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spk10: Good day, everyone, and welcome to the Syndex first quarter 2024 earnings conference call. Today's call is being recorded. At this time, I'd like to turn the call over to Sharon Clary, Head of Investor Relations at Syndex Pharmaceuticals.
spk00: Thank you, Operator. Welcome, and thank you all for joining us today for a review of Syndax's first quarter 2024 financial and operating results. I'm Sharon Clary, and with me this afternoon to provide an update on the company's progress and discuss financial results are Michael Metzger, Chief Executive Officer, Dr. Neil Gallagher, President and Head of R&D, Steve Kloster, Chief Commercial Officer, and Keith Goldant, Chief Financial Officer. Also joining us on the call today for the question and answer session are Dr. Peter O'Dentlick, Chief Scientific Officer, and Dr. Anjali Ganguly, Chief Business Officer. This call is accompanied by a slide deck that has been posted on the investor page of the company's website. You can now turn to our forward-looking statements on slide two. Before we begin, I'd like to remind you that any statements made during the call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors, including those discussed in the risk factor section in the company's most recent quarterly report on Form 10-Q, as well as other reports filed with the SEC. Any forward-looking statements may represent our views as of today, May 8, 2024 only. A replay of this call will be available on the company's website, www.syndax.com, following its completion. With that, I am pleased to turn the call over to Michael Metzger, Chief Executive Officer of Syndax.
spk03: Thank you, Sharon, and good morning, everyone, and thank you for joining us on the call today. I'd like to begin by welcoming Steve Kloster to the call. Steve joined us in March as Chief Commercial Officer. He brings over 30 years of commercial experience to Syndax, which includes establishing winning teams and leading successful product launches. Steve is building on the excellent framework that was in place prior to his arrival, and we are already benefiting from his keen insights as we prepare for commercialization. In the quarter, we made significant progress on executing against our corporate strategy. As you can see on slide three, we achieved several significant milestones this quarter, including securing priority review from the FDA for both the revument of NDA filing and the axotilumab BLA filing. We also completed enrollment, in the NPM-1 AML cohort of Augment 101 Pivotal Trial, bringing us one step closer to expanding the market opportunity for Revumenta. We look forward to reporting data from the initial trial in the fourth quarter of this year, which could serve as the basis for a supplemental NDA filing in the first half of 2025. These accomplishments set us up for an eventful 2024 that we expect will include two full U.S. regulatory approvals, NPM-1 pivotal data readout, additional combination data for Revimenib in KMT2A and NPM-1, initiation of a pivotal trial for Revimenib in frontline KMT2A and NPM-1 acute leukemia in combination with venetoclax, as well as the initiation of two combination trials for axotilamab in frontline chronic graft-versus-host disease. As we approach our expected approvals, we are working to ensure that we are fully prepared to successfully launch at any time during the third quarter with an ability to reach all patients in need as rapidly as possible. Steve will provide additional details on our launch preparations later in the call. Syndex has a differentiated profile as a SMITCAP biotech with two first and best-in-class drugs on the cusp of their potential first approvals. Notably, Revimenib has a potential second significant indication and near-term expansion opportunity in relapsed or refractory NPM1 that meaningfully extends the target patient population in acute leukemia. This is unique in a launch year as it quickly broadens the market opportunity for Revumentive in the relapsed or refractory setting to up to 6,500 patients. Multiple opportunities beyond the initial relapsed or refractory indication exist for both assets, and trials are ongoing that can drive significant long-term value for these franchises for years to come. We are well-funded with $522 million in cash as of March 31st that we expect will provide significant capital through 2026. Our current balance sheet not only supports our planned commercial launches and clinical trials, but also allows us to expand beyond our core registration indications and pursue select business development opportunities. I'll now ask Neil to provide an overview of the pipeline.
spk13: Neil? Thank you, Michael. In the first quarter, the NDA filing for Reviumenib, our highly selective menin inhibitor, was granted priority review by the FDA for the treatment of adult and pediatric relapsed or refractory KM22A rearranged or KM22AR acute leukemia and issued a PDUFA date target date of 26th of September 2024. The filing is being reviewed under the real-time oncology review, which provides a more efficient review process and has historically led to earlier approval timelines. The submission is based on data from the Pivotal Augment 101 trial outlined on slide 4, where single-agent revumenib induced a high percentage of blast-free responses in heavily pretreated KMT2AR acute leukemia patients, thereby enabling many of them to undergo potentially curative hematopoietic stem cell transplant and to continue revumenib monotherapy following transplant. We've also completed enrollment in the final pivotal cohort of the Augment 101 trial of 64 adult relapsed or refractory MPM1 AML patients in March and expect to report the pivotal results from this population in the fourth quarter of this year. I'll take a moment to review the Phase 1 data on Slide 5 that underlines our confidence in the pivotal results for patients with relapsed or refractory MPM1 AML. Multiple presentations generated by us in both the relapsed or refractory and front-line settings have highlighted the consistency of menin inhibition across NPM1 mutations and KMT2A rearrangements, and we see the enthusiasm building for revumenib in NPM1. The Phase 1 NPM1 data that we've reported supports our conviction that revumenib could be an important treatment for this AML population. In the phase one part of Augment 101, 50% of NPM1 patients achieved an overall response and 36% achieved complete remission or CR with partial hematologic recovery. And importantly, all patients with the CR-CRH were MRD negative. Consistent with the CAME2-2AR population, Revimenib also enabled a high percentage of MPM1 responders to proceed to transplant, 43%, and responses have been durable. This is despite many of the patients having failed prior venetoclax therapy and prior stem cell transplants. It's worth noting that Revimenib has been well tolerated in patients with relapsed or refractory MPM1 AML. In the phase one, there were no grade four or five QT prolongation events, no patients experienced greater than grade two differentiation syndrome, and no patients discontinued due to treatment related adverse events. We believe that Revumena will form the backbone of treatment for patients with both KMT2AR and MPM1 acute leukemias. Our clinical strategy extends beyond the initial relapsed or refractory populations and into the frontline and post-transplant maintenance settings, including combinations with approved therapies. We have several combination trials ongoing with different standards of care across the continuum of patients, including in the fit and unfit settings that are listed on slide six. Investigators presented data from multiple phase 1 combination trials, including BeatAML, SaveAML, and Augment101 during the American Society of Hematology conference in December, demonstrating Revimenib's ability to safely and effectively combine with the standards of care. We expect to provide updated data from these trials later this year. In the first quarter, we initiated another phase 1 combination trial with standard of care intensive chemotherapy, also known as 7 plus 3. Beyond acute leukemia, we're investigating the opportunity to expand to solid tumors. Our proof of concept signal-seeking phase 1 clinical trial in metastatic colorectal cancer is ongoing, and we expect to provide an update on the progress of the dose escalation phase of the trial later this quarter. Turning to axotilamab on slide 7. Also in the first quarter, the BLA-filing fraxitilamab or CSF1R antibody was granted priority review by the FDA for the treatment of chronic graft-versus-host disease, or chronic GVHD, after failure of at least two prior lines of systemic therapy, with a PDUFA date of August 28, 2024. The submission is based on data from the Pivotal Agave 201 trial where treatment with single agent axotilamab led to an overall response rate or ORR of 74%, with 60% of responders still in response at one year. Importantly, axotilamab has a differentiated mechanism of action from currently approved therapies for chronic GVHD. It is the first investigational chronic GVHD agent to target inflammation, excuse me, inflammation, inflammation and fibrosis through the inhibition of disease associated macrophages. We're excited about the opportunity to expand exotilamab into the frontline setting in combination with standards of care and other fibrotic diseases where monocyte macrophage lineage plays a key role, including idiopathic pulmonary fibrosis or IPF, where we are currently enrolling a phase two clinical trial. The team has been working hard to increase awareness of the compelling Revimenib Augment 101 and the Axotilamab Agave 201 data ahead of the respective potential approvals. In April, investigators presented pediatric data from Augment 101 in a plenary session of the American Society of Pediatric Hepatology and Oncology that further supports the consistency of the data across subgroups. Also in April, investigators presented additional analyses from Agave 201 at the European Society for Blood and Marrow Transplantation Congress, highlighting axitilumab's impressive clinical activity in fibrosis dominant organs, which, as I mentioned earlier, is a key point of differentiation. We have an ambitious publication plan underway, and we look forward to detailing more of the clinical benefits of axitilumab and revumenib to the prescribing community. I'll now turn the call over to Steve to talk about preparation for our planned commercial launches and the market opportunity. Steve.
spk12: Thank you, Neil. This is an exciting time to be at Syndax, and we're looking forward to launching two first-in-class and meaningfully differentiated agents this year. As Michael indicated earlier, we'll be ready to launch both Revumetab and Axotilamab in the third quarter, and we've made significant progress so far this year to prepare ourselves and the market to realize the full potential of these medicines for patients, for healthcare professionals, and the company. Our key focus areas are highlighted on slide eight. Our pre-commercialization strategy has focused on developing an efficient, effective, and purpose-built infrastructure to support the business and prioritize relationships with important external stakeholders in the healthcare provider as well as the payer space to accelerate uptake at launch. For Rebumentum, our pre-launch activities have been centered around disease awareness, mechanism of disease education and market access, as well as ensuring patient support services are in place at the time of launch. The customer-facing leadership team has been in the field for some time and focused on disease state awareness and building relationships with healthcare providers. The team is actively profiling accounts, understanding workflows, and identifying the patient journey at the largest and most influential academic centers in the country. This has allowed us to have important conversations with healthcare providers and other healthcare organization decision makers and gain valuable insights on the market, which has helped us define our outreach strategy. We launched our non-branded campaign last year, focused on improving the knowledge and understanding around the role of men in inhibition across key segments of acute leukemia, including KMT2A rearrangements, as well as follow-on indications like NPM1 mutant AML. This effort will expand as we approach a potential launch. We've recruited a talented and highly experienced sales team with an average of 22 years of experience, primarily in hematology oncology, with an average of six product launches per representative. This is obviously a very experienced group with existing relationships and proven past success. The customer facing field team will play a multidisciplinary role in supporting health care professionals and patients. With regard to market access, our team has been educating commercial and Medicare payers on the burden of relapse or refractory acute leukemia to prepare them to conduct timely and evidence-based reviews and ultimately access decisions upon potential FDA approval while formulary approval builds over time. We have little doubt that Revumentum will be covered for reimbursement while plans review the product for formulary inclusion. We've been meeting with pharmacy benefit managers and payers since 2023, sharing relevant market and product information, and expect to reach plans covering more than 90% of all lives prior to Revumentum's anticipated approval. Payers are telling us that they recognize the significant unmet need in KMT2AR acute leukemia patients and the benefit that Revumentum could provide as supported by the Augment 101 data. This is important due to the acute nature of the disease and the high mortality and morbidity in relapsed or refractory KMT2AR acute leukemia, making the urgency to treat quickly absolutely critical. I'm excited about our progress to date and look forward to sharing more about our ongoing efforts in the future. Turning now to slide 9. KMT2AR and MPM1 acute leukemias represent up to 40% of all AML patients, and there are no FDA-approved targeted therapies for this population. We believe relapsed or refractory KMT2AR acute leukemia alone represents a total addressable market of approximately $750 million in the U.S. The annual incidence of KMT2AR acute leukemia is about 2,600 patients, and the majority are refractory to frontline standard air treatments. We estimate a median duration of therapy across the treated population of approximately nine months, and we believe the clinical data supports pricing competitively to other targeted therapies in AML, such as the FLT3 or IDH inhibitors. Physicians we've spoken with indicate an eagerness to prescribe Revumetab early during an eligible patient's treatment journey to bring more patients to transplant, and then extend responses by continuing with Revumetab monotherapy following transplant engraftment. We expect that our first mover advantage and the early experience physicians will gain treating patients with will be vitally important to the long-term success of our brand. Our significant market share is likely to extend meaningfully beyond KMT2AR, especially as we will be the first to deliver meaningful pivotal data in other indications such as NPM1AML. We estimate that the two distinct market segments in acute leukemias, KMT2AR and NPM1, avail a total accessible population of 5,000 to 6,500 patients in the relapse or refractory setting and an addressable market opportunity that approaches $2 billion in the US. Turning now to slide 10. Approximately 14,000 US patients suffer from chronic GVHD, 50% of whom require treatment beyond second line due to disease progression, inadequate response, or disease manifestations that aren't wholly addressed with current treatments. There are no cures for this advanced chronic GVHD patient population. Patients initially treated with corticosteroids are then cycled through a variety of additional therapies based on the physician's experience and manifestations of the disease being addressed. The successful commercial launches of Jackify and Resiroc, and importantly, the speed by which both these agents gained adoption, really speak to the unmet need in chronic GVHD. We also know that despite these recent advances, the disease is still inadequately treated, and physicians are looking for an agent that can better address the underlying fibrosis that ultimately leads to organ damage. Further, they are excited to have a drug with such a fast onset of action and impressive durability of response. These key points of differentiation should enable axotilamab to carve out a sizable commercial opportunity within the estimated $1 billion U.S. refractory chronic GVHD market. As you know, Insight is our partner for axotilumab and really the leader in the GVHD space. As of last year, we exercised our option with Insight to co-commercialize axotilumab in the United States and provide 30% of the commercial effort, as we believe there is a considerable benefit to promoting two products simultaneously to a highly overlapping and targeted physician-prescriber universe. We're working closely with Insight to develop our go-to-market strategy for Axotilamab and plan to align more fully with Insight before sharing additional details. However, we expect to follow a similar set of strategic comparatives as we've just outlined for Repumetum. Now I'll turn the call over to Keith to review our financial results.
spk11: Thank you, Steve. Turning to slide 11, as Michael mentioned earlier, the $522 million in cash equivalents and short and long-term investments on our balance sheet at March 31st is expected to provide runway through 2026. Our financial strength allows us to appropriately invest to maximize the value of our pipeline and importantly, to transition into a commercial stage organization this year. Turning to the income statement, operating expenses in the first quarter were $79.5 million, comprised of $56.5 million of research and development expense, and $23.0 million of selling general and administrative expense. Keeping in mind that we've always embraced a disciplined approach to resource allocation, I'd like to provide financial guidance for the second quarter and full year of 2024. For the second quarter, the company expects research and development expenses To be 50 to 55M dollars. And total operating expenses to be 80 to 85M dollars. For the full year 2024, there is no change to the existing guidance. The company continues to expect research and development expenses to be 240 to 260M dollars. And total operating expenses to be 355 to 375M dollars. Note that the guidance range for operating expenses for the full year 2024 is inclusive of an estimated $43 million of non-cash stock compensation expense. In preparing for launch, I wanted to take a minute to lay out how we plan to recognize revenue for Axotilimab. Slide 12 includes an illustrative example of accounting for sales of Axotilimab and is not intended to provide any margin or other guidance. Commercially, our partnership with Insight is a 50-50 split of the economics in the U.S. We will report 50% of revenues earned net of cost of sales and commercial expenses. During a period where there is a net commercial profit for Axotelimab, as in the top example of the slide, our 50% share of the net profit will be recognized on our P&L as collaborative arrangement revenue. During a period where there's a net commercial loss for Exetilmab, as in the bottom example on the slide, our 50% share of the net commercial loss would be included in operating expenses, designated as a separate line item called share of collaboration loss. We also have various future U.S. commercial and regulatory milestones owed to us from Insight that would be recorded as partnership or milestone revenue on our income statement. Development expenses are shared 55-45 in the U.S., and our 45% share is included in the income statement as part of R&D expense. Outside of the U.S., Insight is responsible for 100% of the development and regulatory expenses, and we are entitled to receive milestones plus royalty on ex-U.S. sales. With that, let me now turn the call back over to Michael.
spk03: Thank you, Keith. As you've heard during the call, 2024 is shaping up to be a historic year for Syndex as we prepare to launch two first-in-class products, and I'm confident that we have the expertise, resources, and determination to bring these products to market. As an organization, we are truly excited to evolve into a commercial organization, and we are laser-focused on bringing these important treatment options to patients in need. On slide 13, we lay out our key upcoming milestones for the balance of the year, and I look forward to updating you on our progress in the coming months. As always, I would like to express my sincere appreciation to the Syndax team, our collaborators, and most importantly, the patients, trial sites, and investigators involved with our clinical programs. Through your work and dedication, we are getting ever so close to delivering on our mission of improving the lives of patients with cancer. I'd also like to thank our committed long-term investors who continue to share in our vision and support us in building Syndax. With that, I'd like to open the call for questions. Operator?
spk10: At this time, I'd like to remind everyone, if you'd like to ask a question, please press star and then the number five on your telephone keypad. If you'd like to withdraw your question, press star and the number five once again. We'll pause just a moment to compile the Q&A roster. Our first question is from Peter Lawson at Barclays. Your line is open. Please go ahead.
spk14: Just first question is around how important NCCN guidelines will be for additional indications after you get the initial approval for a few minutes.
spk03: Peter, thanks for the question. Maybe I'll ask Neil to comment on the importance of the guidelines.
spk13: Yeah, thanks, Peter. So, as you know, the 1st approval, we're anticipating that the 1st approval for will come in the 3rd quarter and that will be for came to a rearranged acute leukemias and adults and children. So, the approval will be should be sufficient to actually have that indication included in the guidelines. And in addition to that. We've also guided to the fact that we will, in fact, I referenced or it's been referenced during the bird remarks that we anticipate reporting pivotal data from the NPM one cohort by the end of the year. So, suffice it to say that we have a plan. I mean, prior to approval, you know, presentation at a medical congress along with publication of the data could position us to at least start conversations with the NCCN committee regarding inclusion in the guidelines. As you're aware, the committee meets twice a year, the disease-specific committees meet at least once a year, but they also meet ad hoc once important new data become available. So, we're considering all of that, and clearly, you know, we want to make sure that the best possible information is made available to the committee as well as to prescribers when we publish our data.
spk14: Thank you. And then, as we think about expansion of the menin inhibitor into polytumors, Kind of just if you could detail the kind of the expectations around the CRC data, if that's the 2Q, when we should expect to see that data if it's a medical conference, and kind of the number of patients.
spk03: Thanks, Peter. Thanks for the follow-up. So the question was related to solid tumors and our plans there. And as we've disclosed and mentioned in the prepared remarks, we are continuing to work in the area of colorectal cancer. This is metastatic colorectal cancer, third-line plus. And we are conducting a Phase I trial. We had said that we had planned to disclose some information, update everyone on our progress there in the second quarter, and that remains to be the case. Let me remind everyone, this is a dose escalation trial, so this is Roughly 10 to 20 patients heavily pretreated and what we're essentially looking for looking to see is activity of revenue. Again, in this in this patient population, looking for prolonged, stable disease in the 4 to 6 month. So call it range with perhaps around 15% of the patients in that stable disease category. So that's sort of the. the signal that would be, we think, impactful. Of course, patients don't do very well in this setting, and certainly standard of care doesn't yield prolonged stable disease of that nature. So we'll obviously update when we're ready to do so in the second quarter.
spk14: Perfect. Thank you so much.
spk03: Thank you, Peter.
spk10: Our next question is from Anupam Rama at J.P. Morgan. Your line is open. Please go ahead.
spk04: Hey, guys. Thanks so much for taking the question. Maybe a quick one for Stephen. Just wondering, you know, before you joined Syndax and you were doing your assessments of the opportunities for Revumenev and Nexitilamab, what really attracted you to these products? And then the second one is also actually for Stephen. You know, you mentioned very broadly, you know, what some of the levers for success in slide eight are for both of these launches, but Anything more specific to revenue management in KMT2A that you'd highlight? Thanks so much.
spk12: Yeah, thanks for the question. I'll answer both. First is, you know, why did I probably come here? And it's really a combination of things. I've been pretty careful over the course of my career. I think this is my fourth organization in 30 years. So the bar is pretty high, and I look at all opportunities in, you know, three different factors. The first is there needs to be great products. products that address unmet need, products that have a great amount of clinical data and really provides differentiated attributes. And I think both Rev and AXA have that. I knew that coming in. And as I've seen the data and as I've reviewed lots of market research and actually engaged with KOLs, that's only been amplified. I think the second thing that I really think about is really who I work with, right? Wanting to be at companies with great people and great leaders. And that's exactly what we have here. Michael, the entire ELT, the board are all top tier, very supportive. And even walking in, the commercial leadership team that was in place was strong as well. And the 3rd thing for me is really the willingness to invest and plan for success. And we have that here too. So I'd say my expectations have been exceeded coming in and I'm more excited now than I was even before I started. I think I'm in week 8. The 2nd question is really around levers for success. On, uh, on revenue, there's, you know, there's a lot we're building as a commercial organization and all of that will be in place. I think, as Neil mentioned, and Michael mentioned his remarks will be ready in Q3. so infrastructure processes. All those things will be will be done. I think from a strategic point of view. The three things that I think about that we are very focused on, really, the first is the population of patients is limited. We know that, right? And that opportunity will grow over time. But finding them is critical. Patients are fragile. They need treatment immediately. So we've got focus there. I think the second thing is just the landscape of healthcare delivery. There's multiple stakeholders out there that deliver care to patients, physicians, nurses, Advanced practice providers, pharmacy reimbursement pathology, you name it. We have a customer facing footprint that will address and directly engage with that dynamic. And the 3rd, 3rd, 3rd point is really access. Right? Neil mentioned that CCN guidelines, which will be important. Payers are looking for that. They're looking for other published data, but patients need access to treatment. So we've been deployed against the payer space for some time, making calls directly with payers, and that is in an effort to really expedite formula review. And in addition, we've built a support program to meet the needs of patients, which we know their need. So thanks for the question. I hope that was a good answer.
spk10: Our next question is from Brad Camino at Stiefel. Your line is open. Please go ahead.
spk15: Hi, good morning. Relating to the plan for the Pivotal Veneza combo trial to be initiated by year-end, this will move the emphasis of clinical endpoints from CR towards remission durability and OS. I want to ask, how does the company plan to evaluate data from the uncontrolled trial updates later this year, both from the combos and also the NPM1 pivotal monotherapy, in order to gain confidence in the randomized time-to-event endpoints for the frontline pivotal? Thank you.
spk03: Brad, thanks for the question. I'm going to turn it over to Neil to address that.
spk13: Yeah, thank you for the question. Specific, I mean, of all of the combination studies that we reported on, the one specific to this scenario, in other words, initiating the phase three venasus, refumenta venasic study by the end of the year is the beat AML study. And as you're aware, the group reported data around the ASH meeting last year and anticipate updating those data during the course of this year. Those data are exciting, not only to the company, but also to the investigators and actually not just the BEAT AML investigators, but the broader community. So people are highly enthusiastic about initiating the phase three study. Just to remind you, the response rates, including the CRCRH rates that were observed in the BETA-AML study to date, have exceeded the historical controls observed in VLEA, including in terms of CR. In particular, molecular MRD negative CR was, you know, much, much higher in the BDAML study compared to the LEA. So the emergent data, including the observation that revumenib is highly combinable, it's not adding, it doesn't appear to be adding toxicity to the backbone therapy, as well as providing incremental efficacy in the target patient population. And that's bolstered also by the observations from, for instance, a The SAVE study, which was a combination, is a combination of Reviumenib with Venetoclax and oral Decidabin in a relapsed refractory setting, as well as our own Augment 102 trial, the combination trial in a relapsed refractory population in combination with chemotherapy. So the body of the evidence is that Reviumenib is combinable with backbone standards of care, is not adding toxicity in the target population for the phase three trial. for the phase three trial in the newly diagnosed and fit population, the BAML data are providing evidence that Revimenib is also adding, you know, notable efficacy to the backbone therapy. So, obviously, we will be having conversations with health authorities as we design the trial, and we don't typically comment on those, but we look forward to presenting more details around the study prior to initiation later in the year.
spk10: Our next question is from Phil Nadeau at TB Cohen. Your line is open, please go ahead.
spk17: Morning, congrats on progress. Thanks for taking our questions. First, in terms of the phase two doses in the combo trials, or validating the phase two doses in the combo trials, this morning's press release notes that Some of the trials have been expanded to validate the phase two doses. I was curious whether you'd be willing to disclose whether the full monotherapy dose of Revimanib is being used in those combinations at this point.
spk13: Yeah, thanks. And thanks for the question. So just remind everyone the 3 studies that I just referenced in the in the answer to the previous question are the studies and the studies under discussion. So. I will repeat what those are in all 3 of those studies and all 3 of those trials. There were 2 doses of that were investigated 113 milligrams and 163 milligrams. 163 milligrams is the presumptive monotherapy dose in combination with a strong CYP3 or CYP4 that will be included in the label. So Revimenib has been given at full dose in all three trials. By the time we talked about them at the event around ASH last December, in all three, the dose-limiting toxicity windows for both doses had been cleared, and both doses are being expanded in all three trials at this point in time. So we haven't, when we talk about RP2D, we're continuing to characterize the two doses. But in general, our anticipation is that RevuMed or our observation to date is that RevuMed is combinable at full monotherapy dose with backbone standards of care.
spk17: That is very helpful. Thank you. And then second question, based on the milestone tables that you just presented, it doesn't seem like you're anticipating an advisory committee review for either Revimenib or Axotilimab. Is that accurate? And can you remind us, did the FDA explicitly say in the acceptance letters that adcoms would not be necessary for both drugs?
spk03: Yeah, Phil, thanks for the question. I think our expectation is that neither exotilamab nor brevimanib will require an adcom, but we haven't explicitly stated nor do we comment on regulatory correspondence from the agency relative to things like that. But that is our expectation, that neither will need an adcom.
spk17: Perfect. And then last question from us. You referenced the nine-month period. expected median duration of use for KMT2A patients. Can you remind us what proportion of patients going to transplant is assumed in that nine-month figure?
spk03: Bill, thanks for the question. It's roughly about a third of that half, right? Sorry, of the patients that go transplant.
spk17: So a third of patients who get in the relapsed refractory line would go to transplant is the assumption?
spk01: Yeah, sorry, Phil, it's Angelique. I think what we've been saying is there's basically three groups of patients that seem, based on the trial, seem to all be about an equal-sized population. There were a third of patients that did not respond. Of the two-thirds of patients that responded, half went to transplant. So overall of the entire population, a third go to transplant.
spk17: Got it. That is very helpful. Thanks for taking our questions. Thank you, Phil.
spk10: Our next question is from Michael Schmidt at Guggenheim. Your line is open. Please go ahead.
spk05: Hey, guys. Good morning. Thanks for taking my questions. I just had the one on the Exeterium up launch now that we're obviously closing in on the Purdue for Day later this year. And as we think about this sort of $1.5 to $2 billion opportunity in a relapse refractory setting, just wondering how we should think about perhaps the early launch trajectory you know, subsequent to approval? Are there any good proxies we should look at, for example? And then, you know, what are your expectations for potential off-label use in the NPM-1 subset? Obviously, we will have data later this year. You know, could that help next year to accelerate the launch early on? Thanks so much.
spk03: Yeah, Michael, thank you for the questions. I'm going to ask Angela to comment on the launch.
spk01: Yeah, thanks. Thanks, Michael. No, we're really excited about this opportunity. I think what Revy Medev has in front of us is a very unique situation. As you know, we got through the clinical development in record time, first patient dose to NDA filing in four years. We've generated data that support indications across AML and ALL, adults and pediatrics. And as you said, we're anticipating An approval in the 3rd quarter of this year. And we'll have data for another very important patient population. Treated by the exact same healthcare set of healthcare providers in a disease where positions can choose the best options for their patients. So, and then on top of that, we also talked about all the. Combination data we've generated with recommended that allow them to think about. multiple ways to use this drug and fit it into their treatment plans as they think best. So I think we have a very unique launch curve that we're going to be we're going to be generating in real time. I don't think there's a perfect analog that addresses all of these aspects of What's coming in the next 12 months, but we have seen very significant excitement around revenue around this new class of agents and how they can utilize it. To bring care to patients that have had nothing and, you know, I think you'll recall the last 2 ash meetings. have been very focused on on the data that we've been generating and um i think that that shows how much education is already out there and and you know steve talked about there's a lot more that we're doing to make sure everybody is aware of um the drug that all the um support and um Patient patient support is in place to allow utilization and we're really excited to have a really strong.
spk05: Launch of revenue, maybe just to follow up. Can you just remind us what percentage of the AMR market is is under Medicare and how do you think about. pricing in the Medicare population, any sort of expectations for free drug programs as we sort of think about their early launch again later this year?
spk03: Yeah, let me ask. Thanks, Michael. I'm going to ask Steve to comment on those questions.
spk12: Yeah, I mean, it's a good question. And the pair space is different for KMT2AR versus NPM1. It'll be more of a commercial patient, you know, for the KMT2A launch, just based on the age of the patient. You know, we'll expect coverage, honestly, at launch. Formula acceptance will happen over time, right? Typically takes six to nine months for that to happen. But in the meanwhile, you know, healthcare providers, their staff, are very fluent on how to get through the medical exception process. That's where the NCCN guidelines are helpful and other published data. Medicare payers will be less important for CAMT2AR, but for NPM1, due to the patient population, which is a little bit older, it's going to change. So our approach has been really over the last nine months, even a year, is really to approach all plans. We've been delivering PI information exchanges. That's the pre-approval information exchange. So we've had some very good interactions with payers. They recognize the unmet need. the criticality of patient care. And I think as Anjali said, it's a unique launch where you've got a launch followed by, we'll just say another launch within a year. So we're preparing for both at the same time. It takes time to build coverage. So we've got the whole payer space. And I think in my prepared remarks, we will talk to payers that covered 90% of covered lives in this country, which is as good as it gets in advance of approval. So we're prepared for success.
spk05: Okay, great. And then maybe just a housekeeping question as we think about the filing and potential approval. Are there any milestones due from inside for that that we should incorporate our models this year?
spk11: Yeah, thank you, Michael. Keith, do you have? Yeah, Michael, we do, as disclosed in this queue and as we've disclosed in past queues and Ks, We do have not only development regulatory milestones, but commercial milestones do us from insight. Total milestones for development regulatory under the agreement were $220 million. Total commercial milestones were $230 million. So a total of $450 million do us. You can expect those to come at major levels. um major uh certainly major regulatory uh events such as approval um i think that that's a reasonable expectation but we haven't been more specific as to the amounts thanks so much guys thank you michael our next question is from your gal not to move it at city group your line is open please go ahead
spk06: Yeah, hi, thanks very much for taking the question. Just curious, on the NPM-1 regulatory pathway, if you may follow the CARTOR pathway, or perhaps even the breakthrough, or given the SNDA, are those options not really necessary?
spk03: Yigal, thank you for your question. You broke up a little bit, but I think I captured it. So as you know, we've had breakthrough therapy designation for KMT2A. For NPM1, we have the opportunity to potentially get breakthrough therapy. probably most important for your first indication, and I think the engagement around KMT2A and the molecule and the submission package has been very strong. We have priority review as well. I think for NPM1, we'll look to leverage some of the same access points with the agency, but we're, you know, I'd say pretty well advantaged by what's come our way already. But we'll see. We don't generally comment on regulatory strategy, but the opportunity to submit for BTD at a point in the future is open to us. I think I think it's a obviously a program that will will have data on later this year. We'll have a submission. We hope in the not too distant future beyond that, and then look to get the drug approved in 2025. so that'll be through an SDA process. So it's all I'd say. Call it an expedited pathway through some of the designations we have in hand already, or some of the things that we may avail ourselves in the future.
spk06: Okay, thanks. And then when you think more broadly about the revumenib in terms of the spectrum of pair and AML, both in the frontline and in the relapsed refractory, and given the fact that there's a good chance that you're going to be initiating a pivotal trial in the frontline in combo with venetoclax, when you start to think about the commercial build there, are you making assumptions around the potential retreatment method? Revimenib for patients that received Revimenib in the front line in a combination setting, whether it be with net effects or perhaps even with the 7 plus 3, including those patients in the build for Revimenib in a relapsed refractory setting or once they're treated in the front line, then that wouldn't be part of your assumption set. Thank you.
spk03: Yeah, thanks, Jagal. I think our assumption is that once you're treated with a menin inhibitor, at least from our vantage point, the way we see it today, I think once you're treated in the frontline setting, it's less likely that you're going to be treated in the relapsed refractory setting again with another menin inhibitor. And Neil, I want to make a comment.
spk13: Yeah, I agree. I agree with Michael's comments there that I think that, you know, it is a little bit nuanced because I think longer term, I can foresee, you know, situations where patients could, for instance, if they've been treated and relapsed a long time later around PM1 positive or came to a positive, might be re-exposed. But I think in general, I agree with Michael's points. We shouldn't be sort of expecting a lot of patients to fall into that category.
spk06: And just one on AXA. Do you have any timelines for the IPF trial in terms of enrollment and data?
spk03: Thanks, Michael. No, not at this point. I think we are enrolling. As you know, we started recently bringing up sites and enrolling patients, and it's going nicely. And so we'll have more to say in terms of milestones, both for enrollment as well as data as we get further into the year, maybe into next year.
spk06: Okay. Thank you, Michael.
spk03: Thank you all.
spk10: Our next question is from Kalpit Patel at B Raleigh Security. Your line is open. Please go ahead.
spk09: Can you comment on what proportion of patients that you estimate might be eligible to receive Revumetab as a maintenance treatment after induction and consolidation? I'm trying to understand if that median duration of treatment in that specific frontline setting would be higher than the nine months that you expect in the relapsed refractory setting. Thank you.
spk03: Yeah, but thanks for the question. I think if I interpreted your question correctly, I think in terms of patients who would be eligible for maintenance going in the relapsed refractory setting, I think if you had a successful transplant, there's no reason that all patients wouldn't necessarily be eligible. They need to have you know, be stable and engraft well. And I think that's usually the first step, and physicians remind us of that, that there's an engraftment period. But for all intents and purposes, all patients should be eligible for maintenance. So I think that's That's our assumption, and that's, I think, been discussed with physicians on an ongoing basis. I think when you get to the frontline setting, the assumptions for long-term maintenance and how that would play out in the fit population Could very well differ if you were able to get to patients earlier and treat them successfully through transplant and put them back on therapy. I think the expectation is treat patients earlier, they do better, and they stay on longer. And so that should change how the assumptions work on the time on maintenance in the front line compared to relapse refractory. We don't have a good estimate of that yet. Obviously, we're generating that data. But over time, we'll understand that a little bit better.
spk10: Our next question is from Jason Zemanski at Bank of America. Your line is open. Please go ahead.
spk02: Perfect. Thank you. Good morning and congratulations on the progress. Appreciate you taking our questions. Regarding the commercialization plans for Revumenta and your initial outreach, I have to imagine there's already quite a bit of excitement across at least the more academic-focused community. But what sort of division between rapid adopters and non do you expect? How quickly – Do you expect maybe the more community-based prescribers to come on board as far as awareness and education goes? And maybe bolus isn't quite the right descriptor given patient dynamics this late in treatment, but do you expect an initially large bump in patient numbers or more of a straight line uptake?
spk03: Jason, thank you for the question.
spk12: I'm going to turn it over to Steve to address your questions. Yeah, hey, Jason, thanks for the question. I mean, there's a lot of excitement. I think, you know, predating me coming to the company, the company's done quite a bit of research, market research, advisory boards, met with KOLs, the field medical team has been out there. So there's a lot of, well, to say, demand that's there because of lack of treatment options. I recently actually was out in New York yesterday at Cornell and Sloan, and Meeting with so, so they're ready for the literally cannot wait till it hits the market. So I think certainly at academic centers, Jason, there'll be quick uptake. They are ready for this product. Awareness is already fairly high for whether it's revenue management and inhibitor. I think downstream in the community, it's going to take a little bit of time. Part of it is just, they may not see a lot of patients initially. So it's up to us to be there. So, from a commercialization standpoint, we'll have a adequately sized team that's going to cover 95 plus percent of the opportunity. We'll have a non personal promotional program that will reach folks in places that we may not be at as as frequently. So, I think you'll see a quick uptake across the board and a lot of it's just patients in the office ready to be treated to think leads to your 2nd question. And there's not going to be much of a bolus. Right? We have an EAP that's in place. You know, it's it's a. I'm going to give the number, but it's a certain number of patients. No one's withholding treatment for eligible patients, to your point. The criticality is just too high. So there'll be a little, we'll say, extra use initially from EAP. That'll burn out over the beginning months of the launch. And then after that, we'll expect a typical uptake just based on our assumptions and available patients.
spk02: Got it. Makes sense. And then Maybe just a quick follow-up on your phase one in metastatic colorectal cancer. In terms of go, no-go decision, I know you mentioned disease stabilization as important, but was curious, is there a specific signal, I don't know, maybe a biomarker that you're looking for in terms of Menon's potential or hypothetical role in driving solid tumors that would just make you feel confident about investing significantly in this potential expansion opportunity?
spk03: Jason, thanks for the follow-up on CRC. I'm going to turn it over to Neil to address.
spk13: Yeah, thanks. So in the part of this study that has been conducted to date, just to reiterate Michael's point, I mean, this is primarily a safety part of the study. We are looking at, in addition to clinical responses, I mean, primarily it's a safety study. We're also looking at clinical responses. We're also looking at biomarker data. And, you know, our anticipation is that you know, as we get to a point in the future where we could make a decision on future development in this space that, you know, the totality of the evidence will be taken into consideration. We haven't specifically said what, you know, what correlative data we're looking at, but, you know, at some point in the future, we will provide more details around that. I wouldn't expect necessarily too much data in an update in the second quarter, you know, on, for instance, correlative data. But rest assured that we are pursuing correlative studies and, as I said, we'll take the totality of the evidence into consideration.
spk02: Got it. Well, thank you for the color.
spk03: Thank you, Jason.
spk10: As a reminder, if you'd like to ask a question, please press star 5 on your telephone keypad to raise your hand. Our next question is from Justin Zelen at BTIG. Your line is open. Please go ahead.
spk07: Thanks for taking the question and welcome to Steve. So ahead of two launches this year, I wanted to ask how large of a sales force you're looking to build here. And could you talk to the overlap of providers who treat both leukemia and chronic breast disease for promotion of both products?
spk12: Sure, maybe I'll let Steve take that question. Thanks, Justin. Yeah, I appreciate the question, Justin. In terms of sales size, we're not prepared to provide the exact color and size of the team, but it'll be a team that I think can really address customer needs. Our goal, whether it's providers, Anybody within the healthcare delivery system that it's a great customer experience. So we're prepared to link up to all different aspects of of healthcare organizations to make sure we're meeting the needs and supporting providers and their, their treatment of patients. So, I think I use the term plus 95% coverage. So. We'll cover the opportunity. There's no doubt about that. In terms of overlap between GVHD and Rev, there's high overlap. I mean, we're likely, along with Insight, calling on the same treatment centers, whether it's treatment of AML or treatment of transplant. And we'll leverage that call point. There's probably A third overlap right now of our REV audience with the AXA audience will obviously provide 30% of the effort. So we'll leverage our footprint and we will cover, you know, the market opportunity in really both opportunities.
spk07: Thanks for taking the questions. Thank you, Justin.
spk10: Our next question is from Chris Shibutani at Goldman Sachs. Your line is open. Please go ahead.
spk08: Thank you. Good morning. A lot of questions on the focus have already been asked. So perhaps if we're going to ask a bigger picture, longer term question, it ties a little bit to your guidance in terms of operating expense spend on R&D. The near term question is, it looks as if to reach your full year guidance, we'll have a considerable step up in the second half. Is that primarily attributed to the combination studies? Just to give us a sense there, Keith. And then secondly, Anjali, I think you've done a tremendous amount of work in building this portfolio, and the company is now very focused on trying to launch two products. But as you know, investors are impatient to try and figure out what could come next. What is your thought on capital allocation priorities, further business development? What are you seeing out there? What's your appetite? Thank you.
spk03: Great. Thank you, Chris. Good questions. Maybe, Keith, you want to take the first one on the longer term? Yeah, sure.
spk11: So Chris, I wouldn't, I wouldn't necessarily agree that it's a big step up to to use your words. You know, we did. Um, total operating expenses in 1 queue approach to 80Million. Um, the, the, uh, guidance range for the 2nd quarter is 885. so, you know, if we were just to stay on that trajectory, we'd be. Um, you know, 320Million ish, so there is some increase that I think we would anticipate in the back half of the year and I think yes, you know. Certainly, as IPF ramps, as the first-line 7 plus 3 combination trial with REV continues to accrue, and as we get ready to launch the pivotal Phase 3 BENEZA combo trial with REV, that's certainly going to add to some of our R&D expenses in the back half of the year. Uh, but also don't forget, we're building out a commercial organization. So, um, on the side, we, we would expect some, uh, some growth there for the sales force, all the customers, uh, facing, um, uh, individuals that Steve, uh, commented on earlier as well as, you know, the, the support for those, uh, for that, uh, field force.
spk03: And in terms of your second question, Chris, on business development, maybe I'll start and turn it over to Anjali. So, look, I think our strategy has been, and we've been pursuing the same business model for quite some time, which is to in-license and develop new molecules with differentiated profiles. I think we've Been fortunate to have great success with our in-licensing strategy and having these two molecules that are nearing approval. And so the bar is always quite high with regard to new opportunities. I think it's incumbent upon us to be thoughtful about how we allocate capital. And so we do think that additional molecules, bringing them into the pipeline, backfilling the earlier part of the pipeline is quite important. And we are interested in doing that. And so I don't know if Angela want to make a comment on on on our activities, but we remain quite disciplined about what we're doing.
spk01: Yeah, no, I think you said it well, Michael. We're very actively engaged in the market, looking across a variety of sources for new opportunities and spending a lot of time on diligence. And hopefully we'll have some exciting news to share. But, you know, there's definitely a lot to look at.
spk03: Exciting times. Thank you, Chris.
spk10: Our next question is from George Farmer at Scotiabank. Your line is open. Please go ahead.
spk16: Hi, good morning. Thanks for taking my question. A competitor of yours has talked about combining their menin inhibitor with other targeted therapies like FLT3 inhibitors and the like. There hasn't been too much conversation on the call about that this morning. Is that something that you're thinking about as well in greater detail?
spk03: George, thanks for the question. So, in terms of combinations, maybe I'll let Neil comment on what else is going on with targeted therapies. Obviously, we have the trials ongoing, the pillars of our strategy being Veneza in the unfit population, and then in CoV, if you will, as another interesting option for patients in relapsed refractory and perhaps in earlier patients as well. So just think about it in terms of then combos and then on the fit side of the equation in combination with chemotherapy, we've already demonstrated the drug's ability to be combined with chemotherapy and relapsed refractory study. We'll have data updates on that. We'll also have additional data, as we talked about, on the Venn combos this year, which so far looks extremely good. But I think there's options open to us. And, Neil, I don't know if you want to comment on some of those.
spk13: Yeah, sure. So we have investigator-initiated trials either planned or ongoing, in which Revumetab in combination with Gultaritinib or Mitostorm will be investigated. To Michael's point, You know, conducting, for instance, a pivotal program in the frontline FIT population in patients with both MPM1 and FIT3 mutations is technically very challenging. It's not really core to our strategy. Of course, we haven't revealed overall what our strategy is, but it's not core to our strategy. What we've said is that, obviously, in addition to the unfit phase three that we'll initiate, we plan to initiate by year end, um that were dose ranging in combination with seven plus three um which will position us then to initiate a phase three during 2025 you can anticipate that that will not be in dual mutation patients because that's a very large and complicated study so we've we've we prefer to um uh generate evidence in that population as opposed to uh potentially pursuing a a registration strategy
spk16: Okay, that's very helpful. Thanks. Thank you, George.
spk10: This concludes our question and answer session. I'll now turn the floor over to Mr. Michael Metzger for any additional comments or closing remarks.
spk03: Thank you, Operator, and thank you all for your questions. Appreciate you tuning in today. We look forward to seeing you all at our planned investor events, including the Bank of America Conference in May and the Goldman Sachs Conference in June. And with that, we wish you a great day.
spk10: The meeting has now concluded. Thank you for joining. You may now disconnect.
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