Analysis adds to the body of evidence differentiating INPEFA as a dual oral inhibitor of SGLT2 and SGLT1
THE WOODLANDS, Texas, May 14, 2024 (GLOBE NEWSWIRE) -- Lexicon Pharmaceuticals, Inc. (Nasdaq: LXRX) today announced a new post-hoc analysis of clinical data showing that INPEFA (sotagliflozin), a dual oral inhibitor of SGLT2 and SGLT1, reduced the risk of heart failure-related events across a diverse population of patients, including patients with preserved ejection fraction (HFpEF). Researchers noted that INPEFA appeared to be particularly effective in reducing the risk of heart failure events in patients with an obesity-related HFpEF phenotype. These findings, based on a pooled, patient-level analysis of data from the SOLOST-WHF and SCORED pivotal clinical trials, were presented today at the Annual Congress of the Heart Failure Association of the European Society of Cardiology (ESC) in Lisbon, Portugal.
Obesity and type 2 diabetes (T2D), along with a growing aging population, is contributing to the escalating prevalence of HFpEF. Recent data published in journals of the American College of Cardiology and the American Heart Association suggest that individuals with an obesity-related HFpEF phenotype represent a distinctive and clinically significant subgroup from those with standard HFpEF phenotype. This new analysis assessed the impact of obesity, along with sex and age, on the effects of INPEFA on the primary composite endpoint of cardiovascular (CV) death and heart failure (HF) events in patients with left ventricular ejection fraction (LVEF) ≥ 50%. Previously, SOLOIST-WHF and SCORED data demonstrated that INPEFA, a dual oral inhibitor of SGLT2 and SGLT1, is effective in reducing the risk of CV death and HF-related outcomes across the LVEF range.
Data from a total of 1,932 patients were included in the analysis (mean age: 69.9 years, mean BMI: 34.1 kg/m2; mean HbA1c:8.5%). In this population, 18.1% of patients experienced a primary endpoint event. Males and females demonstrated comparable event rates, 18.3% and 18.0% respectively; however, older age (< 65: 10.9% vs. ≥ 65years: 20.3%) and higher BMI (< 30 kg/m2: 16.6% vs. ≥ 30 kg/m2: 18.7%) were associated with an increased number of patients at risk for primary endpoint events.
Within the subgroup characterized by higher BMI, INPEFA therapy resulted in a favorable response for patients with BMI ≥ 30 kg/m2 (p-value for interaction 0.038). Researchers also noted that both sex and age subgroups had a consistent response to INPEFA (p-value for interaction 0.818 and 0.393, respectively).
"This analysis underscores the importance of identifying patient risk factors such as age, sex, and obesity in patients with HFpEF and adds to the body of evidence differentiating INPEFA as a dual inhibitor of SGLT1 and SGLT2," said Craig Granowitz, M.D., Ph.D., Lexicon's senior vice president and chief medical officer. "Additionally, today's data presentation further highlights the benefits of INPEFA in reducing the risk of heart failure-related events across a wide range of patients with HFpEF, including in patients with an obesity-related HFpEF phenotype."
About INPEFA (sotagliflozin)
Discovered using Lexicon's unique approach to gene science, INPEFA (sotagliflozin) is an oral inhibitor of two proteins responsible for glucose regulation known as sodium-glucose cotransporter types 2 and 1 (SGLT2 and SGLT1). SGLT2 is responsible for glucose and sodium reabsorption by the kidney and SGLT1 is responsible for glucose and sodium absorption in the gastrointestinal tract. Sotagliflozin has been studied in multiple patient populations encompassing heart failure, diabetes, and chronic kidney disease in clinical studies involving approximately 20,000 patients.
INDICATION
INPEFA is indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with:
- heart failure or
- type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors
IMPORTANT SAFETY INFORMATION
Dosing: Assess renal function and volume status and, if necessary, correct volume depletion prior to initiation of INPEFA. INPEFA dosing for patients with decompensated heart failure may begin when patients are hemodynamically stable, including when hospitalized or immediately upon discharge.
Contraindications: INPEFA is contraindicated in patients with hypersensitivity to INPEFA or any of its components.
Ketoacidosis: INPEFA increases the risk of ketoacidosis in patients with type 1 diabetes mellitus (T1DM). Type 2 diabetes Mellitus (T2DM) and pancreatic disorders are also risk factors. The risk of ketoacidosis may be greater with higher doses. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes using sodium glucose transporter 2 (SGLT2) inhibitors. Before initiating INPEFA, assess risk factors for ketoacidosis. Consider ketone monitoring in patients with T1DM and consider ketone monitoring in others at risk for ketoacidosis and educate patients on the signs/symptoms of ketoacidosis. Patients receiving INPEFA may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. INPEFA is not indicated for glycemic control.
Assess patients who present with signs and symptoms of metabolic acidosis or ketoacidosis, regardless of blood glucose level. If suspected, discontinue INPEFA, evaluate, and treat promptly. Monitor patients for resolution of ketoacidosis before restarting INPEFA.
Volume Depletion: INPEFA can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors. Patients with impaired renal function (eGFR < 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INPEFA in patients with one or more of these characteristics, assess volume status and renal function, and monitor for signs and symptoms of hypotension during therapy.
Urosepsis and Pyelonephritis: Treatment with SGLT2 inhibitors, including INPEFA, increases the risk for urinary tract infections. Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly.
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INPEFA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used with INPEFA.
Necrotizing Fasciitis of the Perineum (Fournier's Gangrene): Reports of Fournier's Gangrene, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in post-marketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors. Assess patients who present with pain, tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INPEFA, closely monitor patient signs and symptoms, and provide appropriate alternative therapy for heart failure.
Genital Mycotic Infections: INPEFA increases the risk of genital mycotic infections. Monitor and treat as appropriate.
Urinary Glucose Test and 1,5-anhydroglucitol (1,5-AG) Assay: these are not reliable for patients taking SGLT2 inhibitors. Use alternative testing methods to monitor glucose levels.
Common Adverse Reactions: the most commonly reported adverse reactions (incidence ≥ 5%) were urinary tract infection, volume depletion, diarrhea, and hypoglycemia.
Drug Interactions:
- Digoxin: Monitor patients appropriately as there is an increase in the exposure of digoxin when coadministered with INPEFA 400 mg.
- Uridine 5'-diphospho-glucuronosyltransferase (UGT) Inducer: The coadministration of rifampicin, an inducer of UGTs, with sotagliflozin resulted in a decrease in the exposure of sotagliflozin.
- Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INPEFA initiation and with dosage changes.
Use in Specific Populations:
- Pregnancy and Lactation: INPEFA is not recommended during the second and third trimesters of pregnancy, nor while breastfeeding.
- Geriatric Use: No INPEFA dosage change is recommended based on age. No overall differences in efficacy were detected between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients may be at increased risk for volume depletion adverse reactions, including hypotension.
- Renal Impairment: INPEFA was evaluated in patients with chronic kidney disease (eGFR 25 to 60 mL/min/1.73 m2) and in patients with heart failure with eGFR < 60 mL/min/1.73 m2. The safety profile of INPEFA across eGFR subgroups in these studies was consistent with the known safety profile. There was an increase in volume-related adverse events (e.g., hypotension, dizziness) in patients with eGFR < 30 mL/min/1.73m2 relative to the overall safety population. Efficacy and safety studies with INPEFA did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis. After starting therapy in the studies, patients were discontinued if eGFR fell below 15 mL/min/1.73 m2 or were initiated on chronic dialysis.
- Hepatic Impairment: INPEFA is not recommended in patients with moderate or severe hepatic impairment.
Click here for full Prescribing Information.
About Lexicon Pharmaceuticals
Lexicon is a biopharmaceutical company with a mission of pioneering medicines that transform patients' lives. Through the Genome5000 program, Lexicon's unique genomics target discovery platform, Lexicon scientists studied the role and function of nearly 5,000 genes and identified more than 100 protein targets with significant therapeutic potential in a range of diseases. Through the precise targeting of these proteins, Lexicon is pioneering the discovery and development of innovative medicines to treat disease safely and effectively. Lexicon has commercially launched one of these medicines, INPEFA (sotagliflozin) in the United States, and has a pipeline of other promising drug candidates in discovery and clinical and preclinical development in neuropathic pain, diabetes and metabolism and other indications. For additional information, please visit .
Safe Harbor Statement
This press release contains "forward-looking statements," including statements relating to Lexicon's financial position and long-term outlook on its business, growth and future operating results, discovery, development and commercialization of products, strategic alliances and intellectual property, as well as other matters that are not historical facts or information. All forward-looking statements are based on management's current assumptions and expectations and involve risks, uncertainties and other important factors, specifically including Lexicon's ability to meet its capital requirements, successfully commercialize INPEFA in heart failure, conduct preclinical and clinical development and obtain necessary regulatory approvals of sotagliflozin (in other indications), LX9211, LX9851 and its other drug candidates on its anticipated timelines, achieve its operational objectives, obtain patent protection for its discoveries and establish strategic alliances, as well as additional factors relating to manufacturing, intellectual property rights, and the therapeutic or commercial value of its products and drug candidates. Any of these risks, uncertainties and other factors may cause Lexicon's actual results to be materially different from any future results expressed or implied by such forward-looking statements. Information identifying such important factors is contained under "Risk Factors" in Lexicon's annual report on Form 10-K for the year ended December 31, 2023 and other subsequent disclosure documents filed with the Securities and Exchange Commission. Lexicon undertakes no obligation to update or revise any such forward-looking statements, whether as a result of new information, future events or otherwise.
For Investor Inquiries:
Lisa DeFrancesco
Lexicon Pharmaceuticals, Inc.
lexinvest@lexpharma.com
For Media Inquiries:
Alina Cocuzza
Lexicon Pharmaceuticals, Inc.
acocuzza@lexpharma.com
分析增加了將 INPEFA 區分爲 SGLT2 和 SGLT1 雙重口服抑制劑的大量證據
德克薩斯州伍德蘭茲，2024 年 5 月 14 日（GLOBE NEWSWIRE）— Lexicon Pharmicals, Inc 納斯達克股票代碼：LXRX）今天宣佈了一項新的臨床數據事後分析，顯示INPEFA （sotagliflozin）是 SGLT2 和 SGLT1 的雙重口服抑制劑，可降低包括射血分數（HfpEF）保持不變的患者在內的不同患者發生心力衰竭相關事件的風險。研究人員指出，INPEFA在降低肥胖相關HfPEF表型患者發生心力衰竭事件的風險方面似乎特別有效。這些發現基於對SOLOST-WHF和SCORED關鍵臨床試驗數據的合併患者層面分析，於今天在葡萄牙里斯本舉行的歐洲心臟病學會（ESC）心力衰竭協會年會上公佈。
肥胖和2型糖尿病（T2D），以及不斷增長的人口老齡化，是HfpEF患病率上升的原因。最近發表在美國心臟病學會和美國心臟協會期刊上的數據表明，與具有標準HfpEF表型的人相比，具有肥胖相關HfpEF表型的個體是一個獨特且具有臨床意義的亞組。這項新分析評估了肥胖以及性別和年齡對INPEFA對左心室射血分數（LVEF）≥50％的患者心血管（CV）死亡和心力衰竭（HF）事件的主要複合終點的影響。此前，SOLOIST-WHF和SCORED的數據表明，INPEFA是 SGLT2 和 SGLT1 的雙重口服抑制劑，可有效降低整個LVEF範圍內心血管死亡和HF相關結果的風險。
分析中共納入了來自1,932名患者的數據（平均年齡：69.9歲，平均體重指數：34.1 kg/m2；平均HbA1c：8.5％）。在該人群中，18.1% 的患者經歷了主要終點事件。男性和女性的事件發生率相似，分別爲18.3％和18.0％；但是，年齡較大（<65歲：10.9％對比≥65歲：20.3％）和較高的體重指數（<30 kg/m2：16.6％對≥30 kg/m2：18.7％）與主要終點事件風險的患者數量增加有關。
在以體重指數較高爲特徵的亞組中，INPEFA治療對體重指數≥30 kg/m2（相互作用p值爲0.038）的患者產生了良好的反應。研究人員還指出，性別和年齡亞組對INPEFA的反應一致（相互作用的p值分別爲0.818和0.393）。
Lexicon高級副總裁兼首席醫學官克雷格·格拉諾維茨博士說：“這項分析突顯了識別HfpEF患者年齡、性別和肥胖等患者危險因素的重要性，並增加了區分INPEFA作爲 SGLT1 和 SGLT2 雙重抑制劑的大量證據。”“此外，今天的數據展示進一步強調了INPEFA在降低包括肥胖相關HfpEF表型患者在內的各種HfpEF患者發生心力衰竭相關事件風險方面的益處。”
關於 INPEFA （索塔格列津）
採用 Lexicon 獨特的基因科學方法 INPEFA 發現 （sotagliflozin）是兩種負責調節葡萄糖的蛋白質的口服抑制劑，即2型和1型鈉-葡萄糖協同轉運蛋白（SGLT2 和 SGLT1）。SGLT2 負責腎臟重吸收葡萄糖和鈉，SGLT1 負責胃腸道吸收葡萄糖和鈉。在涉及約20,000名患者的臨床研究中，已對包括心力衰竭、糖尿病和慢性腎臟病在內的多個患者群體進行了Sotagliflozin的研究。
指示
INPEFA可降低患有以下情況的成年人心血管死亡、心力衰竭住院和緊急心力衰竭就診的風險：
- 心力衰竭或
- 2 型糖尿病、慢性腎臟病和其他心血管危險因素
重要的安全信息
劑量：評估腎功能和容量狀態，如有必要，在開始使用INPEFA之前糾正血容量消耗。失代償性心力衰竭患者的INPEFA劑量可以在患者血流動力學穩定時開始，包括住院時或出院後立即給藥。
禁忌症：INPEFA禁用於對INPEFA或其任何成分過敏的患者。
酮症酸中毒：INPEFA會增加1型糖尿病（T1DM）患者發生酮症酸中毒的風險。2 型糖尿病 (T2DM) 和胰腺疾病也是危險因素。劑量越高，酮症酸中毒的風險可能會更大。有上市後報道稱，使用鈉葡萄糖轉運蛋白 2 (SGLT2) 抑制劑的 2 型糖尿病患者會出現酮症酸中毒的致命事件。在啓動INPEFA之前，評估酮症酸中毒的危險因素。考慮對T1DM患者進行酮體監測，考慮對其他有酮症酸中毒風險的患者進行酮監測，並教育患者了解酮症酸中毒的體徵/症狀。在已知易患酮症酸中毒的臨床情況下，接受INPEFA的患者可能需要監測並暫時停止治療。INPEFA 不適用於血糖控制。
評估出現代謝性酸中毒或酮症酸中毒體徵和症狀的患者，無論血糖水平如何。如果懷疑，請立即停用 INPEFA，進行評估並進行治療。在重啓INPEFA之前，監測患者酮症酸中毒的緩解情況。
血容量不足：INPEFA 可導致血管內容量不足，有時可能表現爲症狀性低血壓或肌酐急性短暫變化。已有上市後報道，接受 SGLT2 抑制劑的 2 型糖尿病患者出現急性腎損傷，有些需要住院和透析。腎功能受損患者（eGFR < 60 mL/min/1.73 m2）、老年患者或服用循環利尿劑的患者發生容量耗盡或低血壓的風險可能增加。在對具有其中一種或多種特徵的患者啓動INPEFA之前，評估容量狀態和腎功能，並監測治療期間低血壓的體徵和症狀。
尿毒症和腎盂腎炎：使用包括 INPEFA 在內的 SGLT2 抑制劑進行治療會增加尿路感染的風險。已報告了嚴重的尿路感染，包括尿膿毒症和腎盂腎炎，需要住院治療。評估患者是否有尿路感染的體徵和症狀，並及時治療。
與胰島素和胰島素促分泌劑同時使用會導致低血糖：已知胰島素和胰島素促分泌劑會導致低血糖。INPEFA與胰島素或胰島素促分泌劑合用可能會增加發生低血糖的風險。因此，與INPEFA一起使用時，可能需要較低劑量的胰島素或胰島素促分泌劑，以最大限度地降低低血糖的風險。
會陰壞死性筋膜炎（富尼爾壞疽）：在對接受 SGLT2 抑制劑的糖尿病患者的上市後監測中，已發現富尼爾壞疽是一種罕見但嚴重且危及生命的壞死性感染，需要緊急手術干預。評估生殖器或會****位出現疼痛、壓痛、紅斑或腫脹以及發燒或全身不適的患者。如果懷疑，立即開始使用廣譜抗生素治療，必要時進行手術清創治療。停用INPEFA，密切監測患者的體徵和症狀，併爲心力衰竭提供適當的替代療法。
生殖器真菌感染：INPEFA增加了生殖器真菌感染的風險。進行適當的監測和治療。
尿糖測試和 1,5-脫氫葡萄糖醇 (1,5-AG) 檢測：對於服用 SGLT2 抑制劑的患者來說，這些測試並不可靠。使用其他測試方法監測血糖水平。
常見不良反應：最常報告的不良反應（發生率 ≥ 5%）是尿路感染、容量不足、腹瀉和低血糖。
藥物相互作用：
- 地高辛：適當監測患者，因爲與INPEFA 400 mg聯合使用時，地高辛的暴露量會增加。
- 尿苷5'-二磷酸葡萄糖醛酸轉移酶（UGT）誘導劑：利福平（UGT）誘導劑，與索他格列嗪共同給藥可減少索他列嗪的暴露量。
- 鋰：將 SGLT2 抑制劑與鋰同時使用可能會降低血清鋰濃度。在INPEFA啓動期間和劑量變化期間，更頻繁地監測血清鋰濃度。
在特定人群中使用：
- 懷孕和哺乳：不建議在懷孕的第二和第三個月以及哺乳期間使用 INPEFA。
- 老年用途：不建議根據年齡改變INPEFA劑量。未發現這些患者與年輕患者之間療效的總體差異，其他報告的臨床經驗也沒有發現老年患者和年輕患者之間的反應差異，但不能排除一些老年人更敏感的可能性。老年患者發生容量消耗不良反應（包括低血壓）的風險可能增加。
- 腎功能受損：對慢性腎臟病患者進行了INPEFA評估（eGFR 25 至 60 mL/min/1.73 m）2) 以及表皮生長因子 < 60 mL/min/1.73 m 的心力衰竭患者2。在這些研究中，INPEFA在eGFR亞組中的安全概況與已知的安全性概況一致。表皮生長因子<30 mL/min/1.73m的患者體積相關的不良事件（例如低血壓、頭暈）有所增加2 相對於總體安全人群。INPEFA的療效和安全性研究並未納入表皮生長因子小於25 mL/min/1.73 m的患者2 或者進行透析。在研究中開始治療後，如果表皮生長因子降至15 mL/min/1.73 m以下，患者將停止治療2 或者是開始接受慢性透析的。
- 肝功能受損：不建議中度或重度肝損傷患者使用INPEFA。
點擊此處獲取完整的處方信息。
關於 Lexicon 製藥
Lexicon 是一家生物製藥公司，其使命是開創改變患者生活的藥物。通過Lexicon獨特的基因組學靶點發現平台Genome5000計劃，Lexicon科學家研究了近5,000個基因的作用和功能，並確定了100多個在一系列疾病中具有巨大治療潛力的蛋白質靶標。通過精確靶向這些蛋白，Lexicon開創了安全有效治療疾病的創新藥物的發現和開發。Lexicon已經商業上推出了其中一種藥物，即INPEFA （sotagliflozin）在美國上市，並且在神經病理性疼痛、糖尿病和新陳代謝及其他適應症方面還有其他有前途的候選藥物正在研發、臨床和臨床前開發中。如需更多信息，請訪問。
安全港聲明
本新聞稿包含 “前瞻性陳述”，包括與Lexicon的財務狀況和業務長期展望、增長和未來經營業績、產品的發現、開發和商業化、戰略聯盟和知識產權有關的陳述，以及其他非歷史事實或信息的事項。所有前瞻性陳述均基於管理層當前的假設和預期，涉及風險、不確定性和其他重要因素，特別包括Lexicon滿足其資本需求、成功將INPEFA商業化用於心力衰竭、進行臨床前和臨床開發以及在預期的時間表內獲得索他列津（其他適應症）、LX9211、LX9851 和其他候選藥物的必要監管批准、實現其運營目標、爲其發現獲得專利保護的能力，以及建立戰略聯盟，以及與製造、知識產權及其產品和候選藥物的治療或商業價值相關的其他因素。這些風險、不確定性和其他因素中的任何一個都可能導致Lexicon的實際業績與此類前瞻性陳述所表達或暗示的任何未來業績存在重大差異。確定此類重要因素的信息包含在Lexicon截至2023年12月31日止年度的10-K表年度報告以及隨後向美國證券交易委員會提交的其他披露文件中的 “風險因素” 下。Lexicon沒有義務更新或修改任何此類前瞻性陳述，無論是由於新信息、未來事件還是其他原因。
投資者查詢：
麗莎·德弗朗西斯科
Lexicon Pharmicals, Inc
lexinvest@lexpharma.com
媒體垂詢：
Alina Cocuzza
Lexicon Pharmicals, Inc
acocuzza@lexpharma.com
