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Syndax Pharmaceuticals Inc
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Good day, everyone, and welcome to the Syndax 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 Klahre, Head of Investor Relations at Syndax Pharmaceuticals.
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 am Sharon Klahre 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 Closter, Chief Commercial Officer; and Keith Goldan, Chief Financial Officer. Also joining us on the call today for the question-and-answer session are Dr. Peter Ordentlich, Chief Scientific Officer; and Dr. Anjali Ganguli, Chief Business Officer.
This calls the company by a slide deck that has been posted on the Investors page of the company's website. You can now turn to our forward-looking statements on Slide 2.
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.
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 Closter 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 3, we achieved several significant milestones this quarter including securing priority review from the FDA for both the revumenib NDA filing and the axatilimab BLA filing. We also completed enrollment in the NPM1 AML cohort of AUGMENT 101 pivotal trial, bringing us one step closer to expanding the market opportunity for revumenib. 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 2 full U.S. regulatory approvals, NPM1 pivotal data readout, additional combination data for revumenib in KMT2A and NPM initiation of a pivotal trial for revumenib in frontline KMT2A and NPM1 acute leukemia in combination with venetoclax as well as the initiation of 2 combination trials for axatilimab, 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. Syndax has a differentiated profile as a SMID-cap biotech with 2 1st and best-in-class drugs on the cusp of their potential first approvals. Notably, revumenib 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 revumenib in the relapsed or refractory setting to up to 6,500 patients.
Multiple opportunities beyond the initial relapse or refractory indication exists 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 31 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. Neil?
Thank you, Michael. In the first quarter, the NDA filing for revumenib of our highly selective men inhibitor was granted priority review by the FDA for the treatment of adult and pediatric relapsed or refractory KMT2A rearranged or KMT2R acute leukemia. And this is 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 time.
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 slip free responses and heavily pretreated KMT2R acute leukemia patients, thereby enabling many of them to undergo potentially curative lowest 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 to refractory NPM1 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 I data on Slide 5 that underlines our confidence in the pivotal results for patients with relapsed or refractory NPM1 AML. Multiple presentations generated by us in both the relapsed or refractory and frontline settings have highlighted the consistency of [ men ] inhibition across NPM1 mutations and KMT2A rearrangement and receive the enthusiasm building for the revumenib and NPM1. The Phase I NPM1 data that we've reported supports our conviction that revumenib could be an important treatment for this AML population.
In the Phase I part of AUGMENT-101, 50% of NPM1 patients achieved an overall response and 36% achieved complete remission or CR with partial pathological recovery. And importantly, all patients with the CRCRH were MRD negative. Consistent with the KMT2AR population, revumenib also enabled a high percentage of NPM1 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 revumenib has been well tolerated in patients with relapsed or refractory NPM1 AML. In the Phase I, there were no grade 4 or 5 QT prolongation events. No patients experienced greater than grade 2 differentiation syndrome and no patients discontinued due to treatment-related adverse events. We believe that revumenib will form the backbone of treatment for patients with both KMT2AR and NPM1 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 6. Investigators presented data from multiple Phase I combination trials, including BEAT AML, SAVE AML and AUGMENT-101 during the American Society of Hematology Conference in December demonstrating revumenib'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 I combination trial with standard of care intensive chemotherapy, also known as 7+3. Beyond the acute leukemia, we're investigating the opportunity to expand to solid tumors. Our proof-of-concept signal-seeking Phase I 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 axatilimab on Slide 7. Also in the first quarter, the BLA filing for axatilimab or CSF-1R 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 2 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 for treatment with single-agent axatilimab led to an overall response rate of 74% with 60% of responders still in response at 1 year.
Importantly, axatilimab has a differentiated mechanism of action from currently approved therapies for chronic GVHD. It is the first investigational chronic GVHD agent to target inflammation and fibrosis through the inhibition of disease-associated macrophages. We're excited about the opportunity to expand axatilimab into the frontline setting in combination with the standards of care and that other fibrotic diseases where a monocyte macrophage lineage place [indiscernible] including idiopathic bone [ mineral ] fibrosis or [indiscernible] where we are currently enrolling a Phase II clinical trial.
The team has been working hard to increase awareness of the compelling revumenib, AUGMENT-101 and the axatilimab AGAVE-201 data ahead of the respective potential approvals. In April, investigators presented pediatric data from AUGMENT-101 in the plenary session of the American Society of Pediatric Hematology/Oncology that further supports the consistency of the data across the groups. Also in April, investigators presented additional LCs from AGAVE-201 at the European Society for Blood and Marrow Transplantation Congress, highlighting axatilimab'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 that way, and we look forward to detailing more of the clinical benefits of axatilimab 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?
Thank you, Neil. This is an exciting time to be at Syndax, and we're looking forward to launching 2 first-in-class and meaningfully differentiated agents this year. As Michael indicated earlier, we'll be ready to launch both revumenib and axatilimab in the third quarter and we've made significant progress so far this year to prepare ourselves in the market to realize the full potential of these medicines for patients, for health care professionals and the company.
Our key focus areas are highlighted on Slide 8. 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 health care provider as well as the payer space to accelerate uptake at launch. For revumenib, our prelaunch 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 focus on disease state awareness and building relationships with health care 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 health care providers, another health care organization decision-makers and gain valuable insights on the market, which has helped us define our outreach strategy.
We launched a nonbranded campaign last year, focused on improving the knowledge and understanding around the role of [indiscernible] 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 recruited a talented and highly experienced sales team with an average of 22 years of experience primarily in Hematology/Oncology with an average of 6 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 relapsed 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 revumenib 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 revumenib's anticipated approval. Payers are telling us that they recognize a significant unmet need in KMT2AR acute leukemia patients and the benefit that revumenib 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 and 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 NPM1 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 treatments. We estimate a median duration of therapy across the treated population of approximately 9 months and we believe the clinical data supports pricing competitively to other targeted therapies in AML, such as the [indiscernible] or IDH inhibitors.
Physicians we've spoken with indicate an eagerness to prescribe revumenib early during an eligible patient's treatment journey to bring more patients to transplant and then extend responses by continuing with revumenib monotherapy following transplant engraftment. We expect that our first mover advantage and the early experience physicians will gain treating patients with revumenib 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 NPM1 AML. We estimate that the 2 distinct market segments in acute leukemias, KMT2AR and NPM1, avail a totable accessible population of 5,000 to 6,500 patients in the relapsed or refractory setting and an addressable market opportunity that approaches $2 billion in the U.S. Turning now to Slide 10. Approximately 14,000 U.S. 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 Jakafi and Rezurock 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 axatilimab to carve out a sizable commercial opportunity within the estimated $1 billion U.S. refractory chronic GVHD market. As you know, Incyte is our partner for axatilimab, and really the leader in the GVHD space. As of last year, we exercised their option with Incyte to co-commercialize axatilimab in the United States and provide 30% of the commercial efforts as we believe there is a considerable benefit to promoting 2 products simultaneously to a highly overlapping and targeted physician prescriber universe.
We're working closely with Incyte to develop our go-to-market strategy for axatilimab and plan to align more fully with insight before sharing additional details. However, we expect to follow a similar set of strategic imperatives as we've just outlined for revumenib.
Now I'll turn the call over to Keith to review our financial results.
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 31 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 million to $55 million and total operating expenses to be $80 million to $85 million. 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 million to $260 million and total operating expenses to be $355 million to $375 million.
Note that the guidance range for operating expenses for the full year 2024 is inclusive of an estimated $43 million of noncash stock compensation expense. And preparing for launch, I want to take a minute to lay out how we plan to recognize revenue for axatilimab. Slide 12 includes an illustrative example of accounting for sales for [ axatilimab ] and is not intended to provide any margin or other guidance.
Commercially, our partnership with Incyte 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 the period where there is a net commercial profit for axatilimab, 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 axatilimab, as in the bottom of example on the slide, our 50% share of the net commercial loss would be included in operating expenses designated as a separate line item post share of collaboration laws. We also have various future U.S. commercial and regulatory milestones owed to us from Incyte that will 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., Incyte 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.
Thank you, Keith. As you've heard during the call, 2024 is shaping up to be a historic year for Syndax as we prepare to launch 2 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 all 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?
[Operator Instructions] Our first question is from Peter Lawson at Barclays.
Just first question is just around how important NCCN guidelines will be for additional indications as to get the initial approval of revumenib.
Peter, thanks for the question. Maybe I'll ask Neil to comment on the importance of the guidelines.
Yes. Thanks, Peter. So as you know, the first approval, we're anticipating that the first approval for revumenib will come in the third quarter, and that will be for KMT2A-rearranged acute leukemia in adults and children. So the approval will be -- should be sufficient 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 during the prepared remarks that we anticipate reporting pivotal data from the NPM1 cohort by the end of the year.
So suffice to say that we have a plan, I mean, prior to approval, 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 ultimately ad-hoc, once important new data become available. So we're considering all of that. And clearly, 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.
And then as we think about expansion of the [indiscernible] solid tumors, kind of just if you could detail the kind of the expectations around the CRC data that's still 2Q when we should expect to see that data this medical conference and kind of the number of patients.
Thanks, Peter. Thanks for the follow-up. So 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. So these are -- 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 revumenib again, in this patient population, looking for prolonged stable disease in the 4 to 6 months, call it, range with perhaps around 15% of the patients in that stable disease category. So that's sort of 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.
Our next question is from Anupam Rama at JPMorgan.
Maybe a quick one for Steven. Just wondering, before you joined Syndax and you were being your assessment of the opportunities for revumenib and axatilimab, what really attracted you to these products? And then the second one is also actually for Steven. You mentioned very broadly what some of the levers for success in Slide 8 are for both of these launches, but anything more specific to revumenib and KMT2A that you'd highlight?
Yes. Thanks for the question. I'll answer both. First is, 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 3 different factors. The first is that 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 engage with KOLs, that's only been amplified.
I think the second thing that I really think about is sort who I work with, right, wanting to be a 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 third 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 it was even before I started, I think, I'm in Week 8.
The second question is really around levers for success on revumenib. There's a lot we're building out as a commercial organization, and all of that will be in place. I think as Neil mentioned and Michael mentioned in his remarks, will be ready in Q3. So infrastructure processes. All those things will be done. I think from a strategic point of view of the 3 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? 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 health care delivery. There's multiple stakeholders out there that deliver care to patients, physicians, nervous -- sorry, nurses, advanced practice providers, pharmacy reimbursement, pathology, you name it, we have a customer-facing footprint that we'll address and directly engage with that dynamic.
And the third point is really access. Neil mentioned NCCN guidelines, which will be important payers who 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 formulary review. And in addition, we built a support program to meet the needs of patients, which we know their need. So thanks for the question. Hopefully, that was a good answer.
Our next question is from Brad Canino at Stifel.
Relating to the plan for the pivotal [indiscernible] combo trial to be initiated by year-end. This will move the emphasis of clinical endpoints from CR towards remission durability and OS and 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.
Brad, thanks for the question. I'm going to turn it over to Neil to address that.
Yes. Thank you for the question. Specific -- I mean all of the combination studies that we reported on, the one specific to this scenario, in other words, initiating the Phase III [indiscernible] study by the end of the year is the BEAT AML study. And as you're aware, we -- 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 [ associating ] the Phase III study. Just to remind you, the response rates, including the CR/CRH rates that were observed and the BEAT AML to date have exceeded the historical controls observed in [indiscernible], including in terms of CR, in particular, molecular MRD-negative CR was much, much higher in the BEAT AML study compared to [indiscernible]. 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 being -- providing incremental efficacy in the target patient population.
And that's bolstered also by the observations from, for instance, the SAVE study, which is a combination -- is a combination of revumenib with venetoclax and oral decitabine in a relapsed/refractory setting as well as our AUGMENT-102 trial, the combination trial with -- in a refractory population in combination with chemotherapy. So the body of the evidence is that revumenib is combinable with backbone standard of care is not adding toxicity in the target population for the Phase III trial. For the Phase II/III trial in the NAV diagnosed and fit population the AML data providing evidence that revumenib is also adding 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.
Our next question is from Phil Nadeau at TB Cohen.
Congrats on progress. A few from my side. First, in terms of the phase II doses in the combo trials are validating the Phase II doses in the combo trial. So this morning's press release notes that some of the trials have been expanded to validate the Phase II doses. Just curious whether you'd be going to disclose whether the full monotherapy dose of revumenib is being used in those combinations at this point?
Yes, go ahead.
Yes. Thanks for the question. So just to remind everyone, the 3 studies that I just referenced in the answer to the previous question are the studies under discussion. So I would not repeat what those are. In all 3 of those studies -- in all 3 of those trials, there were 2 doses of revumenib that were investigated. 113 milligrams and 163 milligrams. 163 milligrams is the presumptive monotherapy dose in combination with the strong [indiscernible] that will be included in the label. So revumenib has been given at full dose in all 3 trials by the time we talked about them at the event around ASH last December.
In all 3, the dose-limiting toxicity windows for both doses have been cleared and both doses are being expanded in all 3 trials at this point in time. So we haven't -- when we talk about RP2D, we're continuing to characterize the 2 doses. But in general, our anticipation is that revumenib observation to date is that revumenib is combinable at full monotherapy dose with backbone standards of care.
That is very helpful. And then second question, based on the milestone tables that you just presented. It doesn't seem like you're anticipating an advisory comment review for either revumenib or axatilimab. Is that accurate? And can you remind us that the FDA explicitly say in the acceptance letters the AdCom would not be necessary for both drugs.
Yes, Phil, thanks for the question. I think our expectation is that neither axatilimab nor revumenib will require an AdCom, but we haven't explicitly stated in order we comment on regulatory correspondence from the agency relative to things like that. So -- but that is our expectation that neither will need an AdCom.
Perfect. And then last question from us. You referenced the 9-month expected median duration of use for KMT2A patients. Can you remind us what proportion of patients going to transplant is assumed in that 9-month figure?
Phil, thanks for the question. It's roughly about 1/3 of that path, right? I'm sorry, of the patients that go transplant.
So 1/3 of patients who get in relapsed/refractory in line what you go to transplant is the assumption?
Yes. Sorry, Phil, it's Anjali. I think what we've been saying is there's basically 3 groups of patients that seem based on the trial seem to all be about an equal size population. There were 1/3 of patients that did not respond. Of the 2/3 of patients that responded, half went to transplant. So overall, the entire population of 1/3 go to transplant.
Our next question is from Michael Schmidt at Guggenheim.
I just had one on the axatilimab launch now that they obviously closing in on the PDUFA day later this year. And as we think about the sort of $1.5 billion to $2 billion opportunity in the relapsed/refractory setting, just wondering how we should think about perhaps the early launch trajectory, subsequent to approval? Are there any good proxies we should look at, for example? And then what are your expectations for potential off-label use in the NPM1 subset? Obviously, where you will have data later this year, could that help next year to accelerate the launch early on.
Yes, Michael, thank you for the questions. I'm going to ask Anjali to comment on the launch.
Yes. Thanks, Michael. No. We are really excited about this opportunity. I think it's what revumenib has [indiscernible] a very unique situation. As you know, we got through the clinical development in record time, first patient dose to NDA filing in 4 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 third quarter of this year, and we'll have data for another very important patient population treated by the exact same health care -- set of health care providers in a disease where physicians 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, we've 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 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 [indiscernible] how they can utilize it to bring care to patients that have had nothing.
And I think you'll recall the last 2 ASH meetings have been very focused on the data that we've been generating and I think that shows how much education is already out there. And as Steve talked about, there's a lot more that we're doing to make sure everybody is aware of the drug, all the support and patient support is in place to allow utilization and we're really excited to have a really strong launch of revumenib.
Maybe just a follow-up. Can you just remind us what percentage of the AML market 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 the early launch again later this year.
Yes. Let me ask -- thanks, Michael. I'm going to ask Steve to comment on those questions.
Yes. I mean it's a good question. And the payer space is different for KMT2AR versus NPM1. It will be more of a commercial patient for the KMT2A launch just based on the age of the patient. We'll expect coverage honestly at launch formulary acceptance will happen over time, right, typically takes 6 to 9 months for that to happen. But in the meanwhile, for health care providers, their staff are very fluent on how to get through the medical exception process. That's where the NCCN guidelines are helpful and now they're other published data.
Medicare payers will be less important for KMT2AR, 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 9 months, even a year, it's really to grow all plans. We've been delivering pipe and information exchanges. That's the pre-approval information exchange. So we've had some very good interactions with payers. They recognize the unmet need with the criticality of patient care. And I think as Anjali said, it's a unique launch where you've got a launch followed by 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 cover 90% of covered lives in this country, which is as good as it gets in advance of approval. So we're prepared for success.
Okay. Great. And then maybe just a housekeeping question as we think about the axatilimab filing and potential approval, are there any milestones do from Incyte for that, that you should incorporate our models this year?
Yes. Thank you, Michael. Keith?
Yes, Michael. We do -- as disclosed in the Q and as we've disclosed in past Qs and Ks, we do have not only development and regulatory milestones, but commercial milestones do us from Incyte. Total milestones for development and regulatory under the agreement with $220 million. Total commercial milestones were $230 million. So a total of $450 million do us.
You can expect those to come to major regulatory events such as approval. I think that's a reasonable expectation, but we haven't been more specific as to the amounts.
Our next question is from Yigal Nochomovitz of Citigroup.
Just on the NPM1 regulator path, you may follow our or pathway even break here or given NDA, is that -- are those options not really necessary?
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 a 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, I'd say, pretty well advantaged by what we've -- what's come our way already. But we'll say 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. So I think it's obviously a program that we'll 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 will be through an sNDA 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.
Okay. And then when you think more broadly about the revumenib in terms of the spectrum of care 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 revumenib for patients that received revumenib in the frontline in a commendation setting, whether it be with [indiscernible] or perhaps even with the including those patients in the build for revumenib a relapsed refractory setting or once they're treated in the frontline then that wouldn't be part of your assumption set.
Yes. Thanks, Yigal. I think the -- I think our assumption is that once you're treated with [indiscernible] least from our vantage point, the way we see it today, I think once you're treated with -- 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, do you want to make a comment?
Yes, I agree with Michael's canister that I think that -- it is a little bit nuanced because I think longer term, there -- I can foresee situations where patients could, for instance, had they been treated and relapsed a long time later around NPM1 positive or KMT2A positive might be re-exposed. But I think in general, in general, I agree with Michael's point, we shouldn't be sort of expecting a lot of patients to fall that foot category.
And just one on AXA. Do you have any time lines for the IPF trial in terms of enrollment in data?
Thanks, Yigal. 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?
Our next question is from Kalpit Patel at B. Riley Securities.
Can you comment on what proportion of patients that you estimate might be eligible to receive revumenib as a maintenance treatment after induction and consolidation? I'm trying to understand that median duration of treatment in that specific frontline setting would be higher than the 9 months that you expect in the relapse/refractory study.
Yes. But thanks for the question. I think if I interpret 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're getting -- if you had a successful transplant, there's no reason that all patients would necessarily be eligible. They need to have 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 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 to treat patients earlier, they stay on -- 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 relapsed/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.
Our next question is from Jason Zemansky of Bank of America.
Congratulations on the progress. Regarding the commercialization plans for revumenib 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 to latent treatment, but do you expect an initially large bump in patient numbers or more of a straight-line uptake?
Jason, thank you for the question. I'm going to turn it over to Steve to address your questions.
Jason, thanks for the question. I mean there's a lot of excitement. I think predating me coming to the company, the company has done quite a bit of research, market research, advisory boards and met with KOLs, the [indiscernible] medical team has been out there. So there's a lot of, what to say, demand that's there because of lack of treatment options. I've recently actually was out in New York yesterday at Cornell and Sloan and meeting with KOL. So they're ready for the drug, literally cannot wait until it hits the market. So I think certainly, the academic centers, Jason, there will be a quick uptake. They are ready for this product. Awareness is already fairly high or whether it's [indiscernible] 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 commercial station standpoint, we'll have a adequately sized team, that's going to cover 95-plus percent of the opportunity. We'll have a nonpersonal promotional program that will reach folks in places that we may not be at as frequently. So I think you'll see a quick uptake across the board. And a lot of it is just patients in the office ready to be treated.
So I think leads to your second question, and there's not going to be much of a bolus right? We have an EAP, that's in place. It's -- I cannot give the number, but it's a certain number of patients. No one is 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 will burn out over the beginning months of the launch. And then after that, we'll expect a typical uptick just based on our assumptions and available patients.
Got it. Makes sense. And then maybe just a quick follow-up on your Phase I in metastatic colorectal cancer. In terms of no, no go decision, I know you mentioned disease stabilization is important, but I was curious, is there a specific signal, I don't know, maybe a biomarker that you're looking for in terms of [ menin's ] potential or hypothetical role in driving solid tumors that would just make you feel confident about investing significantly in this potential expansion opportunity?
Jason, thanks for the follow-up on CRC. I'm going to turn it over to Neil to address.
Yes, thanks. So in the part of the study that has been conducted to date, I just reiterate Michael's point, I mean, this is primarily the safety -- a safety part of the study. We are looking at in addition to clinical responses, I mean, primarily a safety study. We're also looking at clinical responses. We're also looking at biomarker data. And our anticipation is that as we get to a point in the future where we could make a decision on future development in this space, but that's solely the will be taking into consideration.
We haven't specifically said what correlative data we're looking at, but at some point in the future, we will provide more details around that. I wouldn't expect necessarily too much data in our update in the second quarter on, for instance, correlative data. But be rest assured that we are pursuing correlative studies. And as I said, we'll take [indiscernible] into consideration.
[Operator Instructions] Our next question is from Justin Zelin at BTIG.
Welcome to Steve. So ahead of 2 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 graft versus host disease for promotion of both products.
Sure. Maybe I'll let Steve take that question.
Yes. I appreciate the question, Justin. In terms of sales size, we're not prepared to provide the exact color and inside of the team. But it will be a team that I think can really address customer needs. Our goal, whether it's providers anybody within the health care delivery system that it's a great customer experience. So we're prepared to link up to all different aspects of health care organizations to make sure we're meeting the needs and supporting providers in their treatment of patients. So I think I used 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 Incyte calling on the same treatment centers, right, 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. We'll obviously provide 30% of of the effort. So we'll leverage our footprint, and we will cover the market opportunity in really both opportunities.
Our next question is from Chris Shibutani at Goldman Sachs.
A lot of questions on the focus have already been asked. So perhaps if I can ask a bigger picture, longer-term question, it ties a little bit to your guidance in terms of operating 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 2 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?
Great. Chris. Good questions. Maybe, Keith, do you want to take the first one on the longer term.
Yes, sure. So Chris, I wouldn't necessarily agree that it's a big step up to use your words. We did total operating expenses in 1Q close to [ $80 million ]. The guidance range for the second quarter is $80 million to $85 million. So if we were just to stay on that trajectory, we'd be $320 million-ish. So there is some increase that I think we would anticipate in the back half of the year. And I think, yes, certainly, as IPF ramps as the first-line 7+3 combination trial with REV continues to accrue. And as we get ready to launch the pivotal Phase III [ Banesa ] combo with REV, that's certainly going to add to some of our R&D expenses in the back half of the year.
But also don't forget, we're building out a commercial organization. So on the SG&A side, we would expect some growth there for the sales force, all the customers facing individuals that Steve commented on earlier as well as the G&A support for those -- for that field force.
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 2 molecules that are nearing approval, and so the bar is always quite high with regard to new opportunities and it gets 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 Anjali, you want to make a comment on our activities, but we remain quite disciplined about what we're doing.
Yes. 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 there's definitely a lot to look at.
Our next question is from George Farmer at Scotiabank.
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?
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 trial is ongoing, the pillars of our strategy being the [ Banesa ] in the unfit population and then and [ Covey ], if you will, is 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 that the drug's ability to be combined with chemotherapy in relapsed/refractory spending.
We'll have data updates on that. We'll also have additional data as we talked about on the Ben 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.
Yes, sure. So we have investigated initiated trials, either planned or ongoing, which we -- in which revumenib in combination with [ gilteritinib ] or mid storm will be invested -- either are or will be investigated. To Michael's point, conducting -- for instance, the pivotal program in the frontline FLT population in patients with both NPM1 and FLT3 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 said is that obviously, in addition to the FIT Phase III that we'll initiate -- we plan to initiate by year-end that were dose ranging in combination with 7+3, which will position us then to initiate a Phase II 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 prefer to generate evidence in that population as opposed to potentially pursuing a registration strategy.
This concludes our question-and-answer session. I will now turn the floor over to Mr. Michael Metzger for any additional comments or closing remarks.
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.
The meeting has now concluded. Thank you for joining. You may now disconnect.