ADC Therapeutics (ADCT) has reported its fourth quarter and full-year 2023 financial results, along with significant business updates. The company, which focuses on the development of antibody-drug conjugates (ADCs) for cancer treatment, has announced a new corporate strategy centered on its most advanced clinical assets.
The hematology asset ZYNLONTA is expected to lead the company to profitability, with plans to expand its use into earlier lines of therapy for diffuse large B-cell lymphoma (DLBCL) and indolent lymphomas. ADC Therapeutics also highlighted its solid tumor pipeline, with ADCT-601 emerging as the most advanced candidate.
Financially, the company sits on a strong cash position and anticipates a cash runway extending into the fourth quarter of 2025.
Key Takeaways
- ADC Therapeutics is refocusing on key clinical assets to drive profitability.
- ZYNLONTA, the company's primary asset, is expected to expand into new therapeutic areas.
- The company's solid tumor pipeline is advancing, with ADCT-601 showing early signs of efficacy.
- Financially stable, ADC Therapeutics has a cash runway into Q4 2025.
- ZYNLONTA net sales reached $16.6 million for the quarter, with the company reporting a net loss of $85 million.
Company Outlook
- ADC Therapeutics plans to drive ZYNLONTA's value and pursue multiple ADC candidates.
- The company is optimistic about ZYNLONTA's commercial profitability within the year.
Bearish Highlights
- The company reported a net loss of $85 million for the quarter.
Bullish Highlights
- ZYNLONTA has shown encouraging response rates in clinical trials.
- ADC Therapeutics' solid tumor candidate, ADCT-601, has reached the recommended dose in trials and displayed antitumor activity.
- The company has a strong financial position, with $280 million in cash reserves.
Misses
- There may be a need to expand patient enrollment in clinical trials beyond the planned 350 participants.
Q&A Highlights
- ADC Therapeutics is refining ZYNLONTA's commercial strategy to bolster demand.
- The LOTIS-7 study is progressing well, with no dose-limiting toxicities and promising anti-tumor activity.
- Discussions for potential partnerships in the NextGen ADC program are ongoing.
ADC Therapeutics, in its latest earnings call, has outlined a focused strategy to leverage its primary asset, ZYNLONTA, for sustained growth and profitability. The company's financial health appears robust, with substantial cash reserves to support operations well into the future.
Clinical trials for ZYNLONTA and the company's solid tumor pipeline are progressing, with promising early results that could potentially expand the drug's market reach. Despite a substantial net loss this quarter, ADC Therapeutics remains confident in its strategic repositioning and its potential to achieve commercial brand profitability for ZYNLONTA within the year.
The company's future updates, particularly those related to the LOTIS-7 trial and presentations at the American Association for Cancer Research (AACR), are highly anticipated by stakeholders.
InvestingPro Insights
ADC Therapeutics (ADCT) has been making strategic moves to position its clinical assets for profitability, with a particular focus on ZYNLONTA for cancer treatment. While the company's direction appears promising, it's important to consider key financial metrics and market performance to gain a comprehensive view of its potential.
InvestingPro Data:
- Market Capitalization: With a market cap of $307.01 million, ADC Therapeutics is a mid-sized biotech player, which is relevant for investors assessing company size and market influence.
- P/E Ratio: The company currently has a negative P/E ratio of -1.34 for the last twelve months as of Q4 2023, indicating that it is not profitable at this time.
- Revenue Growth: ADC Therapeutics experienced a substantial decrease in revenue growth, with a -66.86% change over the last twelve months as of Q4 2023.
InvestingPro Tips:
1. ADC Therapeutics has been quickly burning through cash, which is a crucial factor for investors to consider when evaluating the company's financial sustainability.
2. The stock has experienced significant volatility, with a large price uptick over the last six months, and a strong return over the last three months, yet it has suffered from weak gross profit margins during the last twelve months.
Investors interested in a deeper analysis of ADC Therapeutics can find additional InvestingPro Tips by visiting https://www.investing.com/pro/ADCT. There are over 10 tips available, offering insights into aspects such as stock price movements, profitability forecasts, and liquidity concerns.
For those looking to explore these insights further, use the coupon code PRONEWS24 to get an additional 10% off a yearly or biyearly Pro and Pro+ subscription to InvestingPro, where you can access comprehensive analysis and metrics that can guide your investment decisions.
Full transcript - ADC Therapeutics SA (ADCT) Q4 2023:
Operator: Welcome to the ADC Therapeutics Fourth Quarter and Full-Year 2023 Financial Results Conference Call. My name is Norma and I will be your operator for today's call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. [Operator Instructions]. I will now turn the call over to Nicole Riley, Head of Communications. Nicole, you may now begin.
Nicole Preiss-Riley: Thank you, operator. This morning, we issued a press release announcing our fourth quarter and full year 2023 financial results and business updates. This release is available on the ADCT website at ir.adctherapeutics.com under the Press Releases section. On today's call, Ameet Mallik, Chief Executive Officer; Kristen Herrington-Smith, Chief Commercial Officer; Mohamed Zaki, Chief Medical Officer; Patrick van Berkel, Chief Scientific Officer; and Pepe Carmona, Chief Financial Officer, will discuss recent business highlights and review our fourth quarter and full-year 2023 financial results before opening the call for questions. Before we begin, I would like to remind listeners that some of the statements made during this conference call will contain forward-looking statements within the meaning of the Safe Harbor provisions of the US Private Securities Litigation Reform Act of 1995. These forward-looking statements are subject to certain known and unknown risks and uncertainties, and actual results, performance and achievements could differ materially. They are identified and described in today's press release and the accompanying slide presentation on slide 2 and in the company's filings with the SEC, including Form 10-K, 10-Q and 8-K. ADCT is providing this information as of the date of today's conference call and does not undertake any obligation to update any forward-looking statements contained in this conference call as a result of new information, future events or circumstances after the date hereof, except as required by law or otherwise. The company cautions investors not to place undue reliance on these forward-looking statements. Today's presentation also includes non-GAAP financial measures. These non-GAAP measures have limitations as financial measures and should be considered in addition to, and not in isolation, or as a substitute for, the information prepared in accordance with GAAP. You should refer to the information contained in the company's fourth quarter earnings release for definitional information and reconciliations of historical non-GAAP measures to the comparable GAAP financial measures. It is now my pleasure to pass the call over to our CEO, Ameet Mallik. Ameet?
Ameet Mallik: Thanks, Nicole. And thank you all for joining us today. 2023 was a year of prioritization and focus for the company. We made some tough decisions and firmly believe we are well positioned for success in 2024 and beyond. With enhanced talent in place, we implemented a new corporate and capital allocation strategy, focusing our resources and energy on our most advanced and highest potential clinical value drivers. As you can see here, we enhanced commercialization efforts, prioritized our pipeline, expanded our research platform and reduced organizational costs. This reset in 2023 was critical to enable our strategy moving forward. There are two core pillars to the strategy which we believe will unlock the tremendous value we see in this company. Our first pillar, and primary focus, is hematology. Within this, we have a derisked asset in ZYNLONTA, the key product in our prioritized portfolio, which we expect to carry the company through to profitability. We are deploying the majority of our capital to the ZYNLONTA franchise to commercialize our existing third line and third line plus DLBCL indication and to pursue the substantially larger potential opportunity in earlier lines of DLBCL therapy and indolent lymphomas. We believe these potential opportunities will help expand the ZYNLONTA franchise and have the potential to generate annual peak sales in excess of $0.5 billion. The second pillar of our strategy is grounded in our emerging solid tumor pipeline. Our most advanced asset is ADCT-601. And behind this, we have a number of exciting next generation antibody drug conjugates, which potentially address significant unmet patient needs. Driven by our novel platform, we see the potential to advance a broad portfolio of differentiated ADCs against solid tumor targets of interest. To capture this opportunity, our ambition is to progress multiple assets in parallel, internally and externally, supported by non-dilutive funding from partners. Across each of our presenters today, you will hear about how we are putting this strategy into action, whether through enhancing our commercial execution, prioritizing and accelerating our most promising pipeline assets, advancing high potential early stage research programs, or through our capital allocation strategy. Now, I'd like to expand briefly on the substantially larger potential opportunity that I just mentioned for ZYNLONTA in earlier lines of DLBCL therapy and indolent lymphomas. Pending the results of the LOTIS-5 and LOTIS-7 studies, our goal is to expand usage of ZYNLONTA into second line and second line plus DLBCL. Furthermore, if data supports expansion into the second line and second line plus settings of follicular lymphoma and marginal zone lymphoma, we believe this would further increase the potential for this product. Now I'd like to share a snapshot of the business updates you'll hear about today. I'm pleased to confirm that ZYNLONTA achieved double-digit sequential sales growth in the fourth quarter, with revenues of $16.6 million. Importantly, we saw a resumption of growth both in the community and in academic centers. We are also delighted to share positive pipeline news at the start of this year. For our LOTIS-7 study of ZYNLONTA in combination with bi-specifics, we shared early data from the first dosing cohort. Since that time, we have successfully cleared the second dosing cohort in both arms, with no dose-limiting toxicities. We are encouraged by what we have observed with ADCT-601, our novel AXL-targeting ADC in sarcoma, and a recently initiated screening in pancreatic cancer patients. Lastly, we disclosed that we are advancing an early-stage portfolio of investigational ADCs, which utilize a novel exatecan-based platform. Turning to our financial position. We ended 2023 with close to $280 million in cash. Together with our business plans and strict cost discipline, this provides us with an expected cash runway into Q4 2025, which will support us through multiple value-generating catalysts this year and next. So, taken together, we entered 2024 with great confidence, having repositioned and refocused the company, and with some encouraging early data emerging from our pipeline. With that, I would like to turn the call over to Kristen for a commercial update. Kristen?
Kristen Herrington-Smith: Thanks, Ameet. Today, our strategy is to grow ZYNLONTA in the community, where the third-line, third-line-plus DLBCL setting continues to be fragmented with no standard of care, and to maintain our position in the academic centers for patients who are not eligible for CAR-Ts or bi-specifics or who have progressed following treatment with these complex therapies. Our strategy is supported by real-world data as presented at the recent Tandem Meetings, which demonstrated ZYNLONTA's efficacy pre and post CAR-T. Execution against our strategy was the fundamental driver for our commercial restructuring and resulted in higher ZYNLONTA demand in November and December, similar to the levels in the first half of 2023. We delivered a 17% increase in net revenue in Q4 compared to Q3, with growth in both the community and academic settings. I am especially proud of our performance, given the competitive dynamic with the recent approvals of two bispecifics in the same third-line, third-line-plus setting as ZYNLONTA. We are confident we have the right team and the right strategy to maximize ZYNLONTA in the current approved indication. Now, I want to turn to the future market landscape and the important role we expect ZYNLONTA to play. Within the DLBCL market, a true standard of care only exists in the front line, with R-CHOP and recently pola R-CHIP, as well as in the academic setting in the second line with CAR-T and autologous stem cell transplant. However, accessibility to most patients treated in the community remains a challenge. The market is evolving towards highly effective combinations with off-the-shelf agents as a cornerstone. As polatuzumab moves to the front line, we expect this will create an unmet need in the market as re-treatment in the relapse/refractory setting is unlikely. With our confirmatory Phase 3 trial, LOTIS-5, our plan is to expand the ZYNLONTA label to the second line, second line plus. We have a tremendous opportunity to build share in this broader patient population if this study continues to deliver the competitive efficacy that we have already observed with ZYNLONTA in combination with rituximab in the 20 patient safety run-in. These data, coupled with the potential advantages of accessibility, ease of use, and manageable tolerability, lead us to believe the results from LOTIS-5 will help to cement ZYNLONTA as a standard of care in the second line, second line plus among community centers where R-based regimens are commonly used across all lines of therapy. In addition, these data have the potential to expand the use of ZYNLONTA in both the second line and third line, third line plus academic settings when an alternative to CAR-T and or bispecifics is needed. Moving to LOTIS-7, our Phase 1b trial evaluating ZYNLONTA in combination with bispecifics. As we progress this development program forward, our objective is to demonstrate that the combination can deliver enhanced efficacy compared to bispecifics alone, which could significantly expand ZYNLONTA use. In addition, we hope to demonstrate that ZYNLONTA when compared with bispecifics can reduce levels of CRS and eliminate the need for hospitalizations, expanding accessibility in the community. Ultimately, if successful, this combination has the potential to transform the treatment paradigm in the second line across both settings and substantially enhancing the patient and commercial opportunity for ZYNLONTA. And now, I would like to turn the call over to Mohamed for a clinical update.
Mohamed Zaki: Thanks, Kristen. It's my pleasure to provide an update on our clinical stage pipeline. Starting with LOTIS-5, our Phase 3 confirmatory trial with ZYNLONTA and rituximab, we significantly accelerated the pace of enrollment in 2023, and we reported encouraging updated safety lead-in results in September. While we have been pleased with the increase in patient enrollment, our clinical team recently observed higher than expected sensory in the trial, which was confirmed with the IDMC. As a result, we may need to expand enrollment beyond the planned 350 patients to achieve the required number of pre-specified progression free survival events. Based on the current pace of enrollment, we do not expect this to affect our target to complete enrollment in 2024. Importantly, the IDMC noted no safety concerns and recommended the study to proceed at its most recent meeting held on the 16th of January 2024. Moving to LOTIS-7, this is our Phase 1b study to explore ZYNLONTA in novel combinations. We are focusing on the combination in two bispecifics arm, Roche's glofitamab and mosunetuzumab. Enrollment started in each arm in July 2023. Part 1 is a 3 plus 3 dose escalation and third line plus heavily treated patient, with ZYNLONTA doses starting at 90 microgram per kilogram, and then proceeding to 120 and 150 micrograms. As we discussed in January, we dosed the first three patients in each arm with the 90 microgram dose and cleared the dose limit to 60 period. Since that time, we have cleared the 120 microgram dose for both arms, with no DLTs and we are currently enrolling the 150 microgram dose. Once dose escalation is complete, we plan to expand at the appropriate dose levels. After the first investigator assessment, we have seen evidence of antitumor activity among the majority of patients dosed at the first two levels, with mixed histologists, including DLBCL, follicle lymphoma and marginal zone lymphoma. We expect to share additional data once a larger and more mature data set is available. While we are excited, but what we have seen, we recognize that it is early. And once dose expansion in second line is complete and assuming data are promising, we plan to approach the regulatory agencies to discuss our strategy and potential path forward. Beyond our own studies, there is significant amount of interest from investigators to explore ZYNLONTA in additional indications and combinations. At ASH in December 2023, there was an oral presentation from the University of Miami on their investigator initiated Phase 2 study of ZYNLONTA and rituximab in patients with high risk relapse or refractory follicular lymphoma. This is a unique population not served well by the current standard of care. Initial results from the 33 patients were very encouraging, including a best overall response rate of 96% and a complete response rate of 85%. In terms of safety, the majority of adverse events were primarily grade 1 and manageable. The presentation was extremely well received by the physician community and the trial is now being expanded to other centers with a target enrollment of 100 patients. The University of Miami is also conducting another investigator initiated Phase 2 study of ZYNLONTA in relapse or refractive marginal zone lymphoma, an indication with significant unmet needs. The study is designed to enroll 50 patients and a futility analysis is expected to be conducted in the second quarter of this year. We anticipate the investigators will present the data from both studies at upcoming medical meetings. If these investigator initiated trials are positive, we would move quickly to determine the regulatory and or compendia path forward. I want to turn now to our solid tumor candidate ADCT-601 targeting AXL, which we are investigating in a Phase 1 study in sarcoma, pancreatic cancer, and non-small cell lung cancer. While others have explored AXL as a therapeutic target, we are especially excited by the potentially differentiated profile we see with the 601 D2, its innovative design incorporating a PBD toxin. AXL is expressed in multiple tumor types and it has been shown that high expression of AXL is correlated towards patients' overall survival across many cancer types, including non-small cell lung cancer, pancreatic, and sarcoma. Our Phase 1 trial includes monotherapy as well as combination arms with gemcitabine in sarcoma and pancreatic cancer. Given the high level of AXL expression, sarcoma is serving as the proof of concept. In January, we disclosed that we reached the recommended dose of 13 milligrams. In addition, we also shared that ADCT-601 was well-related at the doses tested and we have been encouraged by the early size of anti-tumor activity in both monotherapy and combination. The study is currently in part two which includes dose optimization and expansion. We plan to share additional data from the trial in a presentation at AACR next month for which abstract is now available online. With regard to the other indications, I am pleased to report that we have initiated screening in the pancreatic cancer monotherapy arm based on an enriched patient population. We also plan to initiate dosing in the non-small cell lung cancer pre-selected patients once we have optimized the assay for non-small cell lung cancer. I am encouraged by the progress we are making with our pipeline and look forward to sharing more in the future. I would now like to hand over to Patrick.
Patrick van Berkel: Thanks, Mohamed. It's a pleasure to update you all on our research activities. As we disclosed at the start of this year, as part of our broad toolbox, we're now developing ADCs utilizing a differentiated payload based on the topoisomerase I inhibitors, exatecan, together with a novel hydrophilic linker. Compared with commercially available toxins such as the DXD platform, our innovative and proprietary approach has shown evidence in preclinical studies for greater potency, stronger bystander activity and excellent tolerability. Initially, we are conducting research utilizing our exatecan-based platform against four highly attractive targets and indications with high unmet needs. The first is Claudin-6, which is a novel target that is highly expressed in ovarian, endometrial, testicular and non-small cell lung cancer. The second target is NaPi2b, a validated ADC target, which is also highly expressed in ovarian, endometrial, and non-small cell lung cancer. The third is PSMA, which is a validated ADC target, highly expressed in metastatic castrate-resistant prostate cancer. We intend to select a clinical candidate based on a novel optimized PSMA-specific antibody. Lastly, we are applying this platform to an undisclosed target. What I can say is that the target is a novel transporter protein, which is highly expressed in multiple hematological and solid tumor malignancies. For Claudin-6, NaPi2b, and the undisclosed target, we have completed in vivo pharmacology and dose range-finding studies in cynomolgus monkey. In each case, we've seen strong antitumor activity with an attractive therapeutic index and no evidence of interstitial lung disease. Based on the encouraging initial data from these three investigational candidates, we believe we have a differentiated ADC platform that can be applied to multiple tumor targets of interest. In terms of next steps, we will share data for Claudin-6 and NaPi2b at AACR next month. The abstracts are available on the AACR website, and I would encourage you to review them. Following AACR, we plan to share additional information on our differentiated research platform at an investor event in the second quarter. With that, I would like to hand over to Pepe.
Jose Carmona: Thank you, Patrick. Before I get into the financials and outstanding catalysts, I want to remind everyone of our corporate business development strategy. Hematology continues to be our primary focus. And within this, our key objective is to drive the value of ZYNLONTA. We will achieve this by fully supporting our commercialization effort in the US directly and through our partnership ex-US. In solid tumors, our aim is to pursue multiple ADC candidates in parallel and increase our shots on goal. We will determine on a case-by-case basis whether we wish to progress candidates internally or seek to partner in order to share the development and financial risk. Turning to our fourth quarter performance, we're now reporting our results under US GAAP as we became a US domestic filer starting January 1st, 2024. Starting with our balance sheet, as of December 31st, we had cash and cash equivalents of approximately $278.6 million or a $32 million decrease from the end of Q3. Moving to the P&L, as you already heard, ZYNLONTA net sales were $16.6 million in the quarter, a decrease of 16% versus prior year, primarily driven by higher gross-to-net due to discounted drug rebate and slightly lower volume, partially offset by higher gross price. Our total operating expenses on a non-GAP basis, which excludes stock-based compensation, were down 24% compared to the fourth quarter of last year. This mainly reflected our focus on driving operating efficiencies, together with reduced R&D expenditure due to focused investment in our clinical studies and lower selling and marketing expenses. For 2024, we will continue to take a very disciplined approach to our operating expenses. This is crucial to funding the development of our key pipeline programs and maintaining our expected cash runway into the fourth quarter of 2025. You will find the reconciliation of GAAP measures to non-GAAP measures in the accompanying financial tables of the press release issued earlier today and in the appendix of this presentation. Moving to the bottom of the P&L, on a GAAP basis, we reported a net loss of $85 million for the quarter or $1.03 per basic and diluted share. This took our full year 2023 net loss to $240 million or $2.94 per basic and diluted shares. My final slide highlights the multiple potential value driving milestones which we expect in 2024. With that, I will turn the call back to Ameet.
Ameet Mallik: Thanks, Pepe. To close, we entered 2024 with a clear strategic roadmap and the capabilities to drive value creation for all our stakeholders. My team and I are excited about the company's prospects and look forward to keeping you updated on our progress. Now we will be available for questions. Operator?
Operator: [Operator Instructions]. Our first question will come from the line of Naureen Quibria with Capital One Securities.
Naureen Quibria: Congrats on the progress. Actually, I was just curious about LOTIS-7. Can you talk about the safety data with bispecifics in combination to date, and what's been seen with other therapies? And relative to that, can you speak to your expectation for LOTIS-7, your level of confidence for this combination? And just on the same topic, you mentioned on the press release that you have a larger data set. You present – I mean, you have a larger data set. Can you just talk about sort of the size and scope of that data set that you would expect to release if it's after the 120 microgram data? Appreciate some granularity.
Ameet Mallik: Maybe I'll turn it over to Mohamed to answer both those questions on the safety profile and what we're hoping for and what we've been seeing as well as on – yeah, so, Mohamed, do you want to take it?
Mohamed Zaki: With regard to LOTIS-7, as you know, it's a dose escalation study of combination of the ZYNLONTA plus two different bispecification, glofitamab and mosunetuzumab in three different disease types, marginal zone, DLPCL, and follicular in third line plus. We are very encouraged by the fact that we have cleared the first dose levels, the 90 microgram per kg and the 120 microgram with no DLTs. And all we have seen so far is either no CRS or low-grade CRS that resolves very quickly. We are very encouraged by the anti-tumor activity we keep seeing in the study to date. It's an open-label study and we see things live. However, it's early days, and we would like to wait until we have more mature data to be able to share more mature cohorts later this year. I think that pretty much answers your question.
Ameet Mallik: Maybe just one thing to add. We're now currently dosing the 150 microgram per kilogram dose in both the glofitamab and the mosunetuzumab arm. Once those are cleared, we'll move right into the dose expansion in second line plus DLBCL with glofitamab. And that'll be the focus. That's where I think we're going to get a better representation of efficacy when we have a broader number of patients, longer follow-up, and in a single histology. And that's really the focus of part two of the study, which we will start as soon as we clear the dose escalation.
Naureen Quibria: I guess I have one for Kristen, and then I'll hop back in the queue. Just curious in terms of the penetration levels with the ZYNLONTA in the academic and community settings, what are those? Can you comment on that, number one? And number two, can you talk about what you saw in terms of how were you able to increase growth in academics, just out of curiosity?
Kristen Herrington-Smith: We don't share exact numbers of penetration. What I can tell you is that we had a strong foundation in the first couple of years of launch and within the academic setting. In 2023, starting in Q2, we really refined our strategy to focus more on the community. Our strategy of driving adoption with the community played out well, and we started to see the impact of that in Q4 2023. So not only did we see more community sites adapt ZYNLONTA, but actually, we also saw an increase in volume in the academic centers as well, post the entrance of two bispecifics. So we see this increased demand, and I would say in November and December, we started to see our demand levels come back to what we saw in the first half of 2023, and we look forward to driving progressive growth with ZYNLONTA with this refined strategy.
Operator: Our next question comes from the line of Brian Cheng with J.P. Morgan.
Brian Cheng: Just a couple. On LOTIS-5, can you talk about a little bit more about the censoring that you mentioned on the call? Specifically, what is the reason for the higher than expected censoring in LOTIS-5? And how much of that is due to safety-related withdrawal? And I have a couple questions left.
Mohamed Zaki: Mohamed, do you want to talk about LOTIS-5 and censoring?
Mohamed Zaki: Just want to highlight that it is not uncommon for initiate the need for increased enrollment in a global open label Phase 3. It's also not uncommon to see a little bit higher censoring when you are dealing with the relapsed/refractory diseases. The main reason we believe, or for the higher than ever censoring, is the lack of convenience from physicians and patients with relation to the control arm, possibly. And that's usually because the physicians usually want to be in the active arm, of course. So, you can expect to see a little bit higher than usual. And there was no concerns by the DMC that met in January with regard to any safety issue that is not related to any safety reason or anything related to do. But it is very important, this is simply replacing possibly missing events to reach the required number of events, clear the [indiscernible] to reach the end of the study. So, it's a replacement procedure that many Phase 3s do in order to make sure they get that on time. The good news is that, even with possible increase in the size of this trial, we do not anticipate to have a delay on finishing enrollment, which we have communicated to be within 2024. The reason for that is, recently, we have observed an acceleration of enrollment and we've seen really a quite high number of enrollments per month compared to month before.
Brian Cheng: Going back to your comment related to commercial branded profitability later this year, what does that actually entail? Can you talk about the gross-to-net we should expect in our model? And related to SG&A expenses, how should we model that for the rest of the year?
Ameet Mallik: Pepe, do you want to take that in terms of gross-to-net evolution? What commercial brand profitability means and the evolution of SG&A?
Jose Carmona: On brand profitability, what we expect this year is that the revenues coming out of ZYNLONTA in the US will be able to pay for all the expenses directly related to commercializing ZYNLONTA, which means all the sales force, marketing team, medical science liaison, and all discretionary spending, which would include A&P, cost of goods, IIT, and other related expenses. So, basically, from a capital allocation perspective, commercializing ZYNLONTA is not a usage of fund. It's more like a source of funds to start funding the pipeline. For modeling purposes, gross to net, if you've heard our messages in 2023, from the first half to the second half of the year, our gross to net increased a high single digit percentage point. We expect that 2024 will have a similar gross-to-net ratio that we had in the second half of 2023. So, we don't expect further increases, but as you model it in the first half of 2024, we'll be fighting over a higher gross to net than what we saw in the first half of 2023, like that same percentage points. So, high single digit increase in the first half of 2024 compared to prior year, but it will be more even in the second half of 2024 compared to the second half 2023. From an expenses perspective, we will continue to drive productivity measures. We are not providing exact guidance on all OpEx levels, but we will keep driving productivity across the board. Importantly, this year, the highest investment level that we have is in LOTIS-5, [indiscernible] trial for ZYNLONTA, which we expect full enrollment this year. So as the full enrollment happens and then the trial winds down into 2025, we expect a decrease of R&D expenses due to LOTIS-5. All that depends obviously on the success of the other trials, but that's the biggest driver of R&D expenses this year, which will decrease as we launch 2025.
Operator: And our next question comes from the line of Gregory Renza with RBC (TSX:RY) Capital Markets.
Gregory Renza: Congrats on the progress. Maybe just building on the commercial strategy. Amet, it's helpful to hear the color of the pull through from the fourth quarter. Just curious if the CD20 bispecific combination was within those expectations and any factors that we should be thinking about going beyond what Kristen and Pepe had indicated on the dynamics of uptake for 2024. And maybe just related to that, if I may, as we think about the longer term opportunity for late line, just curious if you have any updated thoughts on ZYNLONTA's positioning just relative to ADC based combinations and third line. I certainly saw the ECHELON-3, et cetera, triplet meeting its OS endpoint improvement regardless of CD30 expressions. Just curious if you had any updated thoughts on those evolving dynamics as well.
Ameet Mallik: I'll start and then I'll pass it on to Kristen and Mohamed in case they have additional comments. But, yeah, I would say overall bispecifics are definitely gaining ground in that third line setting post CAR-T. You saw there was strong growth. While CAR-Ts are basically kind of flattening out right now when you look at – out of the sales of all the CAR-T [Technical Difficulty] in Q4 versus Q3 is kind of flattening out. Bispecifics continue to grow dynamically and the uptake, particularly in the academic setting, continues to grow. In the community setting, while they've been used in more sophisticated centers, the uptake there is much more limited. I think what we found though is that there's a clear place for ZYNLONTA, either for patients where a bispecific is not suitable, where a patient may need even faster responses for ones that progress post their bispecifics because it doesn't work for every patient. So I think academic positions have sort of figured out how to best use ZYNLONTA around a dynamic where there is a new competitor and when bispecifics are growing. So we saw part of that rebound because I think, in Q3, where there was a big push towards just bispecifics, in Q4 we saw that ZYNLONTA continued to be used with those that progressed or those who were not as suitable as doctors sort of figure out the best patients to go to a bispecific post a CAR-T. In terms of the competitive landscape, I think the whole space is moving towards combinations. I think one of the advances we have is that we're approved as a single agent and we have strong single agent activity. Not many drugs that have been approved as a single agent. In fact, the bispecifics and ZYNLONTA are two of the only drugs [Technical Difficulty] that have been approved as single agents. And so, I think our combination strategy with both LOTIS-5 and LOTIS-7 position us really well. I think we'll have competitive profiles with those two combinations that, in spite of an evolving landscape, will position us really well for growth not only in the third line setting where we are today, but also in the second line setting where we will move with those trials. Kristen and Mohamed, is there anything else that I missed that you would add?
Kristen Herrington-Smith: The only thing that I would add, two things. One, just to add on to your evolving landscape, we see already with polatuzumab moving up to the front line that it is creating a need for a different mechanism in the second line and third line. So definitely carving out a space for ZYNLONTA, whether it's today or in combination once we get LOTIS-5 and LOTIS-7. The other question was around ECHELON-3. We also saw that. We've been tracking – we always track our marketplace and the dynamics. And one, it's nice to see a win for an ADC. It reinforces the efficacy of ADCs. But, two, we haven't seen any data on that trial other than the headline that Pfizer (NYSE:PFE) put out in terms of the overall survival win. R squared is used. It's pretty uncommon use, primarily in the community, but still we'd love to see the data that Pfizer has on their triplet versus the doublet and look forward to that, so that we can better put it into context and understand any impact in the market.
Mohamed Zaki: If I may ask, Kristen, also regarding the [indiscernible] story, is that we need to see how the control arm in the trial actually did to be able to better evaluate the data and understand it better. Specifically, this is in third line plus, if I understand the trial correctly. Our target is for LOTIS-5 and the potential to see this to go to second line plus. So it's not directly, but in a very minimal number of patients. And when you get to third or fourth line, there may be some combo. However, we don't know that in details, of course, to be able to understand it better.
Gregory Renza: Ameet, maybe just a follow up as Patrick has discussed the NextGen platform. Just wondering – and we all look forward to an event later this year, as you mentioned. Just wonder if you could elaborate a bit on just the rationale for selecting NaPi2b, Claudin, and PSMA just for the NextGen ADCs. And do you have a sense at this point which targets or target has the strongest rationale for internal versus the external partnerships that Pepe alluded to?
Ameet Mallik: Maybe, Patrick, do you want to take the first part of the question? And then, Pepe, you can take the second part of the question around partnering.
Patrick van Berkel: We have selected these targets because we think that they fulfill all the criteria for good ADC targets. If you look at what's known for them, it's clear that for each and every target, there's a very good level of validation for targeted approach. Of course, they're all expressed in indications with high unmet need. And we also very carefully looked at the competitive landscape for NaPi2b, Claudin-6, PSMA and the undisclosed targets. And we believe that, in most cases, if not all, we're among the first three to four players studying those targets. But, of course, with a differentiated approach using our novel exatecan-based platform. So to us, that means they really are attractive targets to work on.
Jose Carmona: Let me take the partners discussion. So as we disclosed, the next generation exatecan-based payload and the target earlier this year in January 4th, we did an outreach with several companies and we already started some discussions. These conversations and that potential partnership takes a few quarters. So it's not something that you would do in a short turnaround. But we do see the interest and we will continue to advance those conversations for potential partnerships this year.
Operator: [Operator Instructions]. Our next question comes from the line of Kelly Shi with Jefferies.
Unidentified Participant: This is [indiscernible] for Kelly. First question, just wanted to confirm that – is safety the only thing that you need to clear before moving into second line? And when would you expect to have any data available from second line patient? Secondly, for AXL study, can you remind us if you enroll patient based on expression and we have that biomarker data available when the data is presented at AACR?
Mohamed Zaki: Yes, in terms of the expectation from LOTIS-7 dose escalation is to clear the dose levels. And based on that, [indiscernible] protocol, we are allowed to move directly to second line for expansion. We're expecting to share information focused on safety in the second quarter and more on the expansion of second line in DLBCL specifically in later in 2024. In terms of AXL, so far our enrollment is not with a pre-selection strategy. However, as of the pancreatic enrollment will be enrichment and for non-small cell lung cancer we will be pre-selecting.
Operator: At this time, I'm showing no further questions. I'd like to hand the conference back over to Mr. Mallik for closing remarks.
Mohamed Zaki: Yeah, thanks all for your attention and interest in ADC Therapeutics. Between now and our next earnings call, we expect to share some important updates on LOTIS-7, on the futility analysis and top line data of ZYNLONTA as a single agent in marginal zone lymphoma, and on data being presented at AACR which we will follow up with a research investor event. As such, we look forward to multiple interactions with you in the coming months. With that, I would like to close the call. Thank you all.
Operator: This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.
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