This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk02: Hello and welcome to the Arcus Biosciences full year slash Q4 2023 earnings call. My name is Elliot and I'll be coordinating your call today. If you would like to register a question during today's event, please press star followed by one on your telephone keypad. I'd now like to hand over to Pia Eves, Vice President of Investor Relations. The floor is yours. Please go ahead.
spk11: Hello, everyone, and thank you for joining us on today's conference call to discuss ARCIS' fourth quarter 2023 financial results and pipeline updates. I'd like to remind you that on this call, management will make forward-looking statements, including statements about our cash runway and our expected clinical development milestones and timelines. All statements, other than historical facts, reflect the current beliefs and expectations of management and involve risks and uncertainties that may cause our actual results to differ from those expressed. Those risks and uncertainties are described in our annual report on Form 10-K, which has been filed with the SEC. We strongly encourage you to review our filings. Today, you'll hear from our CEO, Terry Rosen, COO, Jennifer Jarrett, CMO, Dimitri Naughton, and CFO, Bob Gels. We'll also be joined by our President, Juan Jaen, for questions after the prepared remarks. During today's call, we'll refer to slides in our corporate deck, which can be found on the investor section of our website. With that, I'll now turn it over to Terry.
spk08: Thanks very much, Pia, and thank you all for joining us today. We've really come a long way since our founding nine years ago, and I think it's fair to say we have evolved into an integrated biopharmaceutical company. We've got seven molecules in clinical development, a broad late-stage portfolio, multiple mid-stage clinical trials, a robust discovery engine, and now something I think new line of sight to commercialization. With $1.2 billion in cash and equivalents in runway into 2027, we're well positioned to deliver on the promise of the late stage pipeline that we've built. We'll start three new registrational trials. We're going to continue to invest in our early stage programs. We also have a partnership with Gilead, as well as collaborations with Tyho, Exalexis, and AstraZeneca And I think it's very fair to say without these partnerships and the resources that these companies provide, we would not be able to execute on everything that we're doing. All of our programs target markets that are massive and, you know, really are the sweet spots of large pharmaceutical companies. All comer patient populations and lung cancer, gastric cancer, pancreatic cancer, and renal cell carcinoma, RCC. Our funding and partnerships enable us to not only pursue these settings, but to compete and compete effectively and aggressively. We're really doing what we're saying we're doing. We also continue to build for the long term with a broad pipeline of potential best-in-class and first-in-class product candidates that will continue to replenish organically with our drug discovery engine. Today we have three advanced clinical stage programs. Dom plus Zym, our FC silent anti-tigit, it's very differentiated in molecule, and our anti-PD1 antibody. our small molecule CD73 inhibitor, and 8521, our HIF-2-alpha inhibitor, which is, as of today, known by its generic name, Casdataban, or Cas. DomZim is in phase three, and we expect to initiate phase three studies for both Cas and Quimley by early next year. So we'll have four molecules, all with distinct mechanisms in phase three in 2025. We also have some exciting datasets coming in the first half of this year, for another molecule, and these really are exciting, eTRUMA. That's our A2 receptor antagonist, and it's Gilead believes support further investment in the molecule. We made a lot of progress across all these programs in 2023, presenting two large data sets for DomZim and two different cancers, and another large data set just last month for Quimley and pancreatic cancer. I want to start today by reviewing these programs and data sets, then spend a few minutes on the recent Gilead partnership updates, and finish with some new data for Cas, our HIF-2-alpha inhibitor. So starting with our anti-tigit program, DomZim. Our primary competitors in space are Merck and Roche. We have the only FC silent anti-tigit antibody in late-stage clinical development. So with Dom's potentially best-in-class profile, its optimized dosing regimen, as well as a broad development program focused on lung and gastric cancers, we're really in a very strong competitive position. Our conviction in DomZim supported by two data sets that we've presented in the last 12 months and are summarized on slide nine of our corporate deck. First, at ASCO last year, we presented data from our randomized phase two ARC7 study showing a PFS hazard ratio of 0.67 for DomZim relative to Zim monotherapy in first line PD-L1 high non-small cell lung cancer. We also presented data from our Phase II edge gastric study, where we evaluated DomZen plus chemo in first-line upper GI cancers at the escapulinary session in November. These data demonstrated impressive six-month landmark PFS rates of 93% in PD-L1 high patients and 77% overall. This really compares quite favorably to the historical benchmarks for anti-PD-1 plus chemo that are in the 50% to 60% range. Our development program for DomZim is focused on settings where we have the best chance to be a market leader. Today we have three phase three trials enrolling and we expect both STAR-121 and STAR-221, our chemo combo trials and PD-L1 all comers for first line non-small cell lung cancer and upper GI cancers respectively to complete enrollment this year. In fact, we can share now today that we anticipate STAR-221 will be fully enrolled by the middle of this year. Due to the extremely rapid enrollment of STAR-221 and relatively short OS for the standard of care, we expect STAR-221 to be the first of our Phase III trials to read out. And importantly, with no other Phase III trials ongoing with the antitiget antibodies in this setting, we expect to have a significant first-to-market advantage. Meanwhile, we continue to invest in the expansion of our DOMSIM program. We in Gilead will initiate STAR-131, which will evaluate DOMZIM plus chemo and perioperative lung cancer. This is an exciting early stage and potentially curative setting. We also expect to initiate a fourth phase two study in a setting outside of lung and GI cancers. Beyond our DOMZIM program, today we'll be sharing data from the dose escalation phase of our ARC-20 phase 1b trial of Casdatafan or AB521. The 100-milligram expansion cohort of ARC-20 enrolled quickly and then completed enrollment ahead of schedule, November of last year. Later today, we'll touch on what we're seeing so far in these data. The competitor here is Merck with their HIF-2-alpha inhibitor, Belzudifan, which was just approved for advanced clear cell RCC, but we believe that CAS has a best-in-class profile, and that's addressing a very well-recognized limitation of Belzudifan. What we've seen thus far in ARC-20 has given us confidence that our molecule has a superior profile to that of Belzodifan. We're advancing CAS rapidly and are on track to initiate a Phase III study early next year. And last for QEMLI, our CD73 inhibitor, we presented overall survival data in pancreatic cancer from our ARC-8 study at ASCO-GI last month. With a large pooled data set, 122 patients, we showed 15.7 months median overall survival for CoMLE plus chemo, both with and without ZIM. This compares to the median OS from historical GEM-NAP-paclitaxel studies, nine to 11 months in first-line pancreatic cancer. We also conducted a MAPS synthetic control analysis that showed a statistically significant improvement in OS with a hazard ratio of 0.63. Based on the strength of these data, we're on track to initiate a phase three pancreatic cancer trial by early next year. With Gilead's equity investment in January, we had approximately $1.2 billion of cash on hand, and we're really well capitalized to support the breadth of programs that we are pursuing. At a high level, Gilead's investment accomplishes two things. First, it provides us with runway into 2027 while enabling us to fund phase three programs for four different molecules. Second, it enables us to fund our pre-commercial activities and on the other end of the spectrum to continue supporting our robust discovery engine. I'd like to turn things over to Jen right now to spend a few minutes on the details.
spk13: Thanks, Terry. Gilead invested $320 million by purchasing our stock at $21 per share. which represented an effective premium of nearly 40% to our share price just before the announcement, increasing their ownership to 33%. In parallel, Gilead's Chief Commercial Officer, Jonna Mercier, joined our board. Her addition increases their board membership to three, provides representation commensurate with their ownership, and brings a very experienced commercial perspective to the ARCIS board. The investment falls for two dynamics. One, the expansion of our late-stage clinical development plans And two, the extension of our cash runway into 2027 and through multiple data events. Concurrent with the investment, we made a few strategic portfolio changes related to Don Zim and Queveline. First, for Don Zim, we closed enrollment of our phase three ARC-10 study, evaluating Don Zim and PD-L1 High non-small-cell loan to focus our resources and capital on areas with the highest unmet need and greatest market opportunities. A seminal factor that drove our decision was the evolution of the lung cancer treatment paradigm toward increased use of anti-PD-1 plus chemo for patients with PD-L1 high expressing tumors. Therefore, we believe this segment of the patient population is best addressed by our STAR-121 study, our chemo combination study, and PD-L1 all-comer non-small cell lung cancer. The clinical trial landscape for PD-L1 high lungs has also become increasingly crowded with several anti-TIGET and other investigational therapies, and we were not expected to be first or second in the PD-L1 high chemo-free setting. At closing our 10th, we are now able to focus our energy and resources on rapidly completing enrollment for STAR-121, which is addressing a much larger market opportunity. We'll also initiate a fourth stage 3 study for DOMZIM, STAR-121, a potential first-to-market opportunity. Second, for Quimley, we announced that ARCIS will be operationalizing and funding a Phase III study evaluating Quimley and pancreatic cancer. Gilead retains an option to the pancreatic cancer program with the opportunity to pay a premium to their share of the Phase III costs in the future. While Gilead is not co-funding this study, as you might imagine, they are aware that proceeds from the investment will be used to fund the study. I'll now turn it back to Terry.
spk08: Thanks, Jen. Now I'd like to switch gears to Cass our HIF-2-alpha inhibitor. This year is essentially going to be a coming out for this program, as we're planning to release a lot of new data, as well as more information on our future development plans. We believe that by hitting the HIF-2-alpha target harder than Merck's Belzodifan, we can improve outcomes for patients. We'll discuss the pharmacokinetics and pharmacodynamics that support this thesis in more detail shortly, but I'd like to start with the potential areas for differentiation versus Belzudafan. Belzudafan was recently granted approval as monotherapy in third-line clear cell RCC after just a three-month FDA review process. This really validated the mechanism and highlighted the high unmet need for new therapies in this market. In Merck's Phase III LightSpark-005 trial, Belzudafan showed an improvement in PFS over Everolimus with a statistically significant hazard ratio of 0.74, which supported its approval. While these results are absolutely encouraging, the study reveals multiple opportunities for a new agent to prove upon Belzudafan's profile and provide even more benefit to patients. First, on clinical efficacy, in LightSpark 05, Belzudafan had a high rate primary progression, specifically a 34% PD rate, which was actually higher than that of the Everolimus control arm at 22%. This means that over one-third of patients on Belzudifan progressed at or before their first scan. We believe that Casdatafan could stabilize tumor growth faster, resulting in a lower PD rate and therefore longer PFS. With an overall response rate of 21.9% in LightSpark-005, we believe there is room for improvement. Third, while LightSpark-005 showed a statistically significant PFS hazard ratio, the median PFS was only 5.6 months. This may result in more durable tumor stabilization or shrinkage, and therefore longer median PFS. Fourth, and this is an important fourth, we believe there's an opportunity for a better tolerated combination regimen. Belzudifan's TKI partner in earlier line CCRCC studies is lenvatinib, which is perceived, and it really is perceived that way, to be less well tolerated relative to other TKIs such as Cabo and Zanza. Last, we are being very thoughtful in our development strategy for Cas, and we'll focus on settings and combinations. where we believe we can be first to market or differentiated relative to Belzudafan, and you'll hear more about this over the course of the year. As you may know, Merck is now projecting that Belzudafan has blockbuster potential. Given the opportunity, we're pushing this program as hard as possible, and while our data will be more mature later this year, we want to share as much as possible today to illustrate why we're so excited about this program. I'll now turn things over to Dimitri to share new data from our ARC-20 trial, evaluating casts in cancer patients.
spk10: Thanks, Terry. I'll start by turning to slide 29 of our corporate deck, which shows the design of the trial, including both the dose escalation phase and expansion cohorts. The dose escalation portion enrolled patients with any advanced solid tumor, while the dose expansion cohorts are only enrolling patients with second-line or later clear cell RCC. There are three expansion cohorts, each of which will enroll 30 patients. The first evaluated our go-forward dose of 100 milligrams per day and completed enrollment in November. To satisfy the FDA's requirement for dose optimization, we are also evaluating a 50 milligram dose cohort and another cohort at a higher dose than 100 milligram in the expansion phase. Enrollment of the 50 milligram cohort is nearing completion. Collectively, These expansion cohorts will generate a lot of valuable safety data and efficacy data in clear cell RCC patients. The dose escalation portion employed a three-by-three design where three patients received 20 milligrams, followed by three patients who received 50 milligrams, and then three patients who received 100 milligrams, all daily dosing regimens. The safety results of our healthy volunteer trial enabled us to start in R20, our patient trial, at a relatively high and pharmacologically relevant dose, and we saw no dose-limiting toxicities, allowing us to complete the dose escalation phase with only nine patients. We subsequently backfilled the 50 milligram dose cohort with three additional patients, resulting in 12 patient data set for this portion of the study. Of the 12 patients, four patients have clear cell RCC. Slide 30 is important and shows data for CAS and BELS on EPO. reductions, the peripheral or normal tissue biomarker for HIF-2-alpha inhibition. On the left-hand side, the dotted line shows the EPO reductions reported for the 120 milligram or the approved dose of Belsudafen in clear cell RCC patients. In contrast, Cas achieves the same level of EPOS suppression at just 20 milligrams, showing here with the purple line, and that is one-fifth of our go-forward dose of 100 milligrams. This means that 20 milligrams is roughly equivalent from a PD perspective to the approved dose of Belsudafan, and therefore, 100 milligrams of Cas has the potential to achieve a meaningfully greater HIF-2-alpha inhibition. On the right-hand of the slide, you can see that Cas has a linear, almost perfect dose-proportional pharmacokinetic profile. In addition, Cas has a half-life of approximately 21 hours, and this enables daily dosing. Slide 31 emphasizes the ideal PK of Cas relative to that of Belsudafan, and it explains why Belsudafan cannot simply be dosed higher to achieve greater HIF-2-alpha inhibition. On the right, for Cas, we show that we increase to dose from 20 to 100 milligrams at steady state, and we observed roughly five times increase in exposure. By comparison, as you can see on the left, when Bell's dose was increased from 120 to 240 milligrams, the drug exposure only increased by about 30% at steady state. A 30% increase in exposure is less than the typical patient-to-patient variability at any given dose, and therefore is not a clinically meaningful increase. This illustrates why doses higher than 120 milligrams of Belsudafan are unlikely to result in meaningfully better clinical activity. And in fact, this was demonstrated by Merck in the LightSpark 13 trial, comparing the efficacies of 120 milligrams and 200 milligrams of Belsudafan. In summary, these data show exactly what we have been predicting, that Cas has a best-in-class PK-PD profile, which should result in hitting the target harder and potentially in greater clinical activity relative to balsudafen. Turning now to safety, on slide 32, we show the reductions in hemoglobin levels at various doses of Cas relative to the approved dose of balsudafen. Hemoglobin reductions appear to plateau at doses above 50 milligrams for Cas, likely due to compensatory mechanisms. And you can see that 100 milligrams daily of Cas resulted in similar reductions of hemoglobin as Belsudafan, despite the fact that we are achieving higher doses, much higher doses of potency-corrected drug exposure for Cas. For this reason, we expect Cas's safety profile to be manageable and not meaningfully different than Belsudafan. On the next slide, slide 33, we show the AE profile so far in the dose escalation phase of the study. Anemia and hypoxia are expected on-target toxicities related to HIF-2-alpha inhibition. While we are watching very closely with a median follow-up across all those levels of the escalation of about 8.8 months so far, these rates do not appear to be higher than the rates seen with Belsudafen in historical clinical trials. These data demonstrate that while we believe that we are hitting the target harder, Cas appears to have a similar safety profile to that of Belsudafen. So let me tie this together. We are effectively able to deliver an exposure to Cas that is five-fold greater than that which achieves the same level of inhibition of the peripheral biomarker for HIF-2-alpha blockade associated with the approved dose of balsudafen with no apparent differences in safety profile. While efficacy was not the objective of the dose escalation phase, particularly given the advanced stage of patients and the different doses evaluated and the different tumor types included, on slide 34, we do summarize what we observed in RCC patients, specifically clear cell RCC patients. As I mentioned earlier, there are four patients spread across the three different dose levels we evaluated, 20 milligrams, 50 milligrams, and 100 milligrams. These are all late-line patients with a variety of prior treatment regimens, including at least one anti-FETGF treatment and one anti-PD-1 treatment. Three out of four patients are actually fourth, line, or later. And for these four RCC patients, two had meaningful tumor reductions just short of 30%, and a third patient did not experience any tumor growth for over 14 months and still remains on treatment. The time on treatment is impressive for these patients in very late-line setting, ranging from 8.5 to 14.5 months, and two of the four patients still remain on treatment. This indicates the potential of very durable effects of CAS, even with monotherapy in a very advanced patient population. We are also seeing signs of catheter's ability to bring even aggressive tumor growth under control. For example, one of the four patients I mentioned was very heavily pre-treated, had received three prior FETGF TKIs and an anti-PD-1 treatment. And this patient had stable disease early on with slight increase in tumor volume, not meeting formal progression per resist. And after about 18 months, the tumor volume started to come down. And now, after about 10 months and still ongoing on treatment, the patient is nearing a response. I would like to emphasize that while the primary goal of an all-comer dose escalation study is to establish the safety profile and assess the pharmacokinetics and pharmacodynamics, We have already seen clear signs of anti-tumor activity in patients with advanced ClearSoRCC, and we believe the tumor shrinkage and the duration beyond one year for patients who have exhausted all available treatment options are very clinically meaningful. The ongoing expansion portion of the phase is designed to give us a better read on efficacy, and this is already providing clear support for the initial observations in the dose escalation phase. And I would like to make a few comments on the early data of the expansion portion of the study. The 100 milligram cohort has completed enrollment in November, so we have a mature and rich data set in hand for 30 clear cell patients treated at 100 milligrams of Cas. While these data are still early, we are already seeing glimpses of Cas's potential for differentiation over Belsudafan. We'll share the full data set at a medical conference later this year, but we did feel it was important to share some highlights of the data today. First, the majority of patients in the expansion cohort have only had one or two scans, and we scan patients approximately every six weeks, so it's about one and a half to three months of follow-up. Nonetheless, even with this very short duration of follow-up, the response rate we are seeing, which includes unconfirmed responses given how limited the follow-up time is, it's already in line with the response rate seen for Belsudafan in LightSpark 005. We also have a substantial number of patients early on their treatment who have experienced tumor shrinkage but have not yet crossed the formal threshold of 30% to meet a response, but this obviously can happen with longer duration of treatment on future scans. Secondly, we are seeing a relatively low primary progression rate, and this is the percentage of patients whose best overall response is progressive disease. So these patients have tumor progression on the first scan. This may indicate that Cas can stabilize tumor growth early on during treatment, and this will be an important parameter to monitor in the future as it represents an opportunity to prove upon something that was reported for Belsudafen. In summary, we are very encouraged by these early dose escalation and expansion cohort data, which, while early, have provided an encouraging signal that Casus PK PD profile could translate into greater efficacy in the clinic. By mid-year, we will have a minimum of seven months of follow-up for all 30 patients in the 100 milligram expansion cohort, which should provide a mature look at the overall response rate, and we expect to present these data at a medical conference in the second half of the year. As I mentioned earlier, ARC-20 includes two additional expansion cohorts And we expect this to also be presented over the next 12 to 18 months. We also expect data from Stellar 09, our study evaluating casts together with Sansalitinib, also referred to as Sansar, sometime in 2025. We are full speed ahead to our phase three study, and we expect to disclose more on our development plan in the coming months. Terry will outline our other catalysts for 2024, but first I will turn things over to Bob to discuss our fourth quarter and full year financials.
spk15: Thanks, Dimitri. As Terry outlined earlier, ARCIS continues to be in a very strong financial position. Our cash as of December 31st, 2023, was $866 million, an increase to $1.2 billion after Gilead's January equity investment. Importantly, our partnership with Gilead is very capital efficient because we share the majority of costs for option programs 50-50, including multiple Phase III studies for DOM-ZIM. Gilead has also committed to pay the $100 million option continuation payment due in July under the collaboration agreement. So we expect our cash balance at the end of 2024 to be between $870 and $920 million, and now expect our cash to fund operations into 2027. This guidance excludes other potential opt-in payments and approval milestones from our partners. Turning to our P&L, we recognize gap revenue for the fourth quarter of $31 million, which compares to $32 million for the third quarter of 2023. Our revenue is primarily driven by our collaboration with Gilead, and we are evaluating the impact of the recent amendment on our revenue for 2024 and beyond. In addition to our partnership with Gilead, we have a partnership with Taiho for DOM in Japan. In the fourth quarter, we received a milestone payment of $14 million from Taiho related to their participation in our STAR-221 physical study, and we'll receive another $30 million in the first quarter of 2024 related to their participation in our STAR-221 and STAR-121 pivotal studies. We are also eligible for additional milestone payments of $10 million in the first quarter of 2025 from TIHO related to STAR-121. Our R&D expenses for the fourth quarter are stated net of reimbursements from Gilead and were $93 million as compared to $82 million in the third quarter of 2023. In the fourth quarter, non-cash stock compensation represented $9 million of our R&D expenses. The increase in the fourth quarter was related to standard of care purchases for our clinical trials. We continue to expect modest increases in R&D expenses as our phase three studies mature, and spend will fluctuate primarily based on the timing of clinical manufacturing activities and the purchase of standard of care therapeutics for our clinical trials. G&A expenses were $29 million for the fourth quarter of 2023 compared to $30 million in the third quarter of 2023. Non-cash stock compensation represented $9 million of our G&A expenses for the fourth quarter, and we expect G&A to remain stable for 2024. For more details regarding our financial results, please refer to our earnings press release from earlier today and our 10-K. I'll now turn it back to Terry for concluding remarks.
spk08: Thanks very much, Bob. Before we open the floor to questions, I'd like to briefly touch on upcoming catalysts for 2024 beyond the AHRQ 20 datasets that Dimitri highlighted. There's a lot. This will be another data-rich year for AHRQIS. For the anti-tigit program, we'll be presenting updated data from Edge Gastric, our phase two study evaluating DomZim plus chemo in upper GI cancers at ASCO this year. We expect this dataset to include updated ORR and PFS data. We also look forward to announcing the completion of enrollment for STAR-121 and STAR-221, which will obviously start the clock for potential regulatory filings. We also may share data and insights from ARC-10 at a future medical conference. As I mentioned earlier, we presented impressive overall survival data from our Phase 1b ARC-8 trial that was evaluating QEMLI and first-line pancreatic cancer. Also related to the adenosine pathway, We have two randomized data sets that we expect to share in the first half of the year for eTRUMA, our A2 receptor antagonist. And we believe these confirm our findings in ARC-8 that adenosine modulation confer profound improvement on overall survival. So first off, Roche will be presenting data from Morpheus PDAC. This is a randomized study operationalized by Roche that evaluated eTRUMA in combination with chemotherapy and etizole, their anti-PD-L1 antibody, versus chemo in pancreatic cancer. So a randomized study that involves eTRUMA. Second, we submitted data from the third-line cohort of ARC-9 presentation in a medical conference. This cohort enrolled 105 patients and evaluated eTRUMA plus ZIM plus BEV and FOLFOX versus REGO, the current standard of care third-line colorectal cancer. The presentation will include mature PFS and, importantly, OS data, which we believe are also very supportive of the potential for adenosine modulation when combined with immunogenic chemotherapy to robustly, we mean robustly, prolong PFS and OS. So, in conclusion, we've covered a lot today, a lot of material. But if there's one thing to take away from today's call, It's that ARCIS is now fully enabled to execute on its diverse, late-stage portfolio with funding into 2027. And that excludes potential future opt-in payments. Our portfolio includes six ongoing and planned Phase III trials, multiple Phase I and II studies, and a discovery engine that's just capable of generating at least one IND per year. Our trials are focused on huge markets by any standard, lung and GI cancer, pancreatic cancer, and RCC, where we're extremely well positioned to compete with potential first-to-market or best-in-class therapies. We have a lot going on, adding a lot more to come this year. Thanks for your interest and support for ARCIS as we continue to broaden our portfolio of innovative combination cancer therapies, and we're working to bring these treatments to patients as soon as possible. We'll now open the floor to questions.
spk02: Thank you. If you would like to ask a question, please press star followed by one on your telephone keypad. If you would like to withdraw your question, please press star followed by two. When preparing to ask your question, please ensure your device is unmuted locally. First question comes from Terence Flynn with Morgan Stanley. Your line is open. Please go ahead.
spk00: Hi. Thanks for taking the question, two part one for me. Just wondering on CAS, the HIF-2-alpha program, slide 24, the dose expansion data, can you just confirm what the ORR was and how many of those were actually confirmed versus unconfirmed? And then the second part of the question relates to a potential Gilead opt-in on this program. Maybe, Terry, you could just remind us the mechanics of how that type of a decision would work in terms of how little or how much data you would provide to Gilead, and then how long they have to make a decision. Thank you.
spk08: Thanks, Terrence. So on the first question, we didn't share a specific ORR intentionally. Actually, 70% of the patients have only had one or two scans, so we will wait until the second half of the year to give that number, but we're seeing a number of responses And in fact, then there's double digit patients that are stable disease with tumor reduction that may convert to response. The second part with respect to Gilead-Often, we have defined very specific criteria together with them. We haven't shared those exactly, but if you look at what we've described in general for the relationship, that often occurs when we've generated proof of concept data. So you can draw your own conclusions as what's coming later this year. And our belief is that they're very excited about the molecule in the program, but we'll see what they actually decide. I'll make one last final point. That is a program that we obviously wouldn't mind taking forward ourself, and we also have had plenty of inbound interest from other companies that might see a strategic fit with the rest of their portfolio.
spk02: We now turn to Peter Lawson with Barclays. Your line is open. Please go ahead.
spk03: Great. Thanks for the update. Thanks for all the information. On CAS, is that able to reduce the number of fast progressors you were talking about? And are you seeing any complexity in recruiting patients for HIF-2-alpha plus SAMHSA, you know, both two non-approved drugs, if that in any way you think affects the patients you get to see?
spk08: So we actually have had a number of discussions on that topic. We do not see that we're going to be, while we'll define for the rest of the world the future development strategy, We're going into settings that we think make sense, including with ZANZA. And we also, in parallel, will be exploring combination with CABO, so we'll have both of those under our belt. But we feel very good about our ability to enroll. And keep in mind, we're not planning, obviously, in the context of this question, to be going after monotherapy at this point. And so we'll be going against a standard of care that doesn't involve Belazudafan, and we feel like very well positioned to execute on those trials. And in fact, a huge degree of excitement. We've already had a first Ad Board meeting, and the enthusiasm for both HIF-2 as a general mechanism from what investigators have seen with Bells, as well as their anecdotal experience, which is now starting to get to be substantial with Cas, makes the field very exciting. So we actually expect very rapid enrollment, as we've seen already for this molecule.
spk03: And then just on the kind of the rapid progressives, are you kind of seeing that Or a reduction in that, rather?
spk13: Yes. So, if you look at light spark five, which is a phase three study for and you can look at what the primary progression rate was in that study and were lower than that. You know, we talked to investigators about light spark zero zero five, the primary progression rate, which was relatively high. was sort of a thing that stuck out for them. You know, the results overall were very encouraging, but I think that's one thing that they would love to see improved upon was the primary progression rate and just the number of patients that just kind of blew right through Belzutifan treatment. So, like I said, you know, we're seeing a lower number than that. We think it's another opportunity to improve upon Belzutifan, and there'll be more to come on that later in the year.
spk02: Perfect. Thank you so much. We now turn to Kaveri Polman with BTIG. Your line is open. Please go ahead.
spk12: Good evening. Congrats on the progress, and thanks for taking my questions. For 521, those expansion data, the ORR that you provided, can you tell us or provide any color on how precreated these patients were compared to the Light Park 005 trial? And the trial, I believe, excludes patients with prior HIF-2-alpha treatment. But do you think higher exposure could make these patients respond to 521?
spk08: So, Dimitri, why don't you talk a little bit about the, you know, treatment of those patients in the expansion study?
spk10: Sure. Yeah, thanks for the question. So, regarding the prior treatments, The inclusion criteria for the expansion cohort allow for patients in a slightly earlier setting than in the dose escalation phase. So in the dose escalation phase, we required people to have exhausted all reasonable treatment options, and therefore third to fourth line was what we expect. In the expansion cohort, we are still seeing a fairly similar profile of pretreatment, and that's something we think is let's say, what we are expecting. It also puts our early efficacy observations in a positive daylight. Many patients in the expansion cohort also had two or three prior VEGF TKIs, and they all are required to have PD-1. So if I summarize it, we do allow slightly earlier stage patients, second line and beyond, where in the escalation phase, it would have been third line and beyond. But overall, so far, the prior treatments are very, very similar. As to the Belsudivant question, It is an interesting question. It is something I think worthwhile thinking about. However, including patients now with Belsudafen prior treatment I think will make it really hard to interpret the data because one reason could be that patients did not respond because the target wasn't hit hard enough. There could be complete, let's say, resistance for HIF-2 targeting. I think that looking at the Belsudafen data, if you look at the primary progression rate, a number of those patients but presumably would have been hard to get under control. Those might benefit, but there could definitely be patients who have resistance to HIF-2 alpha targeting. So I know it's not a simple answer. I think for a clean efficacy signal right now, that's why we are excluding prior HIF-2 treatments, because it's too complicated, and one patient who progresses on Belsudafen would not be the other patient So that would have to be explored in a more detailed setting where you really capture the detail of prior treatment.
spk13: I think it's very interesting to get a little more granular about prior lines of treatment in that expansion cohort. I can't give you the exact numbers, so it hasn't been in front of me. So four of the 30 were second line, so it was a minority of the patients in that arm. Nine were third line, and then the remainder, so that's 19, were fourth line or later.
spk01: And have all those numbers. As a reminder.
spk13: One other reminder, you know, on Licebark 5, again, you had a phase three study for BELS. The inclusion criteria was one, two, three prior lines. So, patients with more than three prior lines were excluded from that study.
spk08: Go ahead, Kabir. Did you have a follow-up?
spk12: I just have, if I can ask another question. For Morpheus PDAC study, Can you tell us what you're expecting in terms of efficacy, especially OS, and whether you expect a tumor to perform better or worse than Quimley, and if outcomes from this trial could change anything for your plans to initiate a Phase III trial for Quimley?
spk08: So, Kavari, it doesn't change anything. And what you'll see is the OS data, I'll just say, they're going to be, you know, similar to what you saw um for arcade now the the there's two interesting components there's actually they have a gemma braxane control arm in the study so it's randomized our study as you know we conducted that synthetic control analysis which gave us great data the thing about arcade is that um it's a larger end uh but on the other hand um the Morpheus study has the randomized arm, and they both point to the same answer. So, to me, that's the big takeaway is you have two studies that affect adenosine in two different ways, but bottom line are removing the effects of adenosine. They're both producing what we would say are pretty profound effects on overall survival, which is, you know, to us very important. And so far as the TRUMO versus QEMLI, we've had that question in mind for some time. At this point, we'll still say, other than in some very specific settings where there may be known non-CD73 mechanisms for adenosine formation from adenosine triphosphate, we would say we'll hold judgment as to which might be better. You can make rationale for both. Tennovo, if you forced me to pick one, I would still go with CD73 inhibition with the idea being that if you could block the formation of something versus have to reverse the actions of something, that tends to be better, but that will play out over time. But I think by the time The big take-home message is by the time you see these three data sets combined, I think it's going to read very positively on adenosine modulation as a mechanism that has a meaningful role, particularly in the context of immunogenic chemotherapy as a standard of care where there's headroom for improvement.
spk12: That's very helpful. Thank you.
spk08: Thank you.
spk02: Our next question comes from Jonathan Miller with Evercore ISI. Your line is open. Please go ahead.
spk16: Hi, guys. Thanks for taking the question. I would love to ask about HIF-2 time to response and maybe some context about how ORR could evolve from here. Obviously, you're talking about already reaching a similar level to LightSpark and hinting that you would expect ORR to be mature by mid-year. But, you know, what's the, to your expectation, what's the evolution from here to there? How much more ORR would you expect to see in later scans, A? And then relatedly, given, you know, linear PK up to 100 milligrams in the escalation cohort so far, Do you expect that 50 milligrams could also show differentiation versus Merck? Could you put a little bit of that dose optimization in context for me as well?
spk08: Jonathan, great questions. So let me start with the first one that gets a little bit to your kinetics. So that's all anecdotal to date, but let's first put a line in the sand. You know, light spark, 005. is roughly 3.8 months median time to response. The way things are looking, if you played around with the numbers, it looks like, at least at the outset, that we're doing perhaps better than that. And we'll see how that plays out. And obviously, that leads to the opportunity for deeper response, longer PFS. Those are, as you know, those really aren't independent variables. So hitting the target harder at the outset may be driving kinetics that are known to be not particularly fast. Although we have seen a couple of later patients having dramatic tumor reduction after multiple scans. On your second question, even though we didn't say anything about it in the script and it's even earlier, what I'll tell you is the 50 milligram cohort, it's almost fully enrolled. So that's going to be another 30 patients. And honestly, if you just took a look and not even all the patients have had a single scan yet, but it actually looks pretty good. And the kinetics, that's where I would tell you on the first group of patients that have had scans. And so I don't want to get, you know, as you know, I couldn't get ahead of the skis because I tend to be pretty transparent with what we've seen. But the first group of patients are seeing some pretty significant reductions. And so feeling optimistic both about the kinetics and we're looking hard at 50s clearly you know, more than pharmacologically relevant, and it does look like on the early, early efficacy readouts that's playing out. As we stated, 20 milligrams was essentially giving the same effect as the approved dose of Belzodifan on the PD marker, and the 50 milligram dose Certainly, if you didn't know any different and it was labeled 100 from what we've seen, you would say it fits right in. But, you know, that's way too early to say that's how it's going to play out.
spk16: Makes sense. And then one more, also on the escalation side of things, obviously only a very few of those patients were RCC patients. Could you tell us about some of the other indications in that escalation set where you might have seen clinical activity?
spk13: Yeah, so it was a mix of tumor types, and so I'd say, you know, there really wasn't anything, I'd say, in the other tumor types, and they're all, you know, patients that have seen multiple prior lines of therapy. We did have two patients with RCC, so not clear cell, but non-clear cell RCC, and Interestingly, one of those patients has had a nice response and is still on treatment. So not a 30% tumor reduction, but they've been on treatment for many, many months and continues to be on treatment. So, you know, it seems to indicate that the drug has activity in non-clear cell RCC as well.
spk16: Okay. Makes sense. Thank you.
spk03: Thanks, Jonathan.
spk02: We now turn to Yigal Notramovitz with Citigroup. Your line is open. Please go ahead.
spk17: Hi, Terry and team. Did you say what the doses were for the two RCC patients that showed the tumor reductions just short of 30%? And then I have another question on phase three. Why don't you go ahead?
spk13: Yeah, I believe one was the 100 mg. And the other, I think, was the 20 mid, if I remember correctly.
spk08: Yes, Ronnie, because out of the four patients, you had all covered, but I think Jen got that right. Definitely one was 100, and definitely the other one was either 20 or 50. They're probably looking while we speak.
spk17: And then the, so, so, is there like a, right, right. Okay. And then at this point, as far as what you would do for the phase three dose, I mean, you finished the dose extension for a hundred milligram first, but it doesn't mean that that's going to be the base case for phase three, right? I mean, you could, you could go with 50. You also said you have, you're evaluating a higher dose up to 200, although I don't know what that is, but what's the base case for phase three? That's still TBD.
spk08: The base case is 100. It really comes down to, Yigal, unless we see something dramatic from, you know, any of the, either of the other arms, which obviously are being done to support the, you know, that we've got the optimal dose from ultimately a regulatory standpoint. We felt that if you look at the Merck data, and you look at what they've achieved, and you look at their waterfalls, and you look at their kinetics, that once we've established that five-fold increase over matching the peripheral PD marker, that we felt like you should be maximizing the response in the tumor. So it was a practical call. As you know, oftentimes when you, and it's unusual, more unusual in cancer, but when you have a very safe drug, at some point you say, you know, this from a practical standpoint makes sense. But if we see something, you know, in these other expansion cohorts that would cause you to feel like there was something different, you know, we would consider doing something alternatively But right now, we're on a trajectory to that 100 milligram dose. The other thing that's nice about safety profile is appearing very clean.
spk13: Sorry, just to clarify responses. One was 100 mg and one was 50 mg.
spk17: Okay, got it. And then you mentioned LightSpark-05 a bunch of times. So obviously that was versus Everolimus. So for phase three, I'm assuming you'd wanna go up against Belzudifan, but I don't know, is that the right assumption?
spk08: Yeah, so the thing, and once we describe exactly what we're doing, so we're not gonna be going into that same monotherapy setting. So we'll actually be going in a setting where Belzudifan wouldn't be the, standard of care, and we will go against the standard of care. And we'll say a little bit more about that as the year goes along. But that was part of the strategy when we considered what would be the best places to go first.
spk17: Okay. All right. Understood. Thank you.
spk02: Thank you, Doug. Your line is open. Please go ahead.
spk07: Hey, thanks. This is Matt on for Selveen. Maybe just following up on that last question. Could you share any additional details at this point on the phase three design forecast? And then secondly, you cited the changing treatment paradigm in first line PD-L1 high lung cancer away from Keytruda mono as the reason for discontinuing ARC-10 and shifting to 121. I was just curious if you could share any details on what data this shifting trend is based on why you believe this is happening now. Thank you.
spk08: Thanks for the two questions. Now I'm going to walk and chew gum at the same time since those are two different programs. So what I'll comment is you can think about RCC, you know, it's from a standpoint of both development, the need, ultimately commercialization, there's multiple lines where you can think of going. And so we would probably move up a bit from where that third line population was. And you can think about patients that have received anti-PD-1 and or TKI. So you wouldn't have Bell's as a standard of care. We feel like that's a great place to go. And so far as your question about ARC-10 and the strategy there, let me give a couple points on that. So clearly, like with many therapies, and particularly in cancer, it's one of those places where obviously there's a Goldilocks spot, But physicians do, and patients, tend to be more focused on efficacy than safety within reasonable bounds. And I think as time goes along and physicians become both more comfortable with the liabilities of a therapy, how to administer it, as well as a conviction about the real efficacy, that's what's happened in a very continuous way in this high PD-L1 population. Going from anti-PD-1 alone and increasingly to anti-PD-1 plus chemo, particularly in a more healthy patient population or with a patient with a bulkier, more rapidly progressing tumor. We think that's only gonna be more enhanced particularly with a molecule like DOM, which we're already seeing from a study, for example, like edge gastric, that essentially doesn't bring any additional side effect liability on top of anti-PD1 plus chemo. So we think that that's going to further cannibalize that particular approach to treating that population. So we do feel that STAR-121 best addresses that population with the best opportunity to become the standard of care for all comers. What I'll also say from a biological standpoint, I think one of the important things is you move down the spectrum from toxic agents, beta-tubulin inhibitors, to things that you very much understand the biology, what you really want to start thinking about is less the organ that you're treating than the biology that you're treating. And we do feel, and the biology that supports anti-tigit is a couple things. At the highest level, CD155 is a bad thing. If you've got CD155, What CD and what CD155 is doing is it's keeping you from getting all of the mileage that you might otherwise out of anti-PDE1 because anti-PDE1 relies on CD226 to get its full efficacy. And so when you have CD155 engaging that CD226, you're losing part of what you might otherwise gain. And that's the whole rationale and now what's being borne out clinically behind anti-TIGIT and why we feel like the best place to go for anti-TIGIT is where you already know that anti-PD-1 works and that PD-L1 all-comer population with chemo is absolutely right down the middle of the fairway for where you want to go with a molecule like DOM.
spk09: Helpful. Thank you.
spk02: We now turn to Robin Karnorkas with Truist. Your line is open. Please go ahead.
spk04: Hi, team. All right. Several questions. Thinking about the 200 milligrams of Cas, do you think there'll be a diminishing limit of returns if you actually, do you think you could push the efficacy up higher? What are your thoughts in 200 milligrams? Second question is about 801. How is it different from ZANSA? And third might be, do you think you could leapfrog, you know how you cut ARC-10 and you did a different trial, leapfrog into frontline with 521? Is there a strategy there? And how do you incorporate your own 801 into that process. There's a lot going on there, but maybe you can take those at once.
spk08: So the second question, what was that ZANSA question? What was 801 compound?
spk04: So for 801, how is it differentiated from ZANSA? I know it's just AXEL only. Could you incorporate that into your clinical trials going forward, right? You're doing all these ZANSA clinical trials. The second question would be 200 milligrams of cast. Like, what do you think is going to happen there? Are you pushing a little bit already? Do you think you get greater efficacy? And third would be, you know, could you leapfrog ahead giving your phase one to be trial and go into first line RCC? Because you've done brilliant things in the past by cutting things off and like skipping ahead of other people, you know, giving the knowledge you have. to get like first-line indication versus refractory indication. Thanks.
spk08: Great. So I'll start with the 200 milligram, and I'll be brief on that. We do think that's probably overdosing, but we want to see it because we'll also, you know, give us some additional safety data if, you know, if we do go higher, does it do anything else on the other physiological roles of HIF-2-alpha? But we do think that the 100 milligram dose is really hitting the target hard enough. But we'll see what we learn from 150 or 200 milligrams. Juan, you want to take the 801 questions?
spk14: Yeah, sure. Zanza, as well as Cabo, is primarily a VEGF TKI. It inhibits Axel with both molecules with decreased potency. But the clinical activity and the It's really generally accepted to be the result of VEGF inhibition. So the 801, we believe, is going to be a more surgically effective inhibitor of Axil, but probably not the first thing you would reach for in the context of RCC, where the rationale would be primarily to go after a VEGF TKI.
spk08: So the place where we see Axil going are things like, you know, STK11 mutant non-small cell lung cancer. And by the way, on 801, since you asked about it, I might as well call out a bit. We have completed the healthy volunteer dosing. PK profile and safety profile look really good. So this is, in our minds, the first molecule that has the selectivity to really test the actual hypothesis. So we're very excited about that molecule. Chad, do you want to comment, or Dmitri, on the 521 leapfrogging into, you know, a frontline setting? Yeah, sure. I can .
spk13: Go ahead, Dmitri.
spk10: So, we are considering all options, and we could leapfrog into the first line. We could leapfrog into the adjuvant setting. But we really want to make sure we select a setting for the first registrational trial that is a mix of different factors. It has to have the data, let's say safety and early efficacy data to support it. It has to be a sweet spot when it comes to competitive timelines to Merck. There's other considerations about timelines to read out. A first line trial is an interesting market opportunity. But, for example, the bar in first line is higher than in second line. The time to read out is longer, of course, in first line than in second line. So we are considering all these different options, and we'll make a decision and communicate that in the near-term future, what our first opportunity would be that we pursue. But it's a factor of multiple factors. Great.
spk08: Robindel, I would like to just give you, since you asked about that. Yes. I would like to emphasize the point of your question, conceptually, though, is a really good one. HIF-2-alpha is going to end up being really important. I think that's why Merck has started to call it out as blockbuster. AB-521, barring some weird, unforeseen thing, it's a drug. And so the real question is, how do you fully exploit that? If you ask me about our portfolio, it's definitely something that as we aggressively move towards this first study, we want to look at very hard how do you expand the footprint of the HIF2-alpha program. That's a really huge opportunity, and we actually think because it's so hard to get a good molecule, you're not going to have anyone come in with a better molecule than us. We feel we're going to end up better than Bell's, and there's not going to be commodity here.
spk04: I'd like to thank Dimitri for making me feel not so bad pronouncing all these names. So Zanza worked for me. Cass worked for me. Thank you very much, Dimitri. Appreciate it. My pleasure. Absolutely.
spk08: I'm told that Cass is Cass, not Cass. That's what I've been told.
spk04: I'll work on that, Terry. I'll work on that.
spk14: I can't tell the difference.
spk02: We now turn to Diana Gray-Bosch with Lering Partners. Your line is open. Please go ahead.
spk06: Hi, guys. Thanks for the questions. I have three on CAS getting into the PKP data. First, on page 31, where you show the area under the curve, I recall initially talking about the value proposition for CAS that you expected a much higher absolute area to the curve. But what I see here with the 100 milligrams is pretty similar in range to the 120 and 240 milligrams for Belbutafan. So I wonder if you can talk to that, that you're ending up in the same range. And then on pharmacodynamics, you have two different pharmacodynamic readouts here. First is the percent EPO change on page 30. and then the percent hemoglobin or the absolute change in mean hemoglobin on page 32. Which of these PD readouts do you believe is more correlated to what you expect in efficacy? And if I look at the hemoglobin, you know, you're sort of in range of Belzutifan, and you're modestly higher, or it looks to be modestly higher in percent EPO. So my final question is, How much better efficacy do you expect to drive with these similar to modest increases in pharmacodynamic markers versus dulcetofan? Thanks.
spk08: Thanks, Dana. So I'm going to tie it together. So I think the key point, I'm going to define what's better PK and what's better PD. So PD, as you know, encompasses everything, tissue penetration, potency differences, pharmacokinetic differences. So the PD readout, what we're saying, and we think this is the value proposition, no question, is that in 20 milligrams of AB521, you're getting the same horsepower, and let's use EPO as the marker that you get out of the approved and used dose of Belzunafan. Now, the PK advantage has nothing to do with an AUC relative to Belzunafan. The PK advantage is that when we go to five-fold higher doses than the dose that gives you that equivalent activity on the PD marker, we get five-fold higher exposures. So if there's more water to be squeezed out of the activity stone, we're hitting that with five-fold the equivalent PD dose of Belzunafan. So that's the value proposition. The PK advantage is that you can go higher from that maximal effect. With respect to hemoglobin or EPO, We don't look at either of those per se as something that's predictive of, more or less predictive of the activity in the tumor setting.
spk06: Can I state it back? So you're hitting it five-fold more dose than what gets you to the pharmacodynamic marker. and you believe that will give you a much better efficacy, even though neither of these pharmacodynamic markers with five-fold greater dose really had that much more effect than Belzut.
spk08: That is correct, but not only is it correct, that's what's predicted, and that's the difference between the physiological maximal HIF-2. As you know, HIF-2 is a transcription factor, so it regulates 100 things it's a fact on EPO has nothing to do with what's going on in the tumor so we know going in that basically you're going to max out HIF-2 in the or EPO inhibition and so that just becomes a marker for how hard are you hitting this this thing and then the fact that we can go 5x what you can get out of the Merck molecule is what makes us feel good about hitting the tumor harder.
spk06: That's very helpful. Thank you.
spk08: Thanks, Dana.
spk02: We now turn to Leigh Watzek with Cancer Fitzgerald. Your line is open. Please go ahead.
spk05: Hi there. This is Rosemary . Thank you so much for taking our questions. So to start with . Do you happen to see any dose response when it comes to toxicity, the safety profile, and do you have concerns for greater side effects when you go above 100 milligrams? And then one question on your TIDGET program. Sorry, go ahead.
spk08: No, go ahead. You finish your questions. Okay.
spk05: So the question for Tidget. So you said you plan to show some data from the ARC-10 trial, which was discontinued. Do you have any color on when this could be and what kind of data we would expect? And would it potentially impact any thinking around the trials that you still have going on? Thank you.
spk08: Thanks. So the dose response, to be clear, the 20 milligram dose that we you know, used is our lowest dose is already pharmacologically relevant. As we noted, you're seeing essentially a maximal effect on EPO suppression at that point. So I would just say with, you know, three patients on each of the doses with six on the 50, we wouldn't say that we see any meaningful differences nor do we expect that and similarly because of what we know and this was gets back to how I was answering Dana's question there's either feedback mechanisms or other non hip to mediated ways that that EPO is produced and so you hit this maximal effect on that endpoint which is to date has been the primary side effect and is very manageable. So that is the anemia that's a correlate of that eposuppression. And basically that's been very manageable. So at this point, we don't have any expectations that going higher will induce any more of a liability. And we certainly haven't seen it at the 100 milligram dose. The other place where we're keeping a close eye is in fact on hypoxia. That has to do with HIF-2 inhibition in the lung. Again, that may also be something that's maxed out. It's normal physiology. It's something that we're paying attention to. Some of these things may also be dependent on individual patients, particularly when you think about EPO, if they're patients that have you know, compromised kidney function. But to date, we haven't seen anything of concern, and we'll just see what happens when we go to a higher dose. And certainly, on those initial 30 patients, nothing that we've seen to date has caused us concern. And to make the point, we have not yet seen a DLT. On the anti-tigit ARC-10, data. That's just something we're considering. We haven't made a decision on that. But if we did do that, the idea would be that we would do a cut of the data and a cleaning of the data when we would extrapolate that we would have mature PFS minimally. And at this point, with the data that we have in hand from our other studies, it wouldn't affect any of the studies that we're It would not be decision-making data. Thanks for the question.
spk06: Got it. Thanks, Terry.
spk02: Ladies and gentlemen, this concludes our Q&A and today's conference call. We'd like to thank you for your participation. You may now disconnect your lines.
Disclaimer