色顯示）與我們的第一代GalNAc-siRNA形式（以淺藍色顯示）和基於臨牀證明的形式的基準相比，進一步改善了小鼠中沉默的效力和持續時間。對於RNAi，從臨牀前實驗到臨牀的轉化是很好理解的，並且我們期望我們的下一代siRNA形式可以支持六個月或每年的皮下給藥。

福斯特，DJ。等人。Mol Ther. 2018，26（3），708。B6小鼠給予PBS或0.5毫克/公斤的RNA（皮下）。基準：統計數據：混合雙因素方差分析，然後是事後檢驗，比較siRNA與下一代siRNA/天，來源於線性混合效應模型 * P < 0.0001

此外，在體內在非GalNAc RNA研究中，我們證明，我們可以通過單劑量實現有效且持續的沉默，在16周的研究結束時，所有大腦區域的澱粉樣蛋白β前體蛋白（「APP」）轉錄物減少超過75%。

PBS (dotted line) or 100 μg of App siRNA administered ICV (n=5-6). PCR assays for RNA PD, relative fold changes of App to Hprt mRNA normalized to % of PBS; Stats: derived from Three-way ANOVA (treatment, tissue, time point) followed by Bonferroni-adjusted post hoc test comparing condition to PBS (data not shown), Next gen siRNA significantly lower than PBS at week 16 for all tissues at P < 0.0001 level; Immunohistochemical analysis of FFPE Mouse Brain tissue labeling App protein (Color Brown) with CS#19389 followed by a ready to use Polymer-HRP 2nd Detection antibody. Nuclei were counterstained with Hematoxylin (Color Blue). Single 100 ug ICV injection

We further demonstrated how our PN chemistry allows us to access new tissues through eight-week mouse experiments using siRNAs to silence gene expression. On the far left, we highlight the well-described impact of using GalNAc to access hepatocytes in the liver. This graph also highlights the limits of a conjugate, as it is cell and tissue specific, so it does not enable silencing in other tissues of interest, like white adipose, muscle or cardiac tissue. To the right, we demonstrate our ability to alternate designs with PN variants to enable access to new and various combinations of tissues, including liver, adipose and muscle, in the absence of any targeting ligand. Depending on the target and indication, we can deploy the design that best fits the biology. Using PRISM, we can change the physicochemical properties of our oligos to deliver to numerous extrahepatic tissues and achieve potent and durable silencing with a single dose.

With PRISM, we have optimized stereopure oligonucleotides that promote efficient splicing in vitro, ex vivo, and in vivo to restore protein production. In our splicing programs, as with our other modalities, the base modifications and sequence, chemistry and backbone stereochemistry of oligonucleotides impact their activity.

In our Nucleic Acids Research paper (Kandasamy et al., 2022; doi: 10.1093/nar/gkac018), we highlight the impact of PN chemistry on exon skipping. In one application from the paper, we plotted the in vitro skipping efficiency of compounds containing PS / PO backbone chemistry modifications, depicted in the graph below by the teal dots, which are rank-ordered from left-to-right based on their exon-skipping potency in human myoblasts. The more potent molecules are shifted upwards as they are restoring expression. The navy dots represent the impact of a few stereopure PN modifications in compounds with otherwise identical sequences and 2’-ribose chemical modifications. There is an overall shift upwards in activity among the PS / PO / PN compounds, representing a substantial potency gain in most cases.

移動體內，我們在雙敲除小鼠（「dKO」）中證明了成功的exon跳讀，該小鼠缺乏utrophin和肌營養不良蛋白，因此發展出與在DMZ患者中觀察到的情況相當的嚴重肌營養不良表型。在這些小鼠中，exonjopping與肌萎縮蛋白蛋白表達相關，並且PN修飾的寡核酸導致治療六週後檢查的所有肌肉中出現更多的exonjopping和肌萎縮蛋白產生（如下所示，左）。在同一小鼠中，Exon skip和肌營養不良蛋白表達的改善與血清生物標誌物譜的改善相關（如下圖右所示）。這些結果證明了明智地放置PN鍵（沒有遞送載體或結合物）的影響，這可以顯着改善立體純化合物的藥理學特徵。

數據改編自Kandasamy等人，2022年; doi：10.1093/nar/gkac 018（統計數據：單因素方差分析：*P<0.05，** P <0.01，*P<0.001，*P<0.001）

RNase H介導的降解（反義）：在我們的 Nucleic Acids Research 論文（Kandasamy等人，2022; doi：10.1093/nar/gkac 018），我們說明了PN骨架化學修飾對RNase-H介導的沉默模式的影響。除了論文中報告的數據外，我們還進行了篩選以識別iCell神經元中的RNase H靶向序列體外使用自由吸收。該篩選最初是用具有PS和PO骨架化學修飾的立體純分子進行的，並且寡聚體根據其效力從左到右按等級排序。接下來，我們與含有相同序列和相同2 '-核糖化學但在骨架的選擇位置添加PN化學的分子進行了頭對頭比較。引入一些PN鍵顯着增加了絕大多數立體純PS / PO分子的效力，其中約80%產生至少75%的敲除。這些結果（如下所示）表明我們能夠瞄準原本無法訪問的序列空間。

移動體內，我們已經證明了用立體純的PN修飾的寡聚酸對非人靈長類動物中樞神經系統中的多個靶點具有有效的沉默活性。在一項研究中，非人靈長類動物通過囊內注射接受了單劑12毫克PN修飾的MAPT沉默寡聚核寡聚核寡核酸。給藥一個月後，單劑量導致中樞神經系統mRNA大幅且廣泛減少，以及有效的mRNA沉默（如左圖所示）。在一項單獨的研究中（如右圖所示），NHP接受了四個月的三個劑量水平的立體純PN修飾的MAPT沉默寡核酸的椎間盤內給藥。這種重複給藥導致中樞神經系統內80-90%的擊倒。

我們的業務戰略是開發和商業化廣泛的RNA藥物管道。作爲該戰略的一部分，我們已經並可能簽訂新的合作伙伴關係和合作協議，作爲推進我們自己的治療計劃並最大限度地發揮其對患者的潛力的一種手段，投資第三方技術以進一步加強PRism，並利用外部合作伙伴關係將PRism的影響力擴展到我們的平台展示競爭優勢的治療領域。

2022年12月13日，Wave Life Sciences USA，Inc.（「Wave USA」）和Wave Life Sciences UK Limited（「Wave UK」）是我們的兩家直接全資子公司，與GSK簽訂了合作和許可協議（「GSK合作協議」），該協議於2023年1月27日生效。根據葛蘭素史克合作協議，我們和葛蘭素史克同意合作開展寡核寡核酸療法的研究、開發和商業化，包括WVE-006的全球獨家許可。該發現合作最初的研究期限爲四年，並結合了我們專有的發現和藥物開發平台PRISMTM，憑藉葛蘭素史克新穎的基因洞察及其全球開發和商業能力。

根據葛蘭素史克合作協議的條款，我們收到了17000萬美元的預付款，其中包括12000萬美元的現金付款和5000萬美元的股權投資。此外，假設WVE-006和GSK的八個合作計劃實現啓動、開發、啓動和商業化里程碑，我們將有資格獲得高達33億美元的現金里程碑付款，以下段落對此進行了描述。

GSK獲得了WVE-006的全球獨家許可，WVE-006是我們首個針對α-1抗胰蛋白酶缺乏症的A-to-I（G）RNA編輯候選藥物，在我們完成首次患者研究後，開發和商業化責任將轉移給GSK。我們將負責WVE-006在初始I/II期研究（RestorAATion）期間的臨牀前、監管、生產和臨牀活動，費用由我們承擔。此後，GSK將負責推進WVE-006的關鍵研究、註冊和全球商業化，費用由GSK承擔。對於WVE-006計劃，我們將有資格獲得高達22500萬美元的開發和啓動里程碑付款，高達30000萬美元的商業化里程碑付款，以及高達淨銷售額百分比的兩位數分層版稅。

該合作包括三個組成部分：（1）發現合作，使我們能夠利用葛蘭素史克新穎遺傳見解所提供的目標推進多達三個項目;（2）發現合作，使葛蘭素史克能夠利用PRism和我們的寡核酸專業知識和發現能力推進多達八個項目;以及（3）GSK對WVE-006（我們的AATD計劃）的獨家全球許可，該計劃使用我們專有的AIMer技術。Wave將通過完成RestorAATion-2維持WVE-006的開發責任，屆時開發和商業責任將移交給葛蘭素史克。

此次合作將使我們能夠繼續建立基於前列腺病毒的轉型療法管道，並打開疾病生物學的新領域，並充分發揮WVE-006作爲AATD潛在的一流治療方法的全部價值，該治療方法有潛力同時解決該疾病的肝臟和肺部表現。

GSK合作協議包括將研究期限延長最多三年的選項，這將增加雙方可用的項目數量。我們將領導GSK的所有臨牀前研究和我們的合作項目，直至IND啓動研究。我們將爲我們的合作項目領導IND使能研究、臨牀開發和商業化。GSK的合作項目將轉移到GSK進行IND研究、臨牀開發和商業化。假設葛蘭素史克在合作下推進了八個項目，實現了啓動、開發、啓動和商業里程碑，我們將有資格獲得高達12億美元的啓動、開發和啓動里程碑以及高達16億美元的商業化里程碑，以及分層的特許權使用費，以佔淨銷售額的百分比計算。假設我們通過實現預先確定的里程碑來推進我們的合作計劃，葛蘭素史克將有資格從我們那裏獲得特許權使用費和商業里程碑。

根據GSK合作協議，各方向另一方授予雙方各自合作計劃產生的合作產品的某些許可以及特定知識產權許可，以使另一方能夠履行GSK合作協議項下的義務並行使其權利，包括許可授予，使各方能夠進行研究、開發、以及根據GSK合作協議條款進行商業化活動。雙方對彼此的排他性義務根據合作目標逐目標進行限制。

除非提前終止，GSK合作協議將持續到以下日期：（i）對於驗證目標，該驗證目標未推進到協作計劃中的日期;或（ii）對於協作目標，針對適用協作目標的所有協作產品的特許權使用費期限已到期。GSK合作協議包含習慣性終止條款，包括出於方便、違約和其他目的而終止的某些權利，包括基於目標/計劃或整個GSK合作協議。

關於上述5000萬美元的股權投資，在我們簽訂葛蘭素史克合作協議的同時，我們與葛蘭素史克的附屬公司葛蘭素集團有限公司（「GGL」）簽訂了一份股份購買協議，根據該協議

我們同意以每股4.68美元的收購價向GGL出售10，683，761股我們的普通股，總收購價約爲5000萬美元（「GSK股權投資」）。葛蘭素史克股權投資於2023年1月26日結束。GGL在GSK Equity Investment中購買的股份受到鎖止和暫停限制，並具有此類交易的慣例某些登記權。

2019年11月，我們與分子診斷公司Asuragen（於2021年4月被Bio-Techne Corporation收購）達成協議，爲我們針對HD的研究性基因選擇性治療計劃開發伴隨診斷並潛在商業化。此次合作利用Asuragen市場領先的重複序列診斷專業知識來提供可擴展的SNP定相，以支持全球層面的開發計劃和未來商業化。Asuragen利用其AmplideX® PCR技術開發了配套診斷測試，旨在用WVE-003靶向的SNP對HTT MAG重複序列進行大小和定相，我們當前的HD計劃正在正在進行中的SEN CT-HD臨牀試驗中進行研究，以及我們之前的研究治療計劃所針對的SNP。這些測試旨在幫助臨牀醫生通過識別與CAC擴展的基因同相的SNP來選擇HD患者。

爲了提供內部cGMP製造能力並提高我們藥品供應鏈的控制力和可見性，我們於2016年9月租賃了位於馬薩諸塞州列剋星敦的一個約90,000平方英尺的多用途設施，並開始擴建制造空間和相關能力。通過我們的內部製造，我們有能力支持多個發現階段、臨牀前階段和早期臨牀階段的計劃，並擁有成熟的專業知識，以有效地在各種模式下進行寡核苷酸的生產。除了製造空間，列剋星敦工廠還包括額外的實驗室和辦公空間。這一設施是對我們現有的馬薩諸塞州劍橋市實驗室和辦公場所總部的補充，增強了我們爲當前和未來的開發活動確保藥物物質的能力，並可能提供商業規模的製造能力。2017年7月，我們接管了列剋星敦工廠，並於2017年第四季度開始投產。

我們相信，利用我們的內部製造能力以及來自CMO的專業知識可以促進我們的增長，並增強我們爲當前和未來的研究、臨牀和早期商業開發活動確保原料藥的能力。我們相信，我們內部的GMP生產能力，加上我們在外部建立的供應能力，將足以滿足我們未來幾年的預期生產需求。我們監控原料藥和製劑生產產能的可用性，並相信我們與合同製造商的供應協議以及新供應協議的交貨時間將使我們能夠在需要時獲得額外產能。我們相信，我們的候選產品可以大規模生產，並具有生產和採購效率，從而產生具有商業競爭力的成本。

我們相信，我們在立體純寡聚酸的開發和商業化方面擁有強大的知識產權地位。我們的知識產權組合包括旨在保護一般立體純寡聚酸組合物的文件，以及旨在保護具有特定立體化學模式（例如，影響或賦予生物活性）的寡聚酸的立體純組合物的文件。我們的投資組合還包括專有方法和試劑的申請，以及能夠生產此類立體純寡聚核寡聚核酸組合物的各種化學方法的申請。此外，我們的投資組合包括旨在保護使用立體純寡聚酸組合物的方法的文件和旨在保護特定立體純寡聚酸產品的文件，例如具有特定序列、核苷和/或骨架修飾模式、骨架鍵聯模式和/或骨架手握中心模式的產品。

我們擁有或擁有全球專利申請的權利，這些專利保護我們用於製造立體純寡聚酸組合物的專有技術，並且還保護組合物本身以及使用它們的方法，包括用於治療疾病。我們的產品組合包括多項已發佈的專利，包括美國、歐洲和日本等主要市場司法管轄區的專利。我們在世界各地的多個司法管轄區（包括這些主要市場司法管轄區）也有申請待決。

我們的專利組合包括多個系列，保護用於生成立體純寡聚酸組合物的合成方法和/或試劑。

某些此類家庭的有效期爲20年，從2029年到至少2043年不等。其中一些家族已在多個司法管轄區（包括美國、歐洲和/或日本等主要市場司法管轄區）頒發了專利，在多個司法管轄區（包括這些主要市場司法管轄區）有未決申請，或者正在國際階段。

我們還與東京大學共同擁有針對合成寡核酸的某些方法和/或試劑的文件;其20年有效期爲2031年。

我們的某些專利申請保護立體純組合物，特別是治療相關的寡聚酸。一些此類文件針對其寡聚體的特徵在於特定化學修飾模式（包括鹼基、糖和/或核苷間鍵合的修飾）和/或核苷間鍵合立體化學的組合物。某些專利文件描述了設計用於治療特定疾病的特定組合物。我們針對立體純組合物的幾項專利申請已在多個司法管轄區進入國家階段起訴，其中一些已在一個或多個司法管轄區發佈;其他則處於國際階段。某些文件提供了20年的保護期，從2033年到至少2044年。

我們還與新日本生物醫學實驗室有限公司共同擁有各種專利系列，其中一些包括一項或多項已發佈的專利，包括主要市場司法管轄區的專利;這些申請的期限爲20年，延長至2033年至2035年。

我們維持着一項深思熟慮且雄心勃勃的計劃，用於開發和保護額外的知識產權，包括新的合成方法和試劑。我們還打算在最終確定潛在客戶並收集相關數據時準備和提交專門針對保護單個候選產品及其用途的專利文件，其中預計將包括確認我們候選產品新穎和/或有益屬性的比較數據。

新加坡1994年專利法第34條（「新加坡專利法」）規定，居住在新加坡的人必須獲得新加坡專利註冊處的書面授權（「註冊官」）在新加坡境外提交發明專利申請之前，除非滿足以下所有條件：（a）該人已在新加坡境外提交專利申請前至少兩個月在新加坡專利登記處提交了同一發明的專利申請，並且（b）新加坡專利登記處尚未就本專利申請，根據《新加坡專利法》第33條發出指示禁止或限制向任何人或任何類型的人發佈專利申請或其通信中包含的信息，或者如果註冊官已發出任何此類指示，則所有此類指示均已被撤銷。違反第34條屬於刑事犯罪，可處以不超過5，000新元的罰款或不超過兩年的監禁，或兩者兼而有之。在某些情況下，我們在新加坡境外進行了提交，並且在某些情況下，我們可能需要在未來提交此類提交，而無需首先獲得註冊官的書面授權。我們已將此類備案通知註冊官，此後我們已採取措施來滿足第34條的要求。迄今爲止，登記官已提供了一些被考慮的犯罪的複合材料，每個被考慮的案件需支付50至150新元的金額。根據新加坡法律，登記官有權在支付最高2，500新加坡元的金額後提出此類犯罪的複合狀，或起訴犯罪行爲，但須處以上述其他處罰。根據註冊官最近決定中的請求，我們已向新加坡知識產權局（「IPOS」）提交了多個專利系列的約140項專利申請，其中大部分與之前報告的申請有關。根據IPOS當前對第34條的解釋，IPOS可能會認爲部分或全部申請的提交違反了第34條的要求，我們正在等待IPOS對這些申請的決定。我們無法向您保證註冊商將提出對任何此類違反第34條的行爲進行復合，或者任何複合要約的金額將與之前的複合要約相似。

生物技術和製藥市場的特點是技術進步迅速、競爭激烈和對專有產品的高度重視。雖然我們相信我們在寡聚酸、科學知識和知識產權方面的專業知識爲我們提供了競爭優勢，但我們面臨着來自許多不同來源的潛在競爭，包括大型製藥、特種製藥和生物技術公司、學術機構、政府機構以及公共和私人研究機構。我們不僅必須與其他專注於寡聚酸的公司競爭，而且我們成功開發和商業化的任何候選產品都將與現有療法和未來可能推出的新療法競爭。

我們的許多競爭對手可能在研發、製造、臨牀前測試、開展臨牀試驗、獲得監管批准和銷售批准產品方面擁有比我們更多的財務資源和專業知識。這些競爭對手還在招聘和留住合格的科學和管理人員，建立臨牀試驗場所和臨牀試驗的患者登記，以及獲取補充或必要的技術方面與我們競爭。製藥、生物技術和診斷行業的併購可能導致更多的資源集中在少數競爭對手身上。小型或早期公司也可能成爲重要的競爭對手，特別是通過與大型和成熟公司的合作安排。

美國批准有兩種GLP-1受體激動劑用於治療肥胖症：Saxenda（利拉魯肽，諾和諾德）和Wegovy（索馬魯肽，諾和諾德）。Zepbound（替西帕特，Eli Lilly）於2023年11月獲得FDA批准，是一種GLP-1/GIP受體激動劑。除了這些批准的療法之外，還有研究性口服GLP-1受體激動劑和其他GLP-1受體激動劑組合（例如，GLP-1/GIP/胰高血糖素受體激動劑、GLP-1/胰高血糖素受體激動劑、GLP-1/胰高血糖素受體激動劑、GLP-1/GLP-2受體激動劑等）在臨牀發展的各個階段。FDA批准的其他肥胖療法包括Xenical（H2-Pharma）、Qsymia（Vivus）和Contrave（Currax Pharmaceuticals）。

Arrowhead在1/2階段開發中制定了針對INHBE的計劃，Alnylam則制定了臨牀前INHBE計劃。此外，其他多家公司也在尋找與GLP-1受體激動劑互補的肥胖方法，旨在減少脂肪量，同時保持或增加瘦體重。

美國批准了五種AATD治療方法：Prolastin（Grifols）、Prolastin-C（Grifols）、Aralast NP（Takeda）、Zemaira（CSL Behring）和Glasssia（Takeda）。這五種藥物均含有血漿源性人Alpha 1-蛋白酶抑制劑，適用於因先天性缺乏Alpha 1-蛋白酶抑制劑（Alpha 1-PI）而患有肺氣腫的成年人的慢性增強和維持治療。每種藥物的處方信息均指出，任何Alpha 1-蛋白酶抑制劑的加強治療對Alpha 1-PI缺乏症的肺惡化和肺氣腫進展的影響尚未在隨機對照臨牀試驗中得到證實。

除了WVE-006之外，我們還了解到Korro Bio正在開發另一項針對AATD肺病和/或肝臟疾病的臨牀階段RNA編輯計劃（第1/2期）。Beam Therapeutics正在進行一項採用DNA鹼基編輯方法的1/2期研究。還有許多公司正在開發針對AATD肺病的研究藥物：Kamada（第3階段）、KrCrystal Biotech（第1階段）、Mereo BioPharma（第2階段完成）和Sanofi（第2階段）等。Arrowhead Pharmaceuticals和Takeda正在開發一種用於AATD肝臟疾病的3期臨牀開發的研究藥物，而Biomarin正在啓動針對該適應症的1期研究。

美國批准了兩種基因突變治療方法，用於治療確診患有適合53號基因突變的DMZ患者的DMZ：Sarepta Therapeutics的Vyondys 53（Golodirsen）於2019年獲得批准，NS Pharma的Viltepso（viltolarsen）於2020年獲得批准。這兩種療法都根據肌萎縮蛋白的生產獲得了加速批准，根據美國加速批准法規，FDA要求Sarepta和NS Pharma各自進行臨牀試驗，以驗證和描述其藥物的臨牀益處。如果試驗未能驗證臨牀益處，FDA可能會啓動撤銷對相應藥物的批准的程序。迄今爲止，尚未確定Vyondys 53或Viltepso的臨牀益處。

Sarepta Therapeutics的Elevidys是一種微肌營養不良蛋白基因療法，已在美國和一些前歐盟市場上市。其目前在美國的適應症是針對至少四歲且確診患有DMZ基因突變的非臥牀和非臥牀DMZ患者。這包括具有適合第53號exon跳讀的DMZ突變的患者。包括非臥牀DMZ患者的適應症是根據傳統批准獲得的，包括非臥牀DMZ患者的適應症是根據Elevidys微肌營養不良蛋白的表達在加速批准下獲得的。對非臥牀DMZ患者的繼續批准可能取決於驗證性試驗中臨牀受益的驗證和描述。

其他可用於治療DMZ的療法包括Santhera Pharmaceuticals的Agamree（vamorolone），一種替代類固醇，於2023年在美國和歐盟獲得批准，以及Italfarmaco/ITF Therapeutics的Duvyzat（吉維司他），一種組蛋白去乙化酶抑制劑，於2024年在美國獲得批准。

其他幾家公司正在臨牀開發中針對更廣泛的DMZ的研究藥物，包括適合53號exon跳讀的患者。其中包括Capricor Therapeutics（FDA預先註冊）、Dystrogen Therapeutics（第1階段）、Edgewise Therapeutics（第2階段）、Regenxbio（第1/2階段）和Solid Biosciences（第1/2階段）等。根據現有信息，我們不相信還有其他公司專門針對臨牀開發中的53號突變進行研究項目。幾家公司還正在進行鍼對DMZ的臨牀前項目，這些項目可能直接或間接針對容易進行第53號突變的患者。這些公司包括Code Bio、Dyne Therapeutics、PepGen、精密生物科學、Ultragenyx Pharmaceuticals和Vertex Pharmaceuticals等。

目前還沒有批准的治療方法可以減緩HD的進展。Austedo（Teva）、四苯那嗪（仿製藥）和Aristzza（Neurosrine Biosciences）已於2023年獲准用於治療與HD相關的舞蹈病。

根據公開信息，我們相信Annexon Biosciences的Alnylam（第一階段）（第二階段完成）、Ionis Pharmaceuticals和Roche（第二階段）、Mitochon Pharmaceuticals（1/2期），Prilenia Therapeutics（在EMA預先註冊）、PTC Therapeutics（第2階段）、Skyhawk Therapeutics（第1階段）、uniQure（1/2期）和Vico Therapeutics（1/2期）等公司在臨牀開發中擁有旨在減緩HD進展的研究藥物。據我們所知，我們有最先進的臨牀階段計劃，目標是等位基因選擇性mHTT降低。

多家公司正在進行HD的發現或臨牀前項目，包括Atalanta Therapeutics、Ophidion、Roche、Sangamo Therapeutics和Takeda、Spark Therapeutics、Voyager Therapeutics和Novartis等。

治療與HD相關症狀的分子也在開發中。例如，SOM Biotech已經完成了一項針對HD舞蹈病的研究藥物的第二階段研究。

在美國，藥品受到FDA的廣泛監管。《聯邦食品、藥品和化妝品法》（「FDCA」）以及其他聯邦和州法規和法規除其他外，管理藥品的研究、開發、測試、製造、儲存、記錄保存、批准、標籤、促銷和營銷、分銷、批准後監測和報告、抽樣以及進出口。不遵守適用的FDA或其他要求可能會使製藥公司受到各種行政或司法制裁，例如FDA拒絕批准待決申請、臨牀擱置、警告信、召回或扣押藥品、部分或全部停產、從市場撤回藥品、禁令、罰款、民事處罰或刑事起訴。

任何新藥，如新的分子或化學實體，或新劑型，新用途或以前批准的產品的新給藥途徑，都需要FDA批准才能在美國上市。FDA要求的新藥品在美國上市前的流程通常包括：

製造開發、臨牀前和臨牀測試以及監管審查過程需要大量的時間、精力和財政資源。生產開發包括產品化學、配方、生產和控制程序的開發、穩定性評估以及確保持續產品質量的程序的建立。

非臨牀測試可能包括體外和體內（動物模型）研究，評估候選產品的毒性和其他安全特徵，以及藥物藥理學和PD的重要方面。《2023年綜合撥款法》於2022年12月29日簽署成爲法律，（PL 117-328）修訂了FDCA和公共衛生服務法，規定藥物和生物製品的非臨牀測試可以但不要求包括體內動物測試。根據修訂後的語言，申辦者可以通過完成各種體外分析（例如，基於細胞的分析、器官芯片或微生理系統），計算機模擬研究（即，計算機建模）、其他基於人類或非人類生物學的測試（例如，生物打印），或體內動物測試。

非臨牀測試的結果以及生產信息、分析數據和擬議的臨牀試驗方案和其他信息作爲IND的一部分提交給FDA。提交IND後，將繼續進行一些長期非臨牀測試，以進一步確定候選產品的安全性，以及生產工藝開發和藥物質量評價。IND在FDA收到後30天自動生效，除非FDA在30天內提出與擬議臨牀試驗相關的擔憂或問題並暫停IND臨牀。在這種情況下，IND申辦者必須在臨牀試驗開始之前解決所有懸而未決的問題。因此，我們提交的IND可能不會導致FDA授權開始臨牀試驗。產品開發期間進行的每項連續臨牀試驗，或者如果試驗設計發生變更，還必須單獨向現有IND提交申請。即使IND生效並且試驗在沒有FDA最初反對的情況下繼續進行，如果FDA有擔憂（例如出現不可接受的安全風險），FDA也可能會在稍後停止試驗。

此外，每個提議進行臨牀試驗的研究中心的倫理委員會必須在該研究中心開始試驗之前審查和批准任何臨牀試驗的計劃和受試者的知情同意信息，並且必須每年對研究進行持續審查，直到試驗完成。FDA或申辦者可以隨時以各種理由暫停臨牀試驗，包括髮現受試者或患者面臨不可接受的健康風險或試驗未按照臨牀計劃或符合GCP進行。同樣，如果臨牀試驗未按照機構審查委員會的要求進行，或者藥物對患者造成意外嚴重傷害，機構審查委員會可以暫停或終止對其機構臨牀試驗的批准。

臨牀試驗涉及在合格研究者的監督下根據GCP以及其他法規向人類受試者給予候選產品，其中包括要求所有研究受試者就參與任何臨牀試驗提供書面知情同意。某些FDA監管產品的臨牀試驗申辦者通常必須向美國國立衛生研究院（「NIH」）維護的公共登記處註冊並披露某些臨牀試驗信息。特別是，作爲臨牀試驗註冊的一部分，與產品、患者人群、研究階段、研究中心位置和臨牀試驗其他方面相關的信息將公開。競爭對手可以使用這些公開信息來獲取有關開發計劃進展的知識。儘管申辦者也有義務在完成後披露其臨牀試驗的結果，但在某些情況下，此類披露可能會在試驗完成之日後推遲最多兩年。未按照法律規定及時註冊受保臨牀研究或提交研究結果可能會導致民事罰款，並阻止不合規方從聯邦政府獲得未來的贈款資金。NIH關於ClinicalTrials.gov註冊和報告要求的最終規則於2017年生效，政府已對不合規的臨牀試驗申辦者採取執法行動。

人體臨牀試驗通常在以下順序階段進行，這些階段可能重疊或組合：

必須至少每年向FDA提交詳細說明從臨牀試驗中收集的進展和安全數據的進展報告。如果發生某些嚴重不良事件，安全報告將更頻繁地提交。1期、2期和3期臨牀試驗可能無法在任何指定期限內成功完成，甚至根本無法完成。FDA通常會檢查一個或多個臨牀中心，以確保符合GCP以及作爲NDA審查一部分提交的臨牀數據的完整性。

在2023年《綜合撥款法案》中，國會修改了FDCA，要求第三期臨牀試驗或其他支持上市授權的新藥「關鍵研究」的申辦者提交此類臨牀試驗的多元化行動計劃。行動計劃必須包括贊助商的入學多元化目標，以及目標的理由以及贊助商如何實現這些目標的描述。申辦者必須在申辦者向FDA提交試驗方案供FDA審查之前向FDA提交多元化行動計劃。FDA可以豁免多元化行動計劃的部分或全部要求。目前尚不清楚多元化行動計劃會如何影響第三階段試驗的規劃和時間安排，但如果FDA反對申辦者的多元化行動計劃並要求申辦者修改計劃或採取其他行動，則可能會推遲試驗啓動。

假設成功完成所需的臨牀測試，臨牀前研究和臨牀試驗的結果，以及與產品的藥理、化學、製造和控制相關的信息，以及擬議的標籤，將作爲NDA的一部分提交給FDA，請求批准該產品用於一個或多個適應症的市場。數據可能來自公司贊助的臨牀試驗，旨在測試產品使用的安全性和有效性，或者來自許多替代來源，包括研究人員發起的研究。爲了支持上市批准，提交的數據必須在質量和數量上足夠，以確定研究產品的安全性和有效性，使FDA滿意。根據聯邦法律，提交包含臨牀數據的保密協議的費用很高(例如，在2025年財政年度，申請費用超過430美元萬)，獲得批准的保密協議的贊助商還需要繳納年費，目前每項計劃超過400,000美元。這些費用通常每年調整一次，但在某些情況下可能會有豁免和豁免，包括具有孤兒指定的產品的NDA費用。

FDA在收到NDA後有60天的時間來根據該機構的門檻確定申請是否被接受提交，即申請足夠完整，可以進行實質性審查。FDA可能會要求提供更多信息，而不是接受NDA進行審查。任何在拒絕提起訴訟後重新提交的申請都必須接受60天的審查，然後才能接受FDA提交。

根據《處方藥用戶費用法案》（「PDUFA」），對於原始NDA，FDA有自提交之日起十個月的時間完成對標準申請的初步審查並回復申請人，自提交之日起六個月的時間對具有優先審查的申請。對於所有新的分子實體（「NME」）NDA，十個月和六個月的期限從提交日期起計算;對於所有其他原始申請，十個月和六個月的期限從提交日期起計算。儘管有這些審查目標，但FDA對NDA的審查超出目標日期的情況並不罕見。

一旦提交材料被接受提交，FDA就會開始深入審查。如上所述，FDA已同意在NDA審查過程中指定的績效目標。大多數此類申請將在接受提交之日起十個月內進行審查（即，提交之日起12個月內），大多數「優先審查」產品申請都將在申請被接受提交之日起六個月內進行審查（即，提交後八個月內）。FDA可能會將審查過程延長三個月，以考慮新信息，或者申請人提供澄清以解決FDA在原始提交後發現的未決缺陷。

在批准NDA之前，FDA可能會檢查生產產品的一個或多個設施。除非FDA確定生產工藝和設施符合GMP，否則不會批准申請。FDA還可以檢查進行關鍵試驗的一個或多個臨牀中心以及負責監督試驗的合同研究組織設施，以確保符合GCP和研究數據的完整性。

此外，FDA可以將任何NDA（包括提出安全性或有效性難題的新藥候選申請）提交給諮詢委員會。通常，諮詢委員會是一個由獨立專家組成的小組，包括臨牀醫生和其他科學專家，負責審查、評估申請是否應獲得批准以及在何種條件下獲得批准並提供建議。FDA不受諮詢委員會建議的約束，但在做出最終批准決定時會考慮此類建議。FDA可能會重新分析臨牀試驗數據，這可能會導致

FDA和申請人在NDA審查過程中進行了廣泛討論。如果FDA確定有必要進行風險評估和緩解策略（「REMS」）以確保藥物的益處超過其風險並確保藥物或生物製品的安全使用，則FDA還可能要求提交風險評估和緩解策略（「REMS」）。REMS可能包括藥物指南、醫生溝通計劃、評估計劃和/或確保安全使用的要素，例如限制分發方法、患者登記處或其他風險最小化工具。此外，REMS必須包括評估戰略的時間表，通常是在戰略批准後18個月、三年和七年。FDA根據具體情況確定REMS的要求以及具體的REMS條款。如果FDA認爲需要REMS，則NDA的申辦者必須提交擬議的REMS。如果需要，FDA不會批准沒有REMS的NDA。

在確定是否有必要進行REMS時，FDA可能會考慮可能使用該藥物的人群規模、待治療的疾病或病症的嚴重性、藥物的預期益處、治療持續時間、已知或潛在不良事件的嚴重性以及該藥物是否是NME。如果FDA確定需要REMS，藥品申辦者必須在批准時同意REMS計劃，或者在稍後發現重大新風險信息時同意REMS計劃。如果FDA根據新的安全信息確定需要REMS來確保藥物的益處大於風險，則FDA可能會對已上市的藥物實施REMS要求。

根據修訂後的《兒科研究公平法案》（「PREA」），NDA或NDA的補充必須包含足以評估候選產品在所有相關兒科人群中針對聲稱的適應症的安全性和有效性的數據，並支持該產品安全有效的每個兒科人群的劑量和給藥。FDA可以批准推遲提交兒科數據或全部或部分豁免。PREA要求計劃爲包含新活性成分、新適應症、新劑量、新給藥方案或新給藥途徑的產品提交上市申請的申辦者在第2階段會議結束後60天內提交初始兒科研究計劃（「PSP」），或者，如果沒有此類會議，在開始3期或2/3期臨牀試驗之前儘早進行。初始PSP必須包括申辦者計劃進行的兒科研究的大綱，包括試驗目標和設計、年齡組、相關終點和統計方法，或不包括此類詳細信息的理由，以及任何推遲兒科評估的請求或完全或部分豁免提供兒科研究數據以及支持信息的要求。FDA和申辦者必須就PSP達成協議。如果需要根據從臨牀前研究、早期臨牀試驗或其他臨牀開發計劃收集的數據考慮兒科計劃的變更，申辦者可以隨時提交對商定的初始PSP的修訂案。

FDA審查NDA，以確定產品對其預期用途是否安全有效，以及其製造是否符合CGM，以確保和保存產品的身份、強度、質量和純度。批准過程漫長且通常困難，如果不滿足適用的監管標準或可能需要額外的臨牀或其他數據和信息，FDA可能會拒絕批准NDA。根據FDA對NDA的評估和隨附信息（包括生產設施的檢查結果），它可能會發出批准函或完整回應函（「RTL」）。批准函授權該產品的商業營銷，並附有特定適應症的特定處方信息。RTL表明申請的審查週期已完成，並且申請不會以當前形式獲得批准。RTL概述了提交材料中的缺陷，並可能需要大量額外的測試或信息，以便FDA重新考慮申請。RTL可能需要額外的臨牀或其他數據、額外的關鍵3期臨牀試驗和/或與臨牀試驗、非臨牀研究或製造相關的其他重大且耗時的要求。如果發佈了RTL，申請人可以選擇重新提交NDA以解決信函中發現的所有缺陷，或者撤回申請。FDA已承諾在兩個月或六個月內審查此類針對已發佈的RTL的重新提交，具體取決於包含的信息類型。即使提交了這些額外信息，FDA最終也可能決定該申請不符合監管批准標準。如果缺陷已得到令FDA滿意的解決，FDA通常會發出批准函。

如果不符合現行監管要求或產品上市後發現安全問題，FDA可能會撤回產品批准。此外，FDA可能要求進行批准後測試，包括4期研究和監督計劃，以監測已商業化的批准產品的效果，FDA有權根據這些上市後計劃的結果防止或限制產品的進一步營銷。產品只能針對批准的適應症並根據批准的標籤規定銷售，即使FDA批准了產品，FDA也可以限制該產品的批准適應症或施加其他條件，包括標籤或分銷限制或其他風險管理機制，例如盒裝警告，這凸顯了一個嚴重的安全問題，應該通過REMS計劃來緩解該問題。此外，如果對產品進行任何修改，包括適應症、標籤或製造工藝或設施的變更，公司通常需要提交併獲得FDA對補充NDA的批准，這可能需要公司開發額外的數據或進行額外的非臨牀研究和臨牀試驗。

如果某些產品旨在解決治療嚴重或危及生命的疾病或病症中未滿足的醫療需求，FDA有權指定其進行加快開發或審查。這些計劃包括快速通道指定、突破性治療指定和優先審查指定。

爲了有資格獲得快速通道指定，FDA必須根據申辦者的要求確定產品旨在治療嚴重或危及生命的疾病或病症，並證明有可能通過提供不存在的治療或根據療效或安全因素可能優於現有治療來解決未滿足的醫療需求。快速通道指定爲與FDA審查團隊進行更頻繁的互動提供了機會，以加快產品的開發和審查。如果申辦者和FDA就提交申請部分的時間表達成一致，並且申辦者在提交NDA第一部分時支付了任何所需的用戶費用，則FDA還可以在提交完整申請之前滾動審查NDA的快速通道產品部分。此外，如果臨牀試驗過程中出現的數據不再支持快速通道指定，則申辦者可能會撤回或被FDA撤銷。此外，2012年，國會應IND申辦者的要求，爲FDA指定爲「突破性療法」的候選產品制定了監管計劃。突破性療法被定義爲旨在單獨或與一種或多種其他藥物或生物製品聯合治療嚴重或危及生命的疾病或病症的藥物或生物製品，並且初步臨牀證據表明，該藥物或生物製品可能比現有療法在一個或多個具有臨牀意義的終點（例如在臨牀開發早期觀察到的實質性治療效果）方面表現出實質性改善。被指定爲突破性療法的藥物或生物製劑也有資格獲得各自上市申請的加速批准。FDA必須對突破性療法採取某些行動，例如及時與產品申辦者舉行會議並向其提供建議，旨在加快突破性療法批准申請的開發和審查。最後，如果產品是治療嚴重疾病的藥物或生物製品，並且如果獲得批准，將比現有療法在安全性或有效性方面提供顯着改善，FDA可以指定該產品進行優先審查。FDA在提交上市申請時根據具體情況確定與其他可用療法相比，擬議藥物是否在疾病治療、預防或診斷方面取得了顯着改進。顯着改善可以通過以下證據來說明：疾病治療的有效性增強、治療限制性藥物反應的消除或大幅減少、有記錄的患者依從性增強（可能導致嚴重結局改善），或新亞群中安全性和有效性的證據。指定優先審查旨在將整體注意力和資源集中到此類申請的評估上，並將FDA對NME NDA的上市申請採取行動的目標從提交之日起的十個月縮短到六個月。

即使產品符合其中一項或多項計劃的資格，FDA稍後也可能會決定該產品不再符合資格條件或決定FDA審查或批准的時間不會縮短。此外，快速指定、突破性治療指定和優先審查不會改變批准標準，也可能最終不會加快開發或批准過程。

此外，研究其在治療嚴重或危及生命的疾病方面的安全性和有效性，並且比現有治療提供有意義的治療益處的產品可能會獲得FDA的加速批准，並可能在充分且控制良好的臨牀試驗的基礎上獲得批准，這些試驗確定該藥物對合理可能預測臨牀益處的替代終點有影響。當產品對中間臨牀終點產生影響時，FDA還可以加速批准此類藥物或生物製品，該影響可以早於對不可逆轉的發病率或死亡率（「IMG」）的影響進行測量，並且有合理可能預測對IMG或其他臨牀益處的影響，同時考慮到嚴重性、稀有性、或病情的流行程度以及替代治療的可用性或缺乏。作爲批准的條件，FDA將要求獲得加速批准的藥物的申辦者進行上市後臨牀試驗，以驗證和描述對IMG或其他臨牀終點的預測影響，並且該產品可能需要接受加速撤回程序。獲得加速批准的藥物和生物製品必須符合與獲得傳統批准的藥物和生物製品相同的法定安全性和有效性標準。

出於加速批准的目的，替代終點是一種標記物，例如實驗室測量、射線照相圖像、體徵或其他被認爲可以預測臨牀受益但本身不是臨牀受益的指標。替代終點通常比臨牀終點更容易或更快地測量。中間臨牀終點是對治療效果的測量，被認爲有合理可能預測藥物的臨牀益處，例如對IMG的影響。FDA在基於中間臨牀終點的加速批准方面的經驗有限，但表示，如果有根據得出結論，治療效果合理有可能預測藥物的最終長期臨牀效益，那麼這些終點通常可能支持加速批准，當終點衡量的治療效果本身不是傳統批准的臨牀效益和基礎時。

加速批准途徑最常用於疾病病程較長且需要較長時間來衡量藥物預期臨牀益處的環境中，即使對替代或中間臨牀終點的影響迅速發生。例如，加速批准已被廣泛用於治療多種癌症的藥物的開發和批准，其中治療的目標通常是提高生存率或降低發病率，並且典型疾病過程的持續時間需要漫長甚至有時是大型臨牀試驗來證明臨牀或生存益處。

加速批准途徑取決於申辦者同意以勤奮的方式進行額外的批准後確認性研究，以驗證和描述藥物的臨牀益處。因此，在此基礎上批准的藥物必須遵守嚴格的上市後合規要求，包括完成臨牀試驗以確定對臨牀終點的影響。如果未能進行並完成所需的驗證性研究來確認該產品的預期臨牀益處，FDA將撤銷對該藥物的批准。作爲2023年《綜合撥款法案》的一部分，國會向FDA提供了額外的法定權力，以減輕之前獲得加速批准的無效藥物繼續營銷給患者帶來的潛在風險。根據該法案對FDCA的修正案，FDA可能要求產品申辦者進行確認性試驗，作爲加速批准NDA的條件。申辦者還必須每六個月提交一次確認性試驗的進展報告，直到試驗完成，此類報告發佈在FDA網站上。如果申辦者的確認性試驗未能驗證產品聲稱的臨牀益處，這些修正案還賦予FDA使用快速程序撤回產品批准的選擇。

根據加速審批程序正在考慮和批准的所有候選產品的宣傳材料都必須經過FDA的事先審查。

一旦NDA獲得批准，產品將受到FDA的持續監管，其中包括與安全監測和不良事件報告、定期報告、持續GMP合規性和質量監督、遵守上市後承諾、記錄保存、廣告和促銷以及報告製造和標籤變更（如適用）相關的要求。

此外，藥品製造商和參與已批准藥物生產和分銷的其他實體（包括第三方製造商）必須向FDA和一些州機構註冊其機構，並定期接受FDA和一些州機構宣佈或未宣佈的檢查，以評估其對GMP的合規性。製造工藝的變更受到嚴格監管，通常需要事先獲得FDA批准才能實施。FDA法規還要求調查和糾正，有時還要求通知任何與GMP的偏差。這些法規對贊助商和我們可能決定使用的任何第三方製造商提出了報告和文件要求。因此，製造商必須繼續在生產和質量控制領域花費時間、金錢和精力，以保持GMP合規性。

一旦獲得批准，如果未能保持對監管要求和標準的遵守或產品上市後出現問題，FDA可能會撤回批准。發現之前未知的產品問題，包括未收載嚴重程度或頻率的不良事件，或生產工藝，或不符合監管要求，如不符合cGMP或未能糾正之前發現的檢查結果，可能導致對已批准的標籤進行強制性修訂，以添加新的安全性信息;強制進行上市後或臨牀試驗，以評估新的安全性風險;或在REMS計劃下實施分銷或其他限制。其他潛在後果包括：

The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market. While physicians may generally prescribe a drug for off-label uses, manufacturers may only promote the drug in accordance with the approved product label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have promoted false and misleading information about the product may be subject to significant liability, both at the federal and state levels.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act (“PDMA”) which regulates the distribution of drugs and drug samples at the federal level, and sets minimum standards for the registration and regulation of drug distributors by the states. Both the PDMA and state laws limit the distribution of prescription drug product samples and impose requirements to ensure accountability in distribution. Furthermore, the Drug Supply Chain Security Act (“DSCSA”) was enacted with the aim of building an electronic system to identify and trace certain prescription drugs distributed in the United States. The DSCSA mandates phased-in and resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors, and dispensers over a ten‑year period that culminated in November 2023. After an additional one-year stabilization period to give entities subject to the DSCSA additional time to finalize interoperable tracking systems and to ensure supply chain continuity, the applicable requirements under the DSCSA became fully enforceable as of November 27, 2024. From time to time, new legislation and regulations may be implemented that could significantly change the statutory provisions governing the approval, manufacturing and marketing of products regulated by the FDA. It is impossible to predict whether further legislative or regulatory changes will be enacted, or FDA regulations, guidance or interpretations changed or what the impact of such changes, if any, may be.

根據《孤兒藥法》，FDA可以授予用於治療罕見疾病或病症的藥物孤兒藥資格，罕見疾病或病症定義爲影響美國少於20萬人或超過20萬人的藥物，其中沒有合理的預期產品開發成本將從美國的產品銷售中收回。在提交NDA之前必須請求孤兒藥物認定。在FDA授予孤兒藥認定後，FDA將公開披露該藥物的身份及其潛在的孤兒藥用途;該公告還將表明該藥物是否不再被指定爲孤兒藥。一個以上的候選產品可能會獲得同一適應症的孤兒藥認定。孤兒藥指定並不意味着監管審查和批准流程的任何優勢或縮短監管審查和批准流程的持續時間。

根據PREA，對已獲得孤兒藥物認定的產品進行兒科研究不需要提交兒科評估。然而，根據2017年FDA再授權法案（「FDASIA」），PREA的範圍被擴大，要求對旨在治療成人癌症的產品進行兒科研究，該產品針對分子靶點，並且被確定與兒童癌症的生長或進展實質性相關。此外，FDA於2018年最終確定了指南，表明它預計不會對用於常見疾病兒科亞群的產品授予任何額外的孤兒藥稱號。儘管如此，FDA仍打算向符合所有其他指定標準的藥物或生物製品授予孤兒藥稱號，當其預防、診斷或治療（i）包括罕見兒科亞群的罕見疾病，（ii）構成有效孤兒亞群的兒科亞群，或（iii）一種罕見疾病，實際上兒科人群與成人人群的疾病不同。

如果孤兒藥物指定產品隨後獲得FDA針對其設計的疾病的批准，該產品將有權獲得七年的產品排他性，這意味着FDA可能不會批准任何其他申請以相同的適應症銷售相同的藥物，除非在非常有限的情況下(例如通過更有效、更安全的方式顯示出對孤兒排他性產品的臨牀優勢，或者在藥品供應問題的情況下爲患者護理做出重大貢獻)。孤兒排他性並不妨礙不同的藥物或生物製劑對同一罕見疾病或疾病的批准，也不會阻礙同一藥物或生物製劑對不同疾病的批准。如果競爭對手獲得FDA定義的同一藥物的批准，或者如果我們的候選產品被確定爲與競爭對手的相同適應症或疾病的產品相同的藥物，競爭對手的排他性可能會在七年內阻止我們的候選產品在指定的孤立適應症中獲得批准，除非我們的產品被證明在臨牀上優於競爭對手的藥物。

具有孤兒藥指定的產品如果被批准用於比其獲得孤兒藥指定的適應症更廣泛的用途，則可能不會獲得孤兒藥獨家經營權。此外，如果FDA後來確定指定請求存在重大缺陷，或者如果製造商無法確保足夠數量的產品來滿足罕見疾病或病症患者的需求，那麼孤兒藥在美國的獨家營銷權可能會失去。

最近的法庭案件對FDA確定孤兒藥獨家經營範圍的方法提出了質疑;然而，目前該機構繼續適用其對管理法規的長期解釋，並表示不計劃改變任何孤兒藥實施法規。

在歐盟，歐盟委員會（「EC」）對孤兒藥的認定爲公司開發和營銷滿足以下要求的療法提供了監管和財務激勵：（1）該產品旨在用於診斷，

預防或治療危及生命或慢性衰弱的疾病;（2）（a）申請時，此類疾病影響歐盟每一萬人中不超過五人，或（b）產品如果沒有孤兒身份帶來的好處，將不會在歐盟產生足夠的回報來證明投資合理;和（3）歐盟沒有授權上市的令人滿意的診斷、預防或治療此類疾病的方法，或者如果存在此類方法，則該產品將對受該疾病影響的人產生重大益處，如法規（EC）847/2000所定義。要考慮在歐盟獲得孤兒藥認定，公司必須提供數據，證明使用研究性療法治療疾病的可行性，並確定該藥物有潛力提供相關優勢或對患者護理做出重大貢獻。現有療法。

歐洲委員會爲被指定爲孤兒藥物的藥品提供的激勵措施包括：產品批准後在歐盟的十年市場獨家經營權、有條件營銷授權的資格、歐洲藥品管理局在產品開發階段以較低費用提供的方案援助，以及直接獲得歐盟的集中營銷授權。如果在第五年結束時不再符合孤兒藥物指定標準，包括證明該產品的利潤足夠高而不足以證明維持市場排他性是合理的，則專營期可縮短至六年。此外，在十年內，經原孤兒藥品銷售許可持有人同意，或者原孤兒藥品生產企業不能供應足夠數量的產品時，可以對具有相同孤兒適應症的類似藥品授予銷售許可。具有相同孤兒適應症的類似藥品，如果被認爲比原來的孤兒藥品更安全、更有效或在臨牀上更好，也可以批准上市。在提交上市授權申請之前，必須申請指定孤兒藥物。孤兒藥物指定本身並不會在監管審查和授權過程中傳遞任何優勢，也不會縮短監管審查和授權過程的持續時間。

如果滿足某些條件，《兒童最佳藥品法案》（「BPCA」）爲NDA持有者提供了爲期六個月的非專利營銷獨佔權，該獨佔權附加於FDA列出的任何其他獨佔權（專利或非專利）。兒科排他性的條件包括FDA確定與兒科人群使用新藥相關的信息可能會對該人群產生健康益處; FDA對兒科研究的書面請求;申請人同意進行所要求的研究，根據書面請求完成研究，以及FDA在法定時間內接受所要求研究的報告。數據不需要證明該產品對研究的兒科人群有效;相反，如果臨牀試驗被認爲公平地響應了FDA的要求，則會授予額外的保護。如果所要求的兒科研究報告在法定期限內提交給FDA並被其接受，則無論該產品的獨佔權或專利保護的法定或監管期限如何，都將延長六個月。這不是專利期限的延長，但它有效地延長了FDA無法批准同一藥品用於相同適應症的另一項申請的監管期限。發出書面請求並不要求申辦者進行所描述的研究。BPCA下的申請被視爲優先申請。

1984年，隨着FDCA哈奇-韋克斯曼修正案的通過，國會授權FDA批准與FDA之前根據法規的NDA條款批准的藥物相同的仿製藥，並頒佈了FDCA第505（b）（2）條。爲了獲得仿製藥的批准，申請人必須向該機構提交簡短的新藥申請（「ANDA」）。爲了支持此類申請，仿製藥製造商可能會依賴對之前根據NDA批准的藥品（稱爲參考上市藥物（「RLD」））進行的臨牀前和臨牀測試。具體來說，爲了批准ANDA，FDA必須發現仿製藥在活性成分、給藥途徑、劑量和藥物強度方面與RLD相同。與此同時，FDA還必須確定仿製藥與創新藥具有「生物等效性」。

相比之下，第505(B)(2)條允許申請人部分依賴FDA對現有產品的安全性和有效性數據的先前發現，或支持其應用的出版文獻。第505(B)(2)條新藥可爲FDA批准以前批准的產品的新的或改進的配方或新用途提供另一種途徑；例如，申請人可能正在尋求批准將先前批准的藥物用於新的適應症或新的患者群體，這將需要新的臨牀數據來證明安全性或有效性。第505(B)(2)條允許在至少部分批准所需的信息來自不是由申請人或爲申請人進行的研究，並且申請人沒有獲得參考權的情況下，提交NDA。第505(B)(2)條的申請人如果能夠確定對先前批准的產品進行的研究在科學上是適當的，則它可以消除進行某些非臨牀或臨牀研究的需要。與創新藥物生物等效版本的開發商使用的ANDA途徑不同，ANDA途徑不允許申請者提交除生物利用度或生物等效性數據以外的新臨牀數據，505(B)(2)監管途徑不排除後續申請者需要進行額外的臨牀試驗或非臨牀研究的可能性；例如，他們可能正在尋求批准將先前批准的藥物用於新的適應症或新的患者群體，這將需要新的臨牀數據來證明安全性或有效性。然後，FDA可以批准RLD已被批准的所有或部分標籤適應症的新產品，或適用於第505(B)(2)節申請人尋求的任何新適應症。

新化學實體（「NCO」）獲得NDA批准後，該藥物將獲得五年的上市獨佔權，該藥物是一種不含FDA在任何其他NDA中批准的活性部分的藥物。在獨佔期內，如果申請人不擁有或不擁有批准所需的所有數據的合法引用權，FDA不能接受另一家公司就該藥物的另一個版本提交的任何ANDA或505（b）（2）NDA進行審查。然而，如果第IV段認證（其中規定RLD列出的專利無效或不會被後續產品侵犯）已就NCO專利提交，並且如果申請是基於新適應症或新配方提交的，則可以在NCO獨佔權到期前一年提交後續產品申請。

《哈奇-瓦克斯曼法案》還規定，如果FDA認爲申請人進行或贊助的新的臨牀研究(生物利用度研究除外)對批准申請至關重要，例如，現有藥物的新適應症、劑量或強度，則NDA、505(B)(2)NDA或現有NDA的補充產品的數據排他性爲三年。這項爲期三年的排他性只包括與新的臨牀研究相關的使用條件，並不禁止FDA批准含有原始活性物質的藥物的後續申請。如果Orange Book中沒有列出的專利，則可能沒有第四段認證，因此，在排他期到期之前，不能提交ANDA或505(B)(2)NDA。五年和三年的排他性也不會推遲提交或批准根據FDCA第505(B)(1)條提交的傳統保密協議。然而，提交傳統保密協議的申請人將被要求進行或獲得參照權，以證明安全和有效所需的所有臨牀前研究和充分和良好控制的臨牀試驗。

根據FDA批准使用我們的候選治療方法的時間、持續時間和具體細節，我們的一些美國專利可能有資格根據哈奇-韋克斯曼法案獲得有限的專利期限延長。《哈奇-韋克斯曼法案》允許最長五年的專利恢復期，作爲對產品開發和FDA監管審查過程中損失的任何專利期的補償。然而，專利期限恢復不能將專利的剩餘期限延長至自產品批准之日起總共14年以上。專利期恢復期通常爲IND生效日期與NDA提交日期之間時間的一半，加上NDA提交日期與該申請獲得批准之間時間的一半。只有一項適用於已批准藥物的專利有資格獲得延期，並且必須在專利到期前提出延期申請。美國專利商標局（「USPTO」）與FDA協商，審查並批准任何專利期限延長或恢復的申請。未來，我們打算根據臨牀試驗的預期長度和提交相關NDA涉及的其他因素，申請縮短我們目前擁有或許可的一些專利的專利期限，以將專利期限延長到當前有效期之後。

對於我們的一些候選產品，我們計劃與合作者合作開發或獲得體外伴隨診斷測試，以確定適合這些靶向治療的患者。如果申辦者或FDA認爲診斷測試對於安全有效使用相應治療產品至關重要，則申辦者通常會與合作者合作開發適當的體外用於此類用途的診斷產品（「IVD」）。IVD作爲醫療器械受到FDA監管，自2014年以來，該機構已發佈最終和草案指南文件，旨在幫助公司開發體外配套診斷設備和開發依賴於使用特定藥物的治療產品的公司體外用於安全有效使用治療產品的伴隨診斷。

醫療器械（包括IVD）的三種營銷途徑是根據FDCA第510（k）條批准上市前通知（「510（k）」）、批准上市前批准申請（「PMA」）或重新命名的授權分類請求（“從頭”).如果一家公司需要進行臨牀試驗來支持IVD的安全性和有效性，並且IVD被視爲重大風險器械，則申辦者必須向FDA提交研究用器械豁免申請（「IDE」），其格式和功能與IND相似。如果診斷測試和治療藥物一起研究以支持各自的批准，涉及兩種候選產品的任何臨牀試驗都必須滿足IDE和IND要求。

FDA預計治療申辦者將在其治療產品開發計劃中解決對IVD配套診斷設備的需求，並且在大多數情況下，治療產品及其相應的IVD配套診斷設備將同時開發。如果伴隨診斷測試將用於做出關鍵的治療決策，例如患者選擇、治療分配或治療組，則它可能會被視爲需要進行臨牀試驗的重大風險設備。批准後，將在診斷器械和相應治療產品標籤的使用說明書中規定將IVD配套診斷器械與治療產品一起使用。此外，通過PMA流程批准的診斷測試，或者通過510（k）流程批准或通過De Novo分類的診斷測試過程並投放市場將遵守許多適用於已批准藥物的相同監管要求。

然而，FDA可能會決定在未經批准或許可的情況下批准此類治療產品是合適的體外當藥物或治療性生物製品旨在治療嚴重或危及生命的疾病，但沒有令人滿意的替代治療方法，並且FDA確定使用具有以下功能的產品的益處

未經批准或未清除體外配套診斷設備如此明顯，以至於超過了缺乏批准或許可的風險體外配套診斷設備。FDA鼓勵考慮開發需要伴隨診斷的治療產品的申辦者要求與相關設備和治療產品審查部門召開會議，以確保產品開發計劃將產生足夠的數據來確定治療產品和伴隨診斷的安全性和有效性。由於FDA關於伴隨診斷的政策僅在指南中闡述，因此該政策可能會發生變化，並且不具有法律約束力。

除了美國的法規外，我們現在並將直接或通過我們的分銷合作伙伴遵守其他司法管轄區的各種法規，這些法規除其他外，包括臨牀試驗、個人數據隱私以及我們產品的商業銷售和分銷（如果獲得批准）。

無論我們是否獲得FDA對產品的批准，我們都必須在非美國國家/地區開始產品的臨牀試驗或營銷之前獲得這些國家監管機構的必要批准。美國以外的某些國家的流程要求在開始人體臨牀試驗之前提交臨牀試驗申請，就像IND一樣。例如，在歐洲，臨牀試驗申請（「MTA」）必須提交給主管國家衛生當局和公司計劃進行臨牀試驗的每個國家的獨立倫理委員會。一旦根據一個國家的要求獲得批准，臨牀試驗就可以在該國進行。根據2014年4月通過並取代臨牀試驗指令的歐盟臨牀試驗法規，自2022年1月31日起，通過臨牀試驗信息系統（「CTIS」）對整個歐盟的臨牀試驗實施了統一的評估和監督流程。CTIS將包含在歐盟進行的臨牀試驗的集中歐盟門戶和數據庫，並允許集中審查過程。從2023年2月1日開始，新的MTA提交文件必須採用統一的提交流程。然而，正在進行的和新的臨牀試驗受《臨牀試驗法規》管轄的程度各不相同。根據臨牀試驗指令在2022年1月31日之前提交申請的臨牀試驗，或在2022年1月31日至2023年1月31日之間提交申請且申辦者選擇應用臨牀試驗指令的臨牀試驗，在2025年1月31日之前仍受該指令管轄。2025年1月31日之後，所有臨牀試驗，包括正在進行的臨牀試驗，現在均受《臨牀試驗法規》的規定約束。根據新的集中化流程，如果領導MTA審查的歐盟成員國批准或拒絕申請，該決定將適用於所有相關成員國。

儘管歐盟成員國因國家實施歐盟基礎立法而已經實現了一定程度的法律協調，但各國臨牀試驗、產品許可、定價和報銷的要求和流程各不相同。在所有情況下，臨牀試驗均按照GCP和其他適用的監管要求進行。

要獲得新藥或藥品在歐盟的上市許可，申辦者必須獲得上市授權申請（「MAA」）的批准。藥品在歐盟獲得批准的方式取決於藥品的性質。

集中程序導致歐盟委員會授予的單一上市許可在整個歐盟以及冰島，列支敦士登和挪威有效。集中程序對於以下人用藥物是強制性的：（ii）含有指示用於治療某些疾病的新活性物質，所述疾病例如HIV/AIDS、癌症、糖尿病、神經變性疾病、自身免疫和其它免疫功能障礙以及病毒性疾病，（iii）是官方指定的「孤兒藥」（用於治療罕見人類疾病的藥物）;（iv）是先進的治療藥物，如基因治療、體細胞治療或組織工程藥物。應申請人的要求，集中程序也可用於不屬於上述類別的人用藥物，如果（a）人用藥物含有先前未經歐洲共同體授權的新活性物質;或（b）申請人證明該藥品構成重要的治療方法，科學或技術創新，或者在集中程序中授予授權符合歐洲共同體層面患者的利益。

根據歐盟的集中程序，EMA評估上市授權申請的最長時間爲210天（不包括停止時間，因爲申請人將提供額外的書面或口頭信息以回答CHMP提出的問題），此後歐盟委員會將採用實際上市授權。在特殊情況下，當從治療創新的角度來看，藥品預計具有重大公共衛生利益時，CHMP可能會批准加速評估，該治療創新由三個累積標準定義：待治療疾病的嚴重性;缺乏適當的替代治療方法，並預期具有極高的治療效益。在這種情況下，EMA確保在150天內完成對CHMP意見的評估（不包括時鐘停止），並在此後發佈意見。

批准人用藥物的相互承認程序（「MRP」）是促進歐盟內個人國家上市授權的替代方法。基本上，MRP可以適用於所有非強制性集中程序的人用藥物。MRP適用於大多數傳統藥品，並基於

principle of recognition of an already existing national marketing authorization by one or more member states. In the MRP, a marketing authorization for a drug already exists in one or more member states of the European Union and subsequently marketing authorization applications are made in other European Union member states by referring to the initial marketing authorization. The member state in which the marketing authorization was first granted will then act as the reference member state. The member states where the marketing authorization is subsequently applied for act as concerned member states. After a product assessment is completed by the reference member state, copies of the report are sent to all member states, together with the approved summary of product characteristics, labeling and package leaflet. The concerned member states then have 90 days to recognize the decision of the reference member state and the summary of product characteristics, labeling and package leaflet. National marketing authorizations within individual member states shall be granted within 30 days after acknowledgement of the agreement.

Should any member state refuse to recognize the marketing authorization by the reference member state, on the grounds of potential serious risk to public health, the issue will be referred to a coordination group. Within a timeframe of 60 days, member states shall, within the coordination group, make all efforts to reach a consensus. If this fails, the procedure is submitted to an EMA scientific committee for arbitration. The opinion of this EMA committee is then forwarded to the Commission, for the start of the decision-making process. As in the centralized procedure, this process entails consulting various European Commission Directorates General and the Standing Committee on Human Medicinal Products or Veterinary Medicinal Products, as appropriate.

In May 2022, the In Vitro Diagnostic Device Regulation (“IVDR”) (EU) 2017/746 became effective, replacing the previous IVD Directive (EU-Directive 98/79/EC). The IVDR was published in May 2017 and given a five-year transition period until its full implementation on May 26, 2022. Unlike the IVD Directive (EU-Directive 98/79/EC), the IVDR has binding legal force throughout every Member State. The major goals of the IVDR are to standardize diagnostic procedures within the EU, increase reliability of diagnostic analysis and enhance patient safety. Among other things, the IVDR introduces a new risk-based classification system for IVDs and requirements for IVD conformity assessments. Under the IVDR and subsequent amendments, IVDs already certified by a Notified Body under the IVD Directive may remain on the market until December 31, 2027, and IVDs certified without the involvement of a Notified Body may remain on the market for up to two additional years (until December 31, 2029) depending on the classification of the IVD. The manufacturers of such devices remaining on the market must comply with specific requirements in the IVDR, but ultimately, such products, as with all new IVDs, will have to undergo the IVDR’s conformity assessment procedures. In addition, IVDs in the highest risk class will have to be tested by a Designated Reference Laboratory. The IVDR imposes additional requirements relating to post-market surveillance and submission of post-market performance follow-up reports.

The EC has designated thirteen Notified Bodies to perform conformity assessments under the IVDR. MedTech Europe has issued guidance relating to the IVDR in several areas, e.g., clinical benefit, technical documentation, state of art, accessories, and EUDAMED.

In April 2023, the European Commission issued a proposal that will revise and replace the existing general pharmaceutical legislation. If adopted and implemented as currently proposed, these revisions will significantly change several aspects of drug development and approval in the European Union.

As of January 1, 2021, European Union law no longer directly applies in the United Kingdom. The United Kingdom has adopted existing European Union medicines regulation as standalone United Kingdom legislation with some amendments to reflect procedural and other requirements with respect to marketing authorizations and other regulatory provisions.

The Medicines and Healthcare products Regulatory Agency, or MHRA, is responsible for regulating medicinal products in the United Kingdom (Great Britain and Northern Ireland). An MHRA authorization must be obtained for each medicine to be marketed in the regions that comprise the United Kingdom. On January 1, 2021, all existing European Union marketing authorizations were converted to United Kingdom marketing authorizations subject to a manufacturer opt-out. Since then, the United Kingdom has introduced separate, specific processes for regulatory submissions and medicinal product marketing authorization.

The Windsor Framework, which was negotiated between the United Kingdom and the European Commission and became effective as of January 1, 2025, requires changes to the regulatory system that was previously in effect under the Northern Ireland Protocol, including the regulation of drug products in the United Kingdom. Specifically, the MHRA will be responsible for approving all medicines intended to be marketed in the United Kingdom (including Northern Ireland), while the EMA will no longer be involved in approving medicines intended for sale in Northern Ireland.

It is expected that the establishment of a separate United Kingdom authorization system, albeit with transitional recognition procedures in the United Kingdom, will lead to additional regulatory costs.

The requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country. In all cases, the clinical trials must be conducted in accordance with GCP and the other applicable regulatory requirements.

If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension of clinical trials, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions, and criminal prosecution.

Although we currently do not have any products on the market, if our product candidates are approved in the United States, we will have to comply with various U.S. federal and state laws, rules and regulations pertaining to healthcare fraud and abuse, including anti-kickback laws and physician self-referral laws, rules and regulations. Violations of the fraud and abuse laws are punishable by criminal and civil sanctions, including, in some instances, exclusion from participation in federal and state healthcare programs, including Medicare and Medicaid. These laws include the following:

Some state laws require pharmaceutical or medical device companies to comply with the relevant industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government in addition to requiring drug manufacturers to report information related to payments to physicians and other healthcare providers or marketing expenditures.

State and foreign laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts. We also are subject to, or may in the future become subject to, U.S. federal and state, and foreign laws and regulations imposing obligations on how we collect, use, disclose, store and process personal information. Our actual or perceived failure to comply with such obligations could result in liability or reputational harm and could harm our business.

Significant uncertainty exists as to the coverage and reimbursement status of products approved by the FDA and other government authorities. Sales of our products, when and if approved for marketing in the United States, will depend, in part, on the extent to which our products will be covered by third-party payors, such as federal, state, and foreign government healthcare programs, commercial insurance and managed healthcare organizations. The process for determining whether a payor will provide coverage for a product

may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved. Third-party payors may limit coverage to specific products on an approved list, or formulary, which might not include all of the approved products for a particular indication. In addition, these third-party payors are increasingly reducing reimbursements for medical products, drugs and services. Furthermore, the U.S. government, state legislatures and foreign governments have continued implementing cost containment programs, including price controls, restrictions on coverage and reimbursement and requirements for substitution of generic products. Adoption of price controls and cost containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit our net revenue and results. Limited third-party reimbursement for our product candidates or a decision by a third-party payor not to cover our product candidates could reduce physician usage of our products once approved and have a material adverse effect on our sales, results of operations and financial condition.

In Europe and other countries outside of the United States, pricing and reimbursement schemes vary widely from country to country. Some countries provide that drug products may be marketed only after a reimbursement price has been agreed to. Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular product candidate to currently available therapies. In some countries, cross-border imports from low-priced markets exert competitive pressure that may reduce pricing within a country. Any country that has price controls or reimbursement limitations for drug products may not allow favorable reimbursement and pricing arrangements.

In the United States and some foreign jurisdictions, there have been, and continue to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product and therapeutic candidates, restrict or regulate post-approval activities, and affect the ability to profitably sell product and therapeutic candidates that obtain marketing approval. The FDA’s and other regulatory authorities’ policies may change and additional government regulations may be enacted that could prevent, limit or delay regulatory approval of our product and therapeutic candidates. In addition, future legislative and regulatory proposals may materially impact the ability of the FDA and other regulatory agencies to operate as they have historically operated. We cannot be sure whether additional legislative changes will be enacted, or whether any of the FDA’s regulations, guidance or interpretations will be changed, or what the impact of such changes on the agency and its scientific review staff, if any, may be. For example, the next FDA user fee reauthorization package is expected to enter stakeholder negotiations beginning in mid-2025, with any agreement sent to Congress in early 2027 for purposes of initiating the legislative process. Reauthorization of the prescription drug user fee program would need to be finalized by Congress by the end of September 2027 in order to avoid a disruption in FDA’s review goals for NDAs and other activities supported by user fees assessed against industry. If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we otherwise may have obtained and we may not achieve or sustain profitability, which would adversely affect our business, prospects, financial condition and results of operations. Moreover, among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access.

For example, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively, the “ACA”), was enacted in March 2010 and has had a significant impact on the healthcare industry in the United States. The ACA expanded coverage for the uninsured while at the same time containing overall healthcare costs. With regard to biopharmaceutical products, the ACA, among other things, addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, increased the minimum Medicaid rebates owed by such manufacturers under the rebate program and extended the program to individuals enrolled in Medicaid managed care organizations; established annual fees on manufacturers of certain branded prescription drugs; and created a new Medicare Part D coverage gap discount program. We expect that future changes or additions to the ACA, the Medicare and Medicaid programs, and changes stemming from other healthcare reform measures, especially with regard to healthcare access, financing or other legislation in individual states, could have a material adverse effect on the healthcare industry in the United States.

Additionally, on December 20, 2019, the Further Consolidated Appropriations Act for 2020 was signed into law (P.L. 116-94) and includes a piece of bipartisan legislation called the Creating and Restoring Equal Access to Equivalent Samples Act of 2019 (“CREATES Act”). The CREATES Act aims to address the concern articulated by both the FDA and others in the industry that some brand manufacturers have improperly restricted the distribution of their products, including by invoking the existence of a REMS for certain products, to deny generic product developers access to samples of brand products. Because generic product developers need samples of an RLD to conduct certain comparative testing required by the FDA, some have attributed the inability to timely obtain samples as a cause of delay in the entry of generic products. To remedy this concern, the CREATES Act establishes a private cause of action that permits a generic product developer to sue the brand manufacturer to compel it to furnish the necessary samples on “commercially reasonable, market-based terms.” Although lawsuits have been filed under the CREATES Act since its enactment, those lawsuits have settled privately; therefore to date no federal court has reviewed or opined on the statutory language and there continues to be uncertainty regarding the scope and application of the law.

For a drug product to receive federal reimbursement under the Medicaid or Medicare Part B programs or to be sold directly to U.S. government agencies, the manufacturer must extend discounts to entities eligible to participate in the 340B Drug Pricing Program. The maximum amount that a manufacturer may charge a 340B covered entity for a given product is the average manufacturer price, or AMP, reduced by the rebate amount paid by the manufacturer to Medicaid for each unit of that product. As of 2010, the ACA expanded the types of entities eligible to receive discounted 340B pricing, although, under the current state of the law, with the exception of children’s hospitals, these newly eligible entities will not be eligible to receive discounted 340B pricing on orphan drugs. In addition, as 340B drug pricing is determined based on AMP and Medicaid rebate data, the revisions to the Medicaid rebate formula and AMP definition described above could cause the required 340B discount to increase.

Moreover, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products. For example, the 2021 Consolidated Appropriations Act signed into law on December 27, 2020 incorporated extensive healthcare provisions and amendments to existing laws, including a requirement that all manufacturers of drug products covered under Medicare Part B report the product’s average sales price to CMS beginning on January 1, 2022, subject to enforcement via civil money penalties. The U.S. Department of Health and Human Services (“DHHS”) has also solicited feedback on various measures intended to lower drug prices and reduce the out-of-

In August 2022, President Biden signed into the law the Inflation Reduction Act of 2022 (“IRA”). The IRA has multiple provisions that may impact the prices of drug products that are both sold into the Medicare program and throughout the United States. For example, a manufacturer of a drug or biological product covered by Medicare Parts B or D must pay a rebate to the federal government if the drug product’s price increases faster than the rate of inflation. This calculation is made on a product-by-product basis and the amount of the rebate owed to the federal government is directly dependent on the volume of a drug product that is paid for by Medicare Parts B or D. Additionally, starting in payment year 2026, CMS will negotiate drug prices annually for a select number of single source Part D drugs without generic or biosimilar competition. CMS will also negotiate drug prices for a select number of Part B drugs starting for payment year 2028. If a drug product is selected by CMS for negotiation, it is expected that the revenue generated from such drug will decrease. CMS has begun to implement these new authorities and entered into the first set of agreements with drug and biological product manufacturers for negotiated prices of 10 products, which will become applicable for payment year 2026. However, the IRA’s impact on the pharmaceutical industry in the United States remains uncertain, in part because multiple large pharmaceutical companies and other stakeholders (e.g., the U.S. Chamber of Commerce) have initiated federal lawsuits against CMS arguing the program is unconstitutional for a variety of reasons, among other complaints. Those lawsuits are currently ongoing.

Individual states in the United States have also increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. For example, in recent years, several states have formed prescription drug affordability boards (“PDABs”). Much like the IRA’s drug price negotiation program, these PDABs have attempted to implement upper payment limits (“UPLs”) on drugs sold in their respective states in both public and commercial health plans. In August 2023, Colorado’s PDAB announced a list of five prescription drugs that would undergo an affordability review. The effects of these efforts remain uncertain pending the outcomes of several federal lawsuits challenging state authority to regulate prescription drug payment limits. In December 2020, the U.S. Supreme Court held unanimously that federal law does not preempt the states’ ability to regulate pharmaceutical benefit managers (“PBMs”) and other members of the healthcare and pharmaceutical supply chain, an important decision that may lead to further and more aggressive efforts by states in this area. The Federal Trade Commission (“FTC”) in mid-2022 also launched sweeping investigations into the practices of the PBM industry that could lead to additional federal and state legislative or regulatory proposals targeting such entities’ operations, pharmacy networks, or financial arrangements. Significant efforts to change the PBM industry as it currently exists in the United States may affect the entire pharmaceutical supply chain and the business of other stakeholders, including pharmaceutical product developers like us.

We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative or executive action, either in the United States or abroad. We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, including any future drug products for which we secure marketing approval.

We and our third-party manufacturers must comply with applicable cGMP requirements. The cGMP requirements include requirements relating to, among other things, organization of personnel, buildings and facilities, equipment, control of components and drug product containers and closures, production and process controls, packaging and labeling controls, holding and distribution,

laboratory controls, records and reports, and returned or salvaged products. The manufacturing facilities for our products must meet cGMP requirements to the satisfaction of the FDA pursuant to a pre-approval inspection before we can use them to manufacture commercial products. We and our third-party manufacturers are also subject to periodic announced or for-cause unannounced inspections of facilities by the FDA and other authorities, including procedures and operations used in the testing and manufacture of our commercial products, if any, to assess our compliance with applicable regulations. Failure to comply with statutory and regulatory requirements subjects a manufacturer to possible legal or regulatory action, including, among other things, warning or other enforcement letters, voluntary corrective action, the seizure of products, injunctions, consent decrees placing significant restrictions on or suspending manufacturing operations, disgorgement of profits, and other civil and criminal penalties.

We are also subject to various laws and regulations regarding laboratory practices, the experimental use of animals, and the use and disposal of hazardous or potentially hazardous substances in connection with our research. In each of these areas, as above, the FDA has broad regulatory and enforcement authority, including, among other things, the ability to levy fines and civil penalties, suspend or delay issuance of approvals, seize or recall products, and withdraw approvals, any one or more of which could have an adverse effect on our ability to operate our business and generate revenues. Compliance with applicable environmental laws and regulations is expensive, and current or future environmental regulations may impair our research, development and production efforts, which could negatively impact our business, operating results and financial condition.

As of December 31, 2024, we employed 288 employees, of which 287 were full-time employees. A significant number of our management and employees have had prior experience with pharmaceutical, biotechnology or medical product companies. None of our employees are represented by a labor union or covered under a collective bargaining agreement. Management considers relations with our employees to be good.

Social Factors and Supporting Our Workforce: Our approach to how we recruit, develop, retain and manage our talent is driven by our values statement: Making an impact through innovation, inclusion, and inspiration. Our values are at the core of who we are as an organization, and what drive us to reimagine possible for science, for medicine, and for human health. Critical to achieving our strategic imperatives is our ability to build and retain an exceptional team in which each member plays a unique and important role. We were recently recognized by the Boston Business Journal and won the distinction of being one of the 2024 “Best Places to Work”, which underscores our employees’ recognition of our collective focus, resilience, and commitment to our mission. We also value diversity, equity, inclusion, and social responsibility, with the goal of fostering a strong sense of belonging and contributing, while being empowered to make a real difference. This commitment is company-wide. Our Nominating and Corporate Governance Committee of our Board of Directors (“Board”) oversees our strategies and policies related to our people and diversity, equity and inclusion (“DEI”) initiatives, in addition to those for our environmental, social and governance (“ESG”) initiatives.

We recognize that maintaining an engaged and high-performing workforce who share a connection with the communities we serve is critical to our success. Camaraderie and cohesion are key to our collective corporate identity and are integral facets of our human capital strategy. Whether it is coming together throughout the year to connect at our town halls or participating in local walks for the patient communities for whom we work, we take a team and human connections-based approach to our work. We are inspired by the communities we serve, the opportunities to engage and learn from individuals and their families, and the possibilities of what we can achieve together.

We understand that in order to drive innovation, we must continuously improve our people strategies and find ways to foster engagement and growth within our organization. To this end, below are some of our initiatives:

Employee Engagement: Having an engaged and dedicated workforce is essential for us to achieve our goals. It is also more apparent than ever that we set our employees up for success and continue to cultivate their engagement with Wave. We conduct surveys as a means of engaging with employees and gaining their insights. We use the data and input as a tool for improving our human resources management going forward. Engagement is also directly correlated to the interactions our employees have with each other and their teams. We also have a cross functional team dedicated to organizing activities, such as themed social gatherings, charity and volunteer opportunities, and health and wellness events, which enrich our culture and bring employees together. We also work to ensure that we are deeply aligned with our corporate goals as a company, that functional goals are clear and transparent, and that employees understand how their work contributes to the company’s success.

Professional Development Programs and Opportunities: Employees are our most valuable resource, and we focus on providing them with opportunities so that they can continue to grow and excel in their functions and our company. Professional development of our

employees drives engagement and allows us to leverage opportunities to grow and promote key talent from within our organization. We encourage individual development planning and leadership and management development programs for our employees, including our Building Coaching Leaders program that is a learning series designed to build strong coaching capabilities and strengthen a manager’s engagement with their teams, and our Management Essentials Program that is focused on building the leadership skillset of first-time managers and rising leaders. Through development planning, we strive for employees at all levels to focus on strengthening the skills required in their current role and potentially their next role. We conduct annual performance reviews for all employees, but, as importantly, we are focused on building a culture of continuous coaching, feedback and open communication between managers and their direct reports throughout the entire year. We provide managers and employees with training on how to conduct effective forward-looking performance conversations and to set effective goals that are specific, measurable, attainable, relevant and timebound (SMART). We also provide company-wide leadership and development opportunities through the Wave Learning Series, which was developed to build awareness of all functional areas, special areas of interest or importance, timely subject matters and to expand knowledge of industry trends and other matters of interest and relevance within the biopharmaceutical industry. The Wave Learning Series is conducted through company-wide presentations by employees at various levels, providing opportunities for development and cross-functional exposure for our employees. We also offer all full-time employees the option to participate in our Education Assistance Program, where we reimburse employees for tuition and eligible expenses.

Environmental Health and Safety: Compliance with environmental, health and safety (“EH&S”) laws and regulations forms the basis of the EH&S policy and programs we have in place, which include occupational health and safety measures that apply to all of our employees, contractors and visitors. These programs detail the proactive, risk-based approach that we take to prevent workplace injuries and protect the health and safety of our employees and the communities around us. In addition, we engage independent third parties to evaluate and audit our compliance with EH&S laws and regulations. We foster a culture that strives to embed safety into all aspects of our operations, which includes implementing design safeguards for our employees and patients. Our EH&S management system engages all levels of the organization to monitor and track the effectiveness of our programs, ensure EH&S compliance, respond to incidents and manage corrective actions to reinforce safeguards. Our training programs provide training to our employees that is commensurate with their level of risk exposure and are designed to ensure that employees have the knowledge and equipment available to mitigate risk. Our cross-functional Safety Committee meets monthly to discuss any concerns and ways to improve our EH&S programs. Employees are also required to report any incidents, no matter how small, and are encouraged to voice any health or safety concerns to management or a member of our EH&S team.

Health and Well-Being: We believe that the overall well-being of our employees and ensuring that their basic health and wellness needs are met is fundamental for us to achieve success as a company. We understand that a key part of our ongoing efforts to prioritize wellness initiatives includes providing our employees with access to mental health, behavioral health, and/or substance abuse services through our medical plans. We provide an Employee Assistance Program as a cost-free benefit, which is available to help employees and their household members to confidentially manage everyday life, arising work challenges, stress, and other personal issues, by providing consultation, referrals, and resources, along with ongoing webinars on various work-life, mental health, and wellness topics for employees. We prioritize providing mental health resources for our employees, while creating forums for dialogue. In addition, we understand that workplace flexibility is an important component to our employees’ well-being. Prioritizing employee safety while achieving our goals has provided us with a greater appreciation for workplace flexibility, which keeps our employees engaged and motivated, while also creating a sense of trust throughout our organization.

Diversity, Equity and Inclusion (“DEI”): Our commitment to maintaining a top-performing company means investing in and creating ongoing opportunities for employee development in a diverse and inclusive workplace. We believe that a diverse and inclusive workforce positively impacts our performance, fosters innovation and inspires us to achieve greater results. We provide equal employment opportunities without regard to race, color, religion, gender, sexual orientation, national origin, age, disability, veteran status or genetics, among other personal characteristics. Our DEI Steering Group leads various initiatives to help us maintain a diverse, equitable, culturally competent and supportive environment for all of our employees and other stakeholders. In addition to this, our intentional focus on DEI helps ensure that we continue to cultivate the next generation of experienced, diverse leaders and managers necessary to execute on our mission and plans for ambitious growth. As of December 31, 2024, women made up approximately 52% of our global workforce and constitute approximately 52% of senior management (defined as vice president level and above). As of December 31, 2024, racially diverse employees (those self-identifying as Black or African American, Hispanic or Latino, Asian, or being of two or more races) make up approximately 37% of our global workforce and approximately 23% of senior management (defined as vice president level and above) (10% of our employees did not provide us with this information).

Some of our DEI initiatives include DEI-focused training, educational and awareness building events, social hours celebrating various cultural themes, and our summer internship program with Project Onramp, which is an organization working to bridge the opportunity gap for Massachusetts-based college students in under-served and minority communities. We recently established a partnership with Bioversity, a nonprofit launched by MassBio to create and implement industry-aligned workforce training initiatives. Additionally, we encourage the formation of Employee Resource Groups and currently have three – Women+ of Wave, Black Employee Network, and

LGBTQIA+ – with more likely to be formed. We also have a supplier diversity program that identifies and classifies our suppliers, encouraging the use of a more diversified supply base. We believe that having a diverse group of suppliers will allow us to effectively meet the needs of our organization while expanding our pool of suppliers to create more competitive business opportunities, and ultimately creating positive social impact by generating economic opportunities for those in our community who may be disadvantaged.

Patient Advocacy and Community Engagement: Our community engagement activities are focused on seeking to better understand the lived experience of people impacted by rare and prevalent diseases and identifying opportunities to support these communities. We believe that listening to, learning from, and partnering with individuals impacted by the diseases we hope to address, including families and caregivers, connects us more deeply to our mission, and enhances our ability to discover and develop meaningful therapies. Through collaboration with patient communities and advocacy organizations, including participation in community-focused conferences and events, we aim to incorporate community voices and perspectives into every aspect of our work. Insights from the community inform the design and execution of our clinical trials, shape our corporate culture, and drive activities and initiatives that are intended to make a positive impact on people’s lives.

Employee volunteering is another important component of our community engagement initiatives. We partner with advocacy and service organizations to provide opportunities for employees to contribute directly to our local communities, including through our Wave Service Day and holiday giving drives. By participating in a broad range of volunteer activities, our employees donate time and resources to support individuals and families in our community and beyond. We also recognize that external factors and current events, including systems and policies, impact our employees, as well as the communities with which we are connected.

Rewards and Recognition: We have a multi-tiered awards program, including peer-to-peer recognition, which our employees use to recognize and reward one another for their contributions and achievements, taking into consideration the combination of employees who best exemplify our values and the achievement of results. We believe that providing a rewards program not only increases engagement and performance, but meaningfully recognizes those employees who go above and beyond to positively impact our company and culture. In addition, we offer a team rewards and recognition program to provide another opportunity to recognize and reward collaborative teamwork.

Compensation, Equity and Benefits (Total Rewards): Compensation programs are one of the most powerful tools available to companies to attract, retain and motivate employees, as well as align their interests with those of shareholders. We have developed a broad-based compensation program that is designed to attract, retain and motivate our employees, while driving sustainable long-term value creation. We seek to deliver performance-driven, market competitive reward opportunities commensurate with company and individual performance. All of our employees receive competitive base salaries, cash bonus eligibility, new hire equity grants and annual long-term incentive grants eligibility, in addition to our comprehensive benefits package. We believe that providing employees with an ownership interest in Wave through grants of equity awards further strengthens the level of employee engagement. In addition, our Employee Share Purchase Plan, as amended (“ESPP”), provides our U.S. employees with an opportunity to purchase our ordinary shares at a 15% discount to the market price.

Offering a highly competitive, industry-leading benefits package is another integral piece of our total rewards package and differentiated employee value proposition. Notably, we provide our employees with access to choice and offer employees a very progressive health insurance package, with no premiums. We also offer a 401(k) plan with matching contributions for all eligible employees. We provide innovative solutions that are key to attracting, engaging and motivating employees, including (i) our excellent benefits and compensation programs and strategies; (ii) our employee well-being approach and strategy; (iii) our health plan; and (iv) internal communications and education around our total rewards strategy.

We will continue to evolve and strengthen our strategies relating to talent, while furthering our investment in our employees, culture, community partnerships and outreach, and other human capital measures.

We were incorporated under the name Wave Life Sciences Pte. Ltd. (Registration No.: 201218209G) under the laws of Singapore on July 23, 2012. On November 16, 2015, we closed our initial public offering. In preparation for our initial public offering, on November 5, 2015, Wave Life Sciences Pte. Ltd. converted from a private limited company to a public limited company known as Wave Life Sciences Ltd. (“Wave”). Wave has four wholly-owned subsidiaries: Wave Life Sciences USA, Inc. (“Wave USA”), a Delaware corporation (formerly Ontorii, Inc.); Wave Life Sciences Japan, Inc. (“Wave Japan”), a company organized under the laws of Japan (formerly Chiralgen., Ltd.); Wave Life Sciences Ireland Limited (“Wave Ireland”), a company organized under the laws of Ireland; and Wave Life Sciences UK Limited (“Wave UK”), a company organized under the laws of the United Kingdom.

Our registered office is located at 7 Straits View #12-00, Marina One East Tower, Singapore 018936, and our telephone number at that address is +65 6236 3388. Our principal office for Wave USA is located at 733 Concord Avenue, Cambridge, MA 02138, and our telephone number at that address is +1-617-949-2900. Our registered office for Wave Japan is 2438 Miyanoura-cho, Kagoshima-shi, Kagoshima pref. 891-1394, Japan. Our registered office for Wave Ireland is One Spencer Dock, North Wall Quay, Dublin 1, D01 X9R7, Ireland. Our registered office for Wave UK is 1 Chamberlain Square CS, Birmingham B3 3AX, United Kingdom.

Our Internet website address is http://www.wavelifesciences.com. The information contained on, or that can be accessed through, our website is not a part of, or incorporated by reference in, this Annual Report on Form 10-K or our other filings with the SEC. We have included our website address in this Annual Report on Form 10-K solely as an inactive textual reference. We make available free of charge through our website our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act. We make these reports available through the “For Investors & Media – SEC Filings” section of our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the SEC. We also make available, free of charge on our website, the reports filed with the SEC by our executive officers, directors and 10% shareholders pursuant to Section 16 under the Exchange Act as soon as reasonably practicable after copies of those filings are filed with the SEC. You can review our electronically filed reports and other information that we file with the SEC on the SEC’s website at http://www.sec.gov.

In addition, we regularly use our website to post information regarding our business and governance, and we encourage investors to use our website, particularly the information in the section entitled “For Investors & Media,” as a source of information about us.

You should carefully consider the following risk factors, in addition to the other information contained in this Annual Report on Form 10-K, including the section of this report titled “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and our financial statements and related notes. If any of the events described in the following risk factors and the risks described elsewhere in this Annual Report on Form 10-K occurs, our business, operating results and financial condition could be seriously harmed and the trading price of our ordinary shares could decline. This Annual Report on Form 10-K also contains forward-looking statements that involve risks and uncertainties. Our actual results could differ materially from those anticipated in the forward-looking statements as a result of factors that are described below and elsewhere in this Annual Report on Form 10-K.

We are a clinical-stage biotechnology company with a history of losses, and we expect to continue to incur losses for the foreseeable future, and we may never achieve or maintain profitability.

We are a clinical-stage biotechnology company and have incurred significant operating losses since our incorporation in 2012. Our net loss was $97.0 million, $57.5 million, and $161.8 million for the fiscal years ended December 31, 2024, 2023, and 2022, respectively. As of December 31, 2024, and 2023 we had an accumulated deficit of $1,121.9 million and $1,024.9 million, respectively. To date, we have not generated any product revenue. Substantially all of our losses have resulted from expenses incurred in connection with our research and development programs and from general and administrative costs associated with our operations.

We are a clinical-stage biotechnology company focused on unlocking the broad potential of ribonucleic acid (“RNA”) medicines (also known as oligonucleotides), or those targeting RNA, to transform human health. Our RNA medicines platform, PRISM®, combines multiple modalities, chemistry innovation and deep insights into human genetics to deliver scientific breakthroughs that treat both rare and common disorders. Our toolkit of RNA-targeting modalities includes RNA editing, splicing, silencing using RNA interference (“siRNA") and antisense silencing, providing us with unique capabilities for designing and sustainably delivering candidates that optimally address disease biology. Our diversified pipeline includes clinical programs in obesity, alpha-1 antitrypsin deficiency (“AATD”), Duchenne muscular dystrophy (“DMD”), and Huntington’s disease (“HD”), as well as several preclinical programs utilizing our versatile RNA medicines platform. We have not generated, and do not expect to generate, any product revenue for the foreseeable future, and we expect to continue to incur significant operating losses for the foreseeable future due to the cost of research and development, manufacturing, preclinical studies and clinical trials and the regulatory review process for product candidates. The amount of future losses is uncertain. To achieve profitability, we must successfully develop product candidates, obtain regulatory approvals to market and commercialize product candidates, manufacture any approved product candidates on commercially reasonable terms, establish a sales and marketing organization or suitable third-party alternatives for any approved product and raise sufficient funds to finance our business activities. We may never succeed in these activities and, even if we do, may never generate revenues that are significant or large enough to achieve profitability. Even if we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. Our failure to become and remain profitable would decrease the value of our company and could impair our ability to raise capital, maintain our research and development efforts, expand our business or continue our operations. A decline in the value of our company could also cause our shareholders to lose all or part of their investment.

We will require substantial additional funding, which may not be available on acceptable terms, or at all.

We have used substantial funds to develop our programs and PRISM, our proprietary discovery and drug development platform, and will require substantial funds to conduct further research and development, including preclinical studies and clinical trials of our product candidates, seek regulatory approvals for our product candidates and manufacture and market any products that are approved for commercial sale. We believe that our existing cash and cash equivalents will be sufficient to fund our operations for at least the next 12 months.

Our future capital requirements and the period for which we expect our existing resources to support our operations may vary significantly from what we expect. We do not expect to realize any appreciable revenue from product sales or royalties in the foreseeable future, if at all. Our revenue sources will remain extremely limited unless and until our product candidates complete clinical development and are approved for commercialization and successfully marketed. Because we cannot be certain of the length of time or activities associated with successful development and commercialization of our product candidates, we are unable to estimate the actual funds we will require to develop and commercialize them.

Our future capital requirements will depend on many factors, including, but not limited to, the following:

To date, we have primarily financed our operations through sales of our securities and our collaborations with third parties. Through December 31, 2024, we have received an aggregate of approximately $1,578.4 million in net proceeds from these transactions, consisting of $977.8 million in net proceeds from public and other registered offerings of our ordinary shares, $511.3 million from our collaborations, exclusive of any potential future milestone and royalty payments, and $89.3 million in net proceeds from private placements of our debt and equity securities.

On November 12, 2024, we filed an automatic shelf registration statement on Form S-3ASR with the SEC for which we registered for sale an indeterminate amount of any combination of our ordinary shares, debt securities, warrants, rights and/or units from time to time and at prices and on terms that we may determine, which we refer to as the “2024 WKSI Shelf”. Our 2024 WKSI Shelf includes a prospectus covering up to an aggregate of $250.0 million in ordinary shares that we are able to issue and sell from time to time, through Jefferies LLC (“Jefferies”) acting as our sales agent, pursuant to the Open Market Sale Agreement, dated May 10, 2019, as amended by Amendment No. 1, dated as of March 2, 2020, Amendment No. 2, dated as of March 3, 2022, and Amendment No. 3, dated as of November 12, 2024 (collectively, the “Sales Agreement”), for our “at-the-market” equity program.

Our ability to raise additional funds will depend on financial, economic and other factors, many of which are beyond our control. We may seek access to the capital and credit markets for working capital, capital expenditure, and other business initiatives. The capital and credit markets have experienced extreme volatility and disruption, which may lead to uncertainty and liquidity issues for both borrowers and investors. In the event of adverse market conditions, or other factors, additional funds may not be available to us on acceptable terms or at all. For example, the global economy has been experiencing volatility in interest rates and inflation, which could negatively impact our business and our ability to raise additional funds. If we raise additional funds by issuing equity or convertible debt securities, our shareholders will suffer dilution and the terms of any financing may adversely affect the rights of our shareholders. In addition, as a condition to providing additional funds to us, future investors may demand, and may be granted, rights superior to those of existing shareholders. Debt financing, if available, may involve restrictive covenants limiting our flexibility in conducting future business activities, and, in the event of insolvency, debt holders would be repaid before holders of equity securities receive any distribution of corporate assets.

If we are unable to obtain funding on a timely basis or on acceptable terms, we may have to delay, limit or terminate our research and development programs and preclinical studies or clinical trials, limit strategic opportunities or undergo reductions in our workforce or other corporate restructuring activities. We also could be required to seek funds through arrangements with collaborators or others that may require us to relinquish rights to some of our product candidates or technologies that we would otherwise pursue on our own.

Our business may be impacted by macroeconomic conditions, including fears concerning the financial services industry, inflation, volatility in interest rates and volatile market conditions, and other uncertainties beyond our control.

Actual events involving limited liquidity, defaults, non-performance or other adverse developments that affect financial institutions, transactional counterparties or other companies in the financial services industry or the financial services industry generally, or concerns or rumors about any events of these kinds or other similar risks, have in the past and may in the future lead to market-wide liquidity problems. Our ability to effectively run our business could be adversely affected by general conditions in the global economy and in the financial services industry. Various macroeconomic factors could adversely affect our business, including fears concerning the banking sector, volatility in inflation, and interest rates and overall changes in economic conditions and uncertainties. A severe or prolonged economic downturn could result in a variety of risks, including our ability to raise additional funding on a timely basis or on

acceptable terms. A weak or declining economy could also impact third parties upon whom we depend to run our business. Concerns over bank failures and bailouts and their potential broader effects and potential systemic risk on the banking sector generally and on the biotechnology industry and its participants may adversely affect our access to capital and our business and operations more generally. Although we assess our banking relationships as we believe necessary or appropriate, our access to funding sources in amounts adequate to finance or capitalize our current and projected future business operations could be significantly impaired by factors that affect us, the financial institutions with which we have arrangements directly, or the financial services industry or economy in general.

Our management has broad discretion over the use of proceeds received from sales of our securities and our collaborations with third parties and the proceeds may not be used effectively.

Our management has broad discretion as to the use of proceeds we receive from conducting sales of our securities and our collaborations with third parties and could use the proceeds for purposes other than those contemplated at the time of such transactions. It is also possible that the proceeds we have received, or may receive, from securities sales and collaborations will be invested in a way that does not yield a favorable, or any, return for us.

Our operating history as a clinical-stage biotechnology company may make it difficult for shareholders to evaluate the success of our business to date and to assess our future viability.

We are a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines (also known as oligonucleotides), or those targeting RNA, to transform human health. Our RNA medicines platform, PRISM, combines multiple modalities, chemistry innovation and deep insights into human genetics to deliver scientific breakthroughs that treat both rare and common disorders. Our toolkit of RNA-targeting modalities includes RNA editing, splicing, silencing using siRNA and antisense silencing, providing us with unique capabilities for designing and sustainably delivering candidates that optimally address disease biology. Our diversified pipeline includes clinical programs in obesity, AATD, DMD, and HD, as well as several preclinical programs utilizing our versatile RNA medicines platform. We have not yet demonstrated our ability to successfully complete pivotal clinical trials, obtain marketing approvals, or conduct sales and marketing activities necessary for successful product commercialization. We have limited experience manufacturing our products at commercial scale or arranging for a third party to do so on our behalf. Typically, it takes many years to develop and commercialize a therapeutic from the time it is discovered to when it is available for treating patients. Further, drug development is a capital-intensive and highly speculative undertaking that involves a substantial degree of risk. You should consider our prospects in light of the costs, uncertainties, delays and difficulties frequently encountered by biotechnology companies in the early stages of clinical development, such as ours. Any predictions about our future success or viability may not be as accurate as they could be if we had a longer operating history or a history of successfully developing and commercializing pharmaceutical products.

We, or third parties upon whom we depend, may face risks related to local and global health epidemics, which may delay our ability to complete our ongoing clinical trials, initiate additional clinical trials, delay regulatory activities and have other adverse effects on our business and operations.

As a clinical-stage company with multiple programs and multiple clinical trials currently underway, any local or global health issues could impact the execution of our clinical trials. For example, beginning in March 2020, multiple countries throughout the world and their economies, including the United States, were subject to intermittent shutdowns and were adversely affected by the COVID-19 global pandemic. We had clinical trial sites located in countries that had been affected by COVID-19 and variants thereof. Clinical site initiation and patient enrollment was delayed due to prioritization of hospital resources in favor of COVID-19 patients and difficulties in recruiting clinical site investigators and clinical site staff. Some patients were not able to travel or gain access to clinical trial sites due to local restrictions. Similarly, our ability to recruit and retain patients and principal investigators and site staff was negatively impacted, which delayed the timelines of our clinical trial operations.

We rely upon third parties for many aspects of our business, including the raw materials used to make our product candidates and the conduct of our clinical trials and preclinical studies. While we have built up inventory to assist us through this uncertain operating environment, our suppliers may be disrupted now or in the future due to a local or global health epidemic, which could affect our ability to procure items that are essential for our research and development activities and could cause increases to our costs, inflation, and significant disruptions to our business.

While we have adapted our processes to lessen the impact of a potential local or global health epidemic may have on our business, any potential delays or long-term impacts on our business, our clinical trials, healthcare systems or the global economy could be highly uncertain. These effects could materially adversely affect our business, financial condition, results of operations, and prospects.

Risks Related to the Discovery, Manufacturing, Development and Commercialization of Our Product Candidates

The approach we are taking to discover and develop RNA medicines is novel and may never lead to marketable products.

We have concentrated our efforts and research and development activities on RNA medicines (also known as oligonucleotides) and enhancing PRISM, our proprietary discovery and drug development platform. PRISM enables us to target genetically defined diseases with stereopure oligonucleotides across multiple therapeutic modalities. Our future success depends on the successful development of our RNA medicines and the effectiveness of PRISM. The scientific discoveries that form the basis for our efforts to discover and develop new product candidates, including our discoveries about the relationships between oligonucleotide stereochemistry and pharmacology, are relatively new. Our PRISM platform combines multiple modalities, chemistry innovation and deep insights into human genetics to deliver scientific breakthroughs that treat both rare and prevalent disorders. The scientific evidence to support the feasibility of developing medicines based on our discoveries is limited, as we have not yet completed successful clinical development of an oligonucleotide therapeutic.

Because we are developing oligonucleotides, which are considered a relatively new class of drugs, there is increased risk that the outcome of our clinical trials will not be sufficient to obtain regulatory approval.

The FDA and comparable ex-U.S. regulatory agencies have relatively limited experience with RNA medicines (also known as oligonucleotides), which may increase the complexity, uncertainty and length of the regulatory review process for our product candidates. The FDA has approved approximately 20 oligonucleotides for commercial use. The FDA has issued multiple guidance documents on the development and testing of oligonucleotide products, as well as guidance relating to regulatory submissions for such products, including in December 2021 two draft guidance documents relating to IND submissions for individualized antisense oligonucleotide drugs for severely debilitating or life-threatening genetic diseases, one with clinical focus, the other with chemistry manufacturing and controls focus, in June 2024 a final guidance on clinical pharmacology considerations for the development of oligonucleotide therapeutics, and in November 2024 a draft guidance on nonclinical safety assessment of oligonucleotide products. Although guidance documents issued by FDA do not have the force of law and are therefore not binding on the industry, we may decide to revise the design of our ongoing or planned nonclinical studies or clinical trials, or design new nonclinical studies or clinical trials, of our product candidates to align with the agency’s current thinking as set forth in the recently published guidance. The general lack of extensive experience specific to oligonucleotides may hinder or slow review by the FDA or other foreign homologues of any regulatory filings that we may submit. Moreover, the FDA or other foreign homologues may respond to these submissions by defining requirements we may not have anticipated. Addressing such requirements could lead to significant delays in the development of our product candidates. In addition, because there may be approved treatments for some of the diseases for which we may seek approval, in order to receive regulatory approval, we may need to demonstrate through clinical trials that the product candidates we develop to treat these diseases, if any, are not only safe and effective, but safer or more effective than existing products. Furthermore, in recent years, there has been increased public and political pressure on the FDA with respect to the approval process for new drugs. As a result of the foregoing factors, we may never receive regulatory approval to market and commercialize any product candidate.

Even if we obtain regulatory approval, the approval may be for disease indications or patient populations that are not as broad as we intended or desired or may require labeling that includes significant use or distribution restrictions or safety warnings. We may be required to perform additional or unanticipated clinical trials to obtain regulatory approval or be subject to additional post-marketing studies or other requirements to maintain such approval. As a result, we may never succeed in developing a marketable product, we may not become profitable and the value of our ordinary shares could decline.

Our preclinical studies and clinical trials may not be successful. If we are unable to commercialize our product candidates or experience significant delays in doing so, our business may be materially harmed.

We have a robust and diverse pipeline of first- or best-in-class RNA medicines using our RNA editing, splicing, silencing using siRNA and antisense silencing modalities. Our diversified pipeline includes clinical programs in AATD, DMD, HD, and obesity, as well as several preclinical programs utilizing our broad RNA therapeutics toolkit.

However, we currently have no products on the market. We have invested a significant portion of our efforts and financial resources in the identification and preclinical and clinical development of our oligonucleotides, the development of our RNA medicines platform, PRISM, including our RNA editing capability, and our novel chemistry modifications, and the continued growth of our manufacturing capabilities. Our ability to generate product revenue, which we do not expect will occur for many years, if ever, will depend heavily on the successful development, regulatory approvals, and eventual commercialization of our product candidates. Our success will depend on several factors, including the following:

If we do not achieve one or more of these factors in a timely manner or at all, we could experience significant delays or an inability to successfully commercialize our product candidates, which would materially harm our business.

We may not be able to conduct clinical trials successfully due to various process-related factors that could negatively impact our business plans.

The successful initiation and completion of any of our clinical trials, within timeframes consistent with our business plans, is dependent on various factors, which include, but are not limited to, our ability to:

If we are not able to manage the clinical trial process successfully, our business plans could be delayed or be rendered unfeasible for us to execute within our planned or required time frames, or at all.

If we cannot successfully manufacture our product candidates for our research and development and preclinical activities, or manufacture sufficient amounts of our product candidates to meet our clinical requirements and timelines, our business may be materially harmed.

In order to develop our product candidates, apply for regulatory approvals and commercialize our product candidates, we will need to develop, contract for, or otherwise arrange for the necessary manufacturing capabilities. In September 2016, we entered into a lease for a multi-use facility of approximately 90,000 square feet in Lexington, Massachusetts to provide internal cGMP manufacturing capabilities and increase control and visibility of our drug substance supply chain, and we began cGMP manufacturing in this facility at the beginning of 2018. This facility supplements our existing Cambridge, Massachusetts laboratory and office space headquarters, enhances our ability to secure drug substance for current and future development activities and may provide commercial-scale manufacturing capabilities. However, while we have established and continue to enhance our internal cGMP manufacturing capabilities, we have limited experience manufacturing drug substance on a commercial scale, and we will incur significant costs to develop this expertise internally.

In addition to the oligonucleotides that we manufacture internally, we may utilize CMOs to manufacture the oligonucleotides required for our preclinical studies and clinical trials. There are a limited number of manufacturers that supply oligonucleotides. There are risks inherent in pharmaceutical manufacturing that could affect our ability or the ability of our CMOs to meet our delivery time requirements or provide adequate amounts of material to meet our clinical trial demands on our projected timelines. Included in these risks are potential synthesis and purification failures and/or contamination during the manufacturing process, as well as other issues with our facility or the CMOs’ facilities and ability to comply with the applicable manufacturing requirements and quality standards, which could result in unusable product and cause delays in our manufacturing timelines and ultimately delay our clinical trials, as well as result in additional expense to us. To manufacture our oligonucleotides, we rely on third parties to supply the required raw materials. We will likely need to secure alternative suppliers for these raw materials, and such alternative suppliers are limited and may not be readily available, or we may be unable to enter into agreements with them on reasonable terms and in a timely manner. For example, we source certain materials used in the manufacture of our products from China and other countries outside of the United States, and supply chain disruptions could impact our business. Additionally, our cost of goods development is at an early stage. The actual cost to manufacture and process our product candidates could be greater than we expect and could materially and adversely affect the commercial viability of our product candidates.

The process of manufacturing oligonucleotides is complex and we may encounter difficulties in production, particularly with respect to process development or scaling-up of our manufacturing capabilities.

The process of manufacturing oligonucleotides is complex, highly-regulated and subject to multiple risks. The complex processes associated with the manufacture of our product candidates expose us to various manufacturing challenges and risks, which may include delays in manufacturing adequate supply of our product candidates, limits on our ability to increase manufacturing capacity, and the potential for product failure and product variation in quality that may interfere with preclinical studies and clinical trials, along with additional costs. We also may make changes to our manufacturing process at various points during development, and even after commercialization, for various reasons, such as optimizing costs, achieving scale, decreasing processing time, increasing manufacturing success rate, or other reasons. Such changes carry the risk that they will not achieve their intended objectives, and any of these changes could cause our product candidates to perform differently and affect the results of current or future clinical trials, or the performance of the product, once commercialized. In some circumstances, changes in the manufacturing process may require us to perform ex vivo comparability studies, and/or conduct animal studies, and to collect additional data from patients prior to undertaking more advanced clinical trials. For instance, changes in our process during the course of clinical development may require us to provide the FDA and comparable regulatory authorities adequate evidence of the comparability of the product used in earlier clinical trials or at earlier portions of a trial to the product used in later clinical trials or later portions of the trial. We may also make further changes to our manufacturing process before or after commercialization, and such changes may require us to show the comparability of the resulting product to the product produced via earlier manufacturing processes and supplied in clinical studies. We may be required to collect additional preclinical and/or clinical data from any modified process prior to obtaining marketing approval for the product candidate produced with such modified process. If preclinical and/or clinical data are not ultimately comparable to those seen in the earlier trials, we may be required to make further changes to our process and/or undertake additional clinical testing, either of which could significantly delay the clinical development or commercialization of the associated product candidate.

could be affected by cost-overruns, unexpected delays, equipment failures, labor shortages, operator error, natural disasters, unavailability of qualified personnel, difficulties with logistics and shipping, problems regarding yields or stability of product, contamination or other quality control issues, power failures, and numerous other factors that could prevent us from realizing the intended benefits of our manufacturing strategy and have a material adverse effect on our business.

Furthermore, compliance with cGMP requirements and other quality issues may arise during our internal efforts to scale-up manufacturing, and with our current or any future CMOs. If contaminants are discovered in our supply of our product candidates or in our manufacturing facilities or those of our CMOs, such manufacturing facilities may need to be closed for an extended period of time to investigate and remedy the contamination. We cannot assure you that any stability failures or other issues relating to the manufacture of our product candidates will not occur in the future. Additionally, we and our CMOs may experience manufacturing difficulties due to resource constraints or as a result of labor disputes or unstable political environments. If we or our CMOs were to encounter any of these difficulties, our ability to provide our product candidate to patients in clinical trials, or to provide product for treatment of patients once approved, would be jeopardized.

We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.

Because we have limited financial resources, we intend to focus on developing product candidates for specific indications that we identify as most likely to succeed, in terms of both regulatory approval and commercialization. As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that may prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on current and future research and development programs and product candidates for specific indications may not yield any commercially viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate.

Any product candidates we develop may fail in preclinical or clinical development or be delayed to a point where they do not become commercially viable.

Before obtaining regulatory approval for the commercial distribution of any of our product candidates, we must conduct, at our own expense, extensive preclinical studies and clinical trials to demonstrate the safety and efficacy in humans of our product candidates. Preclinical and clinical testing is expensive, difficult to design and implement, can take many years to complete, is uncertain as to outcome, and the historical failure rate for drugs in preclinical and clinical development is high. For example, we depend on the availability of non-human primates to conduct certain preclinical studies. Over the past several years there has been a global shortage of non-human primates available for drug development that has matured into an acute global supply chain issue. The supply of these non-human primates has been constrained due to factors such as their limited worldwide availability, domestic regulatory restrictions and trade relations. If we are unable to obtain access to a sufficient supply of these non-human primates in a timely manner or at all, our timelines and our ability to complete preclinical testing and submit IND/CTA or equivalent foreign applications may be adversely affected.

We, the FDA or comparable foreign regulatory authorities or an IRB, or similar foreign review board or ethics committee, may suspend clinical trials of a product candidate at any time for various reasons, including if we or they believe the healthy volunteer subjects or patients participating in such trials are being exposed to unacceptable health risks. Among other reasons, unacceptable side effects or other more serious adverse events of a product candidate in healthy volunteer subjects or patients in a clinical trial could result in the FDA or comparable foreign regulatory authorities suspending or terminating the trial and refusing to approve a particular product candidate for any or all indications of use.

Clinical trials also require the review, oversight and approval of IRBs or ethics committees, which review the clinical protocols and informed consent form for investigations that will be conducted at their institutions in order to protect the rights and welfare of human subjects. Inability to obtain or delay in obtaining IRB approval can prevent or delay the initiation and completion of clinical trials at particular sites. Furthermore, failure to provide information to the IRB and relevant regulatory authorities, as required throughout the study, such as emergent safety reports and annual updates, may result in suspension of the approval of the trial. Our product candidates may encounter problems during clinical trials that will cause us or regulatory authorities to delay, suspend or terminate these trials, or that will delay or confound the analysis of data from these trials. If we experience any such problems, we may not have the financial resources to continue development of the product candidate that is affected or any of our other product candidates. We may also lose, or be unable to enter into, collaborative arrangements for the affected product candidate and for other product candidates we are developing. The development of one or more of our product candidates can fail at any stage of testing. We may experience numerous unforeseen events during, or as a result of, preclinical studies and clinical trials that could delay or prevent regulatory approval or our ability to commercialize our product candidates, including:

If we do not successfully conduct clinical development, we will not be able to market and sell products derived from our product candidates and to generate product revenues. Even if we do successfully complete clinical trials, those results are not necessarily predictive of results of additional trials that may be needed before we can submit an application for regulatory approval to the FDA or foreign regulatory agencies. If the development of any of our product candidates fails or is delayed to a point where such product candidate is no longer commercially viable, our business may be materially harmed.

Results of preclinical studies and early clinical trials may not be predictive of results of subsequent clinical trials.

The results from preclinical studies or early clinical trials of a product candidate may not predict the results that will be obtained in subsequent subjects or in subsequent clinical trials of that product candidate or any other product candidate. The design of a clinical trial can determine whether its results will support approval of a product candidate and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced. In addition, preclinical and clinical data are often susceptible to varying interpretations and analyses. Product candidates that seemingly perform satisfactorily in preclinical studies may nonetheless fail to reach late development stages or obtain regulatory approval for marketing. For example, our preclinical studies for WVE-004 for C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (“C9-ALS/FTD”) yielded positive results. However, in May 2023, the topline results of the Phase 1b/2a study of WVE-004 for patients with C9-ALS/FTD showed no trends in clinical benefit and reductions in poly(GP) were not correlated with changes in functional outcome and resulted in our discontinuation of the WVE-004 program. There is a high failure rate for drugs proceeding through clinical trials. A number of companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in clinical development even after achieving promising results in earlier studies, and any such setbacks in our clinical development could negatively affect our business and operating results.

If we experience delays or difficulties in the enrollment of patients in clinical trials, our receipt of necessary regulatory approvals could be delayed or prevented.

Clinical trials of a new product candidate require the enrollment of a sufficient number of patients, including patients who are suffering from the disease the product candidate is intended to treat and who meet other eligibility criteria. Rates of patient enrollment are affected by many factors, including local or global health issues, the size of the patient population, the age and condition of the patients, the stage and severity of disease, the nature and requirements of the protocol, the proximity of patients to clinical sites, the availability of effective treatments for the relevant disease, and the eligibility criteria for the clinical trial. Delays or difficulties in patient enrollment or difficulties retaining trial participants, including as a result of the availability of existing or other investigational treatments, can result in increased costs, longer development times or termination of a clinical trial.

In addition, our success may depend, in part, on our ability to identify patients who qualify for our clinical trials, or are likely to benefit from any medicines that we may develop, which will require those potential patients to undergo a screening assay, which we also refer to as a companion diagnostic test, for the presence or absence of a particular genetic sequence. For example, in HD, we are conducting a clinical trial for WVE-003, which targets a SNP associated with the mutant allele of the HTT gene. Approximately 40% of the HD patient population carry this SNP. We have developed a novel screening assay that is intended to identify whether a patient has the particular SNP that our product candidate is targeting, and we have partnered with a third party for testing in future trials. If we, or any third parties that we engage to assist us are unable to successfully identify patients with the appropriate SNP that we are targeting, the percentage of patients with the SNP we are targeting is lower than expected, or we experience delays in testing, we may not realize the full commercial potential of any product candidates we develop.

Congress also recently amended the FDCA to require sponsors of a Phase 3 clinical trial, or other “pivotal study” of a new drug to support marketing authorization, to design and submit a diversity action plan for such clinical trial. The action plan must describe appropriate diversity goals for enrollment, as well as a rationale for the goals and a description of how the sponsor will meet them. Although none of our product candidates has reached Phase 3 of clinical development, we must submit a diversity action plan to the FDA by the time we submit a Phase 3 trial, or pivotal study, protocol to the agency for review, unless we are able to obtain a waiver for some or all of the requirements for a diversity action plan. It is unknown at this time how the diversity action plan may affect the planning and timing of any future Phase 3 trial for our product candidates. However, initiation of such trials may be delayed if the FDA objects to our proposed diversity action plans for any future Phase 3 trial for our product candidates, and we may experience difficulties recruiting a diverse population of patients in attempting to fulfill the requirements of any approved diversity action plan.

If we are unable to successfully develop or obtain regulatory approval for companion diagnostic tests for our product candidates, or experience significant delays in doing so, our clinical trials may be delayed and our business could be materially harmed.

The development programs for some of our product candidates contemplate the development of companion diagnostic tests, which are assays or tests to identify an appropriate patient population. The success of certain of our product candidates will depend on several factors, including the successful development of, and ability to obtain regulatory approval for, companion diagnostic tests that will be used to screen and identify the right patients for our product candidates. Our goal is to develop and commercialize disease-modifying medicines for genetically defined diseases with a high degree of unmet medical need, and to become a fully integrated RNA

medicines company. The target patient populations for several of our product candidates are relatively small, and it will be difficult to successfully identify the appropriate patients for whom our product candidates are being designed without performant, fit-for-purpose, accessible, relatively inexpensive, and easy-to-use companion diagnostic tests.

Companion diagnostic tests are subject to regulation by the FDA and similar regulatory authorities outside the United States as medical devices, often in vitro devices, and require separate regulatory authorization prior to commercialization. We are not a medical device company, and we have limited experience developing medical devices. A more detailed description of the FDA approval process for companion diagnostic tests is included under “Business – Government Regulation – In Vitro Diagnostic Tests for Biomarkers.” Given our limited experience in developing and commercializing companion diagnostic tests, we may seek to collaborate with third parties to assist us in the design, manufacture, regulatory authorization and commercialization of the companion diagnostic tests for some of our product candidates. In November 2019, we entered into a collaboration with Asuragen for the development and commercialization of companion diagnostics for our allele-selective product candidate in HD. We, Asuragen and other potential collaborators may encounter difficulties in developing and obtaining approval for the companion diagnostic tests, including issues relating to sensitivity/specificity, analytical validation, reproducibility, or clinical validation. Any delay or failure by us or our collaborators to develop or obtain regulatory authorization of the relevant companion diagnostic tests could delay or prevent approval of our product candidates. If we, Asuragen or any other third parties that we engage to assist us, are unable to successfully develop, validate, and commercialize companion diagnostic tests for our drug candidates, or experience delays in doing so, our clinical trials and our business could be materially harmed.

We may be unable to obtain regulatory approval in the United States or foreign jurisdictions and, as a result, be unable to commercialize our product candidates and our ability to generate revenue will be materially impaired.

Our product candidates are subject to extensive governmental regulations relating to, among other things, research, testing, development, manufacturing, quality, safety, efficacy, approval, recordkeeping, reporting, labeling, storage, packaging, advertising and promotion, pricing, marketing and distribution of drugs. Rigorous preclinical studies and clinical trials, and an extensive regulatory approval process are required to be successfully completed in the United States and in many foreign jurisdictions before a new drug can be marketed. Satisfaction of these and other regulatory requirements is costly, time consuming, uncertain, and subject to a continuously evolving regulatory environment and unanticipated delays. It is possible that none of the product candidates we may develop will obtain the regulatory approvals necessary for us or our collaborators to begin selling them.

The time required to obtain FDA and other approvals is unpredictable but typically takes many years following the commencement of clinical trials, depending upon the type, complexity and novelty of the product candidate. The standards that the FDA and its foreign counterparts use when regulating companies such as ours are not always applied predictably or uniformly and can change. Any analysis we perform of data from chemistry, manufacturing and controls, preclinical and clinical activities is subject to confirmation and interpretation by regulatory authorities, which could delay, limit or prevent regulatory approval. We may also encounter unexpected delays or increased costs due to new government regulations, for example, from future legislation or administrative action, or from changes in FDA policy during the period of product development, clinical trials and FDA regulatory review. It is impossible to predict whether legislative changes will be enacted, or whether FDA or foreign regulations, guidance or interpretations will be changed, or what the impact of such changes, if any, may be.

Any delay or failure in obtaining required approvals could adversely affect our ability to generate revenues from the particular product candidate for which we are seeking approval. Furthermore, any regulatory approval to market a product may be subject to limitations on the approved uses for which we may market the product or the labeling or other restrictions. In addition, the FDA has the authority to require a Risk Evaluation and Mitigation Strategy (“REMS”), as a condition of approval, which may impose further requirements or restrictions on the distribution or safe use of an approved drug, such as limiting prescribing rights to certain physicians or medical centers that have undergone specialized training, limiting treatment to patients as specially defined by the indication statement or who meet certain safe-use criteria, and requiring treated patients to enroll in a registry, among other requirements. These limitations and restrictions may limit the size of the market for the product and affect reimbursement by third-party payors.

We are also subject to numerous foreign regulatory requirements governing, among other things, the conduct of clinical trials, manufacturing and marketing authorization, pricing and payment. The foreign regulatory approval process varies among countries and may include all of the risks associated with FDA approval described above, as well as risks attributable to the satisfaction of local regulations in foreign jurisdictions. Approval by the FDA does not ensure approval by comparable regulatory authorities outside of the United States and vice versa.

If we are granted orphan drug designations in the United States for any of our product candidates, there can be no guarantee that we will maintain orphan status for these product candidates or receive approval for any product candidate with an orphan drug designation.

Subject to receiving approval from the FDA of an NDA or Biologics License Application, products granted orphan drug designation are provided with seven years of orphan marketing exclusivity in the United States, meaning the FDA generally will not approve applications for other product candidates for the same orphan indication that contain the same active ingredient.

We are not guaranteed to maintain or receive orphan designation for our current or future product candidates, and if our product candidates that were granted orphan designation were to lose their status as an orphan drug or the orphan marketing exclusivity provided to it in the United States, our business and results of operations could be materially adversely affected. While orphan status for any of our products, if granted or maintained, would provide market exclusivity in the United States for the time periods specified above, we would not be able to exclude other companies from manufacturing and/or selling products using the same active ingredient for the same indication beyond the exclusivity period applicable to our product on the sole basis of orphan drug status. In addition, orphan exclusivity does not block the approval of a different drug or biologic for the same rare disease or condition, nor does it block the approval of the same drug or biologic for different conditions. Even if we are the first to obtain approval of an orphan product candidate and are granted exclusivity in the United States, there are circumstances under which a later competitor product may be approved for the same indication during the period of marketing exclusivity, such as if the later product is shown to be clinically superior to our product or if we are not able to provide a sufficient quantity of the orphan drug.

Even if we obtain regulatory approvals, our marketed drugs will be subject to ongoing regulatory oversight. If we or our collaborators or contractors fail to comply with continuing U.S. and foreign requirements, our approvals, if obtained, could be limited or withdrawn, we could be subject to other penalties, and our business would be seriously harmed.

Following any initial regulatory approval of any drugs we may develop, we will also be subject to continuing regulatory oversight, including the review of adverse drug experiences and safety data that are reported after our drug products are made commercially available. This would include results from any post-marketing studies or surveillance to monitor the safety and efficacy of the drug product required as a condition of approval or agreed to by us. Any regulatory approvals that we receive for our product candidates may also be subject to limitations on the approved uses for which the product may be marketed. Other ongoing regulatory requirements include, among other things, submissions of safety and other post-marketing information and reports, registration and listing, as well as continued maintenance of our marketing application, compliance with cGMP requirements and quality oversight, compliance with post-marketing commitments, and compliance with GCP for any clinical trials that we conduct post-approval. Failure to comply with these requirements could result in warning or untitled letters, criminal or civil penalties, recalls, or product withdrawals. In addition, we are conducting our clinical trials and we intend to seek approval to market our product candidates in jurisdictions outside of the United States, and therefore will be subject to, and must comply with, regulatory requirements in those jurisdictions.

The FDA has significant post-market authority, including, for example, the authority to require labeling changes based on new safety information and to require post-market studies or clinical trials for a variety of reasons. The FDA also has the authority to require a REMS plan after approval, which may impose further requirements or restrictions on the distribution or use of an approved drug.

We, our CMOs, and the manufacturing facilities we use to make our product candidates will also be subject to ongoing assessment of product quality, compliance with cGMP, and periodic inspection by the FDA and potentially other regulatory agencies. We or our CMOs may not be able to comply with applicable cGMP regulations or similar regulatory requirements outside of the United States. Our failure, or the failure of our CMOs, to comply with applicable regulations could result in regulatory actions, such as the issuance of FDA Form 483 notices of observations, warning letters or sanctions being imposed on us, including clinical holds, fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of product candidates or drugs, refusal to permit import or export of our products, operating restrictions, consent decrees and criminal prosecutions, any of which could significantly and adversely affect supplies of our products. We may not have the ability or capacity to manufacture material at a broader commercial scale in the future. We and our CMOs currently manufacture a limited supply of clinical trial materials. Reliance on CMOs entails risks to which we would not be subject if we manufactured all of our material ourselves, including reliance on the CMO for regulatory compliance. Our product promotion and advertising will also be subject to regulatory requirements and continuing regulatory review.

Even if we receive regulatory approval to market our product candidates, the market may not be receptive to our product candidates upon their commercial introduction, which will prevent us from becoming profitable.

Our product candidates are based upon new discoveries, technologies and therapeutic approaches. Key participants in pharmaceutical marketplaces, such as physicians, third-party payors and consumers, may not adopt a product intended to improve therapeutic results that is based on the technology employed by oligonucleotides. As a result, it may be more difficult for us to convince the medical community and third-party payors to accept and use our product, or to provide favorable reimbursement.

Other factors that we believe will materially affect market acceptance of our product candidates include:

In addition, our estimates regarding the potential market size may be materially different from what we currently expect at the time we commence commercialization, which could result in significant changes in our business plan and may significantly harm our results of operations and financial condition.

The pharmaceutical industry is intensely competitive. If we are unable to compete effectively with existing drugs, new treatment methods and new technologies, we may be unable to commercialize successfully any drugs that we develop.

The pharmaceutical industry is intensely competitive and rapidly changing. Many large pharmaceutical and biotechnology companies, academic institutions, governmental agencies and other public and private research organizations are pursuing the development of novel drugs for the same diseases that we are targeting or expect to target. Many of our competitors have:

We will face intense competition from drugs that have already been approved and accepted by the medical community for the treatment of the conditions for which we may develop drugs. We also expect to face competition from new drugs that enter the market. We believe a significant number of drugs are currently under development, and may become commercially available in the future, for the treatment of conditions that our current or future product candidates are or may be designed to treat. These drugs may be more effective, safer, less expensive, or marketed and sold more effectively, than any products we develop.

Our competitors may develop or commercialize products with significant advantages over any products we are able to develop and commercialize based on many different factors, including:

Our competitors may therefore be more successful in commercializing their products than we are, which could adversely affect our competitive position and business. Competitive products may make any products we develop obsolete or noncompetitive before we can recover the expenses of developing and commercializing our product candidates. Such competitors could also recruit our employees, which could negatively impact our level of expertise and our ability to execute on our business plan.

If we or our collaborators, manufacturers, service providers or other third parties fail to comply with applicable healthcare laws and regulations, we or they could be subject to enforcement actions, which could affect our ability to develop, market and sell our products and may harm our reputation.

We are currently, or may in the future, be subject to federal, state, local, and comparable foreign healthcare laws and regulations relating to areas such as fraud and abuse and patients’ rights. These laws may constrain the business or financial arrangements and relationships through which we conduct our operations, including how we research, market, sell and distribute our products for which we obtain marketing approval. These laws and regulations include:

If our operations are found to be in violation of any such requirements, we may be subject to penalties, including civil or criminal penalties, criminal prosecution, monetary damages, the curtailment or restructuring of our operations, loss of eligibility to obtain approvals from the FDA, exclusion from participation in federal healthcare programs including Medicare and Medicaid, the imposition of a corporate integrity agreement with the Office of Inspector General for DHHS, disgorgement, individual imprisonment, contractual damages, reputational harm, and diminished profits and future earnings, any of which could adversely affect our financial results and adversely affect our ability to operate our business. We intend to develop and implement a comprehensive corporate compliance program prior to the commercialization of our product candidates. Although effective compliance programs can mitigate the risk of investigation and prosecution for violations of these laws, these risks cannot be entirely eliminated. Any action against us for an alleged or suspected violation could cause us to incur significant legal expenses, could divert our management’s attention from

the operation of our business, and could harm our reputation, even if our defense is successful. In addition, achieving and sustaining compliance with applicable laws and regulations may be costly to us in terms of money, time and resources.

Furthermore, if the FDA or a comparable foreign regulatory authority approves any of our drug candidates, activities such as the manufacturing processes, labeling, packaging, distribution, adverse event reporting, storage, advertising, promotion and record keeping for the products will be subject to extensive and ongoing regulatory requirements. These requirements include submissions of safety and other post-marketing information and reports, registration, as well as continued compliance with cGMP. The FDA or a comparable foreign regulatory authority may also impose requirements for costly post-marketing nonclinical studies or clinical trials (often called “Phase 4 trials”) and post-marketing surveillance to monitor the safety or efficacy of the product. If we or a regulatory authority discover previously unknown problems with a product, such as adverse events of unanticipated severity or frequency, production issues with the facility where the product is manufactured or processed, such as product contamination or significant non-compliance with applicable cGMP requirements, a regulator may impose restrictions on that product, the manufacturing facility or us. If we or our collaborators or third-party service providers, including our CMOs, fail to comply fully with applicable regulations, then we may be required to initiate a recall or withdrawal of our products.

If previously unknown problems with one of our products, if approved, including adverse events of unanticipated severity or frequency, or with our third-party manufacturers or manufacturing processes are discovered, or if we or our collaborators, manufacturers or service providers fail to comply with applicable federal, state or foreign laws or regulations, we could be subject to enforcement actions, which could affect our ability to develop, market and sell our products successfully and could harm our reputation and lead to reduced acceptance of our products by the market. These enforcement actions include, among others:

Moreover, federal, state or foreign laws or regulations are subject to change, and while we, our collaborators, manufacturers and/or service providers currently may be compliant, that could change due to changes in interpretation, prevailing industry standards or other reasons.

Any drugs we develop may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, thereby harming our business.

Because our product candidates represent new approaches to the treatment of genetic-based diseases, we cannot be sure that coverage and reimbursement will be available for, or accurately estimate the potential revenue from, our product candidates or assure that coverage and reimbursement will be available for any product that we may develop. The regulations that govern marketing approvals, pricing and reimbursement for new drugs vary widely from country to country. Some countries require approval of the sale price of a drug before it can be marketed. In many countries, the pricing review period begins after marketing or product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. We are monitoring these regulations as several of our programs move into later stages of development; however, many of our programs are currently in the earlier stages of development and we will not be able to assess the impact of price regulations for a number of years. As a result, we might obtain regulatory approval for a product in a particular country, but then be

subject to price regulations that could delay our commercial launch of the product and negatively impact any potential revenues we may be able to generate from the sale of the product in that country and potentially in other countries due to reference pricing or other measures to reduce drug prices.

Our ability to commercialize any products successfully will also depend in part on the extent to which coverage and adequate reimbursement/payment for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations. Even if we succeed in bringing one or more products to the market, these products may not be considered medically necessary and/or cost-effective, and the amount reimbursed for any products may be insufficient to allow us to sell our products on a competitive basis. At this time, we are unable to determine their cost effectiveness or the likely level or method of reimbursement for our product candidates. Increasingly, third-party payors, such as government and private insurance plans, are requiring that drug companies provide them with predetermined discounts from list prices, and are seeking to reduce the prices charged or the amounts paid for pharmaceutical products. If the price we are able to charge for any products we develop, or the payments provided for such products, is inadequate in light of our development and other costs, our return on investment could be adversely affected.

We currently expect that any drugs we develop may need to be administered under the supervision of a physician on an outpatient basis. Under currently applicable U.S. law, certain drugs that are not usually self-administered (such as most injectable drugs) may be eligible for coverage under the Medicare Part B program if:

There may be significant delays in obtaining coverage for newly-approved drugs, and coverage may be more limited than the indications for which the drug is approved by the FDA or comparable foreign regulatory authorities. Patients who are prescribed medications for the treatment of their conditions, and their prescribing physicians, generally rely on third-party payors to pay all or part of the costs associated with their prescription drugs. Patients are unlikely to use our products unless coverage is provided and payment is adequate to cover all or a significant portion of the cost of our products. Therefore, coverage and adequate payment is critical to new product acceptance. Coverage decisions may depend upon clinical and economic standards that disfavor new drug products when more established or lower cost therapeutic alternatives are already available or subsequently become available. Moreover, eligibility for coverage does not imply that any of our drug products, if approved, will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution. Interim payments for new drugs, if applicable, may also not be sufficient to cover our costs and may not be made permanent. Reimbursement may be based on payments allowed for lower-cost drugs that are already reimbursed, may be incorporated into existing payments for other services and may reflect budgetary constraints or imperfections in Medicare data. Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement rates. However, no uniform policy requirement for coverage and reimbursement for drug products exists among third-party payors in the United States. Therefore, coverage and reimbursement for drug products can differ significantly from payor to payor. As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance. Our inability to promptly obtain coverage and adequate reimbursement rates from both government-funded and private payors for new drugs that we develop and for which we obtain regulatory approval could adversely affect our operating results, our ability to raise capital needed to commercialize products, and our overall financial condition.

Further, there have been, and may continue to be, legislative and regulatory proposals at the U.S. federal and state levels and in foreign jurisdictions directed at broadening the availability and containing or lowering the cost of healthcare. The continuing efforts of the government, insurance companies, managed care organizations and other third-party payors to contain or reduce costs of healthcare may adversely affect our ability to set prices for our products that would allow us to achieve or sustain profitability. In addition, governments may impose price controls on any of our products that obtain marketing approval, which may adversely affect our future profitability.

The Inflation Reduction Act of 2022 (“IRA”) was signed into law in August 2022 (see above “Government Regulation—Healthcare Reform”). In addition, Executive Order 14087, issued October 2022, called for CMS to prepare and submit a report to the White House on potential payment and delivery modes that would complement to IRA, lower drug costs, and promote access to innovative drugs. In February 2023, CMS published its report which described three potential models focusing on affordability, accessibility and feasibility of implementation for further testing by the CMS Innovation Center. The CMS Innovation Center continues to test the proposed models and has started to roll out plans for access model testing of certain product types (e.g., cell and gene therapies) by states and manufacturers. Additional state and federal healthcare reform measures are expected to be adopted in the future, any of

which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for certain biopharmaceutical products or additional pricing pressures.

In some foreign countries, particularly the member states of the European Union, the pricing of prescription pharmaceuticals is subject to governmental control. In these countries, pricing negotiations with governmental authorities can be a long and expensive process after the receipt of marketing approval for a drug candidate. In addition, there can be considerable pressure by governments and other stakeholders on prices and reimbursement levels, including as part of cost containment measures. Political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained. Reference pricing used by various European Union member states and parallel distribution, or arbitrage between low-priced and high-priced member states, can further reduce prices. In some countries, we may be required to conduct additional clinical trials that compare the cost-effectiveness of our drug candidates to other available therapies in order to obtain reimbursement or pricing approval. Publication of discounts by third-party payors or authorities may lead to further pressure on prices or reimbursement levels within the country of publication and other countries. If reimbursement of our products is unavailable or limited in scope or amount in a particular country, or if pricing is set at unsatisfactory levels, we may be unable to successfully commercialize and achieve or sustain profitability for sales of any of our drug candidates that are approved for marketing in that country and our business could be adversely affected.

Changes in laws and regulations affecting the healthcare industry could adversely affect our business.

All aspects of our business, including research and development, manufacturing, marketing, pricing, sales, litigation, and intellectual property rights, are subject to extensive legislation and regulation. Changes in applicable U.S. federal and state laws and agency regulation, as well as foreign laws and regulations, could have a materially negative impact on our business. In the United States and in some other jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of our product candidates or any potential future product candidates of ours, restrict or regulate post-approval activities, or affect our ability to profitably sell any product candidates for which we obtain marketing approval. Increased scrutiny by the U.S. Congress of the FDA’s approval process may significantly delay or prevent marketing approval, as well as subject us to more stringent product labeling and post-marketing testing and other requirements. Congress also must reauthorize the FDA’s user fee programs every five years and often makes changes to those programs in addition to policy or procedural changes that may be negotiated between the FDA and industry stakeholders as part of this periodic reauthorization process. Congress most recently reauthorized the user fee programs in September 2022 without any substantive policy changes. The next FDA user fee reauthorization package is expected to enter stakeholder negotiations beginning in mid-2025, with any agreement sent to Congress in early 2027 for purposes of initiating the legislative process. Reauthorization of the prescription drug user fee program would need to be finalized by Congress by the end of September 2027 in order to avoid a disruption in FDA’s review goals for NDAs and other activities supported by user fees assessed against industry.

Among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access. In the United States, the pharmaceutical industry has been a focus of these efforts and has been significantly affected by major legislative initiatives. For example, in March 2010, Congress passed the ACA, which, among other things, increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program; introduced a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected; extended the Medicaid Drug Rebate Program to utilization of prescriptions of individuals enrolled in Medicaid managed care plans; imposed mandatory discounts for certain Medicare Part D beneficiaries as a condition for manufacturers’ outpatient drugs coverage under Medicare Part D; and established a Center for Medicare Innovation at the CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending.

In addition to the IRA’s drug price negotiation provisions summarized above, Executive Order 14087, issued in October 2022, called for the CMS Innovation Center to prepare and submit a report to the White House on potential payment and delivery modes that would complement to IRA, lower drug costs, and promote access to innovative drugs. In February 2023, CMS published its report which described three potential models focusing on affordability, accessibility and feasibility of implementation for further testing by the CMS Innovation Center. The CMS Innovation Center’s is still testing the majority of the proposed models.

We expect that future changes or additions to the ACA, the Medicare and Medicaid programs, and changes stemming from other healthcare reform measures, especially with regard to healthcare access, financing or other legislation in individual states, could have a material adverse effect on the healthcare industry in the United States.

Additionally, there has been heightened governmental scrutiny in the United States of pharmaceutical pricing practices considering the rising cost of prescription drugs and biologics. Such scrutiny has resulted in several recent congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products. For example, CMS promulgated a regulation permitting Medicare Advantage plans to use step therapy for Part B drugs

beginning January 1, 2020. In addition, the 2021 Consolidated Appropriations Act incorporated extensive healthcare provisions and amendments to existing laws, including a requirement that all manufacturers of drug products covered under Medicare Part B report the product’s average sales price to CMS beginning on January 1, 2022, subject to enforcement via civil money penalties.

At the state level, legislatures are increasingly passing legislation and implementing regulations designed to control pharmaceutical pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. The effects of these efforts remain uncertain pending the outcomes of several federal lawsuits challenging state authority to regulate prescription drug payment limits. In December 2020, the U.S. Supreme Court held unanimously that federal law does not preempt the states’ ability to regulate PBMs and other members of the healthcare and pharmaceutical supply chain, an important decision that may lead to further and more aggressive efforts by states in this area. In mid-2022, the FTC also launched sweeping investigations into the practices of the PBM industry that could lead to additional federal and state legislative or regulatory proposals targeting such entities’ operations, pharmacy networks, or financial arrangements. In addition, in the last few years, several states have formed prescription drug affordability boards (“PDABs”) with the authority to implement upper payment limits (“UPLs”) on drugs sold in their respective jurisdictions. There are several pending federal lawsuits challenging the authority of states to impose UPLs, however.

Risks associated with our operations outside of the United States and developments in international trade by the U.S. and foreign governments could adversely affect our business.

We have operations and conduct business outside the United States, and we plan to continue to expand these operations. Therefore, we are subject to risks related to operating in foreign countries, which include unfamiliar foreign laws or regulatory requirements or unexpected changes to those laws or requirements; other laws and regulatory requirements to which our business activities abroad are subject, such as the Foreign Corrupt Practices Act and the U.K. Bribery Act; changes in the political or economic condition of a specific country or region, including Russia’s invasion of Ukraine, the conflict in the Middle East, and the potential for a wider European or global conflict; fluctuations in the value of foreign currency versus the U.S. dollar; volatility in inflation and interest rates; our ability to deploy overseas funds in an efficient manner; tariffs, trade protection measures, import or export licensing requirements, trade embargoes, and sanctions (including those administered by the Office of Foreign Assets Control of the U.S. Department of the Treasury), and other trade barriers; global instability from an outbreak of pandemic or contagious disease, difficulties in attracting and retaining qualified personnel; and cultural differences in the conduct of business. For example, given developments related to international trade over the past few years, unexpected changes in tariffs could adversely affect our cost of goods sold and/or the foreign sales of our product candidates. Changes impacting our ability to conduct business outside of the United States, or changes to the regulatory regime applicable to our operations in countries outside of the United States (such as with respect to the approval of our product candidates), may materially and adversely impact our business, prospects, operating results, and financial condition.

We or third parties upon whom we depend may be adversely affected by natural disasters and/or health epidemics, and our business, financial condition and results of operations could be adversely affected.

Natural disasters could severely disrupt our operations and have a material adverse effect on our business operations. If a natural disaster, health epidemic, or other event beyond our control occurred that prevented us from using all or a significant portion of our office, manufacturing and/or lab spaces, that damaged critical infrastructure, such as the manufacturing facilities of our third-party contract manufacturers, or that otherwise disrupted operations, it may be difficult for us to continue our business for a substantial period of time. Any outbreak of contagious diseases, or other adverse public health developments, could have a material and adverse effect on our business operations. For example, during the COVID-19 global pandemic, clinical site initiation and patient enrollment in our clinical trials were delayed due to prioritization of hospital resources in favor of COVID-19 patients and difficulties in recruiting clinical site investigators and clinical site staff. Any local or global health issues could impact our business, our preclinical studies and clinical trials, healthcare systems or the global economy. In addition, certain of our research and development efforts are conducted globally. A health epidemic or other outbreak could materially and adversely affect our business, financial condition and results of operations.

The disaster recovery and business continuity plans we have in place may prove inadequate in the event of a serious disaster or similar event. We may incur substantial expenses as a result of the limited nature of our disaster recovery and business continuity plans, which could have a material adverse effect on our business.

There is a substantial risk of product liability claims in our business. If we are unable to obtain or maintain sufficient insurance, a product liability claim against us could adversely affect our business.

Our business exposes us to significant potential product liability risks that are inherent in the development, testing, manufacturing and marketing of human therapeutic products. Product liability claims could delay or prevent completion of our clinical development programs. In addition, if any of our collaboration partners face product liability claims, our programs could also be affected and our business could be harmed. If we succeed in marketing products, such claims could result in an FDA investigation of the safety and effectiveness of our products, our manufacturing processes and facilities or our marketing programs, and potentially a recall of our products or more serious enforcement action, limitations on the approved indications for which they may be used, or suspension or withdrawal of approvals. Regardless of the merits or eventual outcome, liability claims may also result in decreased demand for our products, injury to our reputation, costs to defend the related litigation, a diversion of management’s time and our resources, substantial monetary awards to trial participants or patients and a decline in our share price. Any insurance we obtain may not provide sufficient coverage against potential liabilities. Furthermore, clinical trial and product liability insurance is becoming increasingly expensive. As a result, we may be unable to obtain or maintain sufficient insurance at a reasonable cost to protect us against losses caused by product liability claims that could adversely affect our business.

If we do not comply with laws regulating the protection of the environment and health and human safety, our business could be adversely affected.

Our research, development and manufacturing processes involve the use of hazardous materials. We maintain quantities of various flammable and toxic chemicals in our facilities that are required for our research, development and manufacturing activities. We are subject to federal, state and local laws and regulations governing the use, manufacture, storage, handling and disposal of these hazardous materials. Our procedures for storing, handling and disposing of these materials are reviewed against the relevant guidelines and laws of the jurisdictions in which our facilities are located on a regular basis. Although we believe that our safety procedures for handling and disposing of these materials sufficiently mitigate the risk of accidental contamination or injury from these materials, the risk cannot be completely eliminated. If an accident occurs, we could be held liable for resulting damages, which could be substantial. We are also subject to numerous environmental, health and workplace safety laws and regulations, including those governing laboratory procedures, exposure to blood-borne pathogens and the handling of biohazardous materials. Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of these materials, this insurance may not provide adequate coverage against potential liabilities. We do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us in connection with our storage or disposal of biological or hazardous materials. Additional federal, state and local laws and regulations affecting our operations may become applicable in the future. We may incur substantial costs to comply with, and substantial fines or penalties if we violate any of, these laws or regulations.

We depend on collaborations with third parties for the development and commercialization of certain of our product candidates.

We depend on third-party collaborators for the development and commercialization of certain of our product candidates. Our potential future collaborators include large and mid-size pharmaceutical companies, regional and national pharmaceutical companies and biotechnology companies. In January 2023, we commenced a collaboration with GSK to research, develop, and commercialize oligonucleotide therapeutics, including WVE-006, our first-in-class A-to-I(G) RNA editing candidate for AATD. Collaborations are complex and time-consuming to negotiate and document. We may not be able to negotiate collaborations on a timely basis, on acceptable terms, or at all. We may also be restricted under existing license or collaboration agreements from entering into agreements on certain terms with other potential collaborators. If we are unable to enter into collaborations with respect to a product candidate, we may have to curtail the development of such product candidate, reduce or delay its development program or one or more of our other development programs, delay its potential commercialization or reduce the scope of any sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our expenditures to fund development or commercialization activities on our own, we may need to obtain additional capital, which may not be available to us on acceptable terms or at all. If we do not have sufficient funds, we may not be able to further develop our product candidates or bring them to market and generate product revenue.

Depending on the type of collaborations we enter into, we may have limited control over the amount and timing of resources that our collaborators dedicate to the development or commercialization of our product candidates. Our ability to generate revenues from these arrangements will depend on our collaborators’ abilities and efforts to successfully perform the functions assigned to them in these arrangements.

Collaborations involving our product candidates may pose the following risks to us:

Collaboration agreements may not lead to development or commercialization of product candidates in the most efficient manner, or at all. Further, if a present or future collaborator of ours were to be involved in a business combination, the continued pursuit and emphasis on our product development or commercialization program could be delayed, diminished or terminated.

We may not be able to execute our business strategy optimally if we are unable to maintain our existing collaborations or enter into new collaborations with partners that can provide sales, marketing and distribution capabilities and funds for the development and commercialization of our product candidates.

Depending on the collaborations that we enter into, we may expect our collaborators to provide assistance with development, regulatory affairs, marketing, sales and distribution, among other areas. Our future revenues may depend heavily on the success of the efforts of these third parties. For example, under our collaboration with GSK, GSK is responsible for later clinical development and commercialization of our program in AATD.

We may not be successful in our collaborations due to various factors, including our ability to successfully demonstrate proof of mechanism in humans, our ability to demonstrate the safety and efficacy of our specific product candidates, our ability to manufacture or have third parties manufacture our product candidates, the strength of our intellectual property and/or concerns about potential challenges to or limitations of our intellectual property. To the extent we have entered into, or enter into new, collaborations, we may not be able to maintain them if, for example, development or approval of a product candidate is delayed, challenges are raised as to the validity or scope of our intellectual property or sales of an approved drug are lower than we or our collaboration partner expected.

For certain product candidates that we may develop, we may form collaborations to fund all or part of the costs of drug development and commercialization, such as our collaboration with GSK. We may not, however, be able to enter into additional collaborations for certain other programs, and the terms of any collaboration agreement we do secure may not be favorable to us. If we are not successful in our efforts to enter into future collaboration arrangements with respect to one or more of our product candidates, we may not have sufficient funds to develop that or any other product candidate internally, or to bring any product candidates to market. If we do not have sufficient funds to develop and bring our product candidates to market, we will not be able to generate sales revenues from these product candidates, and this will substantially harm our business.

We rely, and expect to continue to rely, on third parties to conduct some aspects of our compound formulation, research, preclinical studies and clinical trials, and those third parties may not perform satisfactorily, including failing to meet deadlines for the completion of such formulation, research or testing.

We do not independently conduct all aspects of our drug discovery activities, compound formulation research, preclinical studies, or clinical trials of product candidates. We currently rely, and expect to continue to rely, on third parties to conduct some aspects of our research and development, preclinical and clinical studies. Any of these third parties may terminate their engagements with us at any time. If we need to enter into alternative arrangements, it would delay our product development activities. Our reliance on these third parties for research and development activities will reduce our control over these activities but will not relieve us of our responsibilities. For example, for product candidates that we develop and commercialize on our own, we will remain responsible for ensuring that each of our preclinical studies that supports our INDs/CTAs is conducted in accordance with GLP requirements and, likewise, that our clinical trials are conducted in accordance with GCP requirements, the study plan and protocol for each trial. If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct our studies in accordance with regulatory requirements or our stated study plans and protocols, we will not be able to complete, or may be delayed in completing, the necessary preclinical studies to enable us or our strategic alliance partners to select viable product candidates for IND/CTA submissions and will not be able to, or may be delayed in our efforts to, successfully develop and commercialize such product candidates.

We rely on third parties to design, conduct, supervise and monitor our preclinical studies and clinical trials, and if those third parties perform in an unsatisfactory manner, it may harm our business.

We rely on third party clinical investigators, CROs, clinical data management organizations and consultants to design, conduct, supervise and monitor preclinical studies and clinical trials of our product candidates. Because we rely on third parties and do not have the ability to conduct preclinical studies or clinical trials independently, we have less control over the timing, quality and other aspects of preclinical studies and clinical trials than we would if we conducted them on our own, including our inability to control whether sufficient resources are applied to our programs. If any of our CROs are acquired or consolidated, these concerns are likely to be exacerbated and our preclinical studies or clinical trials may be further impacted due to potential integration, streamlining, staffing and logistical changes. These investigators, CROs and consultants are not our employees and we have limited control over the amount of time and resources that they dedicate to our programs. These third parties may have contractual relationships with other entities, some of which may be our competitors, which may draw time and resources from our programs. Further, these third parties may not be diligent, careful or timely in conducting our preclinical studies or clinical trials, resulting in the preclinical studies or clinical trials being delayed or unsuccessful.

If we cannot contract with acceptable third parties on commercially reasonable terms, or at all, or if these third parties do not carry out their contractual duties, satisfy legal and regulatory requirements for the conduct of preclinical studies or clinical trials or meet expected deadlines, our preclinical and clinical development programs could be delayed and otherwise adversely affected. In all events, we are responsible for ensuring that each of our preclinical studies and clinical trials is conducted in accordance with the general investigational plan and protocols for the study or trial. The FDA and other health authorities require clinical trials to be conducted in accordance with GCP, including conducting, recording and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity and confidentiality of clinical trial participants are protected. If we or our CROs fail to comply with these requirements, the data generated in our clinical trials may be deemed unreliable or uninterpretable, and the FDA and other health authorities may require us to perform additional clinical trials. Our reliance on third parties that we do not control does not relieve us of these responsibilities and requirements. Any such event could adversely affect our business, financial condition, results of operations and prospects.

We rely on third parties in the supply and manufacture of our product candidates for our research, preclinical and clinical activities, and may do the same for commercial supplies of our product candidates.

While we have built our own internal manufacturing capabilities, we have not yet manufactured our product candidates on a commercial scale and may not be able to do so for any of our product candidates. In addition, we currently rely on third parties in the supply and manufacture of materials for our research, preclinical and clinical activities and may continue to do so for the foreseeable future. We may do the same for the commercial supply of our drug product. We use third parties to perform additional steps in the manufacturing process, such as the filling, finishing and labeling of vials and storage of our product candidates and we expect to do so for the foreseeable future. There can be no assurance that our supply of research, preclinical and clinical development drug candidates and other materials will not be limited, interrupted or restricted or will be of satisfactory quality or continue to be available at acceptable prices. Replacement of any of the third parties we may engage could require significant effort and expertise because there may be a limited number of qualified replacements. In addition, raw materials, reagents, and components used in the manufacturing process, particularly those for which we have no other source or supplier, may not be available, may not be suitable or acceptable for use due to material or component defects, or may introduce variability into the supply of our product candidates. Furthermore, with

the increase of companies developing oligonucleotides, there may be increased competition for the supply of the raw materials that are necessary to make our oligonucleotides, which could severely impact the manufacturing of our product candidates.

We may be unable to identify manufacturers on acceptable terms or at all because the number of potential manufacturers is limited and they must be acceptable to the FDA or approved by foreign regulatory authorities. Suppliers and manufacturers, including us, must meet applicable manufacturing requirements, including compliance with cGMP regulations, and undergo rigorous facility and process validation tests required by regulatory authorities in order to comply with regulatory standards. In the event that any of our suppliers or manufacturers fail to comply with such requirements or to perform their obligations to us in relation to quality, timing or otherwise, some of which may be out of their or our control, or if our supply of components or other materials becomes limited or interrupted for other reasons, we may be forced to increase the manufacturing of the materials ourselves, for which we currently have limited capabilities and resources, or enter into an agreement with another third party, which we may not be able to do on reasonable terms, if at all. Any interruption of the development or manufacturing of our product candidates, such as order delays for equipment or materials, equipment malfunction, quality control and quality assurance issues, regulatory delays and possible negative effects of such delays on supply chains and expected timelines for product availability, production yield issues, shortages of qualified personnel, discontinuation of a facility or business or failure or damage to a facility resulting from natural disasters, could result in the cancellation of shipments, loss of product in the manufacturing process or a shortfall in available product candidates or materials. In some cases, the technical skills or technology required to manufacture our product candidates may be unique or proprietary to the original manufacturer and we may have difficulty, or there may be contractual restrictions prohibiting us from, transferring such skills or technology to another third party and a feasible alternative may not exist. These factors would increase our reliance on such manufacturer or require us to obtain a license from such manufacturer in order to have another third party manufacture our product candidates. If we are required to change manufacturers for any reason, we will be required to verify that the new manufacturer maintains facilities and procedures that comply with quality standards and with all applicable regulations and guidelines. The delays associated with the verification of a new manufacturer could negatively affect our ability to develop product candidates in a timely manner or within budget.

We may rely on third-party manufacturers if we receive regulatory approval for any product candidate. To the extent that we have existing, or enter into future, manufacturing arrangements with third parties, we will depend on these third parties to perform their obligations in a timely manner consistent with contractual and regulatory requirements, including those related to quality control and assurance. In complying with the manufacturing regulations of the FDA and other comparable foreign regulatory authorities, we and our third-party manufacturers must spend significant time, money, and effort in the areas of design and development, testing, production, record-keeping and quality control to assure that the products meet applicable specifications and other regulatory requirements. Although our agreements with third-party manufacturers require them to perform according to certain cGMP requirements such as those relating to quality control, quality assurance and qualified personnel, we cannot otherwise control the conduct of our third-party manufacturers to implement and maintain these standards. If any of our third-party manufacturers cannot successfully manufacture material that conforms to our specifications and the regulatory requirements of the FDA, or other comparable foreign authorities, we would be prevented from obtaining regulatory approval for our drug candidates unless and until we engage a substitute supplier that can comply with such requirements, which we may not be able to do on commercially reasonable terms or at all. In addition, we and our third-party manufacturers responsible for the manufacture of commercial supplies of our products for which we retain regulatory approval, if any, are subject to inspection and approval by regulatory authorities before we may commence the manufacture and sale of any of such products, and thereafter are subject to ongoing inspection from time to time. Our third-party manufacturers may not be able to comply with applicable cGMP regulations or similar regulatory requirements outside of the United States. Our failure, or the failure of our third-party manufacturers, to comply with applicable regulations could result in regulatory actions, such as the issuance of FDA Form 483 notices of observations, warning letters or sanctions being imposed on us, including clinical holds, fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of product candidates or drugs, operating restrictions and criminal prosecutions, any of which could significantly and adversely affect supplies of our products. Any such failure by us or any of our suppliers would significantly impact our ability to develop, obtain regulatory approval for or market our drug candidates, if approved.

We may also be required to enter into long-term manufacturing agreements that contain exclusivity provisions and/or substantial termination penalties which could have a material adverse effect on our business prior to or after commercialization of any of our product candidates. If we are unable to obtain or maintain third-party manufacturing for product candidates, or to do so on commercially reasonable terms, we may not be able to develop and commercialize our product candidates successfully. Failure to execute on our manufacturing requirements, either by us or by one of our third-party vendors, could adversely affect our business in a number of ways, including:

If any of our product candidates are approved for marketing and commercialization and we are unable to develop sales, marketing and distribution capabilities on our own, or enter into agreements with third parties to perform these functions on acceptable terms, we will be unable to commercialize successfully any such future products.

We currently have no sales, marketing or distribution capabilities. In addition, while our collaboration with GSK will provide us with know-how and experience related to commercialization, we have limited experience of our own. If any of our product candidates is approved, we will need to develop internal sales, marketing and distribution capabilities to commercialize such products, which would be expensive and time-consuming, or rely on or enter into additional collaborations with third parties to perform these services. If we decide to market our products directly, we will need to commit significant financial and managerial resources to develop a marketing and sales force with technical expertise and supporting distribution, administration and compliance capabilities. If we rely on third parties with such capabilities to market our products or decide to co-promote products with collaborators, we will need to establish and maintain marketing and distribution arrangements with third parties, and there can be no assurance that we will be able to enter into such arrangements on acceptable terms or at all. In entering into third-party marketing or distribution arrangements, any revenue we may receive will depend upon the efforts of the third parties and there can be no assurance that such third parties will establish adequate sales and distribution capabilities or be successful in gaining market acceptance of any approved product. If we are not successful in commercializing any product approved in the future, either on our own or through third parties, our business, financial condition, results of operations and prospects would be adversely affected.

If we are unable to attract and retain qualified key management and scientists, staff, consultants and advisors, our ability to implement our business plan may be adversely affected.

We are highly dependent upon our senior management and our scientific, clinical and medical staff and advisors. The loss of the service of any of the members of our senior management or other key employees could delay our research and development programs and materially harm our business, financial condition, results of operations and prospects. In addition, we expect that we will continue to have an increased need to recruit and hire qualified personnel as we advance our programs and expand operations. Failure to successfully recruit and retain personnel could impact our anticipated development plans and timelines. We are dependent on the continued service of our technical personnel because of the highly technical and novel nature of our product candidates, platform and technologies and the specialized nature of the regulatory approval process. Replacing such personnel may be difficult and may take an extended period of time because of the limited number of individuals in our industry with the breadth of skills and experience required to successfully execute our business strategy, and we cannot assure you that we will be able to identify or employ qualified personnel for any such position on acceptable terms, if at all. Many of the biotechnology and pharmaceutical companies with whom we compete for qualified personnel have greater financial and other resources, different risk profiles and longer histories in the industry than we do. Because our management team and key employees are not obligated to provide us with continued service, they could terminate their employment with us at any time without penalty. We do not maintain key person life insurance policies on any of our management team members or key employees. Our future success will depend in large part on our continued ability to attract and retain highly qualified scientific, technical and management personnel, as well as personnel with expertise in preclinical and clinical testing, manufacturing, governmental regulation and commercialization. In order to do so, we may need to pay higher compensation or fees to our employees or consultants than we currently expect, and such higher compensation payments may have a negative effect on our operating results. We face increased competition for personnel from other companies, universities, public and private research institutions, government entities and other organizations. If we are unable to attract and retain qualified personnel, the rate and success at which we may be able to discover and develop our product candidates and implement our business plan will be limited.

As we continue our preclinical studies and clinical trials and advance to further clinical development, we may experience difficulties in managing our growth and expanding our operations.

Although we have assembled a team of employees with experience developing medicines and obtaining regulatory approval to market those medicines, we have limited experience as a company in drug development. We are a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines (also known as oligonucleotides), or those targeting RNA, to transform human health. Our RNA medicines platform, PRISM, combines multiple modalities, chemistry innovation and deep insights into human genetics to deliver scientific breakthroughs that treat both rare and common disorders. Our toolkit of RNA-targeting modalities includes RNA editing, splicing, silencing using siRNA and antisense silencing, providing us with unique capabilities for designing and sustainably delivering candidates that optimally address disease biology. Our diversified pipeline includes clinical programs in

obesity, AATD, DMD, and HD, as well as several preclinical programs utilizing our versatile RNA medicines platform. As we advance product candidates through preclinical studies and clinical trials, we will need to expand our development, regulatory and manufacturing capabilities or contract with other organizations to provide these capabilities for us. In addition, we must manage our relationships with collaborators or partners, suppliers and other organizations, including our collaboration with GSK. Our ability to manage our operations and future growth will require us to continue to improve our operational, financial and management controls, reporting systems and procedures. We may not be able to implement improvements to our management information and control systems in an efficient or timely manner and may discover deficiencies in existing systems and controls. In addition, our future growth may require significant capital expenditures and may divert financial resources from other projects, such as the development of our product candidates. If we are unable to effectively manage our future growth, our expenses may increase and our ability to generate revenue could be reduced.

Our employees, consultants and collaborators may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements.

We are exposed to the risk of fraud and other misconduct by our employees, consultants and collaborators. Such misconduct could include intentional failures to comply with FDA and other foreign agency regulations, provide accurate information to the FDA, comply with manufacturing standards required by the FDA or us, comply with federal and state healthcare fraud and abuse laws and regulations, report financial information or data accurately or disclose unauthorized activities to us. In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements. Such misconduct could also involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation. It is not always possible to identify and deter such misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant fines or other sanctions.

Security breaches, cybersecurity threats, loss of data and other disruptions could compromise sensitive information related to our business, prevent us from accessing critical information or expose us to liability, which could adversely affect our business and our reputation.

In the ordinary course of our business, we, our CROs and other third parties, including our managed service providers (“MSPs”), on which we rely collect and store sensitive data, including legally protected patient health information, personally identifiable information about our employees, intellectual property, vendor information, and proprietary business information. We, along with our MSPs, manage and maintain our applications and data utilizing cloud-based and on-site systems. These applications and data encompass a wide variety of business-critical information, including research and development information and business and financial information.

The secure processing, storage, maintenance and transmission of this critical information by us, or our CROs and other third-party partners, is vital to our operations and business strategy. We also have systems in place at our facilities to mitigate disruptions to our communications systems, including the prevention of a loss to our electrical systems. Although we are proactive in our approach and take measures to protect sensitive information from unauthorized access or disclosure, our information technology and infrastructure, or that of our CROs or other third party partners, may be vulnerable to attacks by hackers, viruses, breaches, interruptions due to employee error, malfeasance or other disruptions, lapses in compliance with privacy and security mandates, or damage from natural disasters, terrorism, war and telecommunication and electrical failures. For example, as previously disclosed in May 2023 and August 2023, we became aware that our mHTT assay vendor experienced a cybersecurity incident in April 2023. None of our data or patient samples were impacted by the incident and we remain in close contact with the vendor as they address this issue. The financial impact of this incident was not material, and there were no changes to the previously released financial results or financial statements. In addition, cyberattacks, malicious internet-based activity and fraud are prevalent and continue to increase in frequency. Any such event, including a cyberattack, could compromise our networks, or that of our CROs or other third parties, and the information stored there could be accessed by unauthorized parties, publicly disclosed, lost or stolen. Furthermore, any such event could subject us to liability, negatively impact our business operations, or result in information theft, data corruption, operational disruption, damage to our reputation, or financial loss.

As part of our robust data protection practices, we regularly conduct business continuity and disaster recovery testing of our key information systems and data. We have measures in place that are designed to detect and respond to such security incidents and breaches of privacy and security mandates. Any such access, disclosure or other loss of information could result in legal claims or proceedings, liability under laws that protect the privacy of personal information (including but not limited to GDPR, HIPAA and HITECH), government enforcement actions and regulatory penalties. Unauthorized access, loss or dissemination could also adversely

affect our business, damage our reputation, and disrupt our operations, including our ability to conduct research and development activities, process and prepare company financial information, and manage various general and administrative aspects of our business. For example, the loss of intellectual property or clinical trial data from completed or ongoing or planned clinical trials, in addition to privacy concerns, could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. In addition, while we take measures to help ensure early detection, there can be no assurance that we, or our CROs and other third party partners, will promptly detect any such disruption or security breach, if at all. To the extent that any disruption or security breach were to result in a loss of or damage to our data or applications, or inappropriate disclosure of personal, confidential or proprietary information, we could incur liability and the further development of our product candidates could be delayed.

Numerous federal, state and international laws address privacy, data protection and the collection, storing, sharing, use, disclosure and protection of personally identifiable information and other user data, including in the context of the development and deployment of artificial intelligence technologies. In the United States, many states have already implemented state laws addressing privacy or are set to enact data protection legislation. In addition, several states have enacted privacy laws to specifically regulate consumer health data that is not subject to HIPAA.

As the patchwork of U.S. privacy laws expands, state enforcement of data privacy and cybersecurity breaches has increased, along with the cost. In addition to state enforcement of privacy laws, the Federal Trade Commission has increased enforcement of cybersecurity and data privacy, and related fines in 2024.

Outside the United States, personally identifiable information and other user data is increasingly subject to legislation and regulations in numerous jurisdictions around the world, the intent of which is to protect the privacy of information that is collected, processed and transmitted in or from the governing jurisdiction. Foreign data protection, privacy, information security, user protection and other laws and regulations are often more restrictive than those in the United States. For example, the General Data Protection Regulation (“GDPR”) adopted by the European legislative bodies applies to any company, regardless of location, that collects or processes personal data of EU residents in connection with offering goods or services in the European Union or monitoring the behavior of EU residents. The GDPR enhances data protection obligations for processors and controllers of personal data, including, for example, expanded disclosures about how personal information is to be used, limitations on retention of information, data minimization obligations, record-keeping requirements, mandatory data breach notification requirements, and correlated obligations on services providers. The GDPR also strictly regulates cross-border transfer of personal data, including requirements for data transfer impact assessments. Non-compliance with the GDPR may result in monetary penalties of up to €20 million or 4% of annual worldwide revenue, whichever is higher. Additionally, post-Brexit the United Kingdom has also adopted its own version of the GDPR.

While we have taken steps to comply with all applicable privacy laws and regulations, including the GDPR, by taking measures including but not limited to enhancing our security procedures, updating our website, revising our clinical trial informed consents, adopting the standard contractual clauses for cross-border transfers of personal data, increasing our cyber insurance, and entering into data processing agreements with relevant CROs and third party partners, we cannot completely assure you that our efforts to remain in compliance will be fully successful. The GDPR and other changes in laws or regulations associated with the enhanced protection of personal data may increase our costs of compliance and result in greater legal risks.

For the years ended December 31, 2024, 2023 and 2022, changes in foreign currency exchange rates did not have a material impact on our historical financial position, our business, our financial condition, the results of our operations or our cash flows. A hypothetical 10% change in foreign currency rates would not have a material impact on our historical financial position or results of operations. However, there can be no assurance that changes in foreign currency exchange rates will not have a material adverse impact on us in the future.

The U.S. tax legislation and future changes to applicable U.S. or foreign tax laws and regulations may have a material adverse effect on our business, financial condition and results of operations.

We are subject to income and other taxes in the United States and foreign jurisdictions. Changes in laws and policy relating to taxes or trade, including increases in tax rates or modifications, technical corrections or clarifications to tax laws, such as the Tax Cuts and Jobs Act of 2017, which eliminates the option to deduct research and development expenditures currently and requires corporations to capitalize and amortize them over a period of years, may have an adverse effect on our business, financial condition and results of operations. This Annual Report on Form 10-K does not discuss any such tax legislation or changes to tax laws and legislation, or the

manner in which it might affect us or purchasers of our securities. We urge our investors to consult with their legal and tax advisors with respect to such legislation and the potential tax consequences of investing in our securities.

We are also subject to different tax regulations in each of the jurisdictions where we conduct our business or where our management is located. We expect the scope and extent of regulation in the jurisdictions in which we conduct our business, or where our management is located, as well as regulatory oversight and supervision, to generally continue to increase. Generally, future changes in applicable U.S. or foreign tax laws and regulations, or their interpretation and application could have an adverse effect on our business, financial condition and results of operations.

Inadequate funding for the FDA, the SEC and other government agencies, or a work slowdown or stoppage at those agencies as part of a broader federal government shutdown, could hinder their ability to hire and retain key leadership and other personnel, prevent new products and services from being developed or commercialized in a timely manner, or otherwise prevent those agencies from performing normal business functions on which the operation of our business may rely, which could negatively impact our business.

The ability of the FDA to review and approve new products can be affected by a variety of factors, including government budget and funding levels, the ability to hire and retain key personnel and accept the payment of user fees, and statutory, regulatory, and policy changes. Average review times at the agency have fluctuated in recent years as a result. In addition, government funding of the SEC and other government agencies on which our operations may rely, including those that fund research and development activities, is subject to the political process, which is inherently fluid and unpredictable.

Disruptions at the FDA and other agencies may also extend the time necessary for new drugs to be reviewed and/or approved by necessary government agencies, which would adversely affect our business. For example, over the last several years, the U.S. government has shut down several times and certain regulatory agencies, such as the FDA and the SEC, have had to furlough critical FDA, SEC and other government employees and stop critical activities. If a prolonged government shutdown or slowdown occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business. Further, future government shutdowns could impact our ability to access the public markets and obtain necessary capital in order to properly capitalize and continue our operations.

If we are not able to obtain and enforce market exclusivity for our technologies or product candidates, development and commercialization of our product candidates may be adversely affected.

In our industry, the majority of an innovative product’s commercial value is usually realized during the period in which it has market exclusivity. Market exclusivity is comprised of both patent and other intellectual property protection, as well as regulatory exclusivity. In the United States and some other countries, when market exclusivity expires and generic versions of a product are approved and marketed, there usually are very substantial and rapid declines in the product’s sales. Accordingly, our success depends in part on our ability to obtain and maintain patents and other forms of intellectual property rights, including trademarks, trade secrets and in-licenses of intellectual property rights of others, for our product candidates and platform technologies, methods used to manufacture our product candidates, methods of patient stratification and methods for treating patients using our product candidates, as well as our ability to preserve our trade secrets, to prevent third parties from infringing upon our proprietary rights and to operate without infringing upon the proprietary rights of others. Certain research and development activities involved in pharmaceutical development are exempt from patent infringement in the United States and other jurisdictions, for example, in the United States by the provisions of 35 U.S.C. § 271(e)(1) (the “Safe Harbor”). However, in the United States and certain other jurisdictions, the Safe Harbor exemption terminates when the sponsor submits an application for marketing approval (e.g., a NDA) in the United States). Therefore, the risk that a third party might allege patent infringement may increase as our products approach commercialization. We may not be able to apply for patents or obtain patent protection on certain aspects of our product candidates or our platform in a timely fashion or at all. Our existing issued and granted patents and any future patents we obtain may not be sufficiently broad to prevent others from using our technology or from developing competing products and technology. There is no guarantee that any of our pending patent applications will result in issued or granted patents, that any of our issued or granted patents will not later be found to be invalid or unenforceable, or that any issued or granted patents will include claims that are sufficiently broad to cover our product candidates, our platform technologies, or any methods relating to them, or to provide meaningful protection from our competitors. Moreover, the patent position of biotechnology and pharmaceutical companies can be highly uncertain and involves complex legal and factual questions. We will be able to protect our proprietary rights from unauthorized use by third parties only to the extent that our current and future proprietary technology and product candidates are covered by valid and enforceable patents or are effectively maintained as trade secrets. If third parties disclose or misappropriate our proprietary rights, it may materially and adversely impact our position in the market.

Legal issues related to the patentability of biopharmaceuticals, and methods of their manufacture and use, are complex and uncertain in some countries. In some countries, applicants are not able to protect methods of treating human beings or medical treatment processes. Intellectual property protection varies throughout the world and is subject to change over time. Certain jurisdictions have enacted various rules and laws precluding issuance of patents encompassing any methods a doctor may practice on a human being or any other animal to treat a disease or condition. Further, many countries have enacted laws and regulatory regimes that do not allow patent protection for methods of use of known compounds. Particularly given that some of our product candidates may represent stereopure versions of previously described oligonucleotides, it may be difficult or impossible to obtain patent protection for them in relevant jurisdictions. Thus, in some countries and jurisdictions, it may not be possible to patent some of our product candidates at all. In some countries and jurisdictions, only composition claims may be obtained, and only when those compositions are or contain compounds that are new and/or novel. Also, patents issued with composition claims (i.e., covering product candidates) cannot always be enforced to protect methods of using those compositions to treat or diagnose diseases or medical conditions. In such countries or jurisdictions, enforcement of patents to protect our product candidates, or their uses, may be difficult or impossible. Lack of patent protection in such cases may have a materially adverse effect on our business and financial condition.

Furthermore, given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates, their manufacture or their use might expire before or shortly after those candidates receive regulatory approval and are commercialized. As a result, our owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours. We expect to seek extensions of patent terms where these are available upon regulatory approval in those countries where we are prosecuting patents. This includes in the United States under the Drug Price Competition and Patent Term Restoration Act of 1984, which permits a patent term extension of up to five years beyond the expiration of the patent. However, the applicable authorities, including the FDA in the United States, and any equivalent regulatory authority in other countries, may not agree with our assessment of whether such extensions are available, and may refuse to grant extensions to our patents, or may grant more limited extensions than we request. If this occurs, our competitors may take advantage of our investment in development and clinical trials by referencing our clinical and preclinical data and launch their product earlier than might otherwise be possible.

The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other provisions during the patent prosecution process. There are situations in which noncompliance can result in abandonment or lapse of a patent or patent application, or loss of right to enforce patent claims, resulting in partial or complete loss of patent rights in the relevant jurisdiction. In such an event, competitors might be able to enter the market earlier than would otherwise have been the case. The standards applied by the USPTO and foreign patent offices in granting patents are not uniform, can vary substantially from country to country, and are not always applied predictably, requiring country-specific patent expertise in each jurisdiction in which patent protection is sought. For example, there is no uniform worldwide policy regarding patentable subject matter or the scope of claims allowable in biotechnology and pharmaceutical patents. As such, we do not know the degree of future protection that we will have on our proprietary products and technologies. While we will endeavor to try to protect our product candidates and platform technology with intellectual property rights such as patents, as appropriate, the process of filing and prosecuting patent applications, and obtaining, maintaining and defending patents is time-consuming, expensive, uncertain, and sometimes unpredictable.

In addition, periodic changes to the patent laws and rules of patent offices around the world, including the USPTO can have a significant impact on our ability to protect our technology and enforce our intellectual property rights. For example, the America Invents Act, enacted in 2011, involved significant changes in patent legislation. Furthermore, the U.S. Supreme Court has ruled on several patent cases in recent years, some of which cases either narrow the scope of patent protection available in certain circumstances or weaken the rights of patent owners in certain situations. The 2013 decision by the U.S. Supreme Court in Association for Molecular Pathology v. Myriad Genetics, Inc. precludes a claim to a nucleic acid having a stated nucleotide sequence which is identical to a sequence found in nature and unmodified. We currently are not aware of an immediate impact of this decision on our patents or patent applications because we are developing oligonucleotides which contain modifications that we believe are not found in nature. However, we cannot make assurances that the interpretations of this decision or subsequent rulings will not adversely impact our patents or patent applications. In addition to increasing uncertainty with regard to our ability to obtain patents in the future, this combination of events has created uncertainty with respect to the value of patents, once obtained. Depending on decisions by the U.S. Congress, the federal courts and the USPTO, and by analogous bodies around the world, the laws and regulations governing patents could change in unpredictable ways that would weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain in the future. For example, in 2012, European countries and the European Parliament agreed to a legislative package that would create a unitary patent protection system in the EU; aspects of this system were implemented beginning in 2023 for at least some European countries. The impact of the proposed unitary patent protection system on patents in Europe is currently unclear.

Once granted, patents may remain open to opposition, interference, re-examination, post-grant review, inter partes review, nullification or derivation action in court or before patent offices or similar proceedings for a given period after allowance or grant, during which time third parties can raise objections against such initial grant. In the course of such proceedings, which may continue

for a protracted period of time, the patent owner may be compelled to limit the scope of the allowed or granted claims attacked or may lose the allowed or granted claims altogether. In addition, there can be no assurance that:

We license patent rights from third-party owners or licensees. If such owners or licensees do not properly or successfully obtain, maintain or enforce the patents underlying such licenses, or if they retain or license to others any competing rights, our competitive position and business prospects may be adversely affected.

We license patent rights from third parties that we may use from time to time to protect certain aspects of our technology and programs. We may license additional third-party intellectual property in the future. To the extent that we use, and ultimately rely on, in-licensed technologies in our platform and our programs, our success will depend in part on the ability of our licensors to obtain, maintain and enforce patent protection for those in-licensed technologies. Our licensors may not successfully prosecute the patent applications licensed to us. Even if patents issue or are granted, our licensors may fail to maintain these patents, may determine not to pursue litigation against other companies that are infringing these patents, or may pursue litigation less aggressively than we would. Further, we may not obtain exclusive rights, which would allow for third parties to develop competing products. Without protection for, or exclusive right to, the intellectual property we license, other companies might be able to offer substantially identical products for sale, which could adversely affect our competitive business position and harm our business prospects. In addition, we may sublicense our rights under our third-party licenses to current or future collaborators or any future strategic partners. Any impairment of these sublicensed rights could result in reduced revenue under any future collaboration agreements we may enter into or result in termination of an agreement by one or more of our current or future collaborators or any future strategic partners.

Other companies or organizations may challenge our or our licensors’ patent rights or may assert patent rights that prevent us from developing and commercializing our products.

Nucleic acid therapeutics is a relatively new scientific field, the commercial exploitation of which has resulted in many different patents and patent applications from organizations and individuals seeking to obtain patent protection in the field. We have obtained grants and issuances of patents in this field. The issued patents and pending patent applications in the United States and in key markets around the world that we own or license claim certain methods, compositions and processes relating to the discovery, development, manufacture and/or commercialization of oligonucleotides and/or our platform.

As the field of oligonucleotides matures, patent applications are being processed by national patent offices around the world. There is uncertainty about which patents will issue, and, if they do, as to when, to whom, and with what claims. It is likely that there will be significant litigation in the courts and other proceedings, such as interference, reexamination and opposition proceedings, in various patent offices relating to patent rights in the oligonucleotides field. In many cases, the possibility of appeal or opposition exists for either us or our opponents, and it may be years before final, unappealable rulings are made with respect to these patents in certain jurisdictions. The timing and outcome of these and other proceedings is uncertain and may adversely affect our business, particularly if we are not successful in defending the patentability and scope of our pending and issued patent claims or if third parties are successful in obtaining claims that cover any of our product candidates or our platform. In addition, third parties may attempt to

invalidate our intellectual property rights. Even if our rights are not directly challenged, invalidated or circumvented, disputes could lead to the weakening of our intellectual property rights. Our defense against any attempt by third parties to challenge, invalidate, circumvent or weaken our intellectual property rights could be costly to us, could require significant time and attention of our management and could adversely affect our business and our ability to successfully compete in the field of oligonucleotides.

We may not be able to protect our intellectual property rights throughout the world.

Obtaining a valid and enforceable issued or granted patent covering our technology in the United States and worldwide can be extremely costly. In jurisdictions where we have not obtained patent protection, competitors may use our technology to develop their own products and further, may export otherwise infringing products to territories where we have patent protection, but where it is more difficult to enforce a patent as compared to the United States. Competitor products may compete with our future products in jurisdictions where we do not have issued or granted patents or where our issued or granted patent claims or other intellectual property rights are not sufficient to prevent competitor activities in these jurisdictions. The legal systems of certain countries, particularly certain developing countries, make it difficult to enforce patents and such countries may not recognize other types of intellectual property protection, particularly relating to biopharmaceuticals. This could make it difficult for us to prevent the infringement of our patents or marketing of competing products in violation of our proprietary rights generally in certain jurisdictions. Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial cost and divert our efforts and attention from other aspects of our business.

We generally file a provisional patent application first (a priority filing) at the USPTO. A Patent Cooperation Treaty (“PCT”) application is usually filed within 12 months after the priority filing. Regional and/or national patent applications may be pursued outside of the United States, either based on a PCT application or as a direct filing, in some cases claiming priority to a prior U.S. or PCT filing. Some of our cases have been filed in multiple jurisdictions, including major market jurisdictions. We also commonly enter the national stage in the United States through a PCT filing. We have so far not filed for patent protection in all national and regional jurisdictions where such protection may be available. In addition, we may decide to abandon national and regional patent applications before grant. Finally, the grant proceeding of each national or regional patent is an independent proceeding which may lead to situations in which applications might in some jurisdictions be refused by the relevant registration authorities, while granted by others. It is also quite common that depending on the country, different scopes of patent protection may be granted on the same product or technology.

The laws of some jurisdictions do not protect intellectual property rights to the same extent as the laws in the United States, and many companies have encountered significant difficulties in protecting and defending such rights in such jurisdictions. If we or our licensors encounter difficulties in protecting, or are otherwise precluded from effectively protecting, the intellectual property rights important for our business in such jurisdictions, the value of these rights may be diminished and we may face additional competition from others in those jurisdictions. Many countries have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties, allowing competitors to manufacture and sell their own versions of our product, thereby reducing our sales. In addition, many countries do not permit enforcement of patents, or limit the enforceability of patents against government agencies or government contractors. In these countries, the patent owner may have limited remedies, which could materially diminish the value of such a patent. If we or any of our licensors, collaborators or present or future partners are forced to grant a license to third parties with respect to any patents relevant to our business, our competitive position in the relevant jurisdiction may be impaired and our business and results of operations may be adversely affected.

The requirements for patentability may differ in certain countries. For example, some jurisdictions may have heightened requirements for patentability compared to others, and may specifically require a detailed description of medical uses of a claimed drug. In some jurisdictions, unlike the United States, there is no link between regulatory approval of a drug and its patent status. Furthermore, generic or biosimilar drug manufacturers or other competitors may challenge the scope, validity or enforceability of our or our licensors’ or collaborators’ patents, requiring us or our licensors or collaborators to engage in complex, lengthy and costly litigation or other proceedings. Generic or biosimilar drug manufacturers may develop, seek approval for, and launch generic versions of our products. Accordingly, our and our licensors’ and collaborators’ efforts to enforce intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we own or license.

We or our licensors, collaborators or any future strategic partners may become subject to third party claims or litigation alleging infringement of patents or other proprietary rights or seeking to invalidate patents or other proprietary rights, and we may need to resort to litigation to protect or enforce our patents or other proprietary rights, all of which could be costly and time consuming, or delay or prevent the development and commercialization of our product candidates, or put our patents and other proprietary rights at risk.

We or our licensors, collaborators or any future strategic partners may be subject to third-party claims for infringement or misappropriation of patent or other proprietary rights. We are generally obligated under our license or collaboration agreements to indemnify and hold harmless our licensors or collaborators for damages arising from intellectual property infringement by us. If we or our licensors, collaborators or any future strategic partners are found to infringe a third-party patent or other intellectual property

rights, we could be required to pay damages, potentially including treble damages, if we are found to have willfully infringed. In addition, we or our licensors, collaborators or any future strategic partners may choose to seek, or be required to seek, a license from a third party, which may not be available on acceptable terms, if at all. Even if a license can be obtained on acceptable terms, the rights may be non-exclusive, which could give our competitors access to the same technology or intellectual property rights licensed to us. If we fail to obtain a required license, we or our collaborator, or any future collaborator, may be unable to effectively market product candidates based on our technology, which could limit our ability to generate revenue or achieve profitability and possibly prevent us from generating revenue sufficient to sustain our operations. In addition, we may find it necessary to pursue claims or initiate lawsuits to protect or enforce our patent or other intellectual property rights. The cost to us in defending or initiating any litigation or other proceeding relating to patent or other proprietary rights, even if resolved in our favor, could be substantial, and litigation would divert our management’s attention. Some of our competitors may be able to sustain the costs of complex patent litigation more effectively than we can because they have substantially greater resources. Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could delay our research and development efforts and limit our ability to continue our operations.

If we were to initiate legal proceedings against a third party to enforce a patent covering one of our products or our technology, the defendant could counterclaim that our patent is invalid or unenforceable. In patent litigation in the United States, defendant counterclaims alleging invalidity or unenforceability are commonplace. Grounds for a validity challenge could be an alleged failure to meet any of several statutory requirements, for example, lack of novelty, lack of written disclosure, obviousness, or non-enablement. Grounds for an unenforceability assertion could be an allegation that someone connected with prosecution of the patent withheld relevant information from the USPTO, or made a misleading statement, during prosecution. The outcome following legal allegations of invalidity and unenforceability during patent litigation is unpredictable. With respect to the validity question, for example, we cannot be certain that there is no invalidating prior art, of which we and the patent examiner were unaware during prosecution. If a defendant were to prevail on a legal assertion of invalidity or unenforceability, we would lose at least part, and perhaps all, of the patent protection on one or more of our products or certain aspects of our platform technology. Such a loss of patent protection could negatively impact our business. Patents and other intellectual property rights also will not protect our technology if competitors design around our protected technology without legally infringing our patents or other intellectual property rights.

Intellectual property rights of third parties could adversely affect our ability to commercialize our product candidates, and we might be required to litigate or obtain licenses from third parties in order to develop or market our product candidates. Such litigation or licenses could be costly or not available on commercially reasonable terms.

Because the oligonucleotide intellectual property landscape is still evolving and our product candidates have not yet reached commercialization, it is difficult to conclusively assess our freedom to operate. There are numerous companies that have pending patent applications and issued patents directed to certain aspects of oligonucleotides. We are aware of third-party competitors in the oligonucleotide therapeutics space, whose patent filings and/or issued patents may include claims directed to targets and/or products related to some of our programs. It is possible that at the time that we commercialize our products these third-party patent portfolios may include issued patent claims that cover our products or critical features of their production or use. Our competitive position may suffer if patents issued to third parties or other third-party intellectual property rights cover, or may be alleged to cover, our products or elements thereof, or methods of manufacture or use relevant to our development plans. In such cases, we may not be in a position to develop or commercialize product candidates unless we successfully pursue litigation to nullify or invalidate the third party intellectual property right concerned or enter into a license agreement with the intellectual property right holder, if available on commercially reasonable terms.

It is also possible that we have failed to identify relevant third-party patents or applications. For example, U.S. applications filed before November 29, 2000, and certain U.S. applications filed after that date that will not be filed outside the United States remain confidential until patents issue. Patent applications in the United States and elsewhere are published approximately 18 months after the earliest filing date for which priority is claimed, with such earliest filing date being commonly referred to as the priority date. Therefore, patent applications covering our products or platform technology could have been filed by others without our knowledge. Additionally, pending patent applications which have been published can, subject to certain limitations, be later amended in a manner that could cover our platform technologies, our products or the use of our products. Third party intellectual property right holders may also actively bring infringement claims against us. We cannot guarantee that we will be able to successfully settle or otherwise resolve such infringement claims. If we are unable to successfully settle future claims on terms acceptable to us, we may be required to engage in or continue costly, unpredictable and time-consuming litigation and may be prevented from or experience substantial delays in marketing our products. If we fail in any such dispute, in addition to being forced to pay damages, we may be temporarily or permanently prohibited from commercializing any of our product candidates that are held to be infringing. We might, if possible, also be forced to redesign product candidates so that we no longer infringe the third-party intellectual property rights. Any of these events, even if we were ultimately to prevail, could require us to divert substantial financial and management resources that we would otherwise be able to devote to our business.

If we fail to comply with our obligations under any license, collaboration or other agreement, we may be required to pay damages and could lose intellectual property rights that are necessary for developing and protecting our product candidates, or we could lose certain rights to grant sublicenses.

There are many issued patents and/or pending patent applications that claim aspects of oligonucleotide compositions, chemistry and/or modifications that we may want or need to apply to our product candidates. There are also many issued patents and/or pending patent applications that claim targeted genes or portions of genes that may be relevant for the oligonucleotides we wish to develop. We are aware of third-party competitors in the oligonucleotide therapeutics space whose patent filings and/or issued patents may include claims directed to targets and/or product candidates related to some of our development programs. It is possible that these third-party patent portfolios may include issued patent claims that cover our product candidates or critical features of their production or use. Thus, it is possible that one or more organizations will hold patent rights to which we will need or want a license. If those organizations refuse to grant us a license to such patent rights on reasonable terms, or at all, we may not be able to market products or perform research and development or other activities covered by these patents.

Our technology licenses and any future licenses we enter into are likely to impose various development, commercialization, funding, milestone, royalty, diligence, sublicensing, insurance, patent prosecution and enforcement, and/or other obligations on us. If we breach any of these imposed obligations, or use the intellectual property licensed to us in an unauthorized manner, we may be required to pay damages and the licensor may have the right to terminate the license, which could result in us being unable to develop, manufacture and sell products that are covered by the licensed technology or enable a competitor to gain access to the licensed technology. Moreover, our licensors may own or control intellectual property that has not been licensed to us and, as a result, we may be subject to claims, regardless of their merit, that we are infringing or otherwise violating the licensor’s rights. In addition, while we cannot currently determine the amount of the royalty obligations we would be required to pay on sales of future products, if any, the amounts may be significant. The amount of our future royalty obligations will depend on the technology and intellectual property we use in products that we successfully develop and commercialize, if any. Therefore, even if we successfully develop and commercialize products, we may be unable to achieve or maintain profitability.

If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.

In addition to seeking patent protection for certain aspects of our product candidates, we also consider trade secrets, including confidential and unpatented know-how, improvements and technological innovation important to the maintenance of our competitive position. We protect trade secrets and confidential and unpatented know-how, improvements and technological innovation, in part, by entering into non-disclosure and confidentiality agreements with parties who have access to such knowledge, such as our employees, corporate collaborators, outside scientific collaborators, CROs, contract manufacturers, consultants, advisors and other third parties. We also enter into confidentiality and invention or patent assignment agreements with our employees and consultants that obligate them to maintain confidentiality and assign their inventions to us. Despite these efforts, any of these parties may breach the agreements and disclose our proprietary information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches. Enforcing a claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive and time-consuming, and the outcome is unpredictable. In addition, some courts in the United States and certain foreign jurisdictions are less willing or unwilling to protect trade secrets. If any of our trade secrets were to be lawfully obtained or independently developed by a competitor, we would have no right to prevent them from using that technology or information to compete with us. If any of our trade secrets were to be disclosed to or independently developed by a competitor, our competitive position would be harmed.

We may be subject to claims that we or our employees or consultants have wrongfully used or disclosed alleged trade secrets of our employees’ or consultants’ former employers or their clients. These claims may be costly to defend and if we do not successfully do so, we may be required to pay monetary damages and may lose valuable intellectual property rights or personnel.

Many of our employees were previously employed at universities or biotechnology or pharmaceutical companies, including our competitors or potential competitors. Although no claims against us are currently pending, we may be subject to claims that these employees or we have inadvertently or otherwise used or disclosed trade secrets or other proprietary information of their former employers. Litigation may be necessary to defend against these claims. If we fail in defending such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel. A loss of key research personnel or their work product could hamper our ability to commercialize, or prevent us from commercializing, our product candidates, which could severely harm our business. Even if we are successful in defending against these claims, litigation could result in substantial costs and be a distraction to management.

If our trademarks and trade names are not adequately protected, then we may not be able to build name recognition in our markets of interest and our business may be adversely affected.

Our trademarks or trade names may be infringed, challenged, invalidated, circumvented, weakened or declared generic or determined to be infringing on other marks. We may not be able to protect our rights to these trademarks and trade names or may be forced to stop using these names, which we need for name recognition by potential partners or customers in our markets of interest. If we are unable to establish name recognition based on our trademarks and trade names, we may not be able to compete effectively and our business may be adversely affected.

We are a Singapore incorporated company and it may be difficult to enforce a judgment of U.S. courts for civil liabilities under U.S. federal securities laws against us, our directors or our officers in Singapore.

We are incorporated under the laws of the Republic of Singapore, and certain of our directors are residents outside the United States. Moreover, a significant portion of our consolidated assets are located outside the United States. Although we are incorporated outside the United States, we have agreed to accept service of process in the United States through our agent designated for that purpose. Nevertheless, because a majority of the consolidated assets owned by us are located outside the United States, any judgment obtained in the United States against us may not be enforceable within the United States.

There is no treaty between the United States and Singapore providing for the reciprocal recognition and enforcement of judgments in civil and commercial matters and a final judgment for the payment of money rendered by any federal or state court in the United States based on civil liability, whether or not predicated solely upon the federal securities laws, would, therefore, not be automatically enforceable in Singapore. There is uncertainty as to whether judgments of courts in the United States based upon the civil liability provisions of the federal securities laws of the United States would be recognized or enforceable in Singapore. In addition, holders of book-entry interests in our shares will be required to be registered shareholders as reflected in our shareholder register in order to have standing to bring a shareholder action and, if successful, to enforce a foreign judgment against us, our directors or our executive officers in the Singapore courts. The administrative process of becoming a registered holder could result in delays prejudicial to any legal proceedings or enforcement action. Consequently, it may be difficult for investors to enforce against us, our directors or our officers in Singapore judgments obtained in the United States which are predicated upon the civil liability provisions of the federal securities laws of the United States.

We are incorporated in Singapore and our shareholders may have more difficulty in protecting their interests than they would as shareholders of a corporation incorporated in the United States.

Our corporate affairs are governed by our constitution and by the laws governing corporations incorporated in Singapore. The rights of our shareholders and the responsibilities of the members of our Board under Singapore law are different from those applicable to a corporation incorporated in the United States. Principal shareholders of Singapore companies do not owe fiduciary duties to minority shareholders, as compared, for example, to controlling shareholders in corporations incorporated in Delaware. Our public shareholders may have more difficulty in protecting their interests in connection with actions taken by our management, members of our Board or our principal shareholders than they would as shareholders of a corporation incorporated in the United States.

In addition, only persons who are registered as shareholders in our shareholder register are recognized under Singapore law as shareholders of our company. Only registered shareholders have legal standing to institute shareholder actions against us or otherwise seek to enforce their rights as shareholders. Investors in our shares who are not specifically registered as shareholders in our shareholder register (for example, where such shareholders hold shares indirectly through the Depository Trust Company) are required to become registered as shareholders in our shareholder register in order to institute or enforce any legal proceedings or claims against us, our directors or our executive officers relating to shareholder rights. Holders of book-entry interests in our shares may become registered shareholders by exchanging their book-entry interests in our shares for certificated shares and being registered in our shareholder register. Such process could result in administrative delays which may be prejudicial to any legal proceeding or enforcement action.

We are subject to the laws of Singapore, which differ in certain material respects from the laws of the United States.

As a company incorporated under the laws of the Republic of Singapore, we are required to comply with the laws of Singapore, certain of which are capable of extra-territorial application, as well as our constitution. In particular, we are required to comply with certain provisions of the Securities and Futures Act 2001 of Singapore (the “SFA”), which prohibit certain forms of market conduct and require certain information disclosures, and impose criminal and civil penalties on corporations, directors and officers in respect of any breach of such provisions. We are required to comply with the Singapore Code on Take-Overs and Mergers (the “Singapore Takeover Code”), which specifies, among other things, certain circumstances in which a general offer is to be made upon a change in effective control, and further specifies the manner and price at which voluntary and mandatory general offers are to be made.

We are also subject to Section 34 of the Singapore Patents Act, which provides that a person residing in Singapore is required to obtain written authorization from the Singapore Registrar of Patents (the “Registrar”) before filing an application for a patent for an invention outside of Singapore, unless certain conditions have been satisfied. A violation of Section 34 is a criminal offense punishable by a fine not exceeding S$5,000, or imprisonment for a term not exceeding two years, or both. There have been some instances where we have undertaken filings outside of Singapore, and there may be instances where we are required to make such filings in the future, without first obtaining written authorization from the Registrar. We have notified the Registrar of such filings and we have since implemented measures to address the requirements of Section 34 moving forward. To date, the Registrar has offered a compound of some of the offences considered against payment of a sum of S$50 to S$150 per considered case. Under Singapore law, the Registrar has discretion to offer a compound of such offences against payment of a sum of money of up to S$2,500, or to prosecute the offence subject to the other penalties noted above. Per requests in the Registrar’s most recent decision, we have submitted approximately 140 patent applications in multiple patent families, most of which are related to previously reported applications, to the Intellectual Property Office of Singapore (“IPOS”). The IPOS may consider the filing of some or all of these applications to have breached Section 34 requirements per IPOS’ current interpretation of Section 34, and we are waiting for IPOS’ decision on these applications. We cannot assure you that the Registrar will offer to compound any such violations of Section 34, or that any offer to compound will be for an amount similar to previous compound offers.

The laws of Singapore and of the United States differ in certain significant respects. The rights of our shareholders and the obligations of our directors and officers under Singapore law (including under the Companies Act 1967 of Singapore (the “Singapore Companies Act”) are different from those applicable to a company incorporated in the State of Delaware in material respects, and our shareholders may have more difficulty and less clarity in protecting their interests in connection with actions taken by our management, members of our Board or our affiliated shareholders than would otherwise apply to a company incorporated in the State of Delaware.

The application of Singapore law, in particular, the Singapore Companies Act may, in certain circumstances, impose more restrictions on us and our shareholders, directors and officers than would otherwise be applicable to a company incorporated in the State of Delaware. For example, the Singapore Companies Act requires directors to act with a reasonable degree of diligence and, in certain circumstances, imposes criminal liability for specified contraventions of particular statutory requirements or prohibitions. In addition, pursuant to the provisions of the Singapore Companies Act, shareholders holding 10% or more of the total number of paid-up shares carrying the right of voting in general meetings may require the convening of an extraordinary general meeting of shareholders by our directors. If our directors fail to comply with such request within 21 days of the receipt thereof, the original requisitioning shareholders, or any of them holding more than 50% of the voting rights represented by the original requisitioning shareholders, may proceed to convene such meeting, and we will be liable for the reasonable expenses incurred by such requisitioning shareholders. We are also required by the Singapore Companies Act to deduct such corresponding amounts from fees or other remuneration payable by us to such non-complying directors.

We are subject to the Singapore Takeover Code, which requires a person acquiring 30% or more of our voting shares to conduct a takeover offer for all of our voting shares. This could have the effect of discouraging, delaying or preventing a merger or acquisition and limit the market price of our ordinary shares.

We are subject to the Singapore Takeover Code. The Singapore Takeover Code contains provisions that may delay, deter or prevent a future takeover or change in control of our company and limit the market price of our ordinary shares for so long as we remain a public company with more than 50 shareholders and net tangible assets of S$5 million (Singapore dollars) or more. For example, under the Singapore Takeover Code, any person acquiring, whether by a series of transactions over a period of time or not, either on its own or together with parties acting in concert with it, 30% or more of our voting shares, or if such person holds, either on its own or together with parties acting in concert with it, between 30% and 50% (both inclusive) of our voting shares, and if such person (or parties acting in concert with it) acquires additional voting shares representing more than 1% of our voting shares in any six-month period, must, except with the consent of Securities Industry Council in Singapore, extend a takeover offer for our remaining voting shares in accordance with the Singapore Takeover Code. Therefore, any investor seeking to acquire a significant stake in our company may be deterred from doing so if, as a result, such investor would be required to conduct a takeover offer for all of our voting shares.

These same provisions could discourage potential investors from acquiring a stake or making a significant investment in our company and may substantially impede the ability of our shareholders to benefit from a change of effective control and, as a result, may adversely affect the market price of our ordinary shares and the ability to realize any benefits from a potential change of control.

For a limited period of time, our directors have general authority to allot and issue new ordinary shares on terms and conditions and for such purposes as may be determined by our Board in its sole discretion.

Under Singapore law, we may only allot and issue new shares with the prior approval of our shareholders in a general meeting. At our most recent annual general meeting of shareholders, our shareholders provided our directors with a general authority, subject to the

provisions of the Singapore Companies Act and our constitution, to allot and issue any number of new ordinary shares and/or make or grant offers, agreements, options or other instruments (including the grant of awards or options pursuant to our equity-based incentive plans and agreements in effect from time to time) that might or would require ordinary shares to be allotted and issued (collectively, the “Instruments”); and unless revoked or varied by us in a general meeting, such authority will continue in force until the earlier of (i) the conclusion of our next annual general meeting of shareholders, or (ii) the expiration of the period within which our next annual general meeting of shareholders is required by law to be held. Subject to the general requirements of the Singapore Companies Act and our constitution, the general authority given to our directors by our shareholders to allot and issue ordinary shares and/or make or grant the Instruments may be exercised by our directors on such terms and conditions, for such purposes and for consideration as they may in their sole discretion deem fit, and with such rights or restrictions as they may think fit to impose and as are set forth in our constitution. Any additional issuances of new ordinary shares and/or any grant of the Instruments by our directors may dilute our shareholders’ interests in our ordinary shares and/or adversely impact the market price of our ordinary shares.

We may be or become a passive foreign investment company, which could result in adverse U.S. federal income tax consequences to U.S. Holders.

The rules governing passive foreign investment companies (“PFICs”) can have adverse effects for U.S. federal income tax purposes. The tests for determining PFIC status for a taxable year depend upon the relative values of certain categories of assets and the relative amounts of certain kinds of income. The determination of whether we are a PFIC, which must be made annually after the close of each taxable year, depends on the particular facts and circumstances (such as the valuation of our assets, including goodwill and other intangible assets) and may also be affected by the application of the PFIC rules, which are subject to differing interpretations. The fair market value of our assets is expected to relate, in part, to (a) the market price of our ordinary shares and (b) the composition of our income and assets, which will be affected by how, and how quickly, we spend any cash that is raised in any financing transaction. Moreover, our ability to earn specific types of income that we currently treat as non-passive for purposes of the PFIC rules is uncertain with respect to future years. Based on our gross income, the average value of our assets, including goodwill and the nature of our active business, we do not expect to be treated as a PFIC for U.S. federal income tax purposes for the taxable year ended December 31, 2024. Because the value of our assets for purposes of determining PFIC status will depend in part on the market price of our ordinary shares, which may fluctuate significantly, there can be no assurance that we will not be considered a PFIC for our current taxable year ending December 31, 2025 or for any future taxable year.

If we are a PFIC, a U.S. Holder (defined below) would be subject to adverse U.S. federal income tax consequences, such as ineligibility for any preferred tax rates on capital gains or on actual or deemed dividends, interest charges on certain taxes treated as deferred, and additional reporting requirements under U.S. federal income tax laws and regulations. A U.S. Holder may in certain circumstances mitigate adverse tax consequences of the PFIC rules by filing an election to treat the PFIC as a qualified electing fund (“QEF”) or, if shares of the PFIC are “marketable stock” for purposes of the PFIC rules, by making a mark-to-market election with respect to the shares of the PFIC. If a U.S. Holder makes a mark-to-market election with respect to its ordinary shares, the U.S. Holder is required to include annually in its U.S. federal taxable income an amount reflecting any year end increase in the value of its ordinary shares. For purposes of this discussion, a “U.S. Holder” is a beneficial owner of ordinary shares that is for U.S. federal income tax purposes: (i) an individual who is a citizen or resident of the United States; (ii) a corporation (or other entity taxable as a corporation for U.S. federal income tax purposes) created or organized in or under the laws of the United States, any state thereof or the District of Columbia; (iii) an estate the income of which is subject to U.S. federal income taxation regardless of its source; or (iv) a trust (a) if a court within the United States can exercise primary supervision over its administration, and one or more U.S. persons have the authority to control all of the substantial decisions of that trust, or (b) that was in existence on August 20, 1996, and validly elected under applicable Treasury Regulations to continue to be treated as a domestic trust.

Investors should consult their own tax advisors regarding all aspects of the application of the PFIC rules to the ordinary shares.

Prospective investors should consult their tax advisors concerning the overall tax consequences of purchasing, owning and disposing of our shares. Singapore tax law may differ from the tax laws of other jurisdictions, including the United States.

We are incorporated under the laws of Singapore. Under Singapore tax law, from January 1, 2024, subject to certain exceptions, gains from the sale or disposal by an entity without adequate economic substance and belonging to a relevant group of entities, of any movable or immovable property situated outside Singapore and that are received in Singapore from outside Singapore, are treated as income chargeable to tax.

We are also subject to income, withholding or other taxes in certain jurisdictions by reason of our activities and operations, and it is also possible that tax authorities in any such jurisdictions could assert that we are subject to greater taxation than we currently anticipate.

Any such Singaporean and non-Singaporean tax liability could materially adversely affect our results of operations.

Tax authorities could challenge the allocation of income and deductions among our subsidiaries, which could increase our overall tax liability.

We are organized in Singapore, and we currently have subsidiaries in the United States, Japan, the United Kingdom, and Ireland. As we grow our business, we conduct, and expect to continue to conduct, increased operations through our subsidiaries in various jurisdictions. If two or more affiliated companies are located in different jurisdictions, the tax laws or regulations of each country generally will require transactions between those affiliated companies to be conducted on terms consistent with those between unrelated companies dealing at arms’ length, and appropriate documentation generally must be maintained to support the transfer prices. We maintain our transfer pricing policies to be compliant with applicable transfer pricing laws, but our transfer pricing procedures are not binding on applicable tax authorities.

If tax authorities were to successfully challenge our transfer pricing, there could be an increase in our overall tax liability, which could adversely affect our financial condition, results of operations and cash flows. In addition, the tax laws in the jurisdictions in which we operate are subject to differing interpretations. Tax authorities may challenge our tax positions, and if successful, such challenges could increase our overall tax liability. In addition, the tax laws in the jurisdictions in which we operate are subject to change. We cannot predict the timing or content of such potential changes, and such changes could increase our overall tax liability, which could adversely affect our financial condition, results of operations and cash flows.

Our financial results reflect the effect of certain tax credits and the operation of certain tax regimes within the United Kingdom. Legislation in the United Kingdom will limit the amount we may be able to claim as a payable tax credit in the future which could impact our financial condition, results of operations and cash flows.

As a company that carries out extensive research and development activities, we benefit from the U.K. research and development tax credit regime for small and medium-sized companies, whereby our subsidiary in the United Kingdom is able to surrender the trading losses that arise from its research and development activities for a payable tax credit of generally up to 18.6% of such expenditures. Expenditures of staff supplied by unconnected third parties incurred are eligible for a cash rebate of generally up to 12.1%.

Due to a change in the U.K. legislation affecting the U.K. research and development tax credit regime for small- and medium-sized companies, our ability to receive a payable tax credit for the surrender of our trading losses from research and development activities may be limited to the amount equal to three times our “pay as you earn” and U.K. national insurance tax liabilities, absent our qualification under an exception from such limitation.

Further, we may not be able to continue to claim a U.K. tax credit for research and development tax credits under the small and medium-sized companies regime in the future if our revenue or turnover exceeds €100 million for two consecutive years. In such an event, we will no longer qualify as a small or medium-sized enterprise.

Recently enacted U.K. legislation merges the small and medium-sized companies regime and the research and development expenditure credit regime generally for large companies. This legislation applies a 20% rate to qualifying research and development expenditures. The legislation also includes changes to other rules and types of qualifying expenditure, such as the treatment of subcontracted and overseas costs. We are currently evaluating the impact of the legislation on our future tax credit claims.

The public market for our ordinary shares may not be liquid enough for our shareholders to sell their ordinary shares quickly or at market price, or at all.

Our ordinary shares are currently listed for trading on the Nasdaq Global Market. There is no assurance that the trading market for our shares will be or remain active. Our shareholders may not be able to sell their ordinary shares quickly or at the market price, or at all. Our executive officers, our directors and their respective affiliates, and our other significant shareholders beneficially own a significant portion of our outstanding ordinary shares, and therefore, liquidity in our ordinary shares is limited. Due to the limited liquidity in our ordinary shares, relatively small orders can have a disproportionate impact on the trading price of our shares. Further, the limited liquidity in our ordinary shares may also impair our ability to raise capital by conducting offerings of our ordinary shares and may impair our ability to enter into strategic partnerships or acquire companies or products by using our ordinary shares as consideration.

The market price of our ordinary shares is likely to be highly volatile, and our shareholders may lose some or all of their investment.

The market price of our ordinary shares is likely to continue to be highly volatile, including in response to factors that are beyond our control. The stock market in general experiences extreme price and volume fluctuations. In particular, the market prices of securities of pharmaceutical and biotechnology companies are extremely volatile, and experience fluctuations that are often unrelated or disproportionate to the operating performance of these companies. These broad and sector-specific market fluctuations can result in extreme fluctuations in the price of our ordinary shares, regardless of our operating performance, and can cause our shareholders to lose some or all of their investment in us.

We issued pre-funded warrants as part of our June 2022 and September 2024 financings, which may cause additional dilution to our shareholders.

In June 2022, we closed an underwritten offering in which we issued and sold 25,464,483 ordinary shares and, to RA Capital Management, L.P. in lieu of additional ordinary shares, pre-funded warrants (the “2022 Pre-Funded Warrants”) to purchase up to 7,093,656 ordinary shares at an exercise price of $0.0001 per share. In September 2024, we closed an underwritten public offering (the “September 2024 Offering”) in which we issued and sold 23,125,001 ordinary shares, and to certain investors in lieu of additional ordinary shares, the pre-funded warrants (the “2024 Pre-Funded Warrants”, and together with the 2022 Pre-Funded Warrants, the “Pre-Funded Warrants”) to purchase up to 1,875,023 ordinary shares at an exercise price of $0.0001 per share. The Pre-Funded Warrants contain a so-called “blocker” provision which provides that they are only exercisable upon receipt of shareholder approval or if such exercise would not cause the aggregate number of ordinary shares or the combined voting power of total securities, in each case, beneficially owned by the holder (together with its affiliates) to exceed, depending on the terms of the applicable Pre-Funded Warrants and in certain cases at the election of the holder, either 4.99%, 9.99% or 19.99% of the number of ordinary shares or total securities, respectively, outstanding immediately after giving effect to the exercise. To the extent the Pre-Funded Warrants above are exercised, additional ordinary shares will be issued and such issuance would dilute existing shareholders and increase the number of shares eligible for resale in the public market.

Our principal shareholders and management own a significant percentage of our ordinary shares and will be able to exert significant control over matters subject to shareholder approval.

Based on information publicly available to us as of December 31, 2024, our executive officers, our directors and their respective affiliates, and our other significant shareholders beneficially own a significant portion of our outstanding ordinary shares. As a result, these shareholders, if acting together, will continue to have significant influence over the outcome of corporate actions requiring shareholder approval, including the election of directors, any merger, consolidation or sale of all or substantially all of our assets and any other significant corporate transaction. The interests of these shareholders may not be the same as or may even conflict with the interests of our other shareholders. For example, these shareholders could delay or prevent a change of control of our company, even if such a change of control would benefit our other shareholders, which could deprive shareholders of an opportunity to receive a premium for their ordinary shares as part of a sale of our company or our assets and might affect the prevailing market price of our ordinary shares. The significant concentration of share ownership may adversely affect the trading price of our ordinary shares due to investors’ perception that conflicts of interest may exist or arise.

We incur significant costs due to operating as a public company, and our management is required to devote substantial time to compliance initiatives.

As a public company, we incur significant legal, accounting and other expenses. We are subject to the reporting and other requirements of the Exchange Act, the Sarbanes-Oxley Act of 2002 (the “Sarbanes-Oxley Act”), and the Dodd-Frank Wall Street Reform and Protection Act, as well as rules subsequently adopted by the SEC and the Nasdaq Stock Market. These rules and regulations require, among other things, that we file annual, quarterly and current reports with respect to our business and financial condition and establish and maintain effective disclosure and financial controls and corporate governance practices. We expect that compliance with these rules and regulations will continue to result in substantial legal and financial compliance costs and will make some activities more time-consuming and costly. Our management and other personnel devote a substantial amount of time to these compliance requirements.

If we fail to maintain proper and effective internal controls, our ability to produce accurate and timely financial statements could be impaired, which could harm our operating results, our ability to operate our business and investors’ views of us.

We are required to comply with Section 404 of the Sarbanes-Oxley Act. Section 404 of the Sarbanes-Oxley Act requires public companies to maintain effective internal control over financial reporting. In particular, we must perform system and process evaluation and testing of our internal control over financial reporting to allow management to report on the effectiveness of our

internal control over financial reporting. Ensuring that we have adequate internal financial and accounting controls and procedures in place so that we can produce accurate financial statements on a timely basis is a costly and time-consuming effort that is evaluated frequently. If we fail to maintain the effectiveness of our internal controls or fail to comply in a timely manner with the requirements of the Sarbanes-Oxley Act, or if we identify deficiencies in our internal control over financial reporting that are deemed to be material weaknesses, this could have a material adverse effect on our business. We could lose investor confidence in the accuracy and completeness of our financial reports, which could have an adverse effect on the price of our ordinary shares and we could be subject to sanctions or investigations by Nasdaq, the SEC or other regulatory authorities, which would require additional financial and management resources. In addition, if our efforts to comply with new or changed laws, regulations, and standards differ from the activities intended by regulatory or governing bodies due to ambiguities related to practice, regulatory authorities may initiate legal proceedings against us and our business may be harmed.

Our ability to successfully implement our business plan and comply with Section 404 of the Sarbanes-Oxley Act requires us to be able to prepare timely and accurate financial statements. We expect that we will need to continue to improve existing, and implement new operational and financial systems, procedures and controls to manage our business effectively. Any delay in the implementation of, or disruption in the transition to, new or enhanced systems, procedures or controls, may cause our operations to suffer and we may be unable to conclude that our internal control over financial reporting is effective and to obtain an unqualified report on internal controls from our independent registered public accounting firm as required under Section 404 of the Sarbanes-Oxley Act. This, in turn, could have an adverse impact on trading prices for our ordinary shares, and could adversely affect our ability to access the capital markets.

Although we determined that our internal controls over financing reporting were effective as of December 31, 2024, we may in the future identify internal control deficiencies that could rise to the level of a material weakness or uncover other errors in financial reporting. During the course of our evaluation of these material weaknesses, we may identify areas requiring improvement and may be required to design additional enhanced processes and controls to address issues identified through this review. There can be no assurance that such remediation efforts will be successful, that our internal control over financial reporting will be effective as a result of these efforts or that any such future deficiencies identified may not be material weaknesses that would be required to be reported in future periods. In addition, we cannot assure you that our independent registered public accounting firm will be able to attest that such internal controls are effective.

The estimates and judgments we make, or the assumptions on which we rely, in preparing our consolidated financial statements could prove inaccurate.

Our consolidated financial statements have been prepared in accordance with accounting principles generally accepted in the United States (“U.S. GAAP”). The preparation of these consolidated financial statements requires us to make estimates and judgments that affect the reported amounts of our assets, liabilities, revenues and expenses, the amounts of charges accrued by us and related disclosure of contingent assets and liabilities. We base our estimates on historical experience and on various other assumptions that we believe to be reasonable under the circumstances. We cannot assure, however, that our estimates, or the assumptions underlying them, will not change over time or otherwise prove inaccurate. For example, our estimates as they relate to anticipated timelines and milestones for our clinical trials or preclinical development may prove to be inaccurate. If this is the case, we may be required to restate our consolidated financial statements, which could, in turn, subject us to securities class action litigation. Defending against such potential litigation relating to a restatement of our consolidated financial statements or otherwise would be expensive and would require significant attention and resources of our management. Moreover, our insurance to cover our obligations with respect to the ultimate resolution of any such litigation may be inadequate. As a result of these factors, any such potential litigation could have a material adverse effect on our financial results, harm our business, and cause our share price to decline.

We do not anticipate paying any cash dividends on our ordinary shares in the foreseeable future.

We have never declared or paid cash dividends on our ordinary shares. We currently intend to retain all of our future earnings, if any, to finance the growth and development of our business, and we do not anticipate paying any cash dividends on our ordinary shares in the foreseeable future. In addition, the terms of any future debt agreements may preclude us from paying dividends. As a result, capital appreciation, if any, of our ordinary shares will be our shareholders’ sole source of gain for the foreseeable future.

We may incur significant costs from class action litigation due to share volatility.

Our share price may fluctuate for many reasons, including as a result of public announcements regarding the progress of our development efforts or the development efforts of our collaborators and/or competitors, the addition or departure of our key personnel, variations in our quarterly operating results and changes in market valuations of pharmaceutical and biotechnology companies. Holders of stock that has experienced significant price and trading volatility have occasionally brought securities class action litigation against the companies that issued the stock. If any of our shareholders were to bring a lawsuit of this type against us, even if the

lawsuit is without merit, we could incur substantial costs defending the lawsuit. The lawsuit could also divert the time and attention of our management, which could harm our business.

Sales of additional ordinary shares could cause the price of our ordinary shares to decline.

Sales of substantial amounts of our ordinary shares in the public market, or the availability of such shares for sale, by us or others, including the issuance of ordinary shares upon exercise of outstanding options or Pre-Funded Warrants or vesting of outstanding restricted share units, or the perception that such sales could occur, could adversely affect the price of our ordinary shares. Certain of our shareholders have required us, or have the right to require us, to register the sales of their shares under the Securities Act under agreements between us and such shareholders. For example, in August 2019, we filed a registration statement on Form S-3, which was declared effective on August 14, 2019, to register the resale from time to time by certain of our executive officers, directors and their affiliates of up to approximately 7.1 million ordinary shares.

If securities or industry analysts do not publish research or publish inaccurate or unfavorable research about our business, our share price and trading volume could decline.

The trading market for our ordinary shares may depend in part on the research and reports that securities or industry analysts publish about us or our business. If too few securities or industry analysts cover our company, the trading price for our ordinary shares would likely be negatively impacted. If one or more of the analysts who cover us downgrade our ordinary shares or publish inaccurate or unfavorable research about our business, our share price would likely decline. If one or more of these analysts cease coverage of our company or fail to publish reports on us regularly, demand for our ordinary shares could decrease, which might cause our share price and trading volume to decline.

Item 1C. Cybersecurity

We recognize the importance of maintaining the trust and confidence of the patients we serve, our business partners, employees and our shareholders and are committed to protecting the confidentiality, integrity and reliance of our business operations and systems. Effective data protection practices, including responsible stewardship of our intellectual property and the secure processing, storage, maintenance and transmission of critical information by us and other third parties with whom we do business is vital to our operations.

Our cybersecurity practices, policies, and standards are based on recognized frameworks established by the National Institute of Standards and Technology (“NIST”) (NIST SP 800-53), the Center for Internet Security (“CIS”), along with adopting best practices from Control Objectives for Information and Related Technologies (“COBIT”) and other applicable industry standards. In general, we seek to address cybersecurity risks through a comprehensive, cross-functional approach that is focused on preserving the confidentiality, security and availability of the information that we collect and store by identifying, preventing and mitigating cybersecurity threats and effectively responding to cybersecurity incidents if they occur.

Cybersecurity Risk Management and Strategy

We may face risks related to cybersecurity, such as unauthorized access, cybersecurity attacks and other security incidents, which could adversely affect our business and operations. To identify and assess material risks from cybersecurity threats, we maintain a robust cybersecurity program to ensure our systems are effective and prepared for information security risks and have integrated these processes into our overall risk management systems and processes. We also identify our cybersecurity threat risks by comparing our processes to standards set by NIST, CIS, and COBIT, as well as by engaging experts to attempt to infiltrate our information systems. We consider risks from cybersecurity threats alongside other company risks as part of our overall risk assessment process. We employ a range of tools, services and capabilities, including regular network and endpoint monitoring, audits, vulnerability assessments, penetration testing, threat modeling, disaster recovery and business continuity planning activities, red team testing, mandatory training for our employees, and tabletop exercises to inform our risk identification and assessment.

Our processes also address cybersecurity threat risks associated with our use of third-party service providers, including our vendors, CROs, suppliers and/or manufacturers who may have access to patient and employee data or our systems. We perform diligence on third parties that have access to our systems, data or facilities that house such systems or data, and continually monitor cybersecurity threat risks identified through such diligence. Additionally, we generally require those third parties that could introduce significant cybersecurity risk to us to agree by contract to manage their cybersecurity risks in specified ways, and to agree to be subject to cybersecurity audits, which we conduct continuously through third-party risk management tools.

Our incident response plan coordinates the activities we take to prepare for, detect, respond to and recover from cybersecurity incidents, which include processes to triage, assess severity for, escalate, contain, investigate and remediate the incident, as well as to comply with potentially applicable legal obligations and mitigate damage to our business and reputation.

As part of the above processes, we regularly engage with consultants and other third parties, including a bi-annual review of our cybersecurity program by an independent Qualified Security Assessor.

In the last three fiscal years, we have not experienced any material cybersecurity incidents and the expenses we have incurred from cybersecurity incidents were immaterial. We describe whether and how risks from identified cybersecurity threats, including as a result of any previous cybersecurity incidents, have materially affected or are reasonably likely to materially affect us, including our business strategy, results of operations, or financial condition, under the heading “Security breaches, cybersecurity threats, loss of data and other disruptions could compromise sensitive information related to our business, prevent us from accessing critical information or expose us to liability, which could adversely affect our business and our reputation,” in Item 1A. Risk Factors, which disclosures are incorporated by reference herein.

Cybersecurity Governance

Our Board is actively involved in oversight of our risk management activities, and cybersecurity represents an important element of our overall approach to risk management. Our Board delegates to the Audit Committee oversight of certain aspects of our risk management process, including risks related to information technology, data privacy and cybersecurity.

We maintain our U.S. corporate offices and research and development facilities in Cambridge, Massachusetts, where we lease office and laboratory space of approximately 44,000 square feet.

We lease approximately 90,000 square feet of office and laboratory space in Lexington, Massachusetts, which we use for our research, development and cGMP manufacturing.

We also occupy laboratory and office space in Japan. We believe our existing facilities are adequate to meet our current needs.

Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities

Our ordinary shares are traded on the Nasdaq Global Market under the symbol “WVE”.

As of February 24, 2025, we had 153,486,021 ordinary shares outstanding and approximately nine shareholders of record of our ordinary shares.

MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS

The following discussion and analysis of our financial condition and results of operations should be read in conjunction with our financial statements and related notes appearing elsewhere in this Annual Report on Form 10-K. Some of the information contained in this discussion and analysis or set forth elsewhere in this Annual Report on Form 10-K, including information with respect to our plans and strategy for our business, includes forward-looking statements that involve risks and uncertainties. As a result of many factors, including those factors set forth in the “Risk Factors” section of this Annual Report on Form 10-K, our actual results could differ materially from the results described in, or implied by, these forward-looking statements.

We were founded on the recognition that there was a significant, untapped opportunity to use chemistry innovation to tune the pharmacological properties of oligonucleotides. We have more than a decade of experience challenging convention related to oligonucleotide design and pioneering novel chemistry modifications to optimize the pharmacological properties of our molecules. We have seen in clinical trials that these chemistry modifications enhance potency, distribution, and durability of effect of our molecules. Our novel chemistry also allows us to avoid using complex delivery vehicles, such as lipid nanoparticles and viruses, and instead use clinically proven conjugates (e.g., N-acetylgalactosamine or (“GalNAc”)) or free uptake for delivery to a variety of cell and tissue types. We maintain strong and broad intellectual property, including for our novel chemistry modifications.

Our best-in-class chemistry capabilities have also unlocked new areas of biology, such as harnessing adenosine deaminases acting on RNA (“ADAR”) enzymes for messenger RNA (“mRNA”) correction and upregulation, selectively silencing a mutant allele, and more. By opening up new areas of biology, we have also opened up new opportunities to slow, stop or reverse disease and have expanded the possibilities offered through our platform.

The inspiration for our multimodal platform is based on the recognition that the biological machinery (i.e., enzymes) needed to address human disease already exists within our cells and can be harnessed for therapeutic purposes with the right tools. We believe that we have built the most versatile toolkit of RNA-targeting modalities in the industry, with multiple means of repairing, restoring, or reducing proteins and designing best-fit solutions based on the unique biology of a given disease target. We are actively advancing programs using four distinct modalities, including novel A-to-I RNA editing oligonucleotides (“AIMers”).

We intentionally focus on targeting the transcriptome using oligonucleotides rather than other nucleic acid modalities such as gene therapy and DNA editing. This focus enables us to:

We have a robust and diverse pipeline of potential first-or best-in-class programs addressing both rare and common diseases:

Our RNA editing capability affords us the dexterity to address both rare and common diseases, as well as those diseases impacting large patient populations. AIMers are designed to target single bases on an RNA transcript and recruit proteins that exist in the body, called ADAR enzymes, which naturally possess the ability to change an adenine (A) to an inosine (I), which cells read as guanine (G). This approach enables both the correction of G-to-A point mutations and the modulation of RNA to either upregulate protein expression, modify protein-protein interactions, or alter RNA folding and processing. AIMers enable simplified delivery and avoid the risk of permanent changes to the genome and irreversible off-target effects with DNA-targeting approaches. AIMers are short in length, fully chemically modified, and use our novel chemistry, which make them distinct from other ADAR-mediated editing approaches.

In December 2022, we announced a strategic collaboration with GlaxoSmithKline Intellectual Property (No. 3) (“GSK”) to advance transformative oligonucleotide therapeutics, including WVE-006. The collaboration combines GSK’s novel genetic insights, as well as its global development and commercial capabilities, with our PRISM platform and oligonucleotide expertise. The collaboration will enable us to continue building a pipeline of first-in-class oligonucleotide-based therapeutics and unlock new areas of disease biology, as well as realize the full value of WVE-006 as a potential best-in-class treatment for AATD that has the potential to simultaneously address both liver and lung manifestations of the disease.

(1) a discovery collaboration which enables us to advance up to three programs leveraging targets informed by GSK’s novel genetic insights;

(2) a discovery collaboration which enables GSK to advance up to eight programs leveraging PRISM and our oligonucleotide expertise and discovery capabilities; and

(3) an exclusive global license for GSK to WVE-006, our AATD program, that uses our proprietary AIMer technology. We will maintain development responsibilities for WVE-006 through completion of RestorAATion-2, at which point development and commercial responsibilities will transition to GSK.

In February 2018, we entered into a global strategic collaboration with Takeda Pharmaceutical Company Limited (“Takeda”), pursuant to which we agreed to collaborate with Takeda on the research, development and commercialization of oligonucleotide therapeutics for disorders of the CNS. On October 11, 2024, we were notified by Takeda that Takeda did not intend to exercise and therefore elected to terminate its option for the HD target under the collaboration. As HD was the last active collaboration target under the collaboration, the collaboration expired with immediate effect. As a result of the option termination, we are now free to advance WVE-003, our clinical-stage Huntington’s disease program, as well as any other programs targeting HTT, independently or with other partners.

We have never been profitable, and since our inception, we have incurred significant operating losses. Our net loss was $97.0 million in 2024, $57.5 million in 2023, and $161.8 million in 2022. As of December 31, 2024 and 2023, we had an accumulated deficit of $1,121.9 million and $1,024.9 million, respectively. We expect to incur significant expenses and operating losses for the foreseeable future.

We recognize collaboration revenue under the GSK Collaboration Agreement, which became effective in January 2023, and the Takeda Collaboration Agreement, which became effective in April 2018 and expired in the fourth quarter of 2024, (both of which are defined in Note 5 in the notes to the consolidated financial statements appearing elsewhere in this Annual Report on Form 10-K). We have not generated any product revenue since our inception and do not expect to generate any revenue from the sale of products for the foreseeable future.

Our operating expenses since inception have consisted primarily of research and development expenses and general and administrative expenses.

Research and development expenses consist primarily of costs incurred for our research activities, including our discovery efforts, and the development of our product candidates, which include:

We recognize research and development costs as incurred. We recognize external development costs based on an evaluation of the progress to completion of specific tasks using information provided to us by our vendors. Payments for these activities are based on the terms of the individual agreements, which may differ from the pattern of costs incurred, and are reflected in our financial statements as prepaid or accrued expenses.

Our primary research and development focus has been the development of our RNA medicines platform, PRISM. We are using PRISM, which includes our novel chemistry modifications, to design, develop and commercialize a broad pipeline of first- or best-in class RNA medicines using our editing, splicing, RNAi, and antisense modalities.

Our research and development expenses consist primarily of expenses related to our CROs, CMOs, consultants, other external vendors and fees paid to global regulatory agencies to conduct our clinical trials, in addition to compensation-related expenses, internal manufacturing expenses, facility-related expenses and other general operating expenses. These expenses are incurred in connection with research and development efforts and our preclinical studies and clinical trials. We track certain external expenses on a program-by-program basis. However, we do not allocate compensation-related expenses, internal manufacturing expenses, equipment repairs and maintenance expense, facility-related expenses or other operating expenses to specific programs. These expenses, which are not allocated on a program-by-program basis, are included in the “Other research and development expenses(1), including INHBE, RNA

editing, PRISM, others” category along with other external expenses related to our discovery and development programs, as well as platform development and identification of potential drug discovery candidates.

Product candidates in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials. We expect to continue to incur significant research and development expenses in the foreseeable future as we continue to manage our existing clinical trials, initiate additional clinical trials for certain product candidates, pursue later stages of clinical development for certain product candidates, maintain our manufacturing capabilities and continue to discover and develop additional product candidates in multiple therapeutic areas.

General and administrative expenses consist primarily of compensation-related expenses, including salaries, bonuses, share-based compensation and other related benefits costs for personnel in our executive, finance, corporate, legal and administrative functions, as well as compensation-related expenses for our Board. General and administrative expenses also include legal fees; expenses associated with being a public company; professional fees for accounting, auditing, tax and consulting services; insurance costs; travel expenses; other operating costs; and facility-related expenses.

Other income, net is comprised of refundable tax credits from tax authorities, dividend and interest income earned on cash and cash equivalents balances, gains and losses on foreign currency transactions, and real estate taxes. We recognize refundable tax credits when there is reasonable assurance that we will comply with the requirements of the refundable tax credit and that the refundable tax credit will be received.

We are a Singapore multi-national company subject to taxation in the United States and various other jurisdictions.

As of December 31, 2024 and 2023, we have recorded a full valuation allowance against our net operating loss carryforwards and federal and state tax credits in all jurisdictions due to uncertainty regarding future taxable income.

In this section, we discuss the results of our operations for the year ended December 31, 2024 compared to the year ended December 31, 2023 and for the year ended December 31, 2023 compared to the year ended December 31, 2022.

Comparison of the Year Ended December 31, 2024 to the Year Ended December 31, 2023

Revenue for the years ended December 31, 2024 and 2023, was $108.3 million and $113.3 million, respectively, and was earned under the GSK Collaboration Agreement and the Takeda Collaboration Agreement.

The $5.0 million decrease in revenue year over year was driven by the revenue recognized under the GSK Collaboration Agreement, partially offset by the increase in revenue recognized under the Takeda Collaboration Agreement. The $108.3 million in revenue recognized during the year ended December 31, 2024 was comprised of $37.0 million in revenue recognized under the GSK Collaboration Agreement and $71.3 million of revenue recognized under the Takeda Collaboration Agreement. The $113.3 million in revenue recognized during the year ended December 31, 2023 was comprised of $66.3 million in revenue recognized under the GSK Collaboration Agreement and $47.0 million of revenue recognized under the Takeda Collaboration Agreement. The increase in the Takeda Collaboration revenue earned year over year was primarily due to the termination of the collaboration in October 2024, which led to the recognition of the remainder of the deferred revenue related to the research and development services, as well as the license related to the HD program. This was offset by the decrease in the GSK revenue earned year over year primarily related to the AATD program.

The following table summarizes our research and development expenses incurred for the years ended December 31, 2024 and 2023:

Research and development expenses were $159.7 million for the year ended December 31, 2024, compared to $130.0 million for the year ended December 31, 2023. The increase of $29.7 million was due to the following:

General and administrative expenses were $59.0 million for the year ended December 31, 2024, compared to $51.3 million for the year ended December 31, 2023. The increase of $7.7 million is primarily driven by increases in compensation related expenses and administrative expenses.

Other income, net for the years ended December 31, 2024 and 2023 was $13.4 million and $9.8 million, respectively. The increase of $3.6 million in other income, net was primarily driven by an increase in estimated refundable tax credits as well as an increase in dividend income during the year ended December 31, 2024.

During the years ended December 31, 2024 and 2023, we recorded no income tax benefit or provision and an income tax benefit of $0.7 million, respectively. The income tax benefit for the year ended December 31, 2023 was due to a change in estimate in connection with U.S. tax guidance relating to the capitalization of research and development expenditures.

Comparison of the Year Ended December 31, 2023 to the Year Ended December 31, 2022

Revenue for the year ended December 31, 2023 was $113.3 million and was earned under the GSK Collaboration Agreement and the Takeda Collaboration Agreement. Revenue for year ended December 31, 2022 was $3.6 million and was earned primarily under the Takeda Collaboration Agreement, as the GSK Collaboration Agreement became effective in January 2023.

The $109.7 million increase in revenue year over year was driven by the revenue recognized under the new GSK Collaboration Agreement, after it became effective in January 2023, as well as the increase in revenue recognized under the Takeda Collaboration Agreement. The $113.3 million in revenue recognized during the year ended December 31, 2023 was comprised of $66.3 million in revenue recognized under the GSK Collaboration Agreement and $47.0 million of revenue recognized under the Takeda Collaboration Agreement. The $3.6 million in revenue recognized during the year ended December 31, 2022 was primarily related to the research and development services under the Takeda Collaboration Agreement related to the HD, C9, and SCA3 programs. During the year ended December 31, 2023, the Company recognized revenue of $47.0 million under the Takeda Collaboration. The increase in revenue earned year over year related to the Takeda Collaboration is primarily due to the termination of the C9 and SCA3 programs in 2023 which led to the recognition of the remainder of the deferred revenue related to the research and development services, as well as the options related to the C9 and SCA3 programs.

The following table summarizes our research and development expenses incurred for the years ended December 31, 2023 and 2022:

Research and development expenses were $130.0 million for the year ended December 31, 2023, compared to $115.9 million for the year ended December 31, 2022. The increase of $14.1 million was due to the following:

General and administrative expenses were $51.3 million for the year ended December 31, 2023, compared to $50.5 million for the year ended December 31, 2022. The increase of $0.8 million was primarily driven by increases in other general and administrative operating expenses, partially offset by a decrease in compensation-related expenses.

Other income, net for the years ended December 31, 2023 and 2022 was $9.8 million and $1.6 million, respectively. The increase of $8.2 million in other income, net was primarily driven by an increase in dividend income as well as an increase in estimated refundable tax credits during the year ended December 31, 2023.

During the years ended December 31, 2023 and 2022, we recorded an income tax benefit of $0.7 million and an income tax provision of $0.7 million, respectively. The income tax benefit for the year ended December 31, 2023 was due to a change in estimate in connection with recent U.S. tax guidance relating to the capitalization of research and development expenditures. The income tax provision for the year ended December 31, 2022 was primarily due to the requirement under the Tax Cuts and Jobs Act of 2017 for taxpayers to capitalize and amortize research and development expenditures over five or fifteen years pursuant to Section 174 of the Internal Revenue Code of 1986, as amended.

Since our inception, we have not generated any product revenue and have incurred recurring net operating losses. To date, we have primarily funded our operations through public and other registered offerings of our ordinary shares and other securities, collaborations with third parties and private placements of debt and equity securities. Through December 31, 2024, we have received an aggregate of approximately $1,578.4 million in net proceeds from these transactions, consisting of $977.8 million in net proceeds from public and other registered offerings of our ordinary shares and other securities, $511.3 million from our collaborations and $89.3 million in net proceeds from private placements of our debt and equity securities.

In January 2024, the representatives of the underwriters in connection with the previously disclosed underwritten public offering (the “December 2023 Offering”) exercised their option to purchase an additional 3,000,000 ordinary shares at a price of $5.00 per ordinary share as a part of the December 2023 Offering. We received an additional $14.0 million in net proceeds from the December 2023 Offering in January 2024.

On September 27, 2024, we closed the September 2024 Offering in which we issued and sold 23,125,001 of our ordinary shares and the 2024 Pre-Funded Warrants to purchase up to 1,875,023 of our ordinary shares. The gross proceeds to us from the September 2024 Offering were $200.0 million before deducting underwriting discounts and commissions and other offering expenses. On October 1, 2024, the representatives of the underwriters exercised their option in full to purchase an additional 3,750,000 ordinary shares, for additional net proceeds to us of approximately $28.2 million.

As of December 31, 2024, we had cash and cash equivalents of $302.1 million, restricted cash of $3.8 million and an accumulated deficit of $1,121.9 million.

We expect that our existing cash and cash equivalents will be sufficient to fund our operations for at least the next twelve months. We have based this expectation on assumptions that may prove to be incorrect, and we may use our available capital resources sooner than we currently expect. In addition, we may elect to raise additional funds before we need them if the conditions for raising capital are

favorable due to market conditions or strategic considerations, even if we expect we have sufficient funds for our current or future operating plans.

Our operating lease commitments as of December 31, 2024 total $29.1 million, of which $9.6 million is related to payments in 2025 and approximately $19.5 million is related to payments beyond 2025.

On November 12, 2024, we filed a shelf registration statement on Form S-3ASR with the SEC for which we registered for sale an indeterminate amount of any combination of our ordinary shares, debt securities, warrants, rights and/or units from time to time and at prices and on terms that we may determine, which we refer to as the “2024 WKSI Shelf”. Our 2024 WKSI Shelf includes a prospectus covering up to an aggregate of $250.0 million in ordinary shares that we are able to issue and sell from time to time, through Jefferies LLC (“Jefferies”) acting as our sales agent, pursuant to the Open Market Sale Agreement, dated May 10, 2019, as amended by Amendment No. 1, dated as of March 2, 2020, Amendment No. 2, dated as of March 3, 2022, and Amendment No. 3, dated November 12, 2024, (collectively, the “Sales Agreement”), for our “at-the-market” equity program. For the three months ended December 31, 2024, we received $5.2 million in net proceeds from sales under our “at-the-market" equity program.

Adequate additional financing may not be available to us on acceptable terms, or at all. Our inability to raise capital as and when needed would have a negative impact on our financial condition and our ability to pursue our business strategy. We will need to generate significant revenue to achieve profitability, and we may never do so.

The following table summarizes our sources and uses of cash for each of the periods presented:

During 2024, operating activities used $151.0 million of cash, primarily due to our net loss of $97.0 million, partially offset by non-cash charges of $21.8 million and changes in our operating assets and liabilities of $75.8 million. The non-cash charges for 2024 related to share-based compensation expense of $13.1 million, amortization of right-of-use assets of $4.8 million, and depreciation expense of $3.9 million. The largest change in operating assets and liabilities was a $93.6 million decrease in deferred revenue, mainly driven by our Takeda Collaboration Agreement, which was partially offset by the second largest change in operating assets and liabilities, the $19.7 million decrease in accounts receivable primarily due to the collection of receivables related to the GSK Collaboration Agreement.

During 2023, operating activities used $19.4 million of cash, primarily due to our net loss of $57.5 million, partially offset by non-cash charges of $19.0 million and changes in our operating assets and liabilities of $19.1 million. The non-cash charges for 2023 related to share-based compensation expense of $9.8 million, amortization of right-of-use assets of $4.2 million, and depreciation expense of $5.0 million. The largest change in operating assets and liabilities was a $54.3 million increase in deferred revenue, mainly driven by our GSK Collaboration Agreement, which became effective in January 2023, which was partially offset by the second largest change in operating assets and liabilities, the $21.1 million increase in accounts receivable primarily related to the achievement of a milestone under the GSK Collaboration Agreement.

During 2022, operating activities used $127.8 million of cash, primarily due to our net loss of $161.8 million, partially offset by non-cash charges of $27.3 million and changes in our operating assets and liabilities of $6.7 million. The non-cash charges for 2022 related mainly to share-based compensation expense of $17.2 million and depreciation expense of $6.6 million. The largest change in operating assets and liabilities was a $9.3 million increase in accounts payable.

During 2024, investing activities used $0.9 million of cash, primarily consisting of purchases of property and equipment.

During 2023, investing activities used $1.1 million of cash, primarily consisting of purchases of property and equipment.

During 2022, investing activities used $1.3 million of cash, primarily consisting of purchases of property and equipment. Additionally, we purchased $75.0 million of short-term investments during 2022, all of which matured in 2022.

During 2024, net cash provided by financing activities was $253.9 million, which was primarily due to the $215.8 million in net proceeds from the September 2024 Offering of ordinary shares and the 2024 Pre-Funded Warrants; as well as the $14.0 million in net proceeds from the January 2024 exercise of the underwriters’ option to purchase an additional 3,000,000 shares under the December 2023 Offering. Additionally, we received $20.4 million in net proceeds from sales under our “at-the-market” equity program.

During 2023, net cash provided by financing activities was $132.5 million, primarily due to the $93.6 million in net proceeds from the December 2023 Offering, which comprised of sales of ordinary shares, as well as $34.6 million in net proceeds from the GSK Equity Investment. Additionally, there were $3.1 million in net proceeds from our "at-the-market" equity program.

During 2022, net cash provided by financing activities was $67.2 million, primarily due to the $65.5 million in net proceeds from the underwritten offering we completed in June 2022, which was comprised of sales of ordinary shares and the 2022 Pre-Funded Warrants. Additionally, there were $1.1 million in net proceeds from our "at-the-market" equity program.

We expect to continue to incur significant expenses in connection with our ongoing research and development activities and our internal cGMP manufacturing activities. Furthermore, we anticipate that our expenses will continue to vary if and as we:

We may experience delays or encounter issues with any of the above, including but not limited to failed studies, complex results, safety issues or other regulatory challenges.

Because of the numerous risks and uncertainties associated with the development of drug candidates and because the extent to which we may enter into collaborations with third parties for development of product candidates is unknown, we are unable to estimate the amounts of future capital outlays and operating expenses associated with completing the research and development for our therapeutic programs. Our future capital requirements for our therapeutic programs will depend on many factors, including:

Identifying potential product candidates and conducting preclinical testing and clinical trials is a time-consuming, expensive and uncertain process that takes years to complete, and we may never generate the necessary data or results required to obtain marketing approval and achieve product sales. In addition, our product candidates, if approved, may not achieve commercial success. Our product revenue, if any, will be derived from sales of products that we do not expect to be commercially available for many years, if ever. Accordingly, we will need to obtain substantial additional funds to achieve our business objectives.

Adequate additional funds may not be available to us on acceptable terms when we need them, or at all. We do not currently have any committed external source of funds, except for possible future payments from GSK under our collaborations with them. To the extent that we raise additional capital through the sale of equity or convertible debt securities, the ownership interest of our existing shareholders will be diluted, and the terms may include liquidation or other preferences that adversely affect the rights of our shareholders. Additional debt financing and preferred equity financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends and may require the issuance of warrants, which could potentially dilute our shareholders’ ownership interests.

If we raise additional funds through collaborations, strategic alliances or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates or grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings when needed, we may be required to delay, limit, reduce or terminate our product development programs or any future commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.

For detailed information regarding recently issued and adopted accounting pronouncements and the expected impact on our consolidated financial statements, see Note 2 “Significant Accounting Policies” in the notes to the consolidated financial statements appearing elsewhere in this Annual Report on Form 10-K.

Our consolidated financial statements are prepared in accordance with U.S. GAAP. The preparation of our financial statements and related disclosures requires us to make estimates and assumptions that affect the reported amount of assets, liabilities, revenue, costs and expenses and related disclosures. We believe that our revenue recognition policy, particularly (a) assessing the number of performance obligations; (b) determining the transaction price; (c) allocating the transaction price to the performance obligations in the contract; and (d) determining the pattern over which performance obligations are satisfied, including estimates to complete performance obligations, and the assumptions and estimates used in our analysis of contracts with CROs and CMOs to estimate the contract expense, involve a greater degree of judgment, and therefore we consider them to be our critical accounting policies. We evaluate our estimates and assumptions on an ongoing basis. Our actual results may differ from these estimates under different assumptions and conditions.

The Company recognizes revenue in accordance with Accounting Standards Codification (“ASC”) Topic 606, Revenue from Contracts with Customers (“ASC 606”). This standard applies to all contracts with customers, except for contracts that are within the scope of other standards, such as leases, insurance, and financial instruments. Under ASC 606, an entity recognizes revenue when its customer obtains control of promised goods or services, in an amount that reflects the consideration that the entity expects to receive in exchange for those goods or services. To determine revenue recognition for arrangements that an entity determines are within the scope of ASC 606, the entity performs the following five-step analysis: (i) identify the contract(s) with a customer; (ii) identify the performance obligations in the contract; (iii) determine the transaction price; (iv) allocate the transaction price to the performance obligations in the contract; and (v) recognize revenue when (or as) the entity satisfies a performance obligation. The Company only applies the five-step analysis to contracts when it is probable that the entity will collect the consideration to which it is entitled in exchange for the goods or services it transfers to the customer. At contract inception, once the contract is determined to be within the scope of ASC 606, the Company assesses the goods or services promised within each contract, determines those that are performance obligations, and assesses whether each promised good or service is distinct. The Company then recognizes as revenue the amount of the transaction price that is allocated to the respective performance obligation when (or as) the performance obligation is satisfied.

The Company has entered into collaboration agreements for research, development, and commercial services, under which the Company licenses certain rights to its product candidates to third parties. The terms of these arrangements typically include payment to the Company of one or more of the following: non-refundable, upfront license fees; prepayment or reimbursement of certain costs; customer option exercise fees; development, regulatory and commercial milestone payments; and royalties on net sales of licensed products. Any variable consideration is constrained, and therefore, the cumulative revenue associated with this consideration is not recognized until it is deemed not to be at significant risk of reversal.

In determining the appropriate amount of revenue to be recognized as the Company fulfills its obligations under each of its agreements for which the collaboration partner is also a customer, the Company performs the following steps: (i) identification of the promised goods or services in the contract; (ii) determination of whether the promised goods or services are performance obligations, including whether they are distinct in the context of the contract; (iii) measurement of the transaction price, including the constraint on variable consideration; (iv) allocation of the transaction price to the performance obligations; and (v) recognition of revenue when (or as) the Company satisfies each performance obligation. As part of the accounting for these arrangements, the Company must use significant judgment to determine: (a) the number of performance obligations based on the determination under step (ii) above; (b) the transaction price under step (iii) above; and (c) the timing of satisfaction of performance obligations as a measure of progress in step (v) above. The Company uses significant judgment to determine whether milestones or other variable consideration, except for royalties, should be included in the transaction price as described further below. The transaction price is allocated to the optional goods and services the Company expects to provide. The Company uses estimates to determine the timing of satisfaction of performance obligations.

Amounts received prior to being recognized as revenue are recorded as deferred revenue. Amounts expected to be recognized as revenue within the 12 months following the balance sheet date are classified as current portion of deferred revenue in the accompanying consolidated balance sheets. Amounts not expected to be recognized as revenue within the 12 months following the balance sheet date are classified as deferred revenue, net of current portion.

Licenses of intellectual property: In assessing whether a promise or performance obligation is distinct from the other promises, the Company considers factors such as the research, development, manufacturing and commercialization capabilities of the customer and the availability of the associated expertise in the general marketplace. In addition, the Company considers whether the customer can benefit from a promise for its intended purpose without the receipt of the remaining promise, whether the value of the promise is dependent on the unsatisfied promise, whether there are other vendors that could provide the remaining promise, and whether it is separately identifiable from the remaining promise. For licenses that are combined with other promises, the Company utilizes judgment to assess the nature of the combined performance obligation to determine whether the combined performance obligation is satisfied over time or at a point in time and, if over time, the appropriate method of measuring progress for purposes of recognizing revenue. The Company evaluates the measure of progress each reporting period and, if necessary, adjusts the measure of performance and related revenue recognition.

Research and development services: If an arrangement is determined to contain a promise or obligation for the Company to perform research and development services, the Company must determine whether these services are distinct from other promises in the arrangement. In assessing whether the services are distinct from the other promises, the Company considers the capabilities of the customer to perform these same services. In addition, the Company considers whether the customer can benefit from a promise for its intended purpose without the receipt of the remaining promise, whether the value of the promise is dependent on the unsatisfied promise, whether there are other vendors that could provide the remaining promise, and whether it is separately identifiable from the remaining promise. For research and development services that are combined with other promises, the Company utilizes judgment to assess the nature of the combined performance obligation to determine whether the combined performance obligation is satisfied over time or at a point in time and, if over time, the appropriate method of measuring progress for purposes of recognizing revenue. The

Company evaluates the measure of progress each reporting period and, if necessary, adjusts the measure of performance and related revenue recognition.

Customer options: If an arrangement is determined to contain customer options that allow the customer to acquire additional goods or services, the goods and services underlying the customer options are not considered to be performance obligations at the outset of the arrangement, as they are contingent upon option exercise. The Company evaluates the customer options for material rights, that is, the option to acquire additional goods or services for free or at a discount. If the customer options are determined to represent a material right, the material right is recognized as a separate performance obligation at the outset of the arrangement. The Company allocates the transaction price to material rights based on the standalone selling price. Amounts allocated to any material right are not recognized as revenue until the option is exercised and the performance obligation is satisfied.

Milestone payments: At the inception of each arrangement that includes milestone payments, the Company evaluates whether a significant reversal of cumulative revenue provided in conjunction with achieving the milestones is probable, and estimates the amount to be included in the transaction price using the most likely amount method. If it is probable that a significant reversal of cumulative revenue would not occur, the associated milestone value is included in the transaction price. Milestone payments that are not within the control of the Company or the licensee, such as regulatory approvals, are not considered probable of being achieved until those approvals are received. For other milestones, the Company evaluates factors such as the scientific, clinical, regulatory, commercial, and other risks that must be overcome to achieve the particular milestone in making this assessment. There is considerable judgment involved in determining whether it is probable that a significant reversal of cumulative revenue would not occur. At the end of each subsequent reporting period, the Company reevaluates the probability of achievement of all milestones subject to constraint and, if necessary, adjusts its estimate of the overall transaction price. Any such adjustments are recorded on a cumulative catch-up basis, which would affect revenues and earnings in the period of adjustment.

Royalties: For arrangements that include sales-based royalties, including milestone payments based on a level of sales, and the license is deemed to be the predominant item to which the royalties relate, the Company recognizes revenue at the later of (i) when the related sales occur, or (ii) when the performance obligation to which some or all of the royalty has been allocated has been satisfied (or partially satisfied). To date, the Company has not recognized any royalty revenue resulting from any of its licensing arrangements.

Contract costs: The Company recognizes as an asset the incremental costs of obtaining a contract with a customer if the costs are expected to be recovered. As a practical expedient, the Company recognizes the incremental costs of obtaining a contract as an expense when incurred if the amortization period of the asset that it otherwise would have recognized is one year or less. To date, the Company has not incurred any incremental costs of obtaining a contract with a customer.

For additional discussion of accounting for collaboration revenues, see Note 5 of our consolidated financial statements.

As we prepare our consolidated financial statements, we are required to estimate our prepaid and accrued expenses. For certain contracts with our CROs and CMOs, if the billing terms do not align with the pattern in which the work is completed by the CRO or CMO as of the end of the period, we are required to perform an analysis to estimate the expense, for the period and to date for each contract.

Contracts that are subject to this analysis generally relate to the following services: research and development services, manufacturing services, toxicology studies and clinical trial services. Once we have completed our analysis, we will record the estimated expense in the period for each contract and, depending on the invoicing activity related to each contract, we either have a prepayment or accrual as of the end of the period. We base our estimates on communications with internal study managers, our knowledge of the ongoing and past work at the CROs and CMOs, and communications and reporting from our CROs and CMOs, where applicable.

Market risk represents the risk of loss that may impact our financial position due to adverse changes in financial market prices and rates. Our market risk exposure is primarily the result of fluctuations in interest rates and foreign exchange rates as well as, to a lesser extent, inflation and capital market risk.

We are exposed to interest rate risk in the ordinary course of our business. Our cash and cash equivalents are comprised of funds held in checking accounts and money market accounts.

Due to our operations outside of the United States, we are exposed to market risk related to changes in foreign currency exchange rates. Historically, we have not hedged our foreign currency exposure. Changes in the relative values of currencies occur regularly and, in some instances, could materially adversely affect our business, our financial condition, our results of operations or our cash flows. For the years ended December 31, 2024, 2023, and 2022, changes in foreign currency exchange rates did not have a material impact on our historical financial position, our business, our financial condition, our results of operations or our cash flows.

We do not believe that inflation had a material effect on our business, financial condition, results of operations, or cash flows in the last two years. If global inflation trends continue, we expect appreciable increases in clinical trial, labor, and other operating costs.

We currently have no product revenues and depend on funds raised through other sources. One possible source of funding is through further equity offerings. Our ability to raise funds in this manner depends upon capital market forces affecting our share price, including global economic uncertainty on the capital markets.

The information required by this Item 8 is included at the end of this Annual Report on Form 10-K beginning on page F-1.

Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosure

Our management, with the participation of our principal executive officer and principal financial officer, evaluated the effectiveness of our disclosure controls and procedures as of December 31, 2024. The term “disclosure controls and procedures,” as defined in Rules 13a-15(e) and 15d-15(e) under the Exchange Act, means controls and other procedures of a company that are designed to ensure that information required to be disclosed by a company in the reports that it files or submits under the Exchange Act is recorded, processed, summarized and reported, within the time periods specified in the SEC’s rules and forms. Disclosure controls and procedures include, without limitation, controls and procedures designed to ensure that information required to be disclosed by a company in the reports that it files or submits under the Exchange Act is accumulated and communicated to its management, including its principal executive and principal financial officers, as appropriate to allow timely decisions regarding required disclosure. Management recognizes that any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance of achieving their objectives and management necessarily applies its judgment in evaluating the cost-benefit relationship of possible controls and procedures. Based on the evaluation of our disclosure controls and procedures as of December 31, 2024, our principal executive officer and principal financial officer concluded that, as of such date, our disclosure controls and procedures were effective at the reasonable assurance level.

There were no changes in our internal control over financial reporting identified in connection with the evaluation of such internal control required by Rule 13a-15(d) and 15d-15(d) of the Exchange Act that occurred during the fiscal quarter ended December 31, 2024 that have materially affected, or are reasonably likely to materially affect, our internal control over financial reporting.

Our management is responsible for establishing and maintaining adequate internal control over financial reporting. Internal control over financial reporting is defined in Rules 13a-15(f) and 15d-15(f) under the Securities Exchange Act of 1934, as amended, as a process designed by, or under the supervision of, the company’s principal executive and principal financial officers and effected by the company’s Board, management and other personnel to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles and includes those policies and procedures that:

Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.

Our management assessed the effectiveness of our internal control over financial reporting as of December 31, 2024. In making this assessment, management used the criteria set forth by the Committee of Sponsoring Organizations of the Treadway Commission (“COSO”) in Internal Control-Integrated Framework (2013).

Based on our assessment, management believes that, as of December 31, 2024, our internal control over financial reporting is effective based on those criteria.

The effectiveness of our internal control over financial reporting as of December 31, 2024 has been audited by KPMG LLP, an independent registered public accounting firm, as stated in their report.

The issue or transfer of ownership of our ordinary shares would be exempt from GST, although the sale of our ordinary shares by a GST-registered investor may be considered to be a taxable supply subject to GST at 0% if certain conditions are met. Services consisting of arranging, brokering, underwriting or advising on the issue, allotment or transfer of ownership of our ordinary shares rendered by a GST-registered person to an investor belonging in Singapore for GST purposes in connection with the investor’s purchase, sale or holding of our ordinary shares will be subject to GST at the prevailing standard rate of 9%. Similar services rendered by a GST-registered person contractually to an investor belonging outside Singapore and for the direct benefit of an investor belonging outside Singapore or a GST-registered person in Singapore should generally, subject to the satisfaction of certain conditions, be subject to GST at 0%.

During the three months ended December 31, 2024, certain of our officers (as defined in Rule 16a-1(f) of the Exchange Act) entered into contracts, instructions or written plans (each, a “Rule 10b5-1 Trading Plan” and collectively, the “Rule 10b5-1 Trading Plans”) for the purchase or sale of our securities that are intended to satisfy the conditions specified in Rule 10b5-1(c) under the Exchange Act for an affirmative defense against liability for trading in securities on the basis of material nonpublic information. We describe the material terms of these Rule 10b5-1 Trading Plans below.

Information required by this item will be contained in our definitive proxy statement to be filed with the SEC on Schedule 14A in connection with our 2025 Annual General Meeting of Shareholders, (the "Proxy Statement"), if the Proxy Statement is filed not later than 120 days after the end of our fiscal year ended December 31, 2024, in the sections titled “Management and Corporate Governance,” and “Code of Business Conduct and Ethics,” and is incorporated herein by reference. If the Proxy Statement is not filed within such 120-day period, the information required by this item will be contained in an amendment to this Annual Report on Form 10-K to be filed with the SEC (the "Form 10-K/A").

The information required by this item is incorporated by reference to the information set forth in the section titled “Executive Officer and Director Compensation” in our Proxy Statement. The section entitled “Pay Versus Performance” in our Proxy Statement is not incorporated by reference herein. If the Proxy Statement is not filed within 120 days after the end of our fiscal year ended December 31, 2024, the information required by this item will be contained in the Form 10-K/A.

Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters

The information required by this item is incorporated by reference to the information set forth in the sections titled “Security Ownership of Certain Beneficial Owners and Management” and “Equity Compensation Plan Information” in our Proxy Statement. If the Proxy Statement is not filed within 120 days after the end of our fiscal year ended December 31, 2024, the information required by this item will be contained in the Form 10-K/A.

Item 13. Certain Relationships and Related Transactions, and Director Independence

The information required by this item is incorporated by reference to the information set forth in the sections titled “Certain Relationships and Related Person Transactions” and “Management and Corporate Governance – Director Independence” in our Proxy Statement. If the Proxy Statement is not filed within 120 days after the end of our fiscal year ended December 31, 2024, the information required by this item will be contained in the Form 10-K/A.

The information required by this item regarding principal accountant fees and services is incorporated by reference to the information set forth in the sections titled “Principal Accountant Fees and Services” and “Policy on Audit Committee Pre-Approval of Audit and Permissible Non-Audit Services of Independent Public Accounting Firm” in our Proxy Statement. If the Proxy Statement is not filed within 120 days after the end of our fiscal year ended December 31, 2024, the information required by this item will be contained in the Form 10-K/A.

Our independent registered public accounting firm is KPMG LLP, Boston, MA, Auditor Firm ID: 185.

See Index to Consolidated Financial Statements on page 108 of this Annual Report on Form 10-K.

All schedules are omitted because they are not applicable, or the required information is shown in the financial statements or notes thereto.

The following is a list of exhibits filed as part of this Annual Report on Form 10-K.

(*) The certification attached as Exhibit 32 that accompanies this Annual Report on Form 10-K is not deemed filed with the SEC and is not to be incorporated by reference into any filing of Wave Life Sciences Ltd. under the Securities Act of 1933, as amended, or the

Securities Exchange Act of 1934, as amended, whether made before or after the date of this Form 10-K, irrespective of any general incorporation language contained in such filing.

(†) Confidential treatment has been granted with respect to certain portions of this exhibit. Omitted portions have been filed separately with the SEC.

(††) Certain confidential portions of this Exhibit were omitted by means of marking such portions with brackets (“[***]”) because the identified confidential portions (i) are not material and (ii) is the type that the Registrant treats as private or confidential.

Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, as amended, the Registrant has duly caused this Report to be signed on its behalf by the undersigned, thereunto duly authorized.

Each person whose individual signature appears below hereby authorizes and appoints Paul B. Bolno, M.D. with full power of substitution and resubstitution and full power to act, as his or her true and lawful attorney-in-fact and agent to act in his or her name, place and stead and to execute in the name and on behalf of each person, individually and in each capacity stated below, and to file any and all amendments to this Report and to file the same, with all exhibits thereto, and other documents in connection therewith, with the Securities and Exchange Commission, granting unto said attorney-in-fact and agent, full power and authority to do and perform each and every act and thing, ratifying and confirming all that said attorney-in-fact and agent or his substitute or substitutes may lawfully do or cause to be done by virtue thereof.

Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, this Report has been signed below by the following persons on behalf of the Registrant and in the capacities and on the dates indicated.

The Company’s management is responsible for these consolidated financial statements, for maintaining effective internal control over financial reporting, and for its assessment of the effectiveness of internal control over financial reporting, included in the accompanying Management's Annual Report on Internal Controls over Financial Reporting. Our responsibility is to express an opinion on the Company’s consolidated financial statements and an opinion on the Company’s internal control over financial reporting based on our audits. We are a public accounting firm registered with the Public Company Accounting Oversight Board (United States) (PCAOB) and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities and Exchange Commission and the PCAOB.

We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audits to obtain reasonable assurance about whether the consolidated financial statements are free of material misstatement, whether due to error or fraud, and whether effective internal control over financial reporting was maintained in all material respects.

Our audits of the consolidated financial statements included performing procedures to assess the risks of material misstatement of the consolidated financial statements, whether due to error or fraud, and performing procedures that respond to those risks. Such procedures included examining, on a test basis, evidence regarding the amounts and disclosures in the consolidated financial statements. Our audits also included evaluating the accounting principles used and significant estimates made by management, as well as evaluating the overall presentation of the consolidated financial statements. Our audit of internal control over financial reporting included obtaining an understanding of internal control over financial reporting, assessing the risk that a material weakness exists, and testing and evaluating the design and operating effectiveness of internal control based on the assessed risk. Our audits also included performing such other procedures as we considered necessary in the circumstances. We believe that our audits provide a reasonable basis for our opinions.

A company’s internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles. A company’s internal control over financial reporting includes those policies and procedures that (1) pertain to the maintenance of records that, in reasonable detail, accurately and fairly reflect the transactions and dispositions of the assets of the company; (2) provide reasonable assurance that transactions are recorded as necessary to permit preparation of financial statements in accordance with generally accepted accounting principles, and that receipts and expenditures of the company are being made only in accordance with authorizations of management and directors of the company; and (3) provide reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use, or disposition of the company’s assets that could have a material effect on the financial statements.

Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Also, projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.

The critical audit matter communicated below is a matter arising from the current period audit of the consolidated financial statements that was communicated or required to be communicated to the audit committee and that: (1) relates to accounts or disclosures that are material to the consolidated financial statements and (2) involved our especially challenging, subjective, or complex judgments. The communication of a critical audit matter does not alter in any way our opinion on the consolidated financial statements, taken as a whole, and we are not, by communicating the critical audit matter below, providing a separate opinion on the critical audit matter or on the accounts or disclosures to which it relates.

As discussed in Note 5 to the consolidated financial statements, the Company is party to a collaboration agreement with GlaxoSmithKline (GSK) which has two performance obligations, including the promise to provide research and development (R&D) services. The Company recognizes R&D services revenue over time using an input method. This method measures progress based on costs incurred in relation to the R&D activities and the costs expected to be incurred in the future to satisfy each performance obligation. Amounts received by the Company before performance are recorded as deferred revenue. For the year ended December 31, 2024, the Company recognized over-time revenue under the GSK collaboration agreement of $37.0 million. In addition, as of December 31, 2024, a portion of the Company’s current and long-term deferred revenue relates to R&D services.

We identified the evaluation of revenue recognition for certain R&D services as a critical audit matter. Specifically, evaluating the estimate of total costs expected to be incurred in satisfying certain R&D performance obligations required especially challenging auditor judgment. This involved an assessment of the nature of work to be performed and the method for measuring progress.

The following are the primary procedures we performed to address this critical audit matter. For a selection of R&D performance obligations, we read the underlying contract with the customer, evaluated the determination of the method for measuring progress, and tested the Company’s estimate of total contract costs to be incurred by (1) comparing the Company’s initial estimates to actual costs incurred to assess the Company’s ability to estimate accurately, (2) inspecting underlying documentation and third-party evidence and comparing them to management’s assumptions and inputs, (3) inquiring of R&D personnel of the Company to evaluate factors related to the nature of the work to be performed and their impact on the total contract costs to be incurred, including progress to date and the estimate of remaining contract costs, and (4) assessing the Company’s history of estimating costs to be incurred in satisfying R&D performance obligations under similar contracts.

The accompanying notes are an integral part of the consolidated financial statements.

CONSOLIDATED STATEMENTS OF SERIES A PREFERRED SHARES AND SHAREHOLDERS’ EQUITY (DEFICIT)

The accompanying notes are an integral part of the consolidated financial statements.

Going Concern

At each reporting period, the Company evaluates whether there are conditions or events that raise substantial doubt about the Company’s ability to continue as a going concern within one year after the date that the financial statements are issued. The Company is required to make certain additional disclosures if the Company concludes substantial doubt exists and it is not alleviated by the Company’s plans or when the Company’s plans alleviate substantial doubt about the Company’s ability to continue as a going concern. The Company’s evaluation entails analyzing prospective operating budgets and forecasts for expectations of the Company’s cash needs and comparing those needs to the current cash and cash equivalent balance.

Foreign Currency Translation

The functional currency is the U.S. dollar for all of the Company’s entities aside from Wave Japan, which has the Japanese Yen as its functional currency. Assets and liabilities of Wave Japan are translated at period end exchange rates while revenues and expenses of Wave Japan are translated at average exchange rates for the period. Net unrealized gains and losses from foreign currency translation are reflected as other comprehensive income (loss) within the consolidated statements of Series A preferred shares and shareholders’ equity (deficit) and the consolidated statements of operations and comprehensive loss. Gains and losses on foreign currency transactions are included in the consolidated statements of operations and comprehensive loss within other income, net.

Fair Value of Financial Instruments

The Company is required to disclose information on all assets and liabilities reported at fair value that enables an assessment of the inputs used in determining the reported fair values. The fair value hierarchy is a hierarchy of inputs used in measuring fair value that maximizes the use of observable inputs and minimizes the use of unobservable inputs by requiring that the observable inputs be used when available. Observable inputs are inputs that market participants would use in pricing the financial instrument based on market data obtained from sources independent of the Company. Unobservable inputs are inputs that reflect the Company’s assumptions about the inputs that market participants would use in pricing the financial instrument and are developed based on the information available in the circumstances. The fair value hierarchy applies only to the valuation inputs used in determining the reported fair value of the investments and is not a measure of the investment credit quality. The hierarchy defines three levels of valuation inputs:

Level 1—Unadjusted quoted prices in active markets that are accessible at the measurement date of identical, unrestricted assets.

Level 2—Quoted prices for similar assets, or inputs that are observable, either directly or indirectly, for substantially the full term through corroboration with observable market data. Level 2 includes investments valued at quoted prices adjusted for legal or contractual restrictions specific to the security.

Level 3—Pricing inputs are unobservable for the asset, that is, inputs that reflect the reporting entity’s own assumptions about the assumptions market participants would use in pricing the asset. Level 3 includes private investments that are supported by little or no market activity.

Cash, cash equivalents and restricted cash are Level 1 assets which are comprised of funds held in checking and money market accounts. Cash, cash equivalents and restricted cash were recorded at fair value as of December 31, 2024 and 2023, totaling $305.8 million and $204.1 million, respectively. The carrying amounts of accounts payable and accrued expenses approximate their fair values due to their short-term maturities.

Concentration of Credit Risk

Cash, cash equivalents, restricted cash and short-term investments are financial instruments that potentially subject the Company to concentration of credit risk. The Company uses several financial institutions to maintain its cash, cash equivalents, restricted cash and short-term investments, all of which are high quality, accredited financial institutions and, accordingly, such funds are subject to minimal credit risk. The Company has not experienced any losses in such accounts and management believes that the Company is not exposed to significant credit risk due to the financial position of the depository institutions in which those deposits are held. The Company has no financial instruments with off-balance sheet risk of loss.

Restricted Cash

Restricted cash consists primarily of cash placed in separate restricted bank accounts as required under the terms of the Company’s lease agreements for its Cambridge, Massachusetts and Lexington, Massachusetts facilities (refer to Note 8). As of December 31, 2024 and 2023, the Company had $3.8 million and $3.7 million of restricted cash, respectively, of which $2.8 million and $2.7 million related to the Lexington facility, respectively, and $1.0 million related to the Cambridge facility.

Property and Equipment

Property and equipment, which consists primarily of equipment, furniture, software and leasehold improvements, are stated at cost less accumulated depreciation. Depreciation is calculated on a straight-line basis over the following estimated useful lives of the assets:


Equipment, Furniture and Software	3-7 years
Leasehold Improvements	Shorter of asset life or lease term

Depreciation begins at the time the asset is placed in service. Maintenance and repairs are charged to operations as incurred. Upon retirement or sale, the cost of the disposed asset and the related accumulated depreciation are removed from the accounts and any resulting gain or loss is reflected in the consolidated statements of operations and comprehensive loss.

Impairment of Long-Lived Assets

Long-lived assets consist of property and equipment. Long-lived assets are reviewed for impairment whenever events or other changes in circumstances indicate that the carrying amount may not be recoverable. Certain factors may exist or events may occur that indicate that impairment exists including, but not limited to, the following: significant underperformance relative to historical or projected future operating results; significant changes in the manner of use of the underlying assets; and significant adverse industry or market economic trends.

When performing the impairment assessment for long-lived assets, the Company compares the carrying value of such assets to the estimated undiscounted future net cash flows expected from the use of the assets and their eventual disposition. In the event that the carrying value of the assets is determined to be unrecoverable, the Company would estimate the fair value of the assets and record an impairment charge for the excess of the carrying value over the fair value.

Revenue Recognition

The Company has entered into collaboration agreements for research, development, and commercial services, under which the Company licenses certain rights to its product candidates to third parties. The terms of these arrangements typically include payment to the Company of one or more of the following: non-refundable, upfront license fees; reimbursement of certain costs; customer option exercise fees; development, regulatory and commercial milestone payments; and royalties on net sales of licensed products. Any variable consideration is allocated to a performance obligation, and the cumulative revenue associated with this consideration is not recognized until it is deemed not to be at significant risk of reversal.

Research and Development Expenses

Research and development expenses are expensed as incurred. External development costs are recognized based on an evaluation of the progress to completion of specific tasks. Payments for these activities are based on the terms of the individual agreements, which may differ from the pattern of costs incurred, and are reflected in the accompanying consolidated balance sheets as prepaid or accrued expenses.

License Agreements and Patent Costs

Costs associated with licenses of technology and patent costs are expensed as incurred and are generally included in research and development expense in the consolidated statements of operations and comprehensive loss.

Refundable Tax Credits

The Company is eligible for refundable tax credits with tax authorities for certain qualified operating expenses. The Company recognizes refundable tax credits when there is reasonable assurance that the Company will comply with the requirements of the refundable tax credit and that the refundable tax credit will be received. Refundable tax credits are recorded as income and classified in other income, net in the consolidated statements of operations and comprehensive loss.

Net Loss per Share

Basic net loss per share is computed using the weighted-average number of ordinary shares outstanding during the period. The outstanding Pre-Funded Warrants (as defined in Note 6) are included in the weighted-average number of ordinary shares outstanding used in the calculation of basic net loss per share as the exercise price is negligible and the warrants are fully vested and exercisable. Diluted net loss per share is computed using the sum of the weighted-average number of ordinary shares outstanding during the period and, if dilutive, the weighted-average number of potential ordinary shares, including the assumed exercise of share options and the assumed vesting of RSUs (as defined in Note 7). The Company’s Series A preferred shares do not entitle the holders of such shares to participate in dividends and do not contractually require the holders of such shares to participate in losses of the Company.

Share-Based Compensation

The Company measures and recognizes share-based compensation expense, for both employee and director option awards, based on the grant date fair value of the awards. The Company calculates the fair value of awards based on the grant date fair value of the underlying ordinary shares. The Company determines the fair value of share-based awards granted to non-employees as either the fair value of the consideration received or the fair value of the equity instruments issued, whichever is more reliably measurable. Equity instruments issued to non-employees as consideration for goods or services received by the Company have been accounted for based on the fair value of the equity instruments issued. The Company recognizes share-based compensation expense on a straight-line basis over the requisite service period of the awards, which is generally the vesting period. The Company accounts for forfeitures as they occur.

The Company classifies share-based compensation expense in its consolidated statements of operations and comprehensive loss in the same manner in which the award recipient’s compensation costs are classified or in which the award recipient’s service payments are classified.

The fair value of each share option grant was determined using the methods and assumptions discussed below. These inputs are generally subjective and require significant judgment and estimation by management.

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Fair Value of Ordinary Shares The fair value of the ordinary shares underlying the Company’s share-based awards is based on the closing price of the Company’s ordinary shares as reported by the Nasdaq Global Market on the date of grant.

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Expected Term The expected term of share options represents the weighted-average period that the share options are expected to remain outstanding. The Company estimated the expected term using the simplified method, which is an average of the contractual term of the option and the vesting period.

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Expected Volatility Since there was limited historical data for the Company’s ordinary shares and limited company-specific historical volatility through the third quarter of 2021, the Company determined the share price volatility for options granted based on an analysis of the volatility used by a peer group of publicly traded companies. In evaluating similarity, the Company considers factors such as industry, stage of life cycle and size. Beginning in the fourth quarter of 2021, the Company had sufficient historical volatility data for its ordinary shares and as such no longer relies on an analysis of the volatility from a peer group to calculate expected volatility.

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Risk-free Interest Rate The risk-free interest rate is based on the U.S. Treasury yield in effect at the time of the grant for zero-coupon U.S. Treasury notes with remaining terms similar to the expected term of the options.

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Dividend Rate The expected dividend was assumed to be zero as the Company has never paid dividends and has no current plans to do so.

Income Taxes

The Company accounts for income taxes using an asset and liability approach, which requires recognition of deferred tax assets and liabilities for the expected future tax consequences of events that have been recognized in the consolidated financial statements but have not been reflected in taxable income. A valuation allowance is established to reduce deferred tax assets to their estimated realizable value. Therefore, the Company provides a valuation allowance to the extent that it is more likely than not that all or a portion of the deferred tax assets will not be realized in the future.

The Company accounts for uncertainty in income taxes recognized in the financial statements by applying a two-step process to determine the amount of tax benefit to be recognized. First, the tax position must be evaluated to determine the likelihood that it will be sustained upon external examination by the tax authorities. If the tax position is deemed more-likely-than-not to be sustained, the tax position is then assessed to determine the amount of benefit to recognize in the financial statements. The amount of the benefit that may be recognized is the largest amount that has a greater than 50% likelihood of being realized upon ultimate settlement. The provision for income taxes includes the effects of any resulting tax reserves, or unrecognized tax benefits, that are considered appropriate as well as the related net interest and penalties. The Company recognizes interest and penalties related to uncertain tax positions in the income tax provision on the consolidated statements of operations and comprehensive loss.

The Company has certain service arrangements in place between its U.S., Japan, U.K. and Singapore entities, which include transfer pricing assumptions. The determination of the appropriate level of transfer pricing requires judgment based on transfer pricing analyses of comparable companies. The Company monitors the nature of its service arrangements for changes in its operations as well as economic conditions. The Company also periodically reviews the transfer pricing analyses for changes in the composition in the pool of comparable companies as well as the related ongoing results of the comparable companies.

Leases

The Company accounts for leases in accordance with ASC Topic 842, Leases (“ASC 842”). At the inception of an arrangement, the Company determines whether the arrangement is or contains a lease based on the unique facts and circumstances present in the arrangement. Most leases with a term greater than one year are recognized on the balance sheet as right-of-use assets and short-term and long-term lease liabilities, as applicable. The Company typically only includes an initial lease term in its assessment of a lease arrangement. Options to renew a lease are not included in the Company’s assessment unless there is reasonable certainty that the Company will renew the lease. The Company monitors its plans to renew its leases on a quarterly basis.

Certain lease agreements include rental payments that are adjusted periodically for inflation or other variables. In addition to rent, the leases may require the Company to pay additional amounts for taxes, insurance, maintenance, or other expenses, which are generally referred to as non-lease components. Such adjustments to rental payments and variable non-lease components are treated as variable lease payments and recognized in the period in which the obligation for these payments are incurred. Variable lease components and variable non-lease components are not measured as part of the right-of-use asset and lease liability. Only when lease components and their associated non-lease components are fixed are they accounted for as a single lease component and are recognized as part of a right-of-use asset and lease liability. Total contract consideration is allocated to the combined fixed lease and non-lease component. This policy election applies consistently to all asset classes under lease agreements.

Operating lease liabilities and their corresponding right-of-use assets are recorded based on the present value of lease payments over the expected remaining lease term. Certain adjustments to the right-of-use asset may be required for items such as incentives received. The interest rate implicit in lease contracts is typically not readily determinable. As a result, the Company utilizes its incremental borrowing rate, which reflects the fixed rate at which the Company could borrow on a collateralized basis the amount of the lease payments in the same currency, for a similar term, in a similar economic environment.

Recently Issued Accounting Pronouncements

In November 2023, the Financial Accounting Standards Board (the “FASB”) finalized Accounting Standards Update No. 2023-07, Segment Reporting (Topic 280): Improvements to Reportable Segment Disclosures (“ASU 2023-07”). ASU 2023-07 requires enhanced disclosures about reportable segments and the chief operating decision maker. The Company adopted ASU 2023-07 for the Company's fiscal year 2024 annual reporting period and applied it retrospectively. The adoption did not have a material impact on the Company's consolidated financial statements.

In December 2023, the FASB finalized Accounting Standards Update No. 2023-09, Income Taxes (Topic 740): Improvements to Income Tax Disclosures (“ASU 2023-09”). ASU 2023-09 requires a company's annual financial statements to include consistent categories and greater disaggregation of information in the rate reconciliation, and income taxes paid disaggregated by jurisdiction. ASU 2023-09 is effective for the Company’s annual reporting periods beginning after December 15, 2025. Adoption is either with a

development and commercial capabilities. On January 27, 2023, the GSK Collaboration Agreement became effective, and GSK paid Wave an upfront payment of $120.0 million.

Simultaneously with the execution of the GSK Collaboration Agreement, Wave entered into a Share Purchase Agreement (the “SPA”) on December 13, 2022, with Glaxo Group Limited (“GGL”), an affiliate of GSK, pursuant to which Wave agreed to sell 10,683,761 of its ordinary shares to GGL at a purchase price of $4.68 per share (the “GSK Equity Investment”). The GSK Equity Investment closed on January 26, 2023, following the completion of customary closing conditions. The ordinary shares purchased by GGL in the GSK Equity Investment are subject to lock-up and standstill restrictions and carry certain registration rights, customary for transactions of this kind. The Company did not incur any material costs in connection with the issuance of the ordinary shares under the SPA.

The GSK Collaboration Agreement has three components: (1) a discovery collaboration which enables the Company to advance up to three programs leveraging targets informed by GSK’s novel genetic insights (“Wave’s Collaboration Programs”); (2) a discovery collaboration which enables GSK to advance up to eight programs leveraging PRISM and the Company’s oligonucleotide expertise and discovery capabilities (the “Discovery Research Collaboration”); and (3) an exclusive global license for GSK to WVE-006, the Company’s alpha-1 antitrypsin deficiency (“AATD”) program, that uses the Company’s proprietary AIMer technology (the "AATD Collaboration"). The Company will be responsible for preclinical, regulatory, manufacturing, and clinical activities for WVE-006 through the initial Phase 1/2 study, at the Company’s sole cost. Thereafter, GSK will be responsible for advancing WVE-006 through pivotal studies, registration, and global commercialization at GSK’s sole cost.

Under the GSK Collaboration Agreement, each party grants to the other party certain licenses to the collaboration products to enable the other party to perform its obligations and exercise its rights under the GSK Collaboration Agreement, including license grants to enable each party to conduct research, development and commercialization activities pursuant to the terms of the GSK Collaboration Agreement. The parties’ exclusivity obligations to each other are limited on a target-by-target basis with regard to targets in the collaboration. GSK may terminate the GSK Collaboration Agreement for convenience, in its entirety or on a target-by-target basis. Subject to certain exceptions, each party has the right to terminate the GSK Collaboration Agreement on a target-by-target basis if the other party, or a related party, challenges the patentability, enforceability or validity of any patents within the licensed technology that cover any product that is subject to the GSK Collaboration Agreement. In the event of any material breach of the GSK Collaboration Agreement by a party, subject to cure rights, the other party may terminate the GSK Collaboration Agreement in its entirety if the breach relates to all targets or on a target-by-target basis if the breach relates to a specific target. In the event that GSK and its affiliates cease development, manufacturing and commercialization activities with respect to compounds or products subject to the GSK Collaboration Agreement and directed to a particular target, the Company may terminate the GSK Collaboration Agreement with respect to such target. Either party may terminate the GSK Collaboration Agreement for the other party’s insolvency. In certain termination circumstances, the Company would receive a license from GSK to continue researching, developing and manufacturing certain products.

The GSK Collaboration Agreement, unless terminated earlier, will continue until the date on which: (i) with respect to a validation target, the date on which such validation target is not advanced into a collaboration program; or (ii) with respect to a collaboration target, the royalty term has expired for all collaboration products directed to the applicable collaboration target. The GSK Collaboration Agreement includes options to extend the research term for up to three additional years, which would increase the number of programs available to both parties. The Company will lead all preclinical research for GSK and the Company’s collaboration programs up to investigational new drug (“IND”)-enabling studies. The Company will lead IND-enabling studies, clinical development and commercialization for the Company’s collaboration programs. GSK collaboration programs will transfer to GSK for IND-enabling studies, clinical development and commercialization.

The GSK Collaboration Agreement is managed by a joint steering committee in which both parties are represented equally. In addition, the AATD Collaboration is overseen by a joint development committee, a joint patent committee advises on intellectual property activities, and the Discovery Research Collaboration is overseen by a joint research committee. Both parties are represented equally for these committees and report to the joint steering committee.

The Company assessed this arrangement in accordance with ASC 606, Revenue from Contracts with Customers ("ASC 606") and concluded that the contract counterparty, GSK, is a customer for the AATD Collaboration prior to GSK exercising its option and, for the Discovery Research Collaboration programs during the target validation research term. The Company identified the following material promises under the arrangement: (1) the exclusive global license for WVE-006; (2) the research and development services for WVE-006 through the Phase 1/2 study; (3) the discovery research services under the Discovery Research Collaboration to perform target validation programs; (4) research and development license for the Discovery Research Collaboration; and (5) the research and development services for the GSK collaboration programs through completion of a candidate selection. The research and development services for WVE-006 were determined to not be distinct from the exclusive global license and should therefore be combined into a single performance obligation for the AATD Collaboration. The research and development services for the Discovery Research Collaboration were determined to not be distinct from the research and development license for the Discovery Research Collaboration and should therefore be combined into a single performance obligation. In addition, the Company determined the standalone selling price for the option to advance up to eight programs from the Discovery Research Collaboration and determined it did not provide a material right to GSK.

Based on these assessments, the Company identified two performance obligations in the GSK Collaboration Agreement: (1) AATD Collaboration consisting of the research and development services through completion of the Phase 1/2 study and research and development license for WVE-006 and (2) Discovery Research Collaboration which consists of research and development services for validating the targets and license for research and development license for targets.

At the outset of the arrangement, the transaction price included fixed consideration of the $120.0 million upfront, the $15.4 million in premium related to the GSK Equity Investment and the fixed consideration related to the additional target validation research funding. The Company allocated the estimated variable consideration relating to the target validation research to the Discovery Research Collaboration and the variable consideration relating to the development milestone to the AATD Collaboration and then allocated the fixed consideration to the performance obligations on a relative standalone selling price basis. The Company determined that the GSK Collaboration Agreement did not contain a significant financing component. The program initiation fees to advance up to eight programs from the Discovery Research Collaboration to preclinically develop the GSK collaboration programs and the additional potential milestone payments were excluded from the transaction price, as all milestone amounts were fully constrained at the inception of the GSK Collaboration Agreement. The Company will reevaluate the transaction price at the end of each reporting period, and as uncertain events are resolved or other changes in circumstances occur, the Company will adjust its estimate of the transaction price.

Under the GSK Collaboration Agreement, GSK can advance up to eight programs leveraging the Company's PRISM platform and multiple RNA-targeting modalities (RNA editing, splicing, siRNA, and antisense) with target validation work ongoing across multiple therapy areas. GSK selected its first two programs to advance to development candidates following achievement of target validation in the three months ended June 30, 2024. These programs utilize the Company's next generation GalNAc-siRNA format and are in hepatology. Under the GSK Collaboration Agreement, GSK was required to provide an aggregate initiation payment of $12.0 million to the Company for these two oligonucleotide programs, which was received during the three months ended June 30, 2024.

The following table summarizes the allocation of the total transaction price to the identified performance obligation under the GSK Collaboration Agreement, and the amount of the transaction price unsatisfied as of December 31, 2024 (in thousands):


	Transaction Price Allocated		Transaction Price Unsatisfied (1)
Performance Obligations:
AATD Collaboration	$	156,778	$	59,392
Discovery Research Collaboration		18,098		13,737
GSK Collaboration Program		12,000		10,472
Total	$	186,876	$	83,601

(1) The Unsatisfied transaction price will be recognized over the remaining applicable research or program term.

The Company developed the estimated standalone selling price for the global license for WVE-006, under the AATD Collaboration, using a discounted cash flow model. For the performance obligation associated with the research and development services under the Discovery Research Collaboration and the research and development services for WVE-006 under the AATD Collaboration, the Company determined the standalone selling price using estimates of the costs to perform the research and development services, including expected internal and external costs for services and supplies, adjusted to reflect a profit margin. The total estimated cost of the research and development services reflected the nature of the services to be performed and the Company’s best estimate of the length of time required to perform the services.

Revenue associated with the AATD Collaboration performance obligation is being recognized as the research and development services are provided using an input measure, according to the costs incurred and the total costs expected to be incurred to satisfy the performance obligation. The revenue associated with the Discovery Research Collaboration performance obligation is being recognized as the research and development services are provided using an input measure, according to the costs incurred and the total costs expected to be incurred to satisfy the performance obligation. The amounts received that have not yet been recognized as revenue are recorded in deferred revenue on the Company’s consolidated balance sheet. Additional funding related to the Company’s research activities related to Discovery Research Collaboration will be recorded as accounts receivable when contractually enforceable and recorded as deferred revenue, or as revenue as the services are provided.

During the year ended December 31, 2023, the Company achieved a developmental milestone which pertained to the initiation of dosing in healthy volunteers in the RestorAATion clinical trial program, triggering a $20.0 million milestone payment to the Company from GSK. As of December 31, 2023, the $20.0 million related to the achievement of the milestone was included in the current portion of accounts receivable and payment was received from GSK in the first quarter of 2024.

Under the GSK Collaboration Agreement, during the years ended December 31, 2024 and December 31, 2023, the Company recognized revenue of $37.0 million and $66.3 million, respectively, using the input method described above.

The aggregate amount of the transaction price allocated to the Company’s unsatisfied and partially unsatisfied performance obligations which are recorded in deferred revenue as of December 31, 2024 is approximately $72.1 million, of which approximately $66.0 million is included in current liabilities and $6.1 million is included in long-term liabilities. The aggregate amount of the transaction price allocated to the Company’s unsatisfied and partially unsatisfied performance obligations which were recorded in deferred revenue as of December 31, 2023 was approximately $94.3 million, of which approximately $78.7 million was included in current liabilities and $15.6 million was included in long-term liabilities.

Takeda Collaboration and Equity Agreements

In February 2018, Wave USA and Wave UK entered into a global strategic collaboration (the “Takeda Collaboration”) with Takeda Pharmaceutical Company Limited (“Takeda”), pursuant to which Wave USA, Wave UK and Takeda agreed to collaborate on the research, development and commercialization of oligonucleotide therapeutics for disorders of the Central Nervous System (“CNS”). The Takeda Collaboration provided the Company with at least $230.0 million in committed cash and Takeda with the option to co-develop and co-commercialize the Company’s CNS development programs in (1) Huntington’s disease (“HD”); (2) amyotrophic lateral sclerosis (“ALS”) and frontotemporal dementia (“FTD”); and (3) the Company’s discovery-stage program targeting ATXN3 for the treatment of spinocerebellar ataxia 3 (“SCA3”) (collectively, “Category 1 Programs”). In addition, the Takeda Collaboration provided Takeda the right to exclusively license multiple preclinical programs for CNS disorders, including Alzheimer’s disease and Parkinson’s disease (collectively, “Category 2 Programs”). In April 2018, the Takeda Collaboration became effective and Takeda paid the Company $110.0 million as an upfront payment. Takeda also agreed to fund the Company’s research and preclinical activities in the amount of $60.0 million during the four-year research term and to reimburse the Company for any collaboration-budgeted research and preclinical expenses incurred by Wave that exceed that amount.

Simultaneously with Wave USA and Wave UK’s entry into the collaboration and license agreement with Takeda dated February 19, 2018, as amended (the “Takeda Collaboration Agreement”), the Company entered into a share purchase agreement with Takeda (the “Takeda Equity Agreement,” and together with the Takeda Collaboration Agreement, the “Takeda Agreements”) pursuant to which it agreed to sell to Takeda 1,096,892 of its ordinary shares at a purchase price of $54.70 per share. In April 2018, the Company closed the Takeda Equity Agreement and received aggregate cash proceeds of $60.0 million. The Company did not incur any material costs in connection with the issuance of the shares.

With respect to Category 1 Programs, the Company was responsible for researching and developing products and companion diagnostics for Category 1 Programs through completion of the first proof of mechanism study for such products. Takeda had an exclusive option for each target and all associated products and companion diagnostics for such target, which it could exercise at any time through completion of the proof of mechanism study. If Takeda had exercised this option, the Company would have received an opt-in payment and would have led manufacturing and joint clinical co-development activities and Takeda would have led joint co-commercial activities in the United States and all commercial activities outside of the United States. Global costs and potential profits would have been shared 50:50 and the Company would have been eligible to receive development and commercial milestone payments. In addition to its 50% profit share, the Company was eligible to receive option exercise fees and development and commercial milestone payments for each of the Category 1 Programs.

With respect to Category 2 Programs, the Company granted Takeda the right to exclusively license multiple preclinical programs during a four-year research term (subject to limited extension for programs that were initiated prior to the expiration of the research term, in accordance with the Takeda Collaboration Agreement) (“Category 2 Research Term”). During that term, the Takeda Collaboration provided that the parties may collaborate on preclinical programs for up to six targets at any one time. The Company was responsible for researching and preclinically developing products and companion diagnostics directed to the agreed upon targets through completion of Investigational IND enabling studies in the first major market country. Thereafter, Takeda would have an exclusive worldwide license to develop and commercialize products and companion diagnostics directed to such targets, subject to the Company’s retained rights to lead manufacturing activities for products directed to such targets. Takeda agreed to fund the Company’s research and preclinical activities in the amount of $60.0 million during the research term and reimburse the Company for any collaboration-budgeted research and preclinical expenses incurred by the Company that exceeded that amount. The Company was also eligible to receive tiered high single-digit to mid-teen royalties on Takeda’s global commercial sales of products from each Category 2 Program.

Under the Takeda Collaboration Agreement, each party granted to the other party specific intellectual property licenses to enable the other party to perform its obligations and exercise its rights under the Takeda Collaboration Agreement, including license grants to enable each party to conduct research, development and commercialization activities pursuant to the terms of the Takeda Collaboration Agreement.

The term of the Takeda Collaboration Agreement commenced on April 2, 2018 and, unless terminated earlier, would have continued until the date on which: (i) with respect to each Category 1 Program target for which Takeda does not exercise its option, the expiration or termination of the development program with respect to such target; (ii) with respect to each Category 1 Program target for which Takeda exercises its option, the date on which neither party is researching, developing or manufacturing any products or companion diagnostics directed to such target; or (iii) with respect to each Category 2 Program target, the date on which royalties are no longer payable with respect to products directed to such target.

Takeda had the right to terminate the Takeda Collaboration Agreement for convenience on 180 days’ notice, in its entirety or on a target-by-target basis. Subject to certain exceptions, each party had the right to terminate the Takeda Collaboration Agreement on a target-by-target basis if the other party, or a third party related to such party, challenges the patentability, enforceability or validity of any patents within the licensed technology that cover any product or companion diagnostic that was subject to the Takeda Collaboration Agreement. In the event of any material breach of the Takeda Collaboration Agreement by a party, subject to cure rights, the other party had the right to terminate the Takeda Collaboration Agreement in its entirety if the breach related to all targets or on a target-by-target basis if the breach related to a specific target. In the event that Takeda and its affiliates ceased development, manufacturing and commercialization activities with respect to compounds or products subject to the Takeda Collaboration Agreement and directed to a particular target, the Company had the right to terminate the Takeda Collaboration Agreement with respect to such target. Either party had the right to terminate the Takeda Collaboration Agreement for the other party’s insolvency. In certain termination circumstances, the Company would have received a license from Takeda to continue researching, developing and manufacturing certain products, and companion diagnostics.

The Takeda Collaboration was managed by a joint steering committee in which both parties were represented equally. The joint steering committee was tasked with overseeing the scientific progression of each Category 1 Program and, prior to the Amendment (discussed below), the Category 2 Programs.

The Company assessed this arrangement in accordance with ASC 606 and concluded that the contract counterparty, Takeda, is a customer for Category 1 Programs prior to Takeda exercising its option, and for Category 2 Programs during the Category 2 Research Term. The Company identified the following material promises under the arrangement: (1) the non-exclusive, royalty-free research and development license for each Category 1 Program; (2) the research and development services for each Category 1 Program through completion of the first proof of mechanism study; (3) the exclusive option to license, co-develop and co-commercialize each Category 1 Program; (4) the right to exclusively license the Category 2 Programs; and (5) the research and preclinical development services of the Category 2 Programs through completion of IND-enabling studies. The research and development services for each Category 1 Program were determined to not be distinct from the research and development license and should therefore be combined into a single performance obligation for each Category 1 Program. The research and preclinical development services for the Category 2 Programs were determined to not be distinct from the exclusive licenses for the Category 2 Programs and therefore were combined into a single performance obligation.

Additionally, the Company determined that the exclusive option for each Category 1 Program was priced at a discount and, as such, provide material rights to Takeda, representing three separate performance obligations. Based on these assessments, the Company identified seven performance obligations in the Takeda Collaboration Agreement: (1) research and development services through completion of the first proof of mechanism and non-exclusive research and development license for HD; (2) research and development services through completion of the first proof of mechanism and non-exclusive research and development license for ALS and FTD; (3) research and development services through completion of the first proof of mechanism and non-exclusive research and development license for SCA3; (4) the material right provided for the exclusive option to license, co-develop and co-commercialize HD; (5) the material right provided for the exclusive option to license, co-develop and co-commercialize ALS and FTD; (6) the material right provided for the exclusive option to license, co-develop and co-commercialize SCA3; and (7) the research and preclinical development services and right to exclusively license the Category 2 Programs.

At the outset of the arrangement, the transaction price included the $110.0 million upfront consideration received and the $60.0 million of committed research and preclinical funding for the Category 2 Programs. The Company determined that the Takeda Collaboration Agreement did not contain a significant financing component. The option exercise fees to license, co-develop and co-commercialize each Category 1 Program that could have been received were excluded from the transaction price until each customer option was exercised. The potential milestone payments were excluded from the transaction price, as all milestone amounts were fully constrained at the inception of the Takeda Collaboration Agreement. The Company would have reevaluated the transaction price at the end of each reporting period and, as uncertain events were resolved or other changes in circumstances occurred, if necessary, would have adjusted its estimate of the transaction price.

The Company allocated the transaction price to the performance obligations on a relative standalone selling price basis. For the performance obligations associated with the research and development services through completion of the first proof of mechanism and non-exclusive research and development license for HD; the research and development services through completion of the first proof of mechanism and non-exclusive research and development license for ALS and FTD; the research and development services through completion of the first proof of mechanism and non-exclusive research and development license for SCA3; and the research and preclinical development services and right to exclusively license the Category 2 Programs, the Company determined the

standalone selling price using estimates of the costs to perform the research and development services, including expected internal and external costs for services and supplies, adjusted to reflect a profit margin. The total estimated cost of the research and development services reflected the nature of the services to be performed and the Company’s best estimate of the length of time required to perform the services. For the performance obligations associated with the material right provided for the exclusive option to license, co-develop and co-commercialize HD; the material right provided for the exclusive option to license, co-develop and co-commercialize ALS and FTD; and the material right provided for the exclusive option to license, co-develop and co-commercialize SCA3, the Company estimated the standalone fair value of the option to license each Category 1 Program utilizing an adjusted market assessment approach, and determined that any standalone fair value in excess of the amounts to be paid by Takeda associated with each option represented a material right.

Revenue associated with the research and development services for each Category 1 Program performance obligation were recognized as the research and development services were provided using an input method, according to the costs incurred on each Category 1 Program and the total costs expected to be incurred to satisfy each Category 1 Program performance obligation. Prior to the Amendment described below, revenue associated with the research and preclinical development services for the Category 2 Programs performance obligation was recognized as the research and preclinical development services that were provided using an input method, according to the costs incurred on Category 2 Programs and the total costs expected to be incurred to satisfy the performance obligation. The amount allocated to the material right for each Category 1 Program option would have been recognized on the date that Takeda exercised each respective option, or immediately as each option expired unexercised. The amounts received that were not yet recognized as revenue were recorded in deferred revenue on the Company’s consolidated balance sheet.

On October 15, 2021, Wave USA, Wave UK and Takeda entered into the Second Amendment to the Takeda Collaboration Agreement (the “Amendment”), which discontinued the Category 2 component of the Takeda Collaboration. The Category 1 Programs under the Collaboration Agreement remain in effect and are unchanged by the Amendment. Pursuant to the Amendment, Takeda agreed to pay the Company an additional $22.5 million as full payment for reimbursable Category 2 Programs collaboration-budgeted research and preclinical expenses. The Company received this payment from Takeda related to the Category 2 component and recognized the full amount as collaboration revenue in the year ended December 31, 2021. During the year ended December 31, 2021, in addition to the revenue recognized related to the Amendment, the Company recognized another $18.5 million of collaboration revenue related to services pertaining to the Category 1 Programs and Category 2 Programs.

In May 2023, the Company announced its decision to discontinue clinical development of WVE-004 for C9orf72-associated ALS and FTD (“C9 for ALS/FTD”), one of the Category 1 Programs. In July 2023, the joint steering committee that manages the Takeda Collaboration terminated C9 for ALS/FTD as a target under the collaboration (the “C9 Target”) and consequently Takeda and the Company’s rights and obligations under the Takeda Collaboration were terminated with respect to the C9 Target. As a result of the termination of the C9 for ALS/FTD Category 1 Program, the Company recognized $28.0 million in revenue during the three months ended September 30, 2023, which represented the remainder of the deferred revenue for the C9 for ALS/FTD Category 1 Program as of June 30, 2023.

In the third quarter of 2023, the Company achieved a developmental milestone related to the HD Category 1 Program, which pertained to the positive results from a non-clinical study of WVE-003 in non-human primates (“NHPs”). As a result of achieving the milestone, the Company recognized $7.0 million in revenue, which was not previously recorded in deferred revenue, as it was fully constrained at the inception of the Takeda Collaboration.

In December 2023, the joint steering committee that manages the Takeda Collaboration terminated the SCA3 Category 1 Program as a target under the collaboration and consequently Takeda and the Company’s rights and obligations under the Takeda Collaboration were terminated with respect to the SCA3 Category 1 Program. As a result of the termination of the SCA3 Category 1 Program, the Company recognized $9.9 million in revenue during the three months ended December 31, 2023, which represented the remainder of the deferred revenue for the SCA3 Category 1 Program as of September 30, 2023.

In October 2024, the Company was notified by Takeda that Takeda did not intend to exercise and therefore elected to terminate its option (“Option Termination”) for the HD target under the Takeda Collaboration Agreement. As HD was the last active collaboration target under the Takeda Collaboration Agreement, the Takeda Collaboration Agreement expired with immediate effect, and $70.2 million that was previously recorded as deferred revenue was recognized as revenue in the fourth quarter of 2024 related to this expiration.

6. SHARE CAPITAL

The following represents the Company’s financing transactions during the years ended December 31, 2024, 2023, and 2022:

•

The Company entered into the Sales Agreement (as defined below) with Jefferies LLC ("Jefferies". During the years ended December 31, 2024, 2023, and 2022, the Company sold 2,952,591, 751,688, and 458,092 ordinary shares, respectively, under its "at-the-market" equity program for aggregate net proceeds of $20.4 million, $3.1 million, and $1.2 million, respectively, after deducting commissions and offering expenses.

•

On June 16, 2022, the Company closed an underwritten offering (the “June 2022 Offering”) in which the Company issued and sold 25,464,483 of the Company’s ordinary shares at a price of $2.15 per share and pre-funded warrants (the “2022 Pre-Funded Warrants”) to purchase up to 7,093,656 of the Company’s ordinary shares at an offering price of $2.1499 per 2022 Pre-Funded Warrant, which represents the per share offering price for the ordinary shares less the $0.0001 per share exercise price for each 2022 Pre-Funded Warrant. These 2022 Pre-Funded Warrants were recorded as a component of shareholders’ equity within additional paid-in capital. The gross proceeds to the Company from the June 2022 Offering were $70.0 million before deducting underwriting discounts and commissions and other offering expenses. The net proceeds to the Company from the June 2022 Offering were approximately $65.5 million, after deducting underwriting commissions and offering expenses. The 2022 Pre-Funded Warrants are exercisable at any time after their original issuance and on or prior to the five-year anniversary of the original issuance date. A holder of 2022 Pre-Funded Warrants may not exercise the warrant if the holder, together with its affiliates, would beneficially own more than 19.99% of the number of the Company’s ordinary shares outstanding or more than 19.99% of the combined voting power of the Company’s securities outstanding immediately after giving effect to such exercise, unless and until shareholder approval is obtained.

•

On December 11, 2023, the Company closed an underwritten public offering (the “December 2023 Offering”) in which the Company issued and sold 20,000,000 of the Company's ordinary shares at a price of $5.00 per share. The gross proceeds to the Company from the December 2023 Offering were $100.0 million before deducting underwriting discounts and commissions and other offering expenses. The net proceeds to the Company from the December 2023 Offering during the year ended December 31, 2023, were approximately $93.6 million, after deducting underwriting discounts and offering expenses. On January 4, 2024, the Company closed on the sale of an additional 3,000,000 ordinary shares at a price of $5.00 per share after the underwriters exercised their option to purchase the additional shares in full, which increased the aggregate number of ordinary shares sold in the December 2023 Offering to 23,000,000. The Company’s aggregate gross proceeds from the December 2023 Offering were $115.0 million, before deducting underwriting discounts and commissions and offering expenses; $15.0 million of which relates to the exercise of the underwriters’ option in January 2024. Subsequent to December 31, 2023, the Company received $14.0 million in net proceeds after deducting the underwriting discounts and commissions and offering expenses related to the December 2023 Offering.

•

On September 27, 2024, the Company closed an underwritten public offering (the "September 2024 Offering") in which the Company issued and sold 23,125,001 of the Company’s ordinary shares at a price of $8.00 per share and pre-funded warrants (the “2024 Pre-Funded Warrants”) to purchase up to 1,875,023 of the Company’s ordinary shares at an offering price of $7.9999 per 2024 Pre-Funded Warrant, which represents the per share offering price for the ordinary shares less the $0.0001 per share exercise price for each 2024 Pre-Funded Warrant. These 2024 Pre-Funded Warrants were recorded as a component of shareholders’ equity within additional paid-in capital. The gross proceeds to the Company from the September 2024 Offering were $200.0 million before deducting underwriting discounts and commissions and other offering expenses. The net proceeds to the Company from the September 2024 Offering were approximately $187.5 million, after deducting underwriting commissions and offering expenses. The 2024 Pre-Funded Warrants are exercisable at any time after their original issuance and on or prior to the five-year anniversary of the original issuance date. A holder of the 2024 Pre-Funded Warrants may not exercise the warrant if the holder, together with its affiliates, would beneficially own more than 4.99% (or at the election of such holder, 9.99% or 19.99%) of the number of the Company’s ordinary shares outstanding or more than 4.99% (or at the election of such holder, 9.99% or 19.99%) of the combined voting power of the Company’s securities outstanding immediately after giving effect to such exercise, unless and until shareholder approval is obtained.

Options and RSUs

Share option activity is summarized as follows:


	Number of Shares			Weighted- Average Exercise Price		Weighted- Average Remaining Contractual Term (in years)		Aggregate Intrinsic Value (in thousands)(1)
Outstanding as of January 1, 2024		14,107,710		$	6.58
Granted		7,480,600			4.36
Exercised		(770,636	)		3.87
Forfeited or cancelled		(1,364,543	)		7.32
Outstanding as of December 31, 2024		19,453,131		$	5.78		7.11	$	144,819
Options exercisable as of December 31, 2024		9,155,502		$	7.34		5.44	$	62,214

(1)

The aggregate intrinsic value of options is calculated as the difference between the exercise price of the share options and the fair value of the Company’s ordinary shares for those share options that had exercise prices lower than the fair value of the ordinary shares as of the end of the period.

Options generally vest over periods of one to four years, and options that are forfeited or cancelled are available to be granted again. The contractual life of options is generally five or ten years from the grant date.

The assumptions used in the Black-Scholes option pricing model to determine the fair value of share options granted to employees during the period were as follows:


	For the Year Ended December 31,
	2024	2023	2022
Risk-free interest rate	3.56% – 4.64%	3.46% – 4.71%	1.35% – 4.23%
Expected term (in years)	3.0 – 6.1	3.0 – 6.1	3.0 – 6.1
Expected volatility	88% – 100%	87% – 93%	63% – 96%
Expected dividend yield	0%	0%	0%

In October 2022, the compensation committee of the Company’s board of directors (the "Compensation Committee") granted Dr. Verdine, one of the Company’s founders and a member of the Company’s board of directors, a non-qualified share option for 163,467 ordinary shares (“Verdine Scientific Advisory Grant”) as form of payment under Dr. Verdine’s consulting agreement for scientific advisory services (as described in Note 13) for the service period of October 1, 2022 through December 31, 2024, the vesting of which is subject to Dr. Verdine’s continued service under the consulting agreement.

The Verdine Scientific Advisory Grant was granted as a non-employee grant during the year ended December 31, 2022, and there were no equity grants made to non-employees during the years ended December 31, 2023 and 2024. The assumptions used in the Black-Scholes option pricing model to determine the fair value of the Verdine Scientific Advisory Grant were as follows:


		Year Ended December 31, 2022
Risk-free interest rate		4.29%
Expected term (in years)		2.5
Expected volatility		99%
Expected dividend yield		0%

RSU activity for the year ended December 31, 2024 is summarized as follows:


	RSUs			Average Grant Date Fair Value (in dollars per share)
Outstanding as of January 1, 2024		637,557		$	7.08
Granted		379,100			7.04
Vested		(100,326	)		4.90
Forfeited		(84,288	)		5.01
RSUs Outstanding at December 31, 2024		832,043		$	7.54

RSUs can be time-based or performance-based. Vesting of the performance-based RSUs is contingent on the occurrence of certain regulatory or commercial milestones. In March 2021, the Compensation Committee approved an amendment and restatement of the Company’s outstanding 2019 performance-based RSUs to add an additional milestone to the existing milestones. In 2021, the Company also granted performance-based RSUs with the same terms to certain employees who did not receive the 2019 performance-based RSUs. The Company did not recognize expense in 2024 related to the performance-based RSUs as the remaining milestones were not considered probable of achievement. In April 2022, the Company determined that a performance-based RSU milestone was achieved and consequently 50% of the outstanding performance-based RSUs vested, which resulted in the issuance of 384,646 ordinary shares. During the year ended December 31, 2022, the Company recorded share-based compensation expense of approximately $3.8 million related to the performance-based RSUs, which represents all of the expense related to the achievement of this performance-based RSU milestone. During the years ended December 31, 2024, 2023, and 2022, the Company recognized share-based compensation expense of $0.8 million, $1.0 million, and $10.3 million, respectively, related to RSUs.

RSUs that are forfeited are available to be granted again. During the year ended December 31, 2024, 379,100 time-based RSUs were granted to employees. Of the RSUs outstanding at December 31, 2024, 540,779 are time-based RSUs and 291,264 are performance-based RSUs. Time-based RSUs generally vest over periods of one to four years.

During the years ended December 31, 2024, 2023, and 2022, the Company recognized share-based compensation expense related to options of $11.9 million, $8.5 million, and $6.7 million, respectively. The total intrinsic value of options exercised was $4.4 million, $0.3 million, and $0.4 million for the years ended December 31, 2024, 2023, and 2022, respectively. As of December 31, 2024, the unrecognized compensation cost related to outstanding options was $28.9 million. The unrecognized compensation cost related to outstanding options is expected to be recognized over a weighted-average period of approximately 2.67 years. For the years ended December 31, 2024 and 2023, the weighted-average grant date fair value per granted option was $3.38 and $3.45, respectively. The aggregate fair value of options that vested during the years ended December 31, 2024 and 2023 was $11.4 million and $8.4 million, respectively.

The unrecognized compensation costs related to outstanding time-based RSUs was $2.8 million as of December 31, 2024, and is expected to be recognized over a weighted-average period of approximately 2.25 years. The total fair value of RSUs vested during the years ended December 31, 2024, and 2023 was $0.7 million and $2.0 million, respectively.

Employee Share Purchase Plan

The Wave Life Sciences Ltd. Employee Share Purchase Plan, as amended ("ESPP"), allows full-time and certain part-time employees to purchase the Company’s ordinary shares at a discount to fair market value. Eligible employees may enroll in a six-month offering period beginning every January 15th and July 15th. Shares are purchased at a price equal to 85% of the lower of the fair market value of the Company’s ordinary shares on the first business day or the last business day of an offering period. During the years ended December 31, 2024, and 2023, 176,498 and 225,913 ordinary shares were issued under the ESPP, respectively. The aggregate number of ordinary shares authorized for issuance under the ESPP was originally 1,000,000 and was subsequently increased to 3,000,000 in August 2023. As of December 31, 2024, there were 2,314,002 ordinary shares available for issuance under the ESPP.

The following table contains a summary of the lease costs recognized under ASC 842 and other information pertaining to the Company’s operating leases for the years ended December 31, 2024 and 2023:


	For the Year Ended December 31,
	2024			2023			2022
	(in thousands)
Lease cost
Operating lease cost	$	7,365		$	7,365		$	6,458
Variable lease cost		2,998			2,798			2,508
Total lease cost	$	10,363		$	10,163		$	8,966

Other information
Operating cash flows used for operating leases	$	9,311		$	8,655		$	7,226
Increase in operating right-of-use assets	$	—		$	—		$	12,006
Operating lease liabilities arising from obtaining right-of-use assets	$	—		$	—		$	12,006
Weighted average remaining lease term	3 years			4 years			5 years
Weighted average discount rate		9.2	%		9.2	%		9.2	%

Future minimum lease payments under the Company’s non-cancelable operating leases as of December 31, 2024, are as follows:


	As of December 31, 2024
	(in thousands)
2025		9,591
2026		9,584
2027		8,987
2028		886
2029 and thereafter		-
Total lease payments	$	29,048
Less: imputed interest		(3,644	)
Total operating lease liabilities	$	25,404

10. NET LOSS PER ORDINARY SHARE

In connection with the September 2024 Offering, the Company sold 1,875,023 2024 Pre-Funded Warrants, which are included in the total vested and exercisable pre-funded warrants (the 2022 Pre-Funded Warrants and the 2024 Pre-Funded Warrants are referred to together as the “Pre-Funded Warrants”). As of December 31, 2024 and 2023, there were 8,968,679 and 7,093,656, respectively, vested and exercisable Pre-Funded Warrants outstanding to purchase ordinary shares for the exercise price of $0.0001 per share, provided that, unless and until the Company obtains shareholder approval for the issuance of the shares underlying the Pre-Funded Warrants, a holder will not be entitled to exercise any portion of any Pre-Funded Warrant, which, upon giving effect to such exercise, would cause (i) the aggregate number of our ordinary shares beneficially owned by the holder (together with its affiliates) to exceed, depending on the terms of the applicable Pre-Funded Warrants and in certain cases at the election of the holder, either 4.99%, 9.99% or 19.99% of the number of our ordinary shares outstanding immediately after giving effect to the exercise, or (ii) the combined voting power of our securities beneficially owned by the holder (together with its affiliates) to exceed, depending on the terms of the applicable Pre-Funded Warrants and in certain cases at the election of the holder, either 4.99%, 9.99% or 19.99% of the combined voting power of all of our securities then outstanding immediately after giving effect to the exercise, as such percentage ownership is determined in accordance with the terms of the applicable Pre-Funded Warrants. The Pre-Funded Warrants are included in the weighted-average shares outstanding used in the calculation of basic net loss per share as the exercise price is negligible and the warrants are fully vested and exercisable.

Basic loss per share is computed by dividing net loss attributable to ordinary shareholders by the weighted-average number of ordinary shares outstanding.

The Company’s potentially dilutive shares, which include outstanding share options to purchase ordinary shares and RSUs, are considered to be ordinary share equivalents and are only included in the calculation of diluted net loss per share when their effect is dilutive.

The table below sets forth the computation of the Company’s basic and diluted net loss attributable to ordinary shareholders:


	Year Ended December 31,
	2024			2023			2022
	(in thousands except share and per share data)
Numerator:
Net loss attributable to ordinary shareholders	$	(97,008	)	$	(57,513	)	$	(161,823	)
Denominator:
Weighted-average ordinary shares outstanding		138,277,468			106,097,268			78,855,810
Net loss per share, basic and diluted	$	(0.70	)	$	(0.54	)	$	(2.05	)

The following potential ordinary shares, presented based on amounts outstanding at each period end, were excluded from the calculation of diluted net loss per share attributable to ordinary shareholders for the periods indicated because including them would have had an anti-dilutive effect:


	As of December 31,
	2024		2023		2022
Options to purchase ordinary shares		19,453,131		14,107,710		9,682,054
RSUs		832,043		637,557		934,342

under the Tax Cuts and Jobs Act of 2017 for taxpayers to capitalize and amortize research and development expenditures over five or fifteen years pursuant to Section 174 of the Internal Revenue Code of 1986, as amended (the “Code”).

The components of the benefit (provision) for income taxes were as follows:


	Year Ended December 31,
	2024		2023		2022
	(in thousands)
Current benefit (provision) for income taxes:
Singapore	$	—	$	—	$	—
Rest of world		—		677		(681	)
Total current benefit (provision) for income taxes	$	—	$	677	$	(681	)
Deferred benefit for income taxes:
Singapore	$	—	$	—	$	—
Rest of world		—		—		—
Total deferred benefit (provision) for income taxes	$	—	$	—	$	—
Total benefit (provision) for income taxes	$	—	$	677	$	(681	)

A reconciliation of the Singapore statutory income tax rate to the Company’s effective income tax rate is as follows:


	Year Ended December 31,
	2024			2023			2022
Singapore statutory income tax rate		17.0	%		17.0	%		17.0	%
Federal and state tax credits		9.8			11.5			3.3
Permanent differences		(3.1	)		—			0.1
Changes in reserves for uncertain tax positions		(6.0	)		(2.8	)		0.4
Foreign rate differential		7.2			7.4			8.8
Tax rate change		(2.2	)		0.4			—
Return to provision		0.9			4.4			(0.9	)
Other		(0.4	)		0.1			(0.1	)
Change in deferred tax asset valuation allowance		(26.0	)		(36.1	)		7.3
Deferred tax adjustments		2.8			(0.7	)		(36.3	)
Effective income tax rate		0.0	%		1.2	%		(0.4	)%

The components of the Company’s deferred tax assets and liabilities as of December 31, 2024 and 2023 are as follows:


	December 31,
	2024			2023
	(in thousands)
Deferred tax assets:
Net operating loss carryforwards	$	177,639		$	172,547
Federal and state tax credits		15,800			8,155
Share-based compensation		8,649			7,512
Accumulated amortization		578			694
Operating lease liabilities		6,626			8,775
Deferred revenue		8,836			10,716
Capitalized research and development		54,035			41,239
Accumulated depreciation		3,873			3,508
Other		942			237
Total deferred tax assets		276,978			253,383
Valuation allowance		(272,313	)		(247,193	)
Net deferred tax assets		4,665			6,190
Deferred tax liabilities:
Operating lease right-of-use assets		(4,661	)		(6,185	)
Other		(4	)		(5	)
Total deferred tax liabilities		(4,665	)		(6,190	)
Net deferred tax assets (liabilities)	$	—		$	—

A roll-forward of the valuation allowance for the years ended December 31, 2024 and 2023 is as follows:


	Year Ended December 31,
	2024			2023
	(in thousands)
Balance at beginning of year	$	247,193		$	226,273
Increase in valuation allowance		25,169			20,969
Effect of foreign currency translation		(49	)		(49	)
Balance at end of year	$	272,313		$	247,193

As of December 31, 2024, the Company had federal net operating loss carryforwards in the United States of $313.7 million, of which $312.9 million may be available to offset future U.S. federal taxable income indefinitely, while $0.8 million of carryforwards may offset future U.S. federal taxable income through 2037. As of December 31, 2024, the Company had U.S. state net operating loss carryforwards of $64.9 million available to offset future U.S. state taxable income that will begin to expire in 2038. As of December 31, 2024 and 2023, the Company had U.S. federal research and development tax credit carryforwards of approximately $11.2 million and $6.1 million, respectively, available to offset future U.S. federal income taxes and will begin to expire in 2042. As of December 31, 2024 and 2023, the Company had U.S. state research and development tax credit carryforwards of approximately $4.8 million and $2.6 million, respectively, available to offset future U.S. state income taxes and will begin to expire in 2037. As of December 31, 2024, the Company had a U.S. orphan drug credit carryforward of $0.8 million available to offset future U.S. federal income taxes that will begin to expire in 2042.

As of December 31, 2024 and 2023, the Company had net operating loss carryforwards in Japan of $0.7 million and $1.4 million, respectively, which may be available to offset future Japan taxable income and begin to expire in 2025.

As of December 31, 2024 and 2023, the Company had net operating loss carryforwards in Singapore of $132.7 million and $122.0 million, respectively, which may be available to offset future Singapore taxable income and can be carried forward indefinitely.

As of December 31, 2024 and 2023, the Company had net operating loss carryforwards in the United Kingdom (“UK”) of $339.5 million and $335.7 million, respectively, which may be available to offset future UK taxable income and can be carried forward indefinitely.

The Company has evaluated the positive and negative evidence bearing upon its ability to realize its deferred tax assets. As of December 31, 2024, management has considered the Company’s history of cumulative net losses incurred since inception and its lack of commercialization of any products or generation of any revenue from product sales since inception and has concluded that it is more likely than not that the Company will not realize the benefits of the deferred tax assets in all jurisdictions. Accordingly, a full valuation allowance has been established against the Company's deferred tax assets as of December 31, 2024.

The valuation allowance increased by $25.1 million in 2024. The increase in the valuation allowance for 2024 was primarily a result of operating losses generated with no corresponding financial statement benefit. The Company may release this valuation allowance when management determines that it is more-likely-than-not that the deferred tax assets will be realized. Any release of valuation allowance will be recorded as a tax benefit either increasing net income or decreasing net loss.

The Company’s reserves related to income taxes and its accounting for uncertain tax positions are based on a determination of whether and how much of a tax benefit taken by the Company in its tax filings or positions is more-likely-than-not to be realized following resolution of any potential contingencies present related to the tax benefit.

A summary of activity in the Company’s gross unrecognized tax benefits, excluding interest and penalties, is as follows:


	2024		2023		2022
	(in thousands)
Unrecognized tax benefit at the beginning of the year	$	15,790	$	13,945	$	19,864
Tax positions related to prior years		2,091		114		(7,320	)
Tax positions related to the current year		2,917		1,731		1,401
Unrecognized tax benefit at the end of the year	$	20,798	$	15,790	$	13,945

As of December 31, 2024 and 2023, the total amount of gross unrecognized tax benefits, which excludes interest and penalties, was $20.8 million and $15.8 million, respectively. At December 31, 2024, none of the net unrecognized tax benefits would affect the Company’s effective tax rate due to the Company's full valuation allowance.

The Company anticipates that $2.6 million of the total unrecognized tax benefits at December 31, 2024 will decrease within the next twelve months due to certain tax return filings.

14. SEGMENT INFORMATION

Operating segments are defined as components of an entity for which separate financial information is available and that is regularly reviewed by the CODM in deciding how to allocate resources to an individual segment and in assessing performance. The Company operates as a single reporting segment, focused on developing its proprietary RNA medicines platform, PRISM, to develop and commercialize a broad pipeline of RNA medicines in a variety of therapeutic areas. Consistent with our operational structure, our CEO, as the CODM, manages and allocates resources on a consolidated basis at the global corporate level. The results of our operations are reported on a consolidated basis for purposes of segment reporting. The CEO uses consolidated net loss that is reported on the consolidated statements of operations and comprehensive loss for the purposes of assessing performance, allocating resources and planning, monitoring budget versus actual results, and forecasting future periods.

The following table is representative of the significant expense categories regularly provided to the CODM when managing the Company's single reporting segment. A reconciliation to consolidated operating expenses as our single segment operating loss for the years ended December 31, 2024, 2023, and 2022 is included in the table below:


	For the Year Ended December 31,
	2024		2023		2022
	(in thousands)
Research and development expenses:
AATD program	$	11,666	$	8,453	$	3,763
DMD programs		15,536		7,808		2,610
HD programs		11,790		13,086		7,952
Other research and development expenses(1), including INHBE, RNA editing, PRISM, others		119,976		91,617		89,992
ALS and FTD programs (discontinued)		714		9,045		11,539
Total research and development expenses		159,682		130,009		115,856
General and administrative expenses		59,023		51,292		50,513
Total operating expenses	$	218,705	$	181,301	$	166,369

(1) Includes expenses related to other research and development programs, identification of potential drug discovery candidates, compensation-related expenses, internal manufacturing expenses, equipment repairs and maintenance expense, facility-related expenses, and other operating expenses, which are not allocated to specific programs.


新加坡	98-1356880
（成立或組織的州或其他司法管轄區）	（國稅局僱主識別號）

7海峽景觀#12-00, Marina One 東塔新加坡	018936
（主要行政辦公室地址）	(Zip代碼）


每個班級的標題	交易符號	註冊的每個交易所的名稱
0美元面值普通股	WVE	納斯達克全球市場


第一部分
項目1.	業務	6
項目1A.	危險因素	51
項目10億。	未解決的員工評論	88
項目1C.	網絡安全	88
項目2.	性能	89
項目3.	法律訴訟	89
項目4.	礦山安全披露	89

第二部分
項目5.	註冊人普通股市場、相關股東事項和發行人購買股票證券	90
項目6.	[預留]	90
項目7.	管理層對財務狀況和經營成果的討論和分析	91
項目7A.	市場風險的定量和定性披露	104
項目8.	財務報表和補充數據	104
項目9.	會計和財務披露方面的變化和與會計師的分歧	104
項目9A.	控制和程序	104
項目90億。	其他信息	105
項目9 C.	有關阻止檢查的外國司法管轄區的披露	106

第三部分
項目10.	董事、執行官和公司治理	107
項目11.	高管薪酬	107
項目12.	某些受益所有人和管理層的證券所有權以及相關股東事宜	107
項目13.	某些關係和關聯交易以及董事獨立性	107
項目14.	首席會計師費用和服務	107

第四部分
項目15.	展品和財務報表 Sched勒	108
項目16.	表格10-k摘要	112
簽名		113


	For the Year Ended December 31,
	2024			2023			2022
	(in thousands)
Net cash used in operating activities	$	(151,026	)	$	(19,431	)	$	(127,781	)
Net cash used in investing activities		(938	)		(1,115	)		(1,255	)
Net cash provided by financing activities		253,890			132,534			67,188
Effect of foreign exchange rates on cash		(138	)		(95	)		(210	)
Net increase (decrease) in cash, cash equivalents and restricted cash	$	101,788		$	111,893		$	(62,058	)


Exhibit Number	Exhibit Description	Filed with this Report	Incorporated by Reference herein from Form or Schedule	Filing Date	SEC File/Reg. Number

3.1	Constitution (formerly known as Memorandum of Association and Articles of Association)		Amendment No. 5 to Form S-1 (Exhibit 3.2)	11/10/2015	333-207379

4.1	Form of Specimen Ordinary Share Certificate		Amendment No. 3 to Form S-1 (Exhibit 4.1)	11/06/2015	333-207379
4.2	Description of Securities of the Registrant and Comparison of Shareholder Rights	X

4.3.1	Form of Pre-Funded Warrant (2022)		Form 8-K (Exhibit 4.1)	06/14/2022	001-37627

4.3.2	Form of Pre-Funded Warrant (2024)		Form 8-K (Exhibit 4.1)	9/26/2024	001-37627

4.4	Share Purchase Agreement by and between the Registrant and C.P. Pharmaceuticals International C.V., dated as of May 5, 2016		Form 10-Q (Exhibit 10.2)	08/15/2016	001-37627

Lease Agreements

10.1.1	Lease Agreement by and between Wave Life Sciences USA, Inc., the Registrant, and King 733 Concord LLC, dated as of April 6, 2015		Form S-1 (Exhibit 10.7)	10/09/2015	333-207379

10.1.2	First Amendment (to Lease) by and between Wave Life Sciences USA, Inc. and CPI/King 733 Concord Owner, LLC, dated as of December 9, 2020		Form 10-K (Exhibit 10.5.2)	03/04/2021	001-37627

10.1.3	Second Amendment (to Lease) by and between Wave Life Sciences USA, Inc. and CPI/King 733 Concord Owner, LLC, dated as of August 8, 2022		Form 10-Q (Exhibit 10.1)	08/11/2022	001-37627

10.2.1	Lease Agreement by and between Wave Life Sciences USA, Inc. and King 115 Hartwell LLC, dated as of September 26, 2016		Form 8-K (Exhibit 10.1)	01/06/2017	001-37627


☒	根據1934年《證券交易所法》第13或15（d）條提交的年度報告


☐	根據1934年《證券交易所法》第13或15（d）條提交的過渡報告


大型加速文件夾	☐	加速文件管理器	☒
非加速歸檔	☐	小型上市公司	☐
		新興成長型公司	☐


10.2.2	First Amendment (to Lease) by and between Wave Life Sciences USA, Inc. and King 115 Hartwell LLC, dated as of December 31, 2016	Form 8-K (Exhibit 10.1)	01/06/2017	001-37627

Collaboration and License Agreements

10.3††	Collaboration and License Agreement by and between Wave Life Sciences USA, Inc., Wave Life Sciences UK Limited and GlaxoSmithKline Intellectual Property (No. 3), dated as of December 13, 2022	Form 10-K (Exhibit 10.3)	03/23/2023	001-37627

10.4	Share Purchase Agreement by and between Glaxo Group Limited and the Registrant, dated as of December 13, 2022	Form 10-K (Exhibit 10.4)	03/23/2023	001-37627

10.5	Investor Agreement by and between Glaxo Group Limited and the Registrant, dated as of January 26, 2023	Form 10-K (Exhibit 10.5)	03/23/2023	001-37627

Agreements with Executive Officers and Directors

10.6+	Form of Deed of Indemnity by and between the Registrant and each of its directors and certain of its officers	Form S-1 (Exhibit 10.11)	10/09/2015	333-207379

10.7+	Employment Agreement, as amended and restated, between the Registrant and Paul B. Bolno, dated as of May 8, 2020	Form 10-Q (Exhibit 10.1)	08/10/2020	333-207379

10.8+	Employment Agreement, as amended and restated, between the Registrant and Chandra Vargeese, dated as of May 8, 2020	Form 10-Q (Exhibit 10.2)	08/10/2020	333-207379

10.9+	Employment Agreement between the Registrant and Christopher Francis, Ph.D., dated as of November 8, 2022	Form 10-K (Exhibit 10.12)	03/23/2023	001-37627

10.10+	Employment Agreement, as amended and restated, between the Registrant and Kyle Moran, dated as of January 1, 2021	Form 10-K (Exhibit 10.15)	03/04/2021	001-37627

10.11+	Non-Employee Director Compensation Policy, as amended, effective as of August 6, 2024	Form 10-Q (Exhibit 10.2+)	11/12/2024	001-37627

10.12+	Consulting Agreement by and between Ontorii, Inc. (now Wave Life Sciences USA, Inc.) and Gregory Verdine, dated as of April 1, 2012	Form S-1 (Exhibit 10.16)	10/09/2015	333-207379

Equity and Other Compensation Plans

10.13+	Wave Life Sciences Ltd. 2014 Equity Incentive Plan, as amended (the “2014 Equity Plan”)	Form 10-Q (Exhibit 10.1)	11/09/2017	001-37627

10.14+	Wave Life Sciences Ltd. 2021 Equity Plan, as amended, (the “2021 Equity Plan”) effective August 6, 2024	Form 8-K (Exhibit 10.1)	08/12/2024	001-37627

10.15+	Wave Life Sciences Ltd. 2019 Employee Share Purchase Plan, as amended, effective as of August 1, 2023	Form 8-K (Exhibit 10.2)	08/07/2023	001-37627

10.16.1+	Form of Non-qualified Share Option Agreement under the 2014 Equity Plan, effective as of September 20, 2016	Form 10-Q (Exhibit 10.2)	11/09/2017	001-37627



10.16.2+	Form of Non-qualified Share Option Agreement under the 2014 Equity Plan, effective as of January 1, 2018	Form 10-K (Exhibit 10.23.3)	03/01/2019	001-37627

10.16.3+	Form of Non-qualified Share Option Agreement under the 2021 Equity Plan, effective as August 10, 2021	Form 10-K (Exhibit 10.3)	11/10/2021	001-37627

10.17.1+	Form of Incentive Share Option Agreement under the 2014 Equity Plan, effective as of December 2014	Form S-8 (Exhibit 10.1)	12/17/2015	333-208598

10.17.2+	Form of Incentive Share Option Agreement under the 2014 Equity Plan, effective as of September 20, 2016	Form 10-Q (Exhibit 10.3)	11/09/2017	001-37627

10.18.1+	Form of Restricted Share Unit Agreement under the 2014 Equity Plan, effective as of June 16, 2016	Form 10-Q (Exhibit 10.4)	11/09/2017	001-37627

10.18.2+	Form of Restricted Share Unit Agreement under the 2014 Equity Plan, effective as of January 1, 2018	Form 10-K (Exhibit 10.25.2)	03/01/2019	001-37627

10.18.3+	Form of Restricted Share Unit Agreement under the 2014 Equity Incentive Plan, effective as of January 1, 2019	Form 10-Q (Exhibit 10.1)	05/10/2019	001-37627

10.18.4+	Form of Restricted Share Unit Agreement under the 2021 Equity Plan, effective as of August 10, 2021	Form 10-Q (Exhibit 10.4)	11/10/2021	001-37627

10.18.5+	Form of Amended and Restated 2019 Performance-Based Restricted Share Unit Agreement under the 2014 Equity Incentive Plan, effective as of March 17, 2021	Form 10-Q (Exhibit 10.2)	05/13/2021	001-37627

10.18.6+	Form of 2021 Performance-Based Restricted Share Unit Agreement under the 2014 Equity Incentive Plan, effective as of March 17, 2021	Form 10-Q (Exhibit 10.3)	05/13/2021	001-37627

10.19.1+	Form of Non-qualified Share Option Agreement for UK Participants under the 2014 Equity Plan, effective as of June 21, 2017	Form 10-Q (Exhibit 10.5)	11/09/2017	001-37627

10.19.2+	Form of Non-qualified Share Option Agreement for UK Participants under the 2014 Equity Plan, effective as of January 1, 2018	Form 10-K (Exhibit 10.26.2)	03/01/2019	001-37627

10.19.3+	Form of Non-qualified Share Option Agreement for UK Participants under the 2021 Equity Plan, effective as of August 10, 2021	Form 10-Q (Exhibit 10.5)	11/10/2021	001-37627

10.19.4+	Form of Restricted Share Unit Agreement for UK Participants under the 2021 Equity Plan, effective as of August 10, 2021	Form 10-Q (Exhibit 10.6)	11/10/2021	001-37627

10.20.1+	Form of Inducement Non-qualified Share Option Agreement, effective May 2024	Form 10-Q (Exhibit 10.1)	08/08/2024	001-37627

10.20.2+	Form of Inducement Restricted Share Unit Agreement, effective May 2024	Form 10-Q (Exhibit 10.2)	08/08/2024	001-37627


10.21.1	Open Market Sale Agreement, dated as of May 10, 2019, by and between the Registrant and Jefferies LLC		Form S-3ASR (Exhibit 1.2)	05/10/2019	333-231382

10.21.2	Amendment No. 1 to Open Market Sale Agreement, dated as of March 2, 2020, by and between the Registrant and Jefferies LLC		POSASR (Exhibit 1.3)	03/02/2020	333-231382

10.21.3	Amendment No. 2, dated March 3, 2022, to the Open Market Sale Agreement, dated as of May 10, 2019, by and between Wave Life Sciences Ltd. and Jefferies LLC		Form 8-K (Exhibit 10.1)	03/03/2022	001-37627

10.21.4	Amendment No. 3, dated November 12, 2024, to the Open Market Sale Agreement, dated as of May 10, 2019, by and between Wave Life Sciences Ltd. and Jefferies LLC		Form 10-Q (Exhibit 10.1)	11/12/2024	001-37627

19.1	Insider Trading Policy	X

21.1	List of Subsidiaries of the Registrant		Form 10-K (Exhibit 21.1)	03/12/2018	001-37627

23.1	Consent of Independent Registered Public Accounting Firm	X

24.1	Power of Attorney (included on signature page to this Annual Report on Form 10-K)	X

31.1	Certifications of Principal Executive Officer pursuant to Rule 13a-14(a)	X

31.2	Certifications of Principal Financial Officer pursuant to Rule 13a-14(a)	X

32*	Certification pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002, by Principal Executive Officer and Principal Financial Officer	X

97.1	Clawback Policy, effective as of October 2, 2023		Form 10-K (Exhibit 97.1)	03/06/2024	001-37627

101.INS	XBRL Instance Document – The Instance Document does not appear in the Interactive Data File because its XBRL tags are embedded within the Inline XBRL document	X

101.SCH	Inline XBRL Taxonomy Extension Schema With Embedded Linkbase Documents	X

104	The cover page for this Annual Report on Form 10-K for the year ended December 31, 2024 is contained in Exhibit 101 and has been formatted in Inline XBRL	X


	Wave Life Sciences Ltd.

Date: March 4, 2025	By:	/s/ Paul B. Bolno, M.D.
		Paul B. Bolno, M.D.
		President and Chief Executive Officer


Signature	Title	Date

/s/ Paul B. Bolno, M.D. Paul B. Bolno, M.D.	President, Chief Executive Officer and Director (principal executive officer)	March 4, 2025

/s/ Kyle Moran Kyle Moran	Chief Financial Officer (principal financial officer and principal accounting officer)	March 4, 2025

/s/ Christian Henry Christian Henry	Chairman of the Board of Directors	March 4, 2025

/s/ Gregory L. Verdine, Ph.D. Gregory L. Verdine, Ph.D.	Director	March 4, 2025

/s/ Peter Kolchinsky, Ph.D. Peter Kolchinsky, Ph.D.	Director	March 4, 2025

/s/ Aik-Na Tan Aik-Na Tan	Director	March 4, 2025

/s/ Adrian Rawcliffe Adrian Rawcliffe	Director	March 4, 2025

/s/ Ken Takanashi Ken Takanashi	Director	March 4, 2025

/s/ Mark H. N. Corrigan, M.D. Mark H. N. Corrigan, M.D.	Director	March 4, 2025

/s/ Heidi L. Wagner Heidi L. Wagner	Director	March 4, 2025


Report of Independent Registered Public Accounting Firm	F-1
Consolidated Balance Sheets	F-3
Consolidated Statements of Operations and Comprehensive Loss	F-4
Consolidated Statements of Series A Preferred Shares and Shareholders’ Equity (Deficit)	F-5
Consolidated Statements of Cash Flows	F-6
Notes to Consolidated Financial Statements	F-7


	December 31, 2024			December 31, 2023
Assets
Current assets:
Cash and cash equivalents	$	302,078		$	200,351
Accounts receivable		1,422			21,086
Prepaid expenses		9,544			9,912
Other current assets		7,350			4,024
Total current assets		320,394			235,373
Long-term assets:
Property and equipment, net of accumulated depreciation of $46,329 and $42,709 as of December 31, 2024 and 2023, respectively		10,128			13,084
Operating lease right-of-use assets		17,870			22,637
Restricted cash		3,760			3,699
Other assets		55			156
Total long-term assets		31,813			39,576
Total assets	$	352,207		$	274,949
Liabilities, Series A preferred shares and shareholders’ equity
Current liabilities:
Accounts payable	$	16,262		$	12,839
Accrued expenses and other current liabilities		21,081			16,828
Current portion of deferred revenue		65,972			150,059
Current portion of operating lease liability		7,638			6,714
Total current liabilities		110,953			186,440
Long-term liabilities:
Deferred revenue, net of current portion		6,099			15,601
Operating lease liability, net of current portion		17,766			25,404
Total long-term liabilities		23,865			41,005
Total liabilities	$	134,818		$	227,445
Series A preferred shares, no par value; 3,901,348 shares issued and outstanding at December 31, 2024 and 2023	$	7,874		$	7,874
Shareholders’ equity:
Ordinary shares, no par value; 153,037,286 and 119,162,234 shares issued and outstanding at December 31, 2024 and 2023, respectively	$	1,175,181		$	935,367
Additional paid-in capital		156,454			129,237
Accumulated other comprehensive loss		(262	)		(124	)
Accumulated deficit		(1,121,858	)		(1,024,850	)
Total shareholders’ equity		209,515			39,630
Total liabilities, Series A preferred shares and shareholders’ equity	$	352,207		$	274,949


	Series A Preferred Shares				Ordinary Shares				Additional		Accumulated Other						Total
	Shares		Amount		Shares		Amount		Paid-In- Capital		Comprehensive Income (Loss)			Accumulated Deficit			Shareholders’ Equity (Deficit)
Balance at December 31, 2021		3,901,348	$	7,874		59,841,116	$	749,851	$	87,980	$	181		$	(805,514	)	$	32,498
Issuance of ordinary shares, net of offering costs		—		—		25,464,483		51,220		—		—			—			51,220
Issuance of ordinary shares pursuant to the at-the-market equity program, net		—		—		458,092		1,167		—		—			—			1,167
Issuance of pre-funded warrants, net of offering costs		—		—		—		—		14,268		—			—			14,268
Share-based compensation		—		—		—		—		17,194		—			—			17,194
Vesting of RSUs		—		—		904,891		—		—		—			—			—
Option exercises		—		—		90,000		223		—		—			—			223
Issuance of ordinary shares under the ESPP		—		—		166,061		372		—		—			—			372
Other comprehensive loss		—		—		—		—		—		(210	)		—			(210	)
Net loss		—		—		—		—		—		—			(161,823	)		(161,823	)
Balance at December 31, 2022		3,901,348	$	7,874		86,924,643	$	802,833	$	119,442	$	(29	)	$	(967,337	)	$	(45,091	)
Issuance of ordinary shares, net of offering costs		—		—		20,000,000		93,574		—		—			—			93,574
Issuance of ordinary shares, pursuant to the GSK Collaboration Agreement		—		—		10,683,761		34,623		—		—			—			34,623
Issuance of ordinary shares pursuant to the at-the-market equity program, net		—		—		751,688		3,080		—		—			—			3,080
Share-based compensation		—		—		—		—		9,795		—			—			9,795
Vesting of RSUs		—		—		415,658		—		—		—			—			—
Option exercises		—		—		160,571		509		—		—			—			509
Issuance of ordinary shares under the ESPP		—		—		225,913		748		—		—			—			748
Other comprehensive loss		—		—		—		—		—		(95	)		—			(95	)
Net loss		—		—		—		—		—		—			(57,513	)		(57,513	)
Balance at December 31, 2023		3,901,348	$	7,874		119,162,234	$	935,367	$	129,237	$	(124	)	$	(1,024,850	)	$	39,630
Issuance of ordinary shares, net of offering costs		—		—		29,875,001		215,796		—		—			—			215,796
Issuance of ordinary shares pursuant to the at-the-market equity program, net		—		—		2,952,591		20,380		—		—			—			20,380
Issuance of pre-funded warrants, net of offering costs		—		—		—		—		14,076		—			—			14,076
Share-based compensation		—		—		—		—		13,141		—			—			13,141
Vesting of RSUs		—		—		100,326		—		—		—			—			—
Option exercises		—		—		770,636		2,979		—		—			—			2,979
Issuance of ordinary shares under the ESPP		—		—		176,498		659		—		—			—			659
Other comprehensive loss		—		—		—		—		—		(138	)		—			(138	)
Net loss		—		—		—		—		—		—			(97,008	)		(97,008	)
Balance at December 31, 2024		3,901,348	$	7,874		153,037,286	$	1,175,181	$	156,454	$	(262	)	$	(1,121,858	)	$	209,515