Syndax Pharmaceuticals Inc Aktie

All right. Great. So welcome, everyone. We're here in New York City for day 2 of Citi's Biopharma Back-to-school Summit. So sharpen your pencils, take out your notebooks. It's my pleasure to have with me -- I should say, I'm Yigal Nochomovitz, senior biotech analyst here at Citi, and it's my great pleasure to have with me senior management from Syndax Pharmaceuticals. Of course, Michael Metzger, CEO; Nick Botwood, CMO and Head of R&D; and Keith Goldan, Chief Financial Officer. So welcome, all of you. Thank you so much for doing this.

Michael, obviously, a lot is happening in the space. You have 2 FDA approvals, obviously. One of the questions we're getting recently is just how things are going with Revuforj, given now you have the expanded label. So maybe we could start there, talk about NPM1, what are the forces driving your view that you are taking a leading share of that market. And then we'll go from there.

Thanks, Yigal. Good to be with you. Good to be back to school. Well, look, I think it is a very exciting time for the company and a lot going on. Really important launches, 2 important launches. I think what we've done, we've really reset the category in AML in terms of what a launch could look like, which is really exciting. I think people maybe missed that through the trees a little bit. But we're annualizing at about well north of $200 million for the second year of launch, which is fantastic.

And as you pointed out, we have 2 indications, KMT2A and NPM1, very broad label, best-in-class efficacy. And I think the efficacy story is really resonating with physicians using the drug in monotherapy, in combination, and really building the menin story and the leadership that we've exhibited is really coming through. So we're very excited about the forward and excited about what we're building with that franchise. I think NPM1 has become an increasingly important part of our story, both new patient starts and time on therapy. So duration of therapy is an important driving force behind the whole franchise.

Recent data -- Medicare care data as well as script data indicates that we are firmly in the lead in terms of new patient starts for NPM1 as well as KMT2A. So we're really moving well, dominating. We're at 85% market share plus in the category. So thinking about relapsed/refractory, I don't think you can get more dominant than that, really building the business, and it's growing, right? We've shown 6 quarters quarter after quarter of growth, substantial double-digit growth, and we expect that to continue.

So that's where we are today, and we're certainly going to continue to build as we get to frontline, which is, hopefully, right around the corner. I mean we're really moving quickly, enrolling trials, and will talk about how we're doing. And certainly, the data that we have, the upcoming milestones, catalysts, we'll talk about, but really quite exciting year for us.

Okay. And so just you mentioned some specifics there in terms of some of the share numbers. So the 85% share, that's sort of across both categories...

It is. It is.

Okay. All right. And we're getting a lot of questions about the competitive positioning with regard to NPM1. Anything there you want to share more specifically regarding the confidence you have that you are taking the lead in the market there?

Well, I think the numbers speak for themselves. We posted $55 million in the last quarter. Competitor did about $9 million. So you could see that. I do also see or encouraged by what physicians tell us about the profile and how they are using the drug, using it as monotherapy, using it in combination with standard of care, being supported by the real-world data that we're putting out as well as what we're producing in trials and so forth. So there's a lot of support. And when we speak to physicians, they tell us we're the go-to menin inhibitor. And we expect that to continue to build as we produce the data that we have set out to bring forward. And that's really the sentiment is quite positive.

One of the other drivers, obviously, of the revenue picture is the post-transplant restarting and the maintenance there. So can you talk about that aspect of it in terms of getting to a goal? I think you've referenced something in the 70% to 80% range in terms of getting people restarted on Revuforj?

Right. So it's a very important dynamic. As you all know, if you've been following our story, Revuforj is an opportunity to bring people to transplant in numbers that we've never seen before in AML with patients who have KMT2A and NPM1. So we're seeing transplants across both indications, more transplants, of course, on the KMT2A population. And right now, we're about 50% as of last quarter, 50% of the patients going to transplant, which is remarkable. It's remarkable because it drives the ability to get into -- you get into a response first and then you get to transplant and then you have the opportunity to go back on maintenance and maintenance can extend the life of a patient and keep them in remission.

And so that's what we're setting out to do. The target is -- we tend to call it the target for maintenance, it's really what do we think we can achieve, how many patients will go back on maintenance after transplant. We expect the transplant numbers to move up probably not meaningfully beyond 50% of the patients, but could be higher than 50%. But really, the opportunity to bring patients back 70% to 80% is roughly the target. We say that because, unfortunately, some patients don't make it through transplant, having nothing to do with Revuforj but just the transplant procedure themselves. And then you have patients who have choice in the matter.

And obviously, there are some things that intervene and so forth. But a high, high percentage of patients going to maintenance will continue to drive that franchise in terms of TRxs, and we see that steadily increasing each quarter, and that's a very, very positive forward indicator for the growth.

And with that dynamic, where do you see the sort of steady-state duration shaking out long term?

Yes. I mean what we've...

We've loved this for the models.

Yes, it's great for the models. Look, I think we've spoken broadly about 6 to 12 months of duration of therapy in the relapsed/refractory setting. And I think we'll be -- we're going to be there this year, for sure. What's also very encouraging, if you look at the data from the last quarter, we were seeing patients who had come back from transplant beyond. They were on an average of 9-plus months. So again, tracking very, very well to even exceed our expectations, which we were very encouraged by last quarter. We would hope that would continue to move up. No reason to say that it wouldn't. So this is -- again, it's an ongoing and unfolding story, but it's a very positive indicator of what could come in long-term duration.

And of course, there's a ton of interest in the earlier line. You mentioned already the frontline opportunities and love to get Nick's thoughts on the structure and strategy there. But you've referenced Revuforj potentially being a $2 billion product. So I gather that includes contributions from the earlier settings. So maybe we could just kind of walk through what the thinking is there in terms of getting into those earlier lines and then the strategy with the several -- the 2 important frontline studies you're running.

Certainly. The data that we have in combination with Rev and frontline standard of care for newly diagnosed patients is building. So we have data sets you're familiar with, SAVE, Beat AML, our 7+3 trials. Those Phase I/II trials have grown in size and really shown us fantastic category-leading data to date. We'll have updates, important data at the end of this year that will further elucidate that profile. But we think we've really derisked the frontline opportunity quite a bit with these data. And so with category -- a category-leading agent like Revuforj and the ability to move quickly to frontline and be there first with a best-in-class profile with a lot of supporting data helps to just drive the story in the intervening time between now and we get to frontline.

But as you mentioned, we believe it's a $2 billion-plus peak revenue opportunity in the U.S. for Revuforj, driven by a first-mover advantage and best profile. Again, that's across both fit and unfit, and of course, assume some participation again in relapsed/refractory, a leading category in relapsed/refractory, but the market will probably change as we get to frontline, and we think we'll have a dominant share as well. So it's a long-term view, which we feel is very well supported by data today. But maybe Nick can take us through the trial.

Yes. That would be great because I get the question around the reason you're doing 2 frontline studies. That would be great to get into the details there.

Great. Well, firstly, thank you, Yigal, and a pleasure to be here. Thank you for the invitation. Very exciting time at Syndax and happy to talk about the progress we're making in newly diagnosed AML. We really feel this is the next step in terms of the life cycle of Revuforj. And it's an exciting time to be on the program because we're gaining great momentum with both of those 2 pivotal registrational first-line studies. Very satisfying now to see sites being set up worldwide, activated, patients being enrolled, great momentum behind the study, a series of large extensive investigator meetings around the world supporting those studies. And we're making good progress, and it's exciting to see that, and we're just looking forward to those studies completing and reading out.

Now let me just break them down a little bit. I think most people are familiar, but just to remind everybody how we're approaching this, we have 2 pivotal studies, and then there are some additional studies that support innovation and clinical practice, which we think are important as well and could be quite differentiating. But let me start with the 2 pivotal Phase IIIs. We have the EVOLVE-2 study. This is done in collaboration with the HOVON Group, so an internationally renowned well-recognized leadership group in the space of hematology, who we have been working closely with now for 2 years. This was the first pivotal Phase III registration study to get started enrolling for a menin inhibitor, and we started in May 2025.

So this has been set up for quite a long time and is enrolling very well, and we're happy with the progress. We also are working in collaboration with the Beat AML consortium in the U.S. And so we have great support and it's a catalyst to enrollment having that group now enrolling in the U.S., working in collaboration with HOVON. Just as a reminder, this study has dual primary endpoints. So they're independently powered statistically, either one of them could lead to a positive study. One of the dual primary endpoints is complete response and the other is overall survival. So these are very clean endpoints.

Overall survival is obviously the gold standard in heme/onc studies, and we hope to be able to demonstrate a survival benefit and complete response rate is a surrogate endpoint that we believe could support accelerated approval and indeed has been used before for accelerated approvals in this setting. So that's the patients who are unfit for intensive chemotherapy. And then we have a separate international Phase III study called REVEAL. This is done under Syndax sponsorship. We're working with a leading CRO, Parexel, to execute that study internationally. It's a true international study, sites across the United States, throughout Europe and also important, Asia. So we have China, Japan, Korea, all enrolling in that study.

So great momentum behind it. We're going to be at several hundred sites worldwide, and we're doing very well. This is in combination with 7+3 intensive chemotherapy. It again, has dual primary endpoints. We're looking at CR, but in this instance, because the CR rate is quite high for patients that get intensive chemotherapy, it's MRD-negative CR. Now that endpoint has not been used for accelerated approvals in the past, but we feel we have time and sufficient data to support it as a potential for accelerated approval and could really -- that could be quite groundbreaking and innovative, and we're working closely with health authorities to support that endpoint.

And then the other dual primary endpoint is event-free survival. Both of those studies are going well. We haven't guided on the time lines. This is a very competitive space. It's -- we want speed, we want quality, but we also want a good result. So we haven't guided specifically, but you can probably estimate roughly where we are given the start rates and roughly the size of the studies. I would note that these studies are somewhat smaller than the competitors in the menin space, and there are specific reasons for that. Michael alluded to the strength of the data, and we can maybe talk a little bit about that.

We have generated really compelling data for both a ven/aza combination, working with Beat AML and MD Anderson, the so-called SAVE, but also with 7+3 intensive chemotherapy. Those are very supportive. That's allowed us to power the studies appropriately. And also our FIT, newly diagnosed study, is only 2 arms, whereas the competitor studies include 3. And we made a very deliberate and conscious decision to do that, and we can maybe explain why in due course, but that was the decision. So we're feeling very confident about those.

Now I would just mention one last thing, Yigal, which is in addition to those 2 pivotal registrational studies, we want to be differentiated and also to innovate as the leaders in the menin class. And there are a couple of things that we're doing separate to that. One is called the RAVEN study. This is a study we're doing in collaboration with University of North Carolina, Josh Zeidner. And this is for patients who have KMT2A disease, where we have consistently demonstrated the best data. And this is for patients that would otherwise be fit to receive intensive chemotherapy. They're actually going to get ven/aza plus revumenib with the idea of getting them to stem cell transplant without all of the comorbidities usually associated with intensive chemotherapy.

So that's differentiating and we think could offer a viable alternative for those patients. That's number one. And then number two is another study I'm very excited about, the MenTain study. This is a study we're doing with Corey Cutler, Sweta Gooptu at the Dana-Farber Cancer Institute. This is the first prospectively randomized study specifically addressing the question of maintenance. Michael talked about the importance of maintenance. And to be clear, we don't promote maintenance. We still have to establish the burden of proof.

We know physicians want to treat their patients in maintenance after transplant because they know that they have a high likelihood of progression. This will actually attempt to address who should get maintenance and what the benefits of maintenance are and how you optimally manage patients. So that's the kind of overview of our newly diagnosed program, and I know it was a little long, but hopefully, that was helpful.

No, that's excellent. And I'm gathering that the fact that you've split, as you pointed out, the fit and unfit into 2 separate studies, does that increase efficiency? Does that increase speed? Is there a specific reason for that?

Yes, very briefly, that was a conscious decision, and I'm very happy with that design. It allows us flexibility. One's under our sponsorship, one we leverage the benefit of working with HOVON, which is great, and it allows us to be flexible should we need to change or amend either of those studies. So I'm very happy with the model in which we're executing those.

And I know you're not ready to provide time lines yet, but I guess, in next year, would we get a sense as to when we may see the top line? Or is it still a bit too early to know that?

Well, we may guide in due course. But for now, we're just focused on execution, and we'll see. But we're feeling good about the momentum behind those studies.

Okay. There's another mutation, which is less common, this NUP98. Can you just comment briefly on how you're going to get that one into the regimen?

Yes, let me try and be brief because I get excited about all of the science and the opportunity, and I don't want to go off too long because I could talk a lot about NUP98, but this is a very important subtype of AML. And the reason it's exciting is because these patients are highly chemo refractory and previously didn't have really viable treatment options available to them. And we always like focusing on these areas of high unmet need. And because of the breadth and the profile of revumenib across NPM1, KMT2A, NUP98 is a little like KMT2A. It's a relatively small subset of AML, although I think actually more prevalent than we think because physicians are now increasingly looking for it.

So it could be as high as 3% to 5% of AML. And we presented some data at EHA in a series of about 28 patients, which is quite a lot, showing just over 1/4 of those patients actually showing some sort of response, which is really encouraging for a subset of patients who are refractory to chemo who really don't have a treatment option available to them. So that -- those data working with MD Anderson being prepared for manuscript, and we think that, that could be very important data for the NCCN guidelines committee to consider at least as to whether they meet the criteria for guidelines. But given the paucity of options for those patients, that's something we would be keen to submit to them in due course when we have the manuscript.

Okay. Well, look forward to that. Let's move on to Niktimvo for a bit. There's obviously a lot of excitement there as well, not just because of the strong launch with your partner, Incyte, but you have a very important readout coming up, which is highly anticipated in a lung disease called IPF. So we'd love to understand that study a little bit. There's a lot of interest in what you need to show there to be -- have a good target profile to take it forward. So can you introduce that to us and sort of explain how you're thinking about what you want to achieve there?

Well, again, I'm extremely excited about axatilimab and IPF. So I will try and be succinct, but it's very exciting. We could talk about it a lot. And this is an extremely promising and important study, the MAXPIRe study. I mean, to be candid, this could be a novel and groundbreaking outcome for a completely new modality in idiopathic pulmonary fibrosis, and that's important. Nobody has looked at CSF1R and its activity against monocyte-derived macrophages, which we truly believe are the underpinning pathology in idiopathic pulmonary fibrosis. So this is a proof-of-concept trial. It's not a Phase III, and this is why we do the experiments.

But when you look at the totality of the data from mouse models through the data we've already generated in patients with graft-versus-host disease and specifically the lung manifestations of graft-versus-host disease, we're going into that study and the outcome of that study with, I would say, a high degree of confidence. And the MAXPIRe study itself is the most robustly designed proof-of-concept study in the field of idiopathic pulmonary fibrosis. It's a 135-patient randomized study. We actually overenrolled by about 10 patients because of the momentum and enthusiasm in the study. It's randomized 2:1. It's placebo-controlled, double-blind. So we have no indication what the readout is yet.

And it has the most statistically rigorous approach to the derivation of the primary endpoint, which is forced vital capacity, which, of course, is the FDA and worldwide regulatory standards. So this is a very rigorously designed study to give the best possible indication of whether axatilimab would be a study we'd want to take into a confirmatory Phase III. We talk quite a lot about what you would expect to see. And in idiopathic pulmonary fibrosis, obviously, we've spoken to thought leaders worldwide. We have a very eminent steering committee supporting this study. They're very excited about the potential of CSF1R inhibition in idiopathic pulmonary fibrosis.

We will be focused on forced vital capacity. We've guided towards -- it's a 26-week endpoint annualized to 52. We've guided towards about 30, 40 mL, maybe a 40% relative retention of FVC would be encouraging. I think a couple of things I would highlight. Number one is that axatilimab is particularly well suited conceptually to treating in combination because of its unique mechanism of action. Most of the currently approved and in development agents target more the fibroblasts that drive pathology. CSF1R is completely different. It targets monocyte-derived macrophages, both inflammatory and fibrotic. So it's particularly well suited to combination.

So it could be an important addition in the armamentarium, number one. Number two is I think people underestimate the importance of tolerability. We know axatilimab is extremely well tolerated. It's approved at 0.3 mg per kg and has a very favorable profile. Many of the current approved standards of care are associated with quite significant GI toxicities, which we know are problematic for patients, nausea and vomiting. So I think you have to look at the totality of the data, the science supports it. Of course, the FVC, the endpoints, the absolute difference in mLs, the relative difference, but also the tolerability and importantly, the symptoms and some of the other correlators we look at in that study.

So when we read that study out, we'll report on all of that. And I think it will give us a very good sense of whether we should be transitioning into Phase III. What I can say if the study is positive, and we're happy about it, it would be very predictive for success in Phase III because of the way we've designed it. We're using the most rigorous statistical methodology to interpret the study, very similar to how the FDA design and ask for Phase IIIs to be designed and interpreted. So we're feeling very good about that study. We will have the data in Q4, so very soon now. We're tracking well. We're tracking to time in terms of data quality, and we're feeling in very good shape.

And the patients that are enrolling, you mentioned some background therapies. So you're allowing patients to enter that are on background therapies like pirfenidone, for example, as well as ones that are not.

Yes, we allow standard antifibrotics. Most of the patients, as you'd expect, by far the majority are on a background antifibrotic, which I think is good because, again, I think the mechanisms are very complementary. They don't overlap. So we'll see. We'll, of course, look at it by background antifibrotic and that small proportion of patients that aren't on any background antifibrotic, Yigal.

I think we'd like to see consistency of effect. You probably would expect a slightly bigger delta for those patients that aren't on any antifibrotic. We know that from historical studies. But our expectation is we should see pretty -- I mean, if the study is positive, we should see pretty consistent effects across those groups. And we're feeling quite good about that, again, when you think mechanistically about how axatilimab works.

So presuming success there and you go into Phase III, you start to think about the commercial setup, there is a subcu version that you're -- I believe you're working on for axatilimab. How important is that in terms of driving uptake in IPF relative to the current approval -- approved indication in GVHD?

Yes. Maybe just to comment. I think the subcu is going to be very helpful to the franchise. It's not the be all, end all, right? I think having the drug, the activity of the drug, the profile of the drug, is well established as an IV already, and being able to deploy into this population, would be sufficient. But we have, I would say, plans to bring subcu forward, and I think it could be additive to the franchise for sure. So that's a longer-term plan that we integrated into the development.

And then speaking of moving into earlier lines of therapy, if we could go back to chronic GVHD for a second, there's another important study, which I also believe is reading out by the end of the year in combination with Jakafi. So could you just speak to that and what the benchmarks are there in order to advance the combo?

Yes. Briefly, this is a study we're doing in collaboration with our partners, Incyte. It's an important study because steroids, dexamethasone, is the current standard of care for frontline GVHD, but it comes with significant morbidity, and this is a potential steroid-sparing approach. We have another study, again, working with Incyte in combination with dexamethasone, which is a pivotal Phase III with an event-free survival endpoint. So that's also an important study. But this is a different approach. It's a proof-of-concept Phase II. It's about -- it's 3 arms, dexamethasone, Jakafi, and then the combination of Jakafi and axatilimab. Our hope and expectation is both of the experimental arms will be better than dexamethasone.

The question is, does axatilimab add over and above what you might expect with Jakafi alone? Now the response rate at 6 months might be quite high for both of those arms. And it may be important, the addition of axatilimab may actually contribute to the durability of that response. I think that's going to be important. Six months may be too soon to show a benefit, we'll see. But I think that both of those will potentially be better than dexamethasone. We're hopeful that the combination will add something over and above Jakafi alone, and that may be manifest by, number one, the response rate, but importantly, also the duration of the response, the time that patients are able to stay off steroids and also potentially in due course, event-free survival.

So we'll have those data again in Q4, important proof of concept, and that will inform clinicians about how best to manage their patients. And when the frontline study reads out for axatilimab in combination with dexamethasone, that provides a variety of options to select from whether patients want steroids, need steroids, maybe they could have Jakafi or a combination of Jakafi and axatilimab. So we're really covering all of the bases there.

And then that would inform, I gather, a longer Phase III trial once you get the clarity there.

When we see the results, and we'll look at them with Incyte, and we'll make a decision based on the landscape and the other options at that time.

Okay. Important other topic is you had your R&D Day, I guess, it was earlier in the summer, and you introduced some new topics, one of which was this interesting drug that targets EGFR, which is new area, at least from our perspective. So I'd love to hear your thoughts on that in terms of the design of that molecule, how it's different? It has this allosteric inhibition feature, which is currently unique relative to the class. So can you just sort of talk through the design there and the...

No, thank you, Yigal. This is a new topic and incredibly exciting. New to Syndax, maybe not so new to me because I've spent 20 years looking at targeted agents in EGFR-mutated lung cancer. I cannot underestimate the excitement and the importance of having a drug that is unique and targets a completely different binding pocket on the EGFR receptor in a disease like lung cancer. So this is an incredible opportunity to validate an entirely new hypothesis, which we have seen before in diseases like melanoma with allosteric inhibition and leukemia with allosteric inhibition, but it's never been shown before in lung cancer.

Very proud to be working with leading scientists and clinicians at Dana-Farber, who have again been pioneering. They were involved in the original discovery of the activating mutation in EGFR. This is novel. They've been working on it for many years. This is almost their fourth generation. It's a highly potent allosteric inhibitor that we believe could be very good in osimertinib refractory patients and potentially in combination with osimertinib. We're progressing it now through the IND informing studies. As we've said, we should anticipate having it in clinic in 2027.

The really exciting thing about this particular development program because we're taking it in as a monotherapy, we would expect to see activity quite early on in the development program. We will have a dose escalation as typical in a first-time-in-human study. But we will very quickly get to -- from dose 1 onwards, get to doses that we would consider therapeutic. And the first time, should we see responses, either in the lung or in the CNS metastases, that will be validation of an entirely new concept and hypothesis in lung cancer, which is incredibly exciting new science.

And this is a drug that could be very -- from the preclinical models, could be particularly well suited to patients that have resistance mutations to osimertinib. We know that patients with L858R subtype of EGFR do particularly poorly. We know that from the FLAURA study and FLAURA2 with osimertinib, which was an osi/chemo combination. This study has shown preclinical activity in patients with, for example, C797S, which is a common resistance mutation for osimertinib. And that will be our intent going into the first-time-in-human and then dose expansion. Very exciting new science and opportunity for Syndax. Couldn't be more pleased to get that into the clinic next year.

And would this have applicability in the broader set of what people are calling these atypical EGFR mutations? Is there the potential there or that's still to be...

Yes, we're going to learn a lot, Yigal, about this. What we've shown and what Dana-Farber have shown is that the classical exon 19 and exon 20 don't exhibit the allosteric binding pocket. There's an alpha helix in the receptor that obstructs it. But for L858R, which is the highest unmet need and some of the other atypical mutations like L816 (sic) [ L861 ] and other common ones, this drug has very profound activity. And also in preclinical models of -- again, C797S, so refractory models to osimertinib, again, very, very good activity because it's binding a completely separate binding pocket.

And if you think about all of the other drugs that are in development in EGFR-targeted disease, and there are many of them, all of them are targeting -- chasing resistance mutations in the catalytic binding pocket. This targets a completely separate binding pocket. And the other beautiful thing about this hypothesis, which we've shown in the preclinical models is the potential to double drug. So by combining osimertinib, and we'll look at this in our Phase I expansion, osimertinib with 4321 could potentially really block that receptor. And Yigal, we'll learn as we go into the Phase I and expansion, who are the patients that are most likely to benefit.

We know there are some types of resistance that may escape the receptor like c-MET, and we'll look at that whether c-MET amplification are not the patients you want to target, but this is such a high area of unmet need. And there are many patients with these types of diseases. We're not talking about small populations. This is unfortunately a very common disease and a high unmet need. We think this could be an incredibly valuable opportunity if we're able to validate its activity. And based on all of the preclinical data and the very clean profile that we're beginning to now show through all of the IND-informing studies, as we take that into the clinic, I think it bears much promise.

Another topic you introduced, I believe, recently is the SNDX-62122 in myelofibrosis. So if you could speak to the thinking in terms of the therapeutic hypothesis there regarding menin inhibition in MF and what your clinical strategy is?

Yes, briefly, again, I think a nice demonstration of our leadership in the menin class. We were the first working with John Crispino and collaborators to show the potential for menin in myeloproliferative neoplasias. This was based on a hypothesis around thrombocytopenia, and then I'm trying to understand mechanistically what was driving that. And through the very elegant work that John did that got Best of ASH last year and is now published in Cancer Cell, he and his collaborators were able to show that actually normal megakaryopoiesis is dependent on the menin scaffold complex, and that there are certain genes that are transcribed, so MEIS and MEF2C that are very dependent on the menin complex, which if you inhibit, then you can actually reduce normal megakaryopoiesis, which is one of the pathologies in myeloproliferative neoplasias that drives all of the issues like thrombocyte platelet dysfunction, anemia and splenomegaly.

So he's shown this in vitro and in mouse models. We're working with John Mascarenhas, the MPN Research Consortium, to test this hypothesis with revumenib and at the same time, progressing 62122, which is a new and novel menin inhibitor. It's optimized for many aspects of its profile that we think could be particularly well suited to patients with diseases like myelofibrosis. And we should have that in the clinic next year as well. It's progressing through IND-informing studies. And this is a potentially very exciting life cycle management opportunity for us in a new setting where we could generate proof of principle with revumenib and then rapidly follow that, taking all of the learnings with 62122. So another nice opportunity for us to demonstrate our scientific leadership in menin inhibition.

And then just to close out here, Michael, if you could speak to what we should expect at ASH briefly. And then a question we've been asking all the companies, AI, obviously, a big topic. But to what extent are you using AI at Syndax, either just to improve efficiencies internally or with regard to filings or other aspects of the company?

Yes. So Nick highlighted the programs and all the excitement on the pipeline. I think ASH for us is always a very big meeting, wraps up the year, and we're doing a lot of work to get ready for that. Certainly, the presentations on the frontline, newly diagnosed patients, both updates to SAVE, updates to Beat AML and our 7+3 combination trial, those will all be updated, and we're excited about things like overall survival, looking at that over a longer horizon really should continue to derisk our frontline trial. So very important real-world data as well that we'll be presenting. So more to come. You'll see the abstracts, I think, on November 4, but we're excited about how that's looking for us.

And certainly, I think the -- as we think about the pipeline, the excitement around beyond ASH, I'll just make a comment that the pipeline is starting to really bear fruit. It's a first- and best-in-class approach, much like what we've done with Revuforj and Niktimvo, being approaching really high unmet need areas and bringing the best science forward. So we're excited to not only conduct trials but get data early that could be quite informative and exciting. So that's to come. So more on the horizon. And then maybe I'll ask Keith if you want to comment on the AI topic.

Yes. Thanks, Michael. I would just say briefly, we're using AI probably like every company is just to improve individual performance. But I think more importantly, using it where we have large data sets and those large data sets may be in commercial, medical, pharmacovigilance, biostat or biometrics, where we want to look for signal detection in those large data sets, which would be otherwise very time-consuming or impossible. And those -- that signal detection can yield valuable insights. So that's probably where it's most valuable to us.

Okay. Good to hear. Well, we look forward to attending ASH and seeing the next layer of data. So thank you all very much.

Thanks, Yigal. Great to be here.

Thanks, Yigal.

Thank you.

Good day, everyone, and welcome to the Syndax Second Quarter 2026 Earnings Conference Call. Today's call is being recorded. [Operator Instructions]

At this time, I would like to turn the call over to Sharon Klahre, Head of Investor Relations at Syndax Pharmaceuticals.

Great. Thank you, operator. Welcome, and thank you all for joining us today for a review of Syndax's Second Quarter 2026 Financial and Operating Results. I'm 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; Steve Closter, Chief Commercial Officer; Dr. Nick Botwood, Head of R&D and Chief Medical Officer; and Keith Goldan, Chief Financial 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 2. Before we begin, I'd like to remind you that any statements made during this 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 factors 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 made represent our views as of today, August 4, 2026, only. A replay of this call will be available on the company's website, www.syndax.com, following its completion.

And with that, I'm pleased to turn the call over to Michael Metzger, Chief Executive Officer of Syndax.

Thank you, Sharon. Good afternoon, everyone, and thank you for joining us.

Starting with Slide 3. The Syndax team delivered another quarter of solid commercial results and progress across our growing pipeline of programs, targeting areas of high unmet need and substantial commercial opportunity. The business fundamentals are strong. Sales of Revuforj and Niktimvo grew to a combined total of $115 million in the second quarter. Both medicines are now annualizing at well over $200 million each, and we have just started to unlock their multibillion-dollar potential.

Revuforj continued to grow by double digits with net revenue totaling $55 million in the second quarter, up 91% year-over-year and 12% quarter-over-quarter. These results highlight our continued leadership in menin inhibition, robust demand in both NPM1 and KMT2A, and the positive impact of an increasing average treatment duration driven by multiple factors, including a growing number of patients on therapy for an extended period after receiving a stem cell transplant. As the number of patients on therapy post-transplant continues to stack, this recurring base will be an important driver of long-term compounding growth. Encouragingly, the average duration of treatment is also increasing among patients who are not proceeding to a transplant.

As Steve will describe shortly, the positive impact of an extending average treatment duration, which was partially offset this quarter by fluctuation in the number of new patients initiating therapy, one of several drivers of our business. Today, we are even more confident in the forward trajectory and substantial commercial opportunity with Revuforj. Our conviction is underpinned by the multiple drivers for continued growth, including a best-in-class profile valued by physicians, an increasing average duration of therapy, a broad and expanding prescriber base and ample opportunity in NPM1, KMT2A and other menin-dependent acute leukemias. We are well positioned to extend our leadership in menin inhibition into the future and continue driving innovation for patients.

Building on a long history of landmark firsts, we are positioned to be first to frontline AML, driven by strong global site initiation and patient enrollment in our pivotal trials. With future anticipated indications in frontline AML, we expect that Revuforj could reach in excess of $2 billion in peak annual net revenue in the U.S. alone. We have another data-rich period ahead for revumenib.

In the second half of the year, we will report additional practice-informing evidence from multiple trials at major medical meetings, expanding on the prominent presence we had at ASCO and EHA in June. We also expect to publish data in relapsed/refractory NUP98 rearranged acute leukemia in the fourth quarter. These results could inform clinical practice and guidelines in a patient population similarly sized to KMT2A. Patients with NUP98 urgently need new treatment options, including therapies that may reduce the risk of relapse after transplant, as is the case with KMT2A.

Physician feedback indicates that NUP98 rearrangements are more common than once thought, occurring in perhaps 5% or more of AML cases, translating into potentially 1,000 to 2,000 pediatric and adult patients with NUP98 annually. As the first and only company to report clinical data showing activity with a menin inhibitor in this subtype, we have a unique opportunity to pursue a guideline listing that could meaningfully expand the patient population treated with revumenib.

Switching gears to Niktimvo and chronic GVHD. Niktimvo net revenue grew to $60 million in the second quarter, up 67% year-over-year. This performance reflects robust demand and Niktimvo's unique ability to address inflammation and fibrosis. Niktimvo is positioned for further growth with strong adoption in the fourth line and increasing uptake in the third line, driven by a broad base of prescribers who are enthusiastic about the results they've seen in their patients. We also have multiple expansion opportunities and important upcoming catalysts for axatilimab with Phase II data in IPF and frontline chronic GVHD expected in the fourth quarter, poised to unlock new multibillion-dollar opportunities.

Turning to our pipeline assets. At our R&D event last month, we unveiled 2 innovative assets we are advancing into the clinic, leveraging our world-class R&D capabilities and experience taking revumenib and axatilimab from IND to FDA approval in about 5 years. SNDX-4321 is a novel, mutant-selective, CNS-penetrant, allosteric EGFR inhibitor for non-small cell lung cancer that offers a new approach to addressing patient populations with high unmet medical needs, such as those with L858R mutations and CNS metastases.

SNDX-62122 is a next-generation menin inhibitor we are developing for myelofibrosis or MF, building on our extensive experience pioneering menin inhibition in hematology. It is the first molecule from our internally developed and wholly owned library of next-generation menin inhibitors, which we intend to advance into promising new areas.

We are entering into another exciting chapter for the company as we build Revuforj and Niktimvo into major commercial franchises and leverage our proven R&D engine to bring new treatment options to even more patients. We are fully funded to execute on our commercial and R&D priorities and continue to advance towards profitability with growing revenue from the first 2 medicines from our pipeline.

I will now turn the call over to Steve to discuss our commercial results in more detail. Steve?

Thank you, Michael.

Starting with Revuforj on Slide 4. We delivered our sixth consecutive quarter of double-digit Revuforj net revenue and prescription growth and continue to track well above launch benchmarks set by other mutation-directed AML therapies. Net revenue totaled $55 million, up 12% from the prior quarter. Total prescriptions were approximately 1,500, up 15% from the prior quarter.

These results reflect robust demand and an increasing average duration of therapy, one of several important drivers of our business. We have dominant share of the overall menin business today, having treated over 1,600 patients commercially since launch, including 250 new patients added in the second quarter. We saw some fluctuation in new patient starts in Q2 relative to prior quarters, reflecting typical variation quarter-to-quarter in the number of available patients with a rare disease and market dynamics when physicians have more than one drug in class they can consider using depending on the patient's mutational profile.

To ensure we leave no appropriate patient behind, we have optimized our established customer footprint and targeting, expanded our ability to leverage lab data to engage physicians when they have a suitable patient in their care and increased our promotional efforts and educational activities. We remain confident we will continue to lead this market with the strongest efficacy profile in an efficacy-driven market and multiple drivers supporting long-term growth.

Our business in KMT2A and NPM1 is strong, and it is growing. Revuforj is the standard of care for relapsed/refractory KMT2A-translocated acute leukemia and remains the only targeted therapy for an aggressive cancer with no other effective treatment options. We continue to expand into our second indication with NPM1, accounting for at least 40% of new patients in the second quarter and more than 30% of the $55 million in net revenue.

All indicators suggest Revuforj will continue to be the menin inhibitor of choice for all menin-dependent acute leukemias. Physicians value having one efficacious and well-tolerated drug they can use across multiple acute leukemia subtypes in both adults as well as children. They appreciate that the efficacy they see with Revuforj in the real world is consistent with or, in fact, even better than the clinical trial results. They value individualized dosing, not having to worry about reduced efficacy when their patients are taking commonly prescribed gastric acid-reducing agents like PPIs and H2 blockers and the lack of any clinically meaningful pruritus, an adverse event that can be impactful for patients and very difficult for clinicians to manage. This combination of efficacy, tolerability and dosing flexibility is why Revuforj is and will remain the drug of choice for physicians.

Turning to Slide 5. There are 2 fundamental drivers of our business: new patients and average treatment duration, and both are building. The unique breadth of our indication provides us with the opportunity to target approximately 2,000 patients diagnosed annually with relapsed/refractory KMT2A-translocated acute leukemia, plus 4,500 with relapsed/refractory NPM1 mutated AML. And we've made excellent progress reaching this population with more than 1,600 patients treated with commercial drug since launching in KMT2A in the fourth quarter of 2024 and NPM1 in the fourth quarter of last year.

Importantly, there's still plenty of room to reach more patients each quarter. For instance, of the annual 4,500 relapsed/refractory NPM1 patients, we estimate that less than 15% have received a menin inhibitor, highlighting the substantial opportunity for further growth. Compared to KMT2A, where we saw a steep uptake curve due to the lack of other approved or impactful therapies, we expect our NPM1 business will build over time due to other options that physicians may consider for this population depending on their co-mutations or other factors.

The second fundamental driver is average treatment duration, which is increasing due to evolving clinical practice and a product profile that is conducive to patients staying on therapy for extended periods of time. Physicians are reaching for Revuforj early in the relapsed/refractory treatment paradigm and are often choosing to use it in combination with other therapies with the goal of driving responses and extending the duration of effect. Claims data shows 75% of use in the second and third line and approximately 40% of use in combination. Encouragingly, a significant proportion of patients are proceeding to stem cell transplant after receiving Revuforj, which is the goal in the relapsed/refractory setting for both KMT2A and NPM1 patients who are fit enough to receive a transplant.

We continue to observe approximately 50% of KMT2A patients proceeding to transplant. About 50% of those patients have resumed therapy thus far after pausing for 3 to 6 months, up from an estimated 45% last quarter. We expect this percentage will continue to increase as our colleagues in medical affairs report additional evidence from the post-transplant setting in collaboration with leading treatment centers, building on the encouraging data MD Anderson presented at ASCO and EHA this past June.

Over time, we expect that up to 70% to 80% of transplant patients will ultimately return to therapy for 1 to 2 years based on feedback from physicians and clinical trial and real-world experience. These evolving treatment patterns are increasing the average treatment duration, especially the growing number of patients on therapy post-transplant. This group is already averaging at least 9 months of therapy with this duration expected to steadily increase as we continue to follow patients over time.

Among patients who do not receive a transplant, over half are still staying on therapy for a significant period with an average treatment duration that is already over 7 months and building. With a significant addressable patient population and an increasing average treatment duration, we are confident in our ability to build a sustainable business with our first 2 indications for Revuforj.

Moving to Slide 6. We have a solid commercial foundation in place to support the success of Revuforj, including a highly accomplished team with deep and strong customer relationships. Our already robust prescriber base has continued to expand quarter-over-quarter, including our activation of Tier 1 and Tier 2 accounts, the highest volume centers in the U.S. who treat 2/3 of our target population. Nearly 90% of these accounts have ordered, up from 70% prior to the approval of Revuforj in NPM1. Overall, more than 580 accounts have ordered Revuforj, up 11% from the prior quarter, reflecting growing adoption from centers of all sizes, including community practices. Our growing prescriber base reflects physicians' enthusiasm for Revuforj and positions us to drive further penetration for both indications.

We have excellent payer coverage, and physicians can access the menin inhibitor they prefer. As of the end of Q2, Revuforj's formulary coverage was 98% of all covered lives for both indications, a coverage position that leads the class. In addition to having nearly 100% formulary coverage, Revuforj has preferential coverage on plans representing 17% of all covered lives versus less than 2% of lives for the other menin inhibitor.

Turning to Niktimvo on Slide 7. Niktimvo net revenue totaled $60 million in the second quarter, up 67% year-over-year and 9% quarter-over-quarter. This result reflects strong and consistent new patient starts and solid persistency. More than 300 new patients were added and about 5,750 infusions were administered in the second quarter. Niktimvo is annualizing at $240 million and continues to track with the launch of Rezurock, a drug that reached $500 million in annual U.S. net sales within the first 4 years of launch in the same indication.

Moving to Slide 8. The fundamentals of our Niktimvo business are strong with multiple drivers for continued growth. The first is continued adoption in the fourth line and steadily increasing uptake in the third line as clinicians gain experience with Niktimvo. Within 1.5 years of launch, Niktimvo has captured approximately 1/3 of the third line plus chronic GVHD market.

As the patient mix shifts more towards patients with less advanced disease, we expect this will extend the average treatment duration. This is a chronic disease with the potential for patients to stay on therapy for long periods. We've observed solid persistency in the commercial setting with 60% to 70% of patients staying on Niktimvo for at least 12 months. Our clinical trial experience suggests the duration of therapy could be measured in years for a meaningful proportion of patients.

Our Niktimvo business benefits from a broad and productive prescriber base and commercial synergies for both Syndax and Incyte. Nearly every bone marrow transplant center in the U.S. has prescribed Niktimvo and become a repeat customer.

Physicians continue to report impressive activity in multiple organs with particularly notable responses in the lungs and skin, some of the most difficult to treat organs. All these drivers position us to expand our impact in third line plus chronic GVHD, a $2 billion U.S. market opportunity. Looking ahead, the ongoing trials in frontline chronic GVHD and IPF could unlock additional multibillion-dollar opportunities.

With that, I'll hand the call over to Nick to talk about our development programs.

Thank you, Steve.

Turning to Slide 9, I'd like to highlight the progress we've made advancing our scientific leadership in menin inhibition with a strong presence in medical meetings and 2 landmark publications. At ASCO, we had 4 revumenib abstracts, including an oral presentation of post-transplant maintenance data from a cohort of heavily pretreated patients with KMT2A, NPM1, or NUP98 alterations who resumed revumenib post-transplant. This analysis showed a 2-year overall survival rate of 90%, which is nearly double the historical rate observed prior to the introduction of revumenib.

Moving on to EHA. We have 12 revumenib abstracts, highlighting the clinical activity with revumenib in multiple acute leukemia subtypes and settings, including in combination with standard of care therapies in the frontline and relapsed/refractory setting. In June, data from the relapsed/refractory cohort in the Phase I/II SAVE trial were published in the Journal of Clinical Oncology. The results observed with the all-oral combination of revumenib, venetoclax and decitabine/cedazuridine in a heavily pretreated population of patients with NPM1, KMT2A or NUP98 AML are impressive. 88% achieved an overall response. 80% of evaluable CRc responders achieved MRD negativity and 45% of patients proceeded to transplant, with 63% receiving revumenib post-transplant. These results are similar to outcomes observed in real-world cohorts treated with revumenib-based combinations, underscoring the potential to reproduce these results in clinical practice.

In July, we and our collaborators published the results of groundbreaking preclinical studies with revumenib, which showed menin is a novel dependency in a proliferative megakaryocytes, major drivers of myelofibrosis. These data provide the basis for our innovative clinical development program in myelofibrosis.

Looking ahead to the second half of the year, we will deepen our scientific leadership with new revumenib data from across the acute leukemia treatment continuum, including from the maintenance and real-world setting. We also look forward to presenting more mature frontline data in the fourth quarter with updates expected from SAVE and Beat AML trials of revumenib with low-intensity chemotherapy and from the 708 trial with intensive chemotherapy. We expect these data will be impactful for the clinical community and provide strong support for our ongoing pivotal frontline combination trials.

We also expect to publish data in relapsed/refractory NUP98 rearranged acute leukemia in the fourth quarter, followed by submission of this important publication for the clinical guidelines for consideration. Patients with NUP98 rearrangements have poor outcomes, and there is an urgent need for new treatment options with many parallels to the unmet needs in KMT2A prior to the introduction of revumenib. Physicians are positive about the potential for revumenib to provide a new treatment option for this disease subtype based on the data reported.

At EHA, we presented data from 25 heavily pretreated relapsed/refractory NUP98 patients showing a 28% overall response rate with 43% of responders proceeding to a transplant and all resuming revumenib post-transplant.

Turning to our pipeline on Slide 10. I'd like to highlight just a few key points. First, we are rapidly advancing an integrated evidence generation plan designed to establish revumenib as the menin inhibitor of choice across the acute leukemia treatment continuum. Importantly, we maintain good momentum to be the first to deliver pivotal frontline data for menin inhibitor. Global site activations and patient enrollment is well established in our pivotal trials, informed by an extensive body of clinical evidence, allowing for optimization of endpoint assumptions and other aspects of the study design.

Second, we are nearing 2 important axatilimab readouts. We are on track to report top line data from the Phase II MAXPIRe IPF trial in the fourth quarter. Positive data would open a transformative opportunity for axatilimab and provide a strong biological rationale for its mechanism in several other diseases where the pathology is underpinned by fibrosis and inflammation. We also anticipate top line results from the Phase II trial of axatilimab in combination with ruxolitinib in frontline chronic GVHD in the fourth quarter. Positive outcomes with the novel combination could begin to unlock the potential for a steroid-sparing regimen in newly diagnosed chronic GVHD.

Third, as highlighted at our recent R&D event, we announced 2 new pipeline assets, SNDX-4321 and 62122. In line with our focused R&D strategy, these are targeted molecules, both with first- and best-in-class potential supported by compelling preclinical data, mechanistic insights and advocacy of leading researchers and clinicians. With both revumenib and axatilimab, we have demonstrated our ability to efficiently generate clinical data that validates new therapeutic targets, leading to new approvals, a strength we will leverage again as we advance the next chapter of our R&D strategy.

Turning to Slide 11. 4321 is a novel mutant-selective CNS-penetrant allosteric EGFR inhibitor. We're developing it for non-small cell lung cancer patients with high unmet needs, such as those with the L858R mutations, CNS metastases and atypical activating mutations or resistance to current therapies. In contrast to ATP site-directed third- and fourth-generation EGFR inhibitors, 4321 binds at a pocket adjacent to the ATP site. This is only accessible in the presence of L858R and certain other EGFR mutations.

The allosteric approach allows for high selectivity and a double lock approach to inactivating the receptor. 4321 and ATP site-directed therapies can bind EGFR at the same time at different sites on the receptor, potentially enhancing efficacy and delaying resistance. We expect to submit an IND for 4321 by the end of 2026 with an assessment of monotherapy activity expected in early 2028.

62122 is our next-generation menin inhibitor in development for myelofibrosis that could offer a novel and potentially disease-modifying approach. It is the first candidate from our library of internally developed and wholly owned next-generation menin inhibitors that we plan to advance into new areas. We expect to submit an IND and initiate Phase I trial of 62122 in 2027. This program will be informed by a proof-of-principle trial of revumenib in myelofibrosis that will be conducted in partnership with world-leading experts in myelofibrosis. We expect this trial to initiate in the fourth quarter with initial data anticipated in the second half of next year.

In summary, we've made enormous progress advancing our late-stage trials and expanding our pipeline of differentiated assets. We are nearing several important data readouts and have multiple opportunities to transform the standard of care for some of the most difficult-to-treat diseases.

With that, I'll turn the call to Keith to discuss our financials.

Thank you, Nick. Pardon me. Earlier this afternoon, we reported detailed second quarter 2026 financial results.

And I'll highlight a few key points on Slide 12. Total revenue for the second quarter of 2026 was $72.8 million, up 92% over the same period last year. This consisted of $54.7 million of Revuforj net revenue and $18.1 million in Niktimvo collaboration revenue, which equated to 30% of the Niktimvo net revenue reported by our partner, Incyte in the quarter.

We expect Niktimvo margin contribution, defined as the collaboration revenue recorded by Syndax as a percentage of Niktimvo net sales, to continue to be in the 25% to 30% range in the near term and increase longer term as sales grow. We expect revenue from both Revuforj and Niktimvo to continue growing and advancing the company towards profitability. Our guidance for R&D plus SG&A expenses in 2026 remains approximately $400 million, excluding the impact of $50 million in estimated noncash stock compensation expense.

We ended the second quarter with $575 million in cash, equivalents and investments. This includes $244 million in net proceeds from the issuance in June of $250 million of 2.25% convertible notes. That deal provided the lowest cost of capital that Syndax has ever accessed and positions us well to build shareholder value over the long term.

We're fully funded to execute our commercial and R&D priorities, including our late-stage trials of revumenib and axatilimab and the development of our pipeline assets. With relatively modest investments in proof-of-principle trials of SNDX-4321 and 62122, we believe we can quickly generate early clinical data that creates significant value for the company and its shareholders.

With that, I'll hand the call to Michael for closing remarks.

Thank you, Keith. Syndax is well positioned for long-term growth and success with multiple blockbuster opportunities and upcoming milestones as highlighted on Slides 13 and 14. We have a best-in-class menin inhibitor that is positioned to be the first to frontline AML and deliver peak annual net revenue in excess of $2 billion in the U.S. alone. We are nearing data readouts in the fourth quarter that could unlock multibillion-dollar upside for Niktimvo in IPF and frontline chronic GVHD.

We have a proven track record of successfully developing and commercializing novel medicines and are bringing forward 2 new pipeline assets with best-in-class and blockbuster potential in EGFR-mutated lung cancer and myelofibrosis. With $575 million on the balance sheet and growing revenue from 2 products, we are funded through profitability and have the capital to realize our pipeline opportunities and drive significant long-term value.

I will close by thanking our dedicated employees and the many patients, clinicians and scientists who support our work and inspire us to pioneer bold new approaches to some of the most devastating diseases.

And with that, I would like to open the call for questions. Operator?

[Operator Instructions] And the first question is from Anupam Rama with JPMorgan.

This is [ Joyce ] on for Anupam. Could you discuss the physician feedback you received at ASCO and EHA on the Revuforj data that you guys presented there, especially the post-transplant maintenance data? And how soon could those data have positive pull-through to the launch in terms of what you're seeing as the proportion of patients going on maintenance therapy?

Joyce, thanks so much for the question. So I'll direct the first question to Nick.

Thank you for the question. I think the data was very well received. I think it's a remarkable outcome when you look at the proportion of patients alive at 2 years, 90%. It's obviously not randomized, but MD Anderson did a very nice job comparing it to the current standard of care, which is considerably less than that. So I think they're very encouraged by that.

We have significant research efforts ongoing to further elucidate the benefits of giving revumenib in the -- within the post-transplant setting. It's really important, I think, to optimize the dose. We're learning a lot about that, and we have a dedicated Phase I study ongoing to optimize dose, and we hope to report on that later this year.

We also actually have the first prospectively randomized study called the MenTain study that was recently announced on ct.gov in collaboration with Dana-Farber and other collaborators, which will hopefully further elucidate the benefits of maintenance which will be extremely helpful and it's an important study to do.

Generally, however, we are seeing the uptake of maintenance very much in clinical practice, and that will be evidenced by the real-world series we've already reported upon where you see high rates of post-transplant and then patients going back on to transplant -- back on to therapy after transplant. And we'll be updating on those further in the year with more data, which I think support and perhaps even exceed what we've seen to date.

Our next question is from Brad Canino with Guggenheim.

Maybe 2 for me. One, just any quantification you can provide on the duration of treatment increasing, either numerical or some estimation of a relative increase in the DOT you saw? I'm just trying to judge the magnitude of increase.

And then two, have you seen any indication of an inflection in the maintenance rate? It sounds like it was 50% is what you're up to for this past 2Q. But any inflection in July after showing the maintenance data at ASCO and EHA as you've been going out and talking with physicians?

Brad, thanks so much for the question. So first of all, in terms of the duration of treatment, we're very much encouraged by what we're seeing. I think the -- for patients who are actually going on to maintenance, we know that cohort of patients is out beyond 9 months. And so that's an increase from what we've seen previously, and we feel quite encouraged by that. And what's also -- you might have picked up in my remarks, what's also encouraging are patients who don't go to transplant, who remain on therapy for an extended period of time are well beyond 7 months at this point, and building. So that is -- that's sort of new news and very encouraging for what we think will continue to build the recurring revenue within the franchise. Thank you.

And then in terms of inflection in maintenance rate in July, that was a pretty specific question. I'll just say that we are seeing continued buildup in maintenance. I don't think we've quantified it quite for July, but we feel very encouraged by what we've seen coming out of last quarter and into this quarter. And so we believe that will continue to build. We've talked about reaching 70%, 80% of patients getting on maintenance. We believe that assumption will hold as we build beyond the 50% that we saw this quarter. When exactly that will get to the 70, 80 percentile will take a little bit -- 70%, 80% will take a little bit of time, but we do feel quite encouraged by the momentum we're seeing coming out of the last quarter.

The next question is from Faisal Khurshid with Jefferies.

This is Faisal from Jefferies. I just wanted to ask, this looks like the first quarter that you actually took a step down in new starts. Can you give any more specificity on the reasons for this? And also in terms of modeling this going forward, what are the forward trends that we should expect on new starts, each in KMT2A and NPM1?

Thanks so much for the question. So maybe I'll turn it over to Steve to make some comments on new starts for this quarter.

Yes. Thanks for the question. I appreciate you pitching it to me, Michael. Overall, I mean, good performance. I mean, it's a sixth consecutive quarter of double-digit revenue and demand growth. And I think interestingly, we grew 15% on TRx demand, and that was in the face of what you noticed is a falling number of patient starts from Q1 into Q2. And the reasons for that that there are just multiple drivers to the business. A lot of our prepared comments around the KMT2A business, how it's advancing, it's heading exactly in the direction that we predicted it would, higher transplant rates, higher restart rates relative to the clinical trials, which is really driving the DOT.

And I'd say for NPM1, it's still early days, but we know that the business is growing. It's growing nicely. Our revenue and our patients on drug from Q1 into Q2 advanced as well. So new patient starts are simply just a part of the growth story, but not the only part. A couple of things I hit out in the prepared comments, I'll maybe add a different flavor to it as well.

But this is normal. You're going to see, at least in the larger targeted AML therapy class, new starts do jump around. There's typical variability. We see it month-to-month. You're going to see it quarter-to-quarter. We've been largely immune to that, right? Rev has existed in the space, and we've either had the same number of new starts or grown them quarter after quarter. But this is a fundamental aspect of the market that is typically there.

It's -- the other things that we've mentioned, physicians have more than one drug class to consider, right? And there is a big focus on the NPM1 patient. Based on that patient's mutational profile, physicians are going to make a choice. I think they're still figuring out how to -- where the menin fit. So is it before a FLT3, is it during FLT3, or perhaps after. So that will play its way out. But ultimately, patients will relapse and Rev will play a role.

And the last piece are just clinical trials. So when you sign up to be in this business, oncology, hematology, you're advancing drugs through the clinic and you're also commercializing them. And we've done that successfully since the launch of Rev. So this isn't something that's entirely new. But there are new trials that pop up from time to time. As they get established, patient flow will ultimately work its way through and opportunities for commercial patients are going to stabilize. Many of these are placebo-controlled trials. So we expect to still treat many of these patients either when they relapse. Not all patients are obviously eligible for clinical trials. And we made a conscious decision about a year ago to go to a much broader audience. So as we updated in this call, we're approaching 600 accounts that are prescribed. Many of those are medium sized to smaller accounts, less impacted by clinical trials, and we find meaningful patient build there as well.

So these factors can cause some lumpiness and fluctuation quarter-to-quarter, but we were able to flex and change our business as needed. So we're confident in the forward. So I think one of the questions was what is the trend moving forward. We look at this quarter as an anomaly. We feel confident about finding patients and getting back to levels that we've seen historically.

Got it. And Steve, if you don't mind just a quick follow-up. So am I to take your comments to mean that new starts on commercial drug in relapsed AML as a whole were down quarter-over-quarter? And if so, are you able to quantify that at all?

Probably we don't have the full data set to look across all of AML. We're limited in what we can see on our drug. But perhaps that is the case. I would bet that it is. And again, it will jump around from quarter-to-quarter.

The next question is from Phil Nadeau with TD Cowen.

Congrats on the progress. A few commercial questions from us. So first, in the NPM1, I apologize if I missed this. Did you say where you estimate your share of NPM new patient starts was this quarter and how that compared to last quarter? That's first.

And then second, I think you said 15% of NPM1 patients have been on a menin. And that's after approximately 3 quarters of your launch. Is that trend that we should continue into the future? So in another 3 quarters, should we expect maybe 30% of NPM1 patients will be on a menin? Or is there any reason to think that would either accelerate or decelerate?

Then finally, on maintenance, can you kind of tell where -- tell us where maintenance is being used today in terms of what centers and where is the growth going to come from? What new centers could come online over the next several quarters to drive increased use of maintenance across the market?

Great. Phil, thanks for the question. So first question I took as what's our NPM1 share. And I think as we stated in our prepared remarks, we're about 2/3 of the business right now. I mean, if you think about where we were last quarter, it was roughly about the same, 2/3 or more of the overall business. And so we expect that to continue to build over time. But we do have a dominant position. I would also say in terms of relapsed/refractory business, we're probably assuming our competitor gets close to their numbers, we're probably 85-plus percent of relapsed/refractory. So we are quite dominant in the space and expect to continue to build that.

We did make a comment about 15% of the patients, this is your second question, 15% of the NPM1 patients have seen a menin inhibitor, and that's not only our drug, but our understanding of what -- how our competitor contributes as well. So that's 15% total. We do expect that to expand meaningfully. And from quarter-to-quarter, we expect that to grow, accelerate. In a year from now, we'll be at 30%. Well, we would hope that it would be even greater than that. And it's supported by all the data that we're generating. Nick mentioned the presence at our congresses and what we've provided in terms of monotherapy and combinations, and that has shown Revuforj to be a very useful drug in a number of ways. So we expect that we'll be treating NPM1 patients and continuing to penetrate that market very meaningfully, hopefully well beyond 30% in a year.

And then maintenance, maybe I'll turn to Nick on this one. Maintenance, where is it being done? What are those centers? I mean, we won't list them all. Academic centers for sure, maybe Nick can make a comment there. And where is the growth going to come from in terms of maintenance? Nick?

Well, I think the growth will come from a number of drivers. I mean, #1, is patients getting treated earlier on. They're getting treated increasingly in combination. That's just driving response rates higher. We know that if a patient gets a response, they're eligible for transplant. Having had a transplant, the likelihood of them going on to post-transplant maintenance as we gather more data and present more data there. I think physicians are feeling more confident. They understand how to manage the dose better. These patients after transplant are particularly prone to cytopenias generally. So you really do need to manage the dose, and that's something we'll be presenting updated data on later this year, and I think they're getting confidence to do that.

And really just the real-world experience from academic centers. We've seen extremely high rates. They're feeling more confident doing it. Their intent is to treat out to 1 year to 2 years. Most of our clinical trials include therapy out to 2 years. And given the high rates of relapse after transplant without any active therapy, they really want to just do their best for the patients and think that revumenib gives them the best chance of a durable remission. And so we're seeing uptake increase.

From a research perspective, it's our efforts to further confirm that benefit, who's most likely to benefit and how we can make sure that the drug is well tolerated. But I think we're very encouraged by what we're seeing in the uptake, and we'll be presenting more data on that again later this year with a big focus on this whole post-transplant maintenance area.

The next question is from Stephen Willey with Stifel.

Congrats on the progress. I guess Niktimvo sequential growth has kind of flattened out here over the past couple of quarters. So just curious how you're thinking about the near-term growth opportunity for this franchise prior to potential label expansion? And then I was also just wondering if you can confirm whether the definition of event-free survival, which is being used in the Phase II frontline trial that reads out later this year plus Rux is the same as the Phase III frontline trial that's looking at Niktimvo combination with steroids?

Stephen, thanks for the question. Maybe I'll take the first with maybe a comment on the second from Nick. So Niktimvo, look, I don't agree with the characterization that it's flat, first of all, Niktimvo is not flat, it's growing, and we see it tracking very nicely to what Rezurock has done. And so we expect it to continue to grow meaningfully. And what I'm talking about is third and fourth line. So we've penetrated well into the fourth line. Third line, we have about 1/3 of the -- third-line population at this point, which is very meaningful about a year post launch. So I think we will continue to build that and be meaningful in third and fourth line. So you should expect continued growth there.

And then, of course, we have expansion opportunity with the new data coming at the end of the year with combination with ruxolitinib. And so we feel like that's an obvious expansion opportunity as we're on our way to the frontline. And we'll also have steroid combination in early '28. So a lot of data to come. I think physicians are eager to see the combinations and how our drug combines with Jakafi. And in the meantime, we'll have considerable growth, we believe, over the near term with third and fourth line.

And then maybe I'll turn it to Nick on definition for event-free survival.

Steve, the event-free survival endpoint is in the -- for the frontline steroid combination Phase III. So that does have an event-free survival primary endpoint. For the Phase II, 3-arm study, we're actually going to look at overall response rate at 6 months. So as you recall, this is steroids versus Rux versus the combination of Axa and Rux. We expect a benchmark from that based on our publication in 2022 to be about 40% response rate for steroids alone at 6 months. We're looking for a meaningful improvement over that. I think for the combination, it could be considerably higher than that. It's not formally a comparative study. It's randomized 1:1:1, about 120 patients, you'll recall.

So yes, we'll look at overall response rate, but I think also the duration of response will be very important to look at in that study to see whether the combination and Rux alone can offer a meaningful alternative to steroids. So that's what we will report on and looking forward to seeing that readout. So I think it could be very informative and potentially practice and guideline informing readout if either or both of those combinations beat steroids alone.

The next question is from Etzer Darout with Barclays.

A quick one for me. Just wondering for the proof-of-principle trial of revumenib in multiple fibrosis, what is the primary analysis? What will that entail? And what endpoints will you be evaluating there just as a potential, obviously, read through to the next-gen menin inhibitor?

Great, thanks for the question. Maybe I'll turn to Nick on the proof-of-concept trial.

Yes, this is a study we're doing with the MPN Research Consortium with John Mascarenhas and collaborators. It's not under our sponsorship. It was recently posted on clinicaltrials.gov. It's quite a full posting, if you want to look at some of the details of the study there, but I'll just summarize it for you.

Cohort 1, which is primarily the safety assessment, we'll look at just dose-limiting toxicities. It's going to be relatively few patients treated, around 6. In Cohort 2, where we will look for the combination of Rev in combination with Jakafi, we'll be looking at standard response criteria. So we'll be using the ELN response criteria looking at anemia, spleen response and symptom benefit. We'll be looking at SVR less than 35%.

So in patients that have a suboptimal response on Jakafi alone and are stable on Jakafi for 12 weeks, we'll add in revumenib and then we will be looking for using standard ELN response criteria to generate proof-of-principle data, which will be incredibly informative to our development program and really catalyze, I think, when we go into Phase I in 2027 with our next-gen menin inhibitor in myelofibrosis.

Our next question is from Yigal Nochomovitz with Citigroup.

This is [ John Kim ] on for Yigal. I was wondering with regards to your expanded use of lab data, I believe that you had mentioned, to engage physicians when they have a suitable patient. Just wondering, to what extent can that help smooth new start variability, particularly in NPM1, where the population is larger, but co-mutations can help influence the treatment choice?

And then also with regards to the MAXPIRe trial, just wondering, since patients can be on pirfenidone or no background antifibrotic. If the study is positive, how should we think about the extent to which the background therapy could help define axatilimab's role, whether it's add-on or potentially if the patients are not getting much benefit from current treatments?

Great. Thanks for the question. So first, with the use of lab data, maybe, Steve, do you want to make some comments on how we identify patients?

Yes, sure. So we do use lab data, as pointed out in the question, it enables us to find diagnosed patients. We buy lab data. We can identify patients that may be suitable. It's obviously de-identified. We can target accounts that we know patients exist, it's largely worked since launch. I think that really speaks to why we've been so successful, particularly at the KMT2A launch. We've modified our approach over time. We've been able to bring in new lab data sets. We've been able to apply some applied artificial intelligence and machine learning principles. So it still holds.

I think specifically, the question was, can you use that to smooth out new starts? The market is the market. Patients are going to come in at often a random pace. So over a year, you kind of know what it is, but month-to-month, it's going to be different. We will find every possible patient that we can, right? And we've shown we've been able to do that, and we're going to get better simply over time. So that's something we remain committed to.

Maybe, Nick, do you want to talk about MAXPIRe and the background therapy impact?

MAXPIRe has 3 strata. So we stratify it by nintedanib, pirfenidone and then no antifibrotic. As you would expect, consistent with previous studies that looked at IPF, by far the majority of the patients who are on a background antifibrotic, we will obviously look at subtypes in those strata to ensure there isn't an imbalance between the arms. The study is really not powered. Recall it's 2:1 randomized. It's not powered to detect differences between the different types of antifibrotic, it's something we will look at.

In terms of Phase III planning, we would plan to include axatilimab on a background of standard of care antifibrotics and potentially other standards of care. One of the attractive things, I think, about the mechanism of action of axatilimab is that it really does treat what we think is the underpinning pathology by targeting specific these monocyte-derived macrophages, so inflammatory and fibrotic components of the disease. And we really think that that could be a very important differentiator and particularly suitable for combination with the current standards of care.

Our next question is from David Dai with UBS.

So just thinking about the Revuforj new patient starts and KMT2A penetration. Last quarter, you mentioned that you were 50% penetrated into the KMT2A market. How does the number look like this quarter? And how do you envision the peak penetration will look like? And how long do you think that's going to take?

And the same question we'll apply to NPM1. What percentage of NPM1 market we've penetrated so far? And what would the penetration look like?

David, thanks for the question. So maybe I'll address KMT2A first. So first of all, we own the KMT2A market. So this is a part of a business that where we are firmly established as standard of care. NPM1 is building. We firmly acknowledge that we have best-in-class profile for both broadest set of opportunities there. For KMT2A, we have said that we were about 50% penetrated, and that continues to build. And so peak penetration is likely to get to roughly 80% or maybe even more. We've seen examples in the market of companies launching products into targeted areas where they have dominant position and they get to those levels. So KMT2A should reach a very, very deep penetration over the reasonably near term.

NPM1, I would say, is a slower build, mainly because of some of the things that Steve said. It is a bigger patient population for sure. More patients are able to be treated. More patients are being treated. They just happen to be on other therapies. And so our job is to introduce Revuforj to those patients as monotherapy and perhaps combination as physicians want to use the product, and we'll continue to penetrate there.

Again, I think Revuforj is going to have a very high penetration. We already own, as of today, about 2/3 or more of the business in NPM1, and that should continue to build. But our penetration will get to a high percentage over time, maybe not quite as high as KMT2A, but we do think that we'll have a dominant position in both with best offering as we've talked about.

So I think this is -- there are different kinetics of build between KMT2A and NPM1 as described, but high penetration is the name of the game here.

That's helpful. And then just a question on inventory stocking. What did the inventory stock look like this quarter? Any dynamics there?

I'll give this one to Keith, inventory.

Yes. Thanks, David. The guidance that we've been pretty consistent with -- very consistent with since launch, still holds. And again, not just for Syndax, but really for any rare disease targeted oncology product. We're about 2 to 3 weeks. It's been remarkably consistent since we've launched the product. So we'll let you know if there's any changes, but you can assume that we have about 2 to 3 weeks of Revuforj in the channel.

Our next question comes from Salim Syed with Mizuho.

Congrats on the progress, guys. Just one from us on the $2 billion revenue expected in the U.S. alone. Mike or Keith, could you maybe -- I think this is the first time we're formally seeing it in a slide written like that. And I noticed also that I think this is the first time that the bar chart for the TAM has been taken out of the deck. Just wondering if you guys are starting to think here that the $5 billion TAM is a conservative number, you're sort of reworking your numbers internally? Or what your assumptions were exactly going into the $2 billion, how much first line is in there versus second line, et cetera?

And then just one clarification. I think you guys mentioned, I think it was Mike, 85% of relapse is what you guys are getting. I presume that's also inclusive of KMT2A rearranged. But what percentage of NPM1 starts are you guys seeing? I think Kura, on their side, they said 40% is their shares, which would imply you guys are at 60%. Is that ballpark-ish correct in line?

Yes, Salim, lots of parts to your question. So let me see if I can tackle them. So first off, just because I see it on the page here, 85% of what I had mentioned, 85% of the relapsed/refractory business is KMT2A and NPM1 combined. So that's our calculation. And if you look at the numbers for the quarter relative to our competitor, we're at least 85% of the business. So that's one.

When we talk about the estimate of $2 billion plus in revenue peak potential when we include the frontline, you're right, that is the first time we're talking about this in this way. And I think it's important. And why now? We're more confident than ever, and this is clear to us that this is a very large market opportunity. When you look at the data that we've published over the last quarter or 2, all things point to growing relapse, I would say, overall survival, days of therapy. The response rates are higher than we've seen previously.

So the data is all very positive and points -- and gives us confidence that we will -- once we get to the frontline, have a very supportable market position and dominant position in frontline. We will be the first to get there. And with the profile that we have today, we feel quite confident that we will have a very meaningful share, a dominant share of frontline.

But thinking of it, probably the most important driver here is days of therapy or time on therapy. And what we've said today is that we see that elongating. We're quite encouraged by that, which gives us a lot of confidence because it's a very important indicator or a very important component of the calculation for the market, how long patients stay on therapy. And so far, we're -- even relapsed/refractory patients, we're seeing this exceed our expectations. So we are quite confident again that we can reach that level of sales.

And when you talk about the breakdown between frontline and relapsed/refractory, as we've said in our bar chart, nothing has really changed in terms of our evaluation of the overall total addressable market. $5 billion does assume the $2 billion is part of that. So we've always kind of been clear about it that $5 billion is the overall market when you assume that you get to frontline, $2 billion is really our assessment of the relapsed/refractory opportunity.

The next question is from Andres Maldonado with H.C. Wainwright.

Congrats on the progress. First question is a question on Slide 5. You talked about 40% of Revuforj uses in combination. So curious if, are physicians mainly adding Revuforj to a failing venetoclax-based regimen? Or are they beginning a new combination at relapse? And how should we be thinking of the potential kind of those variants and approaches, their potential to produce different treatment durations or transplant rate is the first question? And I have a follow-up.

Great. Andres, thank you for the question. So maybe I'll turn it to Nick to talk a little bit about the combination regimen.

Yes. What we're observing in the real world is multiple combinations. I think you're right that Ven is a common desire, either ven or ven as a combination. Sometimes patients have been exposed to prior ven. I mean, there's some interesting data that revumenib may actually synergize with BCL-2 and it may even be an opportunity to rechallenge. So that's one of the more common combinations.

But we do also see other combinations in use. We have, for example, ongoing studies, which I think is important with FLT3 inhibitors. It's not something we hear that it's a high priority amongst the physician community, but we do want to generate data to confirm both tolerability and efficacy with a FLT3 inhibitor, and then potentially other single-agent therapies as well. But certainly, ven is one of the more common ones.

And what we have observed in our real-world data today is that it does drive response rates up significantly from what you observe with revumenib alone. And so if a patient is able to tolerate it and they want to treat, we're obviously not promoting that indication. It's not within our label to treat in combination. But we do see, in some cases, 50%, up to 80% of patients actually treated in combination because we know it drives a 60% to 80% response rate, which gives the patient a much better chance for durable response and potentially a transplant.

Andres, you have a follow-up question?

Great. A quick one on MAXPIRe.

Yes. Go ahead.

Sure. Yes. A quick one on MAXPIRe. I think you guys have highlighted in the past kind of some of the expectations of the scenarios, whether you expect the FVC curve to separate earlier or maybe potentially later. But in the simulation that -- in the scenario that the curves maybe gives a modest 26-week FVC result with a longer later slope or biomarker effect. How should we interpret that influence on the potential market there?

Nice question, Andres. Maybe I'll turn it to Nick.

Yes, we're pretty confident, I have to say, in that 26-week endpoint, it's been a very good predictor in other studies of IPF. I mean, we model that out to 52 weeks because that's the endpoint we would use in the pivotal Phase III and is the FDA's preferred endpoint. But for a proof-of-concept study like MAXPIRe, 26 weeks is pretty robust. Some other studies have used 12.

We're not anticipating any delayed separation of those curves. We saw in our experience in GVHD very early onset, certainly symptoms were responding within a month, and we were observing responses within the first month or 2. So we are expecting, by week 26, the evidence of activity will be very much in evidence. And that's what we'll be using. We're using the model. We're using a mixed linear regression model after 52 weeks. That's what we will be using, if it's positive, to inform and power the Phase III study. And obviously, the Phase III study size and dimensions will be influenced by what we observe in the Phase II.

But we're feeling very confident, I have to say, in everything we've observed to date that would suggest that study will read out well. Obviously, that's -- it remains a double-blind placebo ongoing study. We don't know what the study will show. But given all of the preclinical and clinical data we've generated and the mechanism of action, we're feeling quite positive, and we're looking forward to that study reading out in the fourth quarter, and we think it will be a very robust proof-of-concept given its design.

The next question is from Jason Zemansky with Bank of America.

This is [ Jackie ] on for Jason. So you previously characterized the decline in new Revuforj starts as an anomaly. But can you quantify how starts changed sequentially within NPM1m and KMT2Ar? Clarify whether the decline primarily reflected clinical trial enrollment, competition, or underlying patient availability? And also could you maybe tell us whether July starts have returned to prior quarter levels?

Jackie, thanks for your question. So first, maybe I'll turn it to Steve to talk a little bit about what the decline in new patient starts, what it reflected.

Yes. I think we talked about the potential reasons why it's difficult to pierce out each -- piece out each one and determine the contribution factor from each. And I'd say it was an overall drop in all new patient starts. I think there's an earlier question on AML in general. So we didn't see a different change in NPM1 relative to KMT2A. So we do believe it's a temporary effect, and we're going to return back to where we were previously. I think there was a question also just on...

On July. Yes.

We're not going to comment on July, at least in the quarter forward. But we feel good. We feel confident in the business plan and in everything that we have going against the brands as shared on this call.

Yes, absolutely. I think we expect to return to growth, as Steve mentioned. And look, in terms of the dynamics for NPM1 and some of these other -- I mean, I think this is a -- these are -- there are different things that impact from quarter-to-quarter, but I think we feel confident we have a plan to make sure that we get back to that positive growth, yes.

The final question today is from Mayank Mamtani with B. Riley Securities.

I'll keep it very tight. Did you say the NPM1 relapse segment, how is the duration of therapy tracking? Sorry if I missed that, relative to what you had in the trials given the context of earlier line use in co-mutation patients? And also curious if there's a year-end exit rate you expect to have in terms of how the split between NPM1 and KMT2A patients you expect to have at the end of the year?

Thanks for the question. So I don't think we gave a specific number for NPM1 tracking. But I'd just say the duration -- most of these patients don't go to transplant. As we commented that very encouraging that the duration for patients who haven't gone to transplant is averaging well over 7 months at this point early on. And a lot of those patients, of course, are NPM1 or I would say the disproportionate amount of NPM1 patients don't go to transplant. So I think that's a potential indicator of how things are going. We're quite encouraged by the overall. And without breaking it out, that's perhaps an indicator.

And then in terms of the number of NPM1 patients at the end of the year, I don't think we've said or guided to that. All I'd say is that we do have a dominant position in the market. We expect that to build over time. We'll continue to use all of our resources to identify patients and build that business. And we feel encouraged by what we see both as monotherapy and in combination, and that's been what the themes have been at our medical congresses. So we're in quite a good position to continue to build and feel good about the forward.

Understood. And maybe just lastly, we are coming off a busy conference season, but you obviously have your biggest conference at the end of the year. If you could just quickly comment on what to expect there, including from the 3 frontline setting trials we have ongoing and if there's any enrollment update we can expect to have on EVOLVE 2 or REVEAL-ND would be good to know?

Yes. Thanks for the follow-up. So end of the year, Nick, do you want...

Yes, very data-rich end of year. Looking forward to the second half of the year, I mean, we hope to carry the momentum I outlined briefly, what we saw at ASCO and EHA. The teams have been working very hard. We're going to see multiple data sets. So I would expect to see updates to all of our frontline studies. There are several, 2 studies in combination with ven and HMA combinations and then, obviously, our combination study with intensive chemotherapy as well. That will be very informative to our ongoing pivotal Phase IIIs, which remains a focus for us.

But expect to also see, as we've talked a lot about further data on the maintenance after transplant, informing practice there, combination and, of course, real-world evidence, that will be very important. I think it will be also important that I know there'll be a lot of interest in looking at how some of the time to event things are coming from our frontline studies like event-free survival and particularly overall survival. And I think we should have sufficient maturity to update on those as well.

So as I say, very data-rich period coming up in the second half of the year, we're looking forward to.

This concludes our question-and-answer session. I will now turn the floor over to Michael Metzger for any additional comments or closing remarks.

Thank you all. We really appreciate everyone tuning in today to discuss our recent progress and the exciting milestones that we have ahead. We look forward to seeing many of you at the upcoming investor conferences in the third quarter. Have a great evening, everyone.

All right. Good morning, everyone. We're going to get started. So it's my pleasure to welcome you this morning. My name is Michael Metzger, I'm the CEO of Syndax. A warm welcome to everybody joining us in person today and also online. We're thrilled to give you an update on our progress as we advance innovation for patients and bring more opportunities for great therapies to patients.

So we will be making forward-looking statements. Here is our disclosure.

Syndax is a company on the move. We're driving innovation and long-term value for patients. And we have what a few companies our size have in terms of accomplishments. We've gotten drugs approved actually and brought them to market. So we are a fully integrated commercial organization now with a track record of success, and we're looking to expand on that success.

We've built world-class R&D capability, both in the company and outside the company through our collaborations. And we have a deep and growing pipeline, which we'll talk about in great length today, which has this opportunity -- multiple opportunities for blockbuster products.

And importantly, we have a solid financial position. We're driving the profitability and we have the opportunity to fund all of our programs fully. So we are well positioned for the next stage of growth.

We're advancing the standard of care in cute leukemia as well as in chronic GVHD with our first -- our 2 first and best-in-class medicines: Revuforj and Niktimvo, as you all know, have done very well last year, this year annualizing about $200 million in revenue, as we're going and growing towards profitability. So very well set up for success.

And really it's about the patients. It's about driving innovation for patients and expanding upon what we've already done. We've treated thousands of patients already. Some of our patients are shown here on this slide. And we're looking to expand on that even more and bring more innovation forward.

I'm excited -- very excited today to talk about our expanding pipeline and our next phase of innovation and growth. All of you know Revuforj and Niktimvo, on the left, we have more work to do with both those assets as we expand. First, with Revuforj, we will be positioned to be the first to front line, and we are expanding in combination with multiple agents in order to bring this product to more and more patients. Niktimvo, likewise, we're going to be in the front line before long with combinations, standard of care agents, and we look to expand upon what we've done already with GVHD.

Furthermore, Niktimvo has the opportunity to go to areas such as IPF, big opportunities. We'll talk about that today, as an adjacency to what we've done in chronic GVHD. Very exciting next phase of growth for Niktimvo as well. So we are building on what we've already done with Revuforj and Niktimvo.

Now we turn the page and focus a little bit today on our next set of assets, our exciting set of assets. First I'll highlight SNDX-4321 and also 62122. Now these are -- this is -- follows our first and best-in-class way of approaching things. For 4322, this is a mutant-selective, allosteric EGFR inhibitor for non-small cell lung cancer. So it's a novel approach, a novel mechanism to bring to this disease where there's high unmet need and we can make a difference.

This is an in-licensed asset from Dana-Farber Cancer Institute, very important leading scientific organization in our community. We were able to in-license this on favorable terms, and drive the science forward. It's really our sweet spot. What we do is we translate the best of early science into the clinic and generate proof of concept quickly. And that's what we think we can do with this agent.

It's targeted for IND submission at the end of the year. So we are really well positioned now to talk about what comes next for this asset. Very exciting.

And then 62122 is a next-generation menin inhibitor for MF. We all know that we learned a lot about menin inhibition. We've been driving the science from the beginning. This is an internally generated asset. So we have a library of menin -- next-generation menin inhibitors, which we think are fit for purpose. This will go into MF. And it's potentially a disease-modifying agent. We've learned, and we've published data as of this week, there was a Cancer Cell paper that was published, really highlighting the importance of this mechanism potentially in myelofibrosis. We had data at ASH as well and really kicked that off. So we're in a very good position to take this science forward and exploit the mechanism in myelofibrosis. And as I said, this is a fully-owned set of assets that we have developed at Syndax. We're targeting submission for this asset in 2027.

So as you look across our pipeline, what's exciting is we have multiple blockbuster opportunities. First, acute leukemia with Revuforj, GVHD, and now potentially IPF with Niktimvo, 4321 in non-small cell lung cancer, and 62122 in myelofibrosis. So a full set and complement of opportunities.

So I'm very excited to be joined today by wonderful group of speakers. In addition to me, I'll have Nick Botwood, our -- Dr. Nick Botwood, our Chief Medical Officer and Head of R&D; as well as Peter Ordentlich, our -- Dr. Peter Ordentlich, our Chief Scientific Officer and Founder. And as well, joining us both in person and online, Dr. Crispino from St. Jude's Research Hospital. He'll be covering the MF portion of our talk today. Dr. Toby Maher from the University of Southern California. He will be covering IPF, he'll be online. And Dr. Michael Eck from Dana-Farber Cancer Institute. He'll talk about the asset that we've in-licensed, 4321, as well as his breaking science and breaking developments and research in lung cancer.

So now just a bit on our agenda for today. Nick, I'll hand the baton to Nick in a minute, and he'll cover both our R&D capabilities as well as take you through our pipeline. That's the first section. We'll also talk about Revuforj and our next-generation menin inhibitors, followed by Niktimvo as well as 4321, which is our allosteric inhibitor. And then we'll close from there.

There'll be Q&A throughout, so you'll see every section, we'll break it up with Q&A. So we'll have an opportunity to pause and ask questions. We'll be closing the session around 11:00. And so just to give everybody a sense of timing, and we'll go from there.

So very exciting day of presentations. I'm looking forward to it. Hopefully, you are as well. I'm going to pass it over to Nick, and we'll go from there. Thank you.

Thank you, Michael, and thank you all for coming. I'm very excited to spend the next couple of hours with you all reviewing with our collaborators, some of the developments in our R&D portfolio and our exciting and evolving pipeline. It's an exciting time to be at Syndax and I'm excited to share the science that we think bear such promise for patients to come.

So let me start a little bit about what I think makes Syndax really special and differentiated as a biotech, that we have built an incredible R&D engine with some of the best talent across the industry to really deliver on this extremely promising portfolio. We have what I would absolutely call now a world-class R&D organization. This is an organization that already has a proven track record of taking great science, translating it into the clinic, coming up with innovative clinical development plans, filing it, approving it and then commercializing it successfully. This is an extraordinary track record for this biotech. I'm incredibly proud to lead this organization.

We have individuals with deep expertise now in menin inhibition, in CSF-1R inhibition, and recently through the hiring of some great new leadership and talent, now deep expertise also in the development of novel assets in non-small cell lung cancer, that as you will hear through the day is going to be foundational to our future success.

We have, and I think today will be a very good showcase of that, we have also incredible relationships and collaborations with leading researchers, and new discoveries, which are really catalyzed by these collaborations we've had over many years now as a biotech, that positions us very strongly to continue to lead the science and to harness innovation and the best science. And I think, again, today will be a great showcase of that in example.

We also have very deep science. We have deep mechanistic understanding. We were the first to identify menin inhibition, we were the first to validate the concept of CSF-1R, receptor antibodies in GVHD. And that is really based on our deep understanding of the science and then translating that science into the clinic. And we have a proven track record of being able to do that.

And we do now also have, and I'm happy you're all able to join us here in our offices in New York, we do also have deep in-house expertise covering all of the key disciplines that support world-class research and development. We have outstanding discovery partnerships. We have a leading development organization, CMC, of course, regulatory, and of course, commercialization organization. And having spent a lot of my career in large pharma, I would also say we're now rightsized to deliver, but also to be extremely efficient and nimble in terms of decision-making and governance. We are able to move extremely quickly to harness the best science and then translate that, making quick and appropriate decisions to really deliver well for our patients.

So just a little bit about the track record before we get into the new stuff, which is really talking about our leadership and our scientific leadership with menin inhibition and Revuforj. And this dates back over a decade now to 2016, where revumenib and axatilimab were in-licensed pre-IND, and we're going to talk about similar models today. We were then the first to clinically validate menin inhibition in acute leukemia. We were the first company to approve the menin inhibitor, now, as you all know, a very hot space, in KMT2A, subsequently an sNDA in NPM1 acute myeloid leukemia. And then we have -- we were also the first to initiate a randomized study in newly diagnosed frontline AML. And we were the first to present and collaborate on data that you'll hear about today, for the potential of menin inhibition in revumenib in the treatment of myeloproliferative neoplasm like myelofibrosis, and we're excited to review that.

Equally, we were the first to clinically validate CSF-1R inhibition in GVHD, and we're the first approved and only approved CSF1R in GVHD.

And the time lines for this are quite impressive. So we achieved 3 FDA approvals between revumenib and axatilimab, both drugs were approved in about 5 years from IND to FDA approval, which is a very impressive track record. And that's something we want to build on, and we believe we have the people and the capabilities to be able to do that.

So let me touch just briefly on the existing portfolio of studies that is probably quite familiar to you. We have obviously a deep and extensive program with revumenib, and I'll talk a little bit more about that in a minute. And we've now added to the revumenib book of work, a proof-of-principle study in myelofibrosis, which you'll hear more about.

We have an extensive program of work with axatilimab our CSF-1R antibody, with now an important proof of concept in idiopathic pulmonary fibrosis, which will be the focus of one of the sessions you'll hear about today.

What I'm really excited about is to add 2 new assets to our pipeline. This is an incredibly exciting portfolio of studies for us to be able to execute against. We will focus today and go deep into the science of allosteric inhibition in EGFR mutant non-small cell lung cancer, and we will talk deeply about the science that underpins the role of menin and menin inhibition in myelofibrosis. And our new menin inhibitor, 62122.

So for the first session, and we're going to have 3 sessions today, I want to talk about advancing our leadership in menin inhibition. So we are very well positioned, and I would say, in a very strong position to continue to drive the leadership in menin in acute leukemia, and we remain laser-focused on acute leukemia, but also into indications beyond that where we feel menin inhibition could have an important role to play.

We come from a foundation of having the broadest indication and clinical activity of any menin inhibitor. We are the only menin inhibitor approved in NPM1 and KMT2A translocated acute leukemia in adults and children. And we're the only menin inhibitor with now presented data in the subset of NUP98r, which we're excited about area of high unmet need.

We have a really broad integrated evidence generation plan. We call it integrated evidence because they're somewhat agonistic to whether that's a company-sponsored, investigator sponsored or a collaborative proposal. We are simply generating data that might support registrations, might support guideline informing data or potentially could generate data that either supports clinical practice or a new signal to take into a new development program.

We have, as you will hear about today, a library of next-gen menin inhibitors. This was an internally developed library, which aligns very nicely with our leadership in menin because we have already revumenib in the clinic to generate proof of principle data that will support accelerate the development of our next-gen menin in 62122.

And we have, of course, underpinning all of this and which you'll hear about today, incredibly strong scientific partnerships, because of our reputation to do this, we have collaborations with world-leading scientists and clinicians that will catalyze these promising scientific discoveries into breakthroughs for patients.

So I'm not going to spend too much time talking about the development program with revumenib. I think it's quite familiar to you now. But suffice to say, we have a very broad development program that supports all of those ambitions, registration, life cycle management, signal seeking and practice informing. But I would like to highlight a couple of things.

First is that we remain a laser focused on our 2 pivotal registrational studies. The EVOLVE-2 study in patients unfit for treatment with intense chemotherapy, which is a combination with ven/aza and our 7+3 combination in frontline patients that are fit to receive intensive chemotherapy. Those studies are both up and running. We have great momentum in terms of site activation internationally, and enrollment is really picking up. And the teams remain laser-focused on executing those studies, to take those, hopefully, with a positive outcome towards new therapeutic options for all patients with newly diagnosed AML.

And we're very excited about the potential of that and the progress we're making with those studies. And that's in blue at the bottom of the slide.

The 2 studies I just wanted to highlight in yellow on this slide were really there just to highlight the innovation that we're doing and continuing to drive our leadership. The first is in maintenance. And the role of menin inhibition in patients that have had a transplant is an area of important research, and we were the first study to now have a prospectively randomized approach, again, in collaboration with the Dana-Farber Cancer Institute, identifying and clarifying the role of Revuforj in a maintenance setting after HSCT. And that study is called the MenTain, it's now on ct.gov.

And then we have the RAVEN study, which is, again, is novel, innovative and differentiated from other menin development programs. This is looking at patients with KMT2A relocated AML, who would be otherwise fit for intensive chemotherapy, and it's actually in combination with ven/aza. The hypothesis being that you can get those patients to transplant without the need for intensive chemotherapy and, therefore, with less associated morbidity. So we have this already well-established and robust overall development program for revumenib.

We will, however, continue to follow the science to unlock the full potential of menin inhibition. And we have a proven track record of doing this now, starting with KMT2A, approvals in NPM1, exciting data as we talked about with NUP98R disease. We now have studies looking at the role of revumenib prospectively randomized in that post-transplant setting.

Today we're going to talk about myelofibrosis and potentially indications beyond that, and it's very exciting science.

Myelofibrosis, so you may ask why myelofibrosis. Why did we pick myelofibrosis as our next life cycle management indication? Well, clearly, this remains an area of high unmet need. These patients are symptomatic associated with significant morbidity and mortality. We have, as you will hear today, compelling preclinical data that Dr. Crispino will review and was awarded Best of ASH, and as Michael highlighted, was recently published. It's an extremely good strategic fit for us with our leadership in the menin inhibition space.

And we also think it has the opportunity for us to generate an early clinical signal, and that allows us, should we be successful, to pivot into more full development in a very rapid time frame. It's not going to take a long time for us to be able to identify whether menin inhibition does indeed have a role in myelofibrosis, which based on the preclinical data, we have a very strong feeling that it might have.

So let me touch a little bit on our leading menin inhibition and leading that into the future with our library of next-gen molecules plus our ability to derisk this library of molecules with revumenib to generate proof of principle data. Our intent is to deploy this next-generation menin inhibitors into new areas, and we will be starting with myelofibrosis. These are rationally designed molecules informed by our deep molecular understanding of revumenib's interaction with menin. Importantly, these are wholly owned assets with no financial encumbrances and it presents multiple distinct scaffolds with composition of patents that last well into the late 2040s.

Now 62122, that you heard a little bit more about today, is a next-gen inhibitor was actually the first molecule to emerge from our library. And we are anticipating the submission of the IND in 2027 and into the clinic in the latter part of 2027. The profile of this so-called next-gen menin inhibitor is very attractive. It has extremely high potency. It has increased selectivity without off-target effects like [ hERG ]. The PK is optimized with extremely little, if any, drug-drug interactions. And it also has quite profound activity against some of the common resistance mutations. So it's an extremely attractive molecule to take into settings like myelofibrosis.

So on that note, I'd like to introduce our next speaker. And I'd like to introduce Dr. John Crispino, who's been a close collaborator of ours for many years. Dr. Crispino is the Director of Division of Experimental Hematology at St. Jude's Children's Research Hospital. He is an internationally recognized hematology researcher, whose pioneering work has significantly advanced the understanding and treatment of myeloproliferative neoplasis as well as other disorders.

We are absolutely thrilled to have him here to discuss the landmark research he recently led with support from our scientific team, which led to the discovery of menin as a novel target in myelofibrosis. So it gives me great pleasure to introduce Dr. Crispino.

Great. Thanks, Nick. It's a real pleasure to be here today to tell you about our research, which was, again, just published last Thursday online in Cancer Cell, and it's an open access paper. So I'll cover some of the highlights of that today, and I encourage you to take a look at the paper to see the primary data.

So myelofibrosis is a myeloproliferative neoplasm in MPN that affects about 20,000 people in the United States. And it's associated with extramedullary hematopoiesis contributing to enlarged spleen and enlarged liver. That's due to the increased amount of [indiscernible] in that tissue. There's increased levels of inflammatory cytokines that mediate debilitating symptom burden, and bone marrow fibrosis that accompanies cytopenias.

Now stem cell transplant is the only curative option, but 90% of MF patients are not candidates for transplants due to age or comorbidities. JAK inhibitors, including ruxolitinib, are the current standard of care for the vast majority of patients. So while these JAK inhibitors reduce symptom burden and splenomegaly, they do not crucially affect or reduce fibrosis or the mutant allele burden. And most patients stop responding to JAK inhibitors within 2 to 3 years with poor outcomes. And this is why it's an area of high unmet medical need.

So myelofibrosis is characterized by an accumulation of atypical megakaryocytes, which are the cells that derive platelets. And these cells contribute directly to the fibrosis by secreting cytokines, which lead to increased collagen deposition. And emerging data from my laboratory has shown that menin is a novel dependency, particularly in the proliferative megakaryocytes, in their progenitor cells, that I'll refer to as MKPs. So we know from our work that menin inhibition suppresses megakaryopoiesis by down-regulating key KMT2A menin target genes such as MEF2C and MEIS1. It selectively affects these MKT cells.

And in our studies, revumenib showed striking antitumor activity in several preclinical models of the MPNs. These include the [ JAK2V617F mouse ], the NPL or NPL W515-L mouse, which I'll show you the data for, and another mouse called MPLS504N, as well as also PDX mice that I'll show you. And our work then supports further investigation of menin inhibition in myelofibrosis.

And interestingly, it targets pathways independent of targeting the JAK-STAT pathway. It's an orthogonal pathway by transcriptional down-regulation of these key target genes.

So our recently published preclinical data show that revumenib selectively inhibits megakaryopoiesis. And first, I'll show you data from liquid culture assays of human CD34 positive cells cultured with revumenib. And on the left, you can see that the percentage as well as the absolute numbers of KPs derived in culture are significantly reduced. We also see subsequent effects on the immature megakaryocyte fraction and the more mature megakaryocytes treated with revumenib.

Not shown here in colony-forming assays of megakaryocytes, revumenib has an IC50, about 300 nanomolar, to block the production of the cells. And by contrast, you see that erythroid colonies and granular site macrophage colonies are not affected by revumenib as doses up to 20 micromolar.

So we importantly show that loss of menin phenocopies the effect of the drug, confirming an on-target effect. So we use single cell RNA sequencing approaches to demonstrate this. And I'll first start on the right, which is the revumenib treated cultures. And again, I'm showing that the numbers here of the MKPs are vastly reduced by treatment with revumenib as are the immature megakaryocyte fraction.

But on the bottom, we're looking at data -- UMAP data, which is a single cell RNA sequencing approach that lets us look at individual cells within the culture. And I'm showing you 7 cell populations. And you can see in the circle is that revumenib has this profound effect to reduce the MKP population and the subsequent development of megakaryocytes.

On the left is using a CRISPR approach to knock out the menin gene. And we use 2 different so-called guide RNAs to down-regulate menin, Guide 1 and Guide 13. And on the left graph, you can see that knockout of menin with 2 different guide RNAs significantly reduces the MKP population and also reduces those immature megakaryocytes.

And then on the bottom, again, through the single cell RNA sequencing data, you can see that the drug -- the knockout again recapitulates the effect of the drug, where there's down-regulation of both the MKP population and the MKs.

So I'm going to show you today just one mouse model. This is the MPLW515L model. It's a very aggressive model of myelofibrosis. And the phenotype predominantly is bone marrow fibrosis, very high increases in the white cell count, high increases in the platelet count, with very modest effects on the erythroid lineage. And they also develop splenomegaly and enlarged livers.

And the vehicle-treated mice in this model succumb to the disease typically 5 weeks post transplant. So what I'm showing you here then is in blue are the control treated mice; in orange are the revumenib-treated; in blue, ruxolitinib; and then in yellow is the combination of ruxolitinib with revumenib. And you can see, first, the white cell count, that all 3 treatment arms show reduced white cell count, but especially the yellow line here, the combination is very effective at normalizing the white cell count.

Similarly, for the platelet count, we can see that all treatment -- 3 treatment groups reduced the platelet count. Ruxolitinib has an intermediate effect compared to revumenib. And then the combination, again, is even stronger at reducing the platelets.

I think on the right, what's the most important takeaway from the right graph where we're looking at hemoglobin is that the drug treatments, including the combination, does not cause anemia in this animal model.

If we will look at the spleen weight in this particular mouse model, you can see in orange that revumenib did not reduce the spleen weight. This is not true in the JAK2V617F model. In the paper, you can see that, that had a very strong reduction in the spleen size. And this NPL-S504N mouse that I'm also telling you about, we see the reduction in spleen size there.

Ruxolitinib in this study led to a significant but modest decrease in spleen size, but the combination importantly normalizes that spleen weight. And then on the right, you can see that all 3 treatment arms are getting enhanced survival, and those untreated mice dying, again, about 5 weeks post-transplant.

Now let's talk about the bone marrow environment and the fibrosis. So we know revumenib alone and in combination with ruxolitinib suppresses the level of TGF-beta, megakaryocyte accumulation and fibrosis more than ruxolitinib alone. So if you first look on the left graph, this is looking at a cytokine TGF beta, which promotes fibrosis. It's produced by megakaryocytes and other cells in the marrow. And revumenib in orange gives a significant reduction in TGF-beta levels, so does ruxolitinib. But the combination is much more potent at that.

In the middle graph, we look at the percentage of megakaryocytes within the bone marrow. Here we again see that revumenib has this very strong ability to eliminate these atypical megakaryocytes that are characteristic of myelofibrosis. Similarly, the combination is as effective.

In contrast, you can see that ruxolitinib, as we know, does not affect this megakaryocyte population significantly in these animal models.

And then finally, on the right, we're looking at the reticulin grade fibrosis, which could be 0, 1, 2 or 3. And typically, these untreated mice have a fibrosis grade of either 1 or 2. With treatment with revumenib as a single agent or in combination with ruxolitinib essentially prevented fibrosis from developing in any of the mice in this study. And I would say we've done a lot of preclinical studies with 4 different mouse models, and only 1 mouse in all of those studies treated with revumenib had a Grade 1 fibrosis. So really the strongest drug that we've seen to eliminate fibrosis or at least prevent the development of fibrosis.

Now ruxolitinib in patients has a very limited activity in fibrosis. Here in the mouse model, it's variable. So some of the mice respond and some still have fibrosis.

So you can see some of this histology here. This is looking at the bone marrow of the treated mice. The top row is hematoxylin is in staining. You can see on the upper left, I don't know if you can appreciate, there's a lot of these large cells there that are clustered. Those are the atypical megakaryocytes that are characteristic of myelofibrosis.

In the revumenib-treated mice, we see that those atypical megakaryocytes are gone. That's compared to ruxolitinib where you can see that there still remains this abundance of clustered atypical megakaryocytes.

And finally, on the far right, you can see combining revumenib with ruxolitinib reduces or eliminates those abnormal megakaryocytes and also normalizes to bone marrow cellularity. So the combination is particularly strong in this model as well as in the JAK2V617F model. Again, you can see that in the manuscript.

And then the bottom is looking at the degree of fibrosis. And we can show that revumenib alone or in combination with rux, again, completely eliminates fibrosis or prevents it. And ruxolitinib, in this example, we're showing you a case where it is active, but it is variable in those mice.

And then finally, we looked at patient samples. So on the top, we're looking at in vitro treatment, a patient samples with revumenib. And these are patients that either have a calreticulin mutation or JAK2 mutation. The NPL mutation is about 5% or 10% of the patients, whereas the calreticulin ticket mutation, maybe 30%, 40% and the rest would primarily be JAK2. There's some patients triple negative.

You can see that those patient samples all responded to revumenib. On the left is the CFU MK, so megakaryocyte colonies. You can see those are significantly reduced in revumenib. Similarly, the megakaryocytes, the immature and the more mature megakaryocytes, are reduced.

And then finally, importantly to us, looking at these MKPs, which we think are disease drivers, those are reduced by treatment of revumenib even with the mutations.

And then finally, on the bottom, we did -- we made -- generated a patient-derived xenograft model of myelofibrosis using MF patient sample injected into immunocompromised mice. This is treated with a single agent revumenib. And you can see that revumenib reduced significantly a proportion of human CD45 tumor cells that are in the peripheral blood. In the bone marrow in the middle, you can see that human CD45-positive cells, the numbers of those cells in the bone marrow are significantly reduced, treatment with revumenib as a single agent.

And then finally, on the far right, hematopoietic progenitor population of CD34-positive, CD38-negative HSPCs are significantly down-regulated upon treatment with the drug.

And then the last data slide is to look at the target genes. And so we can see here, we're looking at 3 key target genes, MEF2C in the middle, MEIS1 on the left and PBX3 on the right. And the top row is looking at these megakaryocyte progenitors cells and you can see that all 3 are significantly reduced upon treatment with revumenib.

And then on the bottom graph, we're looking at the megakaryocytes. In those cells, MEIS1 is not significantly down-regulated, but MEF2C and PBX3 are down regulated.

In the manuscript, what you'll see is we can show that knockout of MEIS1 or MEF2C can phenocopy the effect of revumenib.

But importantly, over-expression of MEF2C can partially alleviate the effect of revumenib on the MKP numbers, indicating that, that is indeed one of the key target genes of the drug in the megakaryocyte lineage.

So I'll summarize our data in this slide. So menin inhibition suppresses megakaryopoiesis. And here, I'm saying in times of stress or disease, when the progenitors are highly proliferative. What I mean by that is in our liquid culture assays, we're expanding the megakaryocytes and cytokines. In the animal models of myelofibrosis as in patients, there's a massive expansion and proliferation of the MKP population. In those settings, menin is a particularly strong vulnerability that can be targeted with revumenib.

This on-target effect of in myelofibrosis is driven in part down-regulation of MEIS1 and MEF2C.

Revumenib has antitumor effects in multiple MPN mouse models as both a single agent and in combination with ruxolitinib. Revumenib and ruxolitinib appear to synergistically suppress myelofibrotic cell growth by targeting regulation of key MKP genes and JAK-STAT signaling, respectively.

And I should point out, in the manuscript, we show, again, that these are targeting orthogonal pathways, that revumenib does not suppress JAK-STAT signaling as a single agent. Instead, it targets, again, those atypical megakaryocyte progenitors through a transcriptional pathway. We do see -- formal synergy treatment with cell lines. And then again, in mice, we see the combination is more effective.

We believe that menin inhibition may be complementary to other emerging targeted therapies in myelofibrosis, such as mutant CALR targeted antibodies and the next-generation type 2 or JAK2 mutant selective inhibitors, which then again target the JAK-STAT pathway orthogonally.

And finally, our study provides the rationale for further clinical investigation of menin inhibitors in the MPNs. And I believe Nick will talk next about the clinical studies.

Thank you very much, Dr. Crispino for that very nice overview. So let me talk briefly about the next steps, building on that groundbreaking research published in Cancer Cell with the very nice editorial accompanying from colleagues at Memorial Sloan Kettering.

We're going to leverage revumenib to inform and derisk the development with our next-gen menin inhibitor 62122 in myelofibrosis, as we've talked about those data now published in manuscript. Our intent is to initiate a revumenib proof-of-principle trial in the fourth quarter of this year.

We will intend and be submitting an IND for our next-gen menin inhibitor, 62122, in 2027. And we're progressing very well with the components of the IND to be able to submit that next year.

We would then intend to initiate a Phase I of Syndax 62122 in myelofibrosis in 2027, so next year, but being able to leverage all of the learnings from the proof of principles study with revumenib as the proof of principle for menin inhibition in myelofibrosis. And we believe that will really offer us the opportunity to accelerate the development from that Phase I in myelofibrosis with a much deeper understanding of the tolerability, the dosing and potential traditional and novel combination approaches in the treatment of myelofibrosis. And Dr. Crispino highlighted the potential of some of those combinations in the future.

I'd like to just highlight briefly the Phase I/II proof of principle trial that we have planned in MF, which we are anticipating starting at the back end of this year. And this study is done in partnership with the Myelo-Productive Neoplasia Research Consortium, or MPNRC consortium. This study is not yet on ClinicalTrials.gov.

We do have permission to share this slide with you today from Dr. [ John Mascarenhas ] who's collaborating with us very closely with Dr. Crispino on this study. And I'll just highlight some of the key components in terms of how we're thinking about this study.

So this is obviously a study in the various forms of myelofibrosis. This is in slightly higher-risk patients in order to be able to demonstrate a benefit for patients with sufficient platelet reserves. It's going to be about 30 patients, and will compose of 2 cohorts. The first cohort will simply establish the tolerability of revumenib and the concept of menin inhibition in the treatment of myelofibrosis for patients that have had a prior treatment with JAK inhibition.

The second cohort will then look at the combination of adding revumenib to ruxolitinib in patients that have had prior treatment with a JAK inhibitor for greater than 12 weeks, but have shown an incomplete or inadequate response. And we will then look to see whether the addition of revumenib actually adds additional efficacy parameters, looking at some of the standard international criteria for responses in myelofibrosis that include things like splenic volume reduction. We'll obviously look at symptom burden.We will also look at a number of [indiscernible] including, of course, platelet count recovery, white cell counts, we will look at MK cells, as Dr. Crispino was just describing. And then importantly, we will look at potential disease-modifying endpoints.

As you just heard, this is not a characteristic of JAK inhibition. Hope and expectation is menin inhibition may actually lead to a decrease in variant allele frequency or mutation burden, reduce inflammatory cytokines, common inflammatory cytokines like TNF alpha, TGF-Beta IL-6, and also reduce the bone marrow fibrosis that is so common in these patients. So we'll look at all of these endpoints, and we -- our expectation is working closely with the MPM Research Consortium, we will generate data that would very much inform and accelerate our development with our next-gen menin 62122 when it's ready to take into the clinic.

So that's just a high-level overview of the study we have planned. And on that note, we'd be very happy to take your questions on this first section to do with revumenib and next-gen menin inhibition. So please.

Great. This is Kevin on for Corinne at Goldman Sachs. Just a question on how you're thinking about the development strategy in the context of next-generation JAK2 inhibitors that are being developed in myelofibrosis.

Maybe I'll start, Dr. Crispino, and you may well want to offer a perspective. So I think that there are certainly new opportunities in myelofibrosis. The approach with the MPN Research Consortium is first and foremost, to validate the preclinical findings, number one.

Number two is to establish additive activity when you combine with a traditional JAK inhibitor like Jakafi. And then as Dr. Crispino was articulating and maybe would like to comment, there are a number of other novel approaches, including CALR antibodies that it might be interesting to preclinical data in, and that's something we have planned, which we might then translate into the clinic. But Dr. Crispino?

Yes, I would just emphasize that, again, we showed the combination with ruxolitinib has this additive or improved activity. I think it's definitely worth doing some more preclinical studies looking at these next-generation JAK inhibitors. And that is one of our intentions as well as the CALR antibody. So I think we will do some preclinical studies that will help inform where to go with it in the clinic.

Brad Canino with Guggenheim. Really interesting data. Question around the additive platelet reduction effect. Maybe first to Dr. Crispino, how -- what proportion of patients will have adequate platelet reserves like are being enrolled into the study? And then maybe both to you and to Nick, confidence level on being able to manage the additive platelet and thrombocytopenia effect that you're seeing while maintaining dose intensity and efficacy in this combination?

Right, correct. I think if you don't mind, I'll flip it over to Nick because he can tell you about the specifics for the trial first. Yes.

Well, yes, one of the -- it's a good question, Brad. One of the criteria of the trial is that patients do have adequate platelet reserves going on to the study. So it has to be greater than 75. So they have to have that. And then obviously, us recording platelet count recovery is one of the important endpoints of the study. Again, we want to be able to translate the preclinical findings into the clinic.

So we will be, first and foremost, assessing tolerability and also identifying the optimal dose of revumenib, whether it's the 160 or the 270 dose will be to be defined in the study and also importantly, the tolerability of the combination with JAK. So those are all things and what that would do to the platelet count. So those are all very much in scope as part of this Phase I/II. And that's one of the benefits of having a program where we can assess those with revumenib and translate all of those findings because we'll be working very closely with the MPN Consortium into our development program with 62122 when that starts in the near future. Do you want to add to that?

No, again, I think the key is going to be to monitor the platelet count throughout. In our animal models, as you saw, the combination with ruxolitinib does reduce the platelet count further than the single agent. So again, I think in the combination studies, in particular, you need to be monitoring those platelet counts very closely.

Great presentations. For Dr. Crispino, I thought it was interesting that the data you showed for the MEN1 knockouts didn't actually look as good as revumenib, which I thought was sort of surprising but interesting. I'm wondering if you could comment further on that first.

Yes, excellent question. So that has to do with the efficiency of the targeting of menin. So we -- I didn't show you the data, it's in the paper. When you sequence to count the number of indels to look at the frequent -- the efficiency of the CRISPR reaction, it's not nearly -- it's not 100%. It may be 70% -- so I think a lot of that represents just those non-targeted cells remaining. Yes.

Okay. And then also, I was wondering if this next-generation menin inhibitor is also metabolized by CYP3A4 or not, or if you don't know yet?

It actually has very little interactions in terms of its PK, and we're not anticipating any significant DDIs. So that's one of its potential advantages as we optimize the molecule given all of our understanding of kind of the menin backbone and the framework. So we're not anticipating that.

Faisal Khurshid from Jefferies. I want to understand for the next-generation menin, in what ways do you think it will improve on what you see with revumenib in these preclinical models in MF? And then with this initial Phase I study that you're doing with revumenib, how does that kind of enable accelerating the next generation if that proves out successful?

Great. Two great questions. Dr. Crispino, do you want to address the first one to do with?

Yes. So we've actually completed the first preclinical study with the 62122 and showed -- we said there's a dose-dependent effect and at the higher dose that we're using, we see essentially the same preclinical outcome as the 0.1% revumenib in chow that we've used in the published data. So it certainly looks as good, if not better, but we haven't pushed the dose at all. We just are at 2 doses, and we show the higher dose has phenocopies, the revumenib.

And then to your second question, we have a compelling preclinical hypothesis. The data are compelling, and we have to validate that in the clinic. That's always the way. I mean, it happens sometimes, not always. So our ability to do that with revumenib really gives us a head start. So it also gives us the opportunity to leverage the extremely good collaborations and relations we have like with the NPM1 consortium. This is a leading academic group across 15 leading centers in the U.S. and working with them is really going to give us an advantage.

There's a lot clinically we still need to understand about menin inhibition in MF. I think there are many questions on hypotheses raised to do with platelet counts, to do with tolerability, to do with the ability to actually impact the disease burden. We'll learn a lot about that through our close collaboration such that when we're ready to start the Phase I, it will catalyze our ability to start the Phase I. We'll understand about the dose, the tolerability. We'll also understand which are the really relevant endpoints we want to be looking at in terms of the extensive splenic volume reduction, the impact on platelets, the impact on fibrosis and many of the other endpoints and correlators we'll look at in the Phase I.

Having a deep understanding of all of those, working closely with John -- Dr. Mascarenhas, Dr. Crispino and the collaborators across the NPM1 consortium, really will help us when we have the 62122 IND ready and able to go into the clinic. So we'll be considerably ahead of the curve than we would be if we were simply starting a Phase I with a new asset without any understanding of the role of menin inhibition in myelofibrosis. So I'm excited about generating all of that data and then having a next-generation menin inhibitor, which has been optimized for all of those characteristics that you would like it to be optimized for in a disease like myelofibrosis, and that will really allow us to accelerate.

Steve Willey from Stifel. Was just wondering if Dr. Crispino could talk about the translatability of these preclinical assays in terms of cytokine reduction. And then what is observed in terms of symptomatic improvement in the clinic? I know you showed SVR reductions in the preclinical models, but it's often on TSS50 where these combo approaches fall short in the clinic.

Yes. So in mice, it's obviously challenging to look at symptoms. What I can tell you is the mice certainly look better. They move around well. They survive much longer. Our take on it is that it's showing that kind of activity. Obviously, in patients, there's different symptoms that we look at. I think it's very hard to translate what we see in the mouse to know how that symptom burden is really going to be changed in people, except, again, to say that the mice seem to be doing better.

The translatability of the TGF-beta levels, that was your other question. Certainly, in the mouse models, as we show, we see really strong reductions in that accompanied by the loss or prevention of fibrosis. I think that, that will likely be seen in the patients, and we will be doing those correlative studies to look at levels of TGF-beta as well as other cytokines with therapy. So we'll be able to answer that in more detail soon.

Salim Syed from Mizuho. Just on the trial for revumenib, I noticed that the data is being generated for second half '27, at least the clinical activity data. And you also listed for 62122 IND submission in '27. Is there a minimum level of data that you're looking for from the revumenib trial before the IND submission?

No, it won't be gated, but I anticipate we'll have preliminary data that would inform a Phase I with our next-gen menin in time for the Phase I. They're not gated. They're not dependent on each other, whether that's being presented or published or not, or whether that's just through dialogue with the NPM1 consortium is to be defined.

But we will have data that will allow us to accelerate in terms of the dose selection, the endpoints we think are of interest and many of the other correlators that we'll be looking at because, again, translating the preclinical findings in the clinic is our first step, but it's not gated. So we could start it in tandem, but with all of the learnings emerging that would inform the Phase I, and we're really quite confident that will accelerate the development.

And you'll be getting data as you're producing it, correct? For the...

Sure. We'll be collaborating really closely with the group. They're very invested in this, and they know the program with 62122 as well. We're progressing well with the IND-informing data, the package. We're feeling confident about that and should have it in clinic in 2027. And that would sync up very nicely, we believe, with data emerging from the work we're doing with the research consortium. So it should all come together very nicely as a development program and enable us to be leading in that space.

Steve Sabba, Dorset Opportunity Fund. Just sort of expanding on the prior question, if the revumenib proof of concept isn't gating, what is rate limiting for -- what is it, 62122? Going into the clinic because 2027, that's a big spread of possible dates.

Peter, do you want to talk a little about that?

Yes. We're going through the IND-enabling work currently. And so that just puts us on track for the IND submission sometime in next year. We just have to get through some of the key rate-limiting tox, things like that. And so it's pretty standard IND submission time lines.

Okay. And just on the proof-of-concept trial, do you have an idea of how you'll be -- will you be giving us data just when you have the full number of patients in the cohort? Or will you be sort of dribbling out data? How do you plan to do that?

Well, this -- it's a great question. It's a collaboration with the NPM1 research consortium. So it's under their sponsorship. We're obviously collaborating closely with them. We're aware this is a very competitive space, and Dr. Crispino's data has obviously generated a lot of interest. We're aware of that. We want to continue to lead in menin inhibition. So we will be working very closely with the NPM1 consortium, MPN consortium. Data availabilities and publication plan is to be defined, but I'm absolutely sure there will be emerging signals and data that will help inform a Phase I program.

This is David Dai from UBS. I'm just kind of double-clicking on the drug profile for 62122. You mentioned that this is higher potency, better PK. Maybe just tell us a little bit more about kind of PK profile that you've seen here that's different from revu. And at the same time, have you done any kind of comparison head-to-head compared to other next-generation menin inhibitors like from other competitors?

Great question. Peter, do you want to address a little bit, the profiles emerging?

Yes. I mean, without talking too much more beyond what we have on the slide, I think clearly, potency has been something we focused on. So the potency is significantly improved compared to revumenib. We talked a little bit about the on-target selectivity. The profile of the molecule is highly attractive in dialing out some of the things that have been observed with menin inhibitors as a class.

And similarly, just in terms of the resistance mutations that we have actually identified and spent some time on. So we've targeted and dialed out quite a bit of that in this molecule. So it's just a better molecule. It's got a lot of features in terms of what you might expect for next-generation molecule, potency selectivity and certainly targeting the mutations that have been identified for the first generation.

And I'd maybe just add that we've been working on this through collaborations for several years now and have a deep understanding of the chemistry of these menin inhibitors, and we have a library of them and have been able to optimize the molecular structure, the chemical structure, if you will, for all of the things you'd want in an optimized next-generation menin inhibitor, including PK potency activity against the menin inhibitor, lack of interaction in terms of metabolism and drug-drug interactions.

So the selection of 62122 was the opportunity to select of a series of molecules that we've been developing over several years to pick the best, which we think will be really well placed to develop in the first instance, myelofibrosis and really accelerate its development there. So it's really optimized from a selection of a number of chemical structures that we have been collaborating on and optimizing over several years now.

This is Ellen Horste from TD Cowen. Just wondering if you think the improved tolerability will allow you to use 62122 in other MPNs like ET or PV.

Well, now I can comment clinically, but I know Dr. Crispino, you had a perspective on this as well. So maybe you want to...

Yes. So certainly, ET patients with elevated platelet counts, many of them are resistant or intolerable to hydroxyurea. I think given our data preclinically and what we've seen in the clinic that there's -- that looking at the activity in ET, I think, is something that should be -- from my perspective, should be pursued.

Yes, I agree clinically. And obviously, the MPN consortium study includes patients that have progressed through essential thrombocythemia to become advanced, also polycythemia rubra vera. But there is interest, I think, once we've established the tolerability and proof of principle to look at some of those other settings. I think that's definitely of interest based on that observation.

Adam from B. Riley, on for Mayank. Great presentation. So I'm curious, the patient sample work that you showed, it was in CALR and JAK2 mutations. So I was wondering if you have any insight as to whether the MKP and HSPC reduction holds across the full mutational spectrum or if there's a specific subset effect there?

Yes. So the mouse models included the JAK mutant and the MPL mutants in 2 different studies. The patient samples were calreticulin mutant or JAK2 mutant. So we can cover -- we can show that there's activity across the board. The calreticulin animal model is actually not so -- it doesn't work very well, right? So we actually attempted that, but we couldn't get the mice to get the disease even after 20-some-odd weeks. But I think with the patient data, I think we can -- I believe it will be active across the mutational spectrum.

Great. Well, that concludes our first session. And it now gives me pleasure to move us on to the next one and bringing Peter to the podium.

Great. Yes. Thanks so much, Nick. So I have to say it's so wonderful to be able to talk and spend a few hours talking about the innovative science that we have going on here at Syndax. So before passing it on to Dr. Maher to tell you more about IPF, I just wanted to spend a couple of minutes reminding you about axatilimab and a little bit overview of the mechanism of action and then spend a little time on an overview of our development program to date.

So axatilimab, as you may know, is a monoclonal antibody. It's an IgG4 subtype that was designed specifically to block to CSF-1R or colony stimulating factor-1 receptor. And its only activity is to block the ligands, the IL-34 and CSF-1 from binding to the receptor. So no effector function was built into the antibody. So think of it just as a ligand-blocking antibody, which we think is important for its function but also the tolerability profile that we've observed to date.

So monocytes and macrophages that are derived from these monocytes are quite important immune cells. They fight infections, like bacteria infections. And they are also going to tissues, and those macrophages are there to have certain functions, including tissue repair. And there's a lot of biology that has gone into sort of describing how these monocytes and macrophages function.

Obviously, important cell types. And CSF-1R signaling pathway is the key growth factor pathway for these cell types. So it regulates the maturation, the proliferation and activation of monocytes and monocytes into macrophages in the tissue. And so blocking CSF-1R has been shown to have this great effect of down-regulating both the levels of monocytes and macrophages, but also importantly, their activity profile.

So in disease settings, like many immune cells, if the disease sort of -- these cells go awry or dysregulated, you have an overabundance of activity. So you can have inflammatory effects through certain cytokines and growth factors, and you can also have this effect of fibrosis, which is really the wound repair or tissue repair that gets uncontrolled. And so we know there are disease settings where inflammation and fibrosis play a role. We'll hear about that certainly with IPF. We have experience in the graft-versus-host disease setting, which I'll tell you a little bit about. But we know that this is an important physiological process. And then when it goes awry, that CSF-1R blockade is quite effective in normalizing it.

And so if we go to the next slide. So basically, just to give you a sense of our development program to date. So we licensed this in, as you heard, a number of years ago. And after some initial development work, we focused in on some science that was very compelling that was published in models of transplant. And in these mouse models that actually develop GVHD that resembles quite a bit the human disease, they have manifestations within lung and skin. And those, in fact, were inhibited by using a CSF-1R antibody in those mouse models. And so based on those data, we started a Phase I program.

And so as you've heard, we have a lot of firsts. And so we, of course, we're the first to clinically validate CSF-1R signaling and inhibition for this particular disease of GVHD. The first patients treated in our Phase I responded, which was incredibly gratifying to see. And we continued the Phase I. We did a cohort expansion. And those data led to our pivotal study called the AGAVE study, which, as we know, read out positively and led to the approval of axatilimab and Niktimvo in 2024.

Subsequently, we along with our partners, Incyte Pharmaceuticals, launched Niktimvo in early 2025. And as you've heard, that launch has gone extremely well. And we continue to see benefit for patients, which we're again super excited about and happy to see.

And so one of the things similar to our revumenib program that we've been focused on with our partners at Incyte is to advance from this setting of the approval is after 2 prior lines of systemic therapy. And the goal is to move this into earlier lines of therapy as a way to basically try to prevent those fibrotic manifestations from happening. And so if we can move that earlier in the disease, we may see a more prolonged benefit for patients, not to mention increasing the number of patients that can ultimately benefit.

And so Incyte has been leading 2 studies in the frontline setting. One of them is actually quite novel. It's combining with ruxolitinib as a steroid-sparing approach. And so the idea here is currently standard of care is for patients to get steroids in the front line. Steroids, they can be on these for years and they have a lot of comorbidities. And so the idea could be, which is extremely exciting for the community and for patients, could you come up with a steroid-sparing regimen? And so that trial has been ongoing. And we've heard and have indicated that those data will be available by the end of this year. So we're really looking forward to those data.

In addition, there is a Phase III study that's ongoing, that's also frontline, that's steroids plus/minus axatilimab. And this is, again, a registration-oriented study that should read out hopefully in 2028. So again, super exciting sort of movement of the axatilimab program from the current setting into the earlier frontline settings.

Now we spent a lot of time thinking about where else can we look for benefit in targeted macrophages and such through CSF-1R inhibition. And we ran a prioritization exercise a number of years ago. And so we had our compelling data from our clinical experience. We have preclinical data in a number of IPF mouse models. And there's a lot of literature actually supporting the role of monocytes and macrophages in pulmonary fibrosis. And so that plus the commercial opportunity allowed us to prioritize and rank IPF as sort of the #1 leading indication for us to move axatilimab into.

And so we started a Phase II study called MAXPIRe a number of years ago, and we reported that we completed enrollment to this study earlier this year. And so that puts us on track to having our top line data in the fourth quarter of this year. So again, from a science perspective, it's a large experiment. So it will be actually really great to see the results because the benefit that we've observed in the patients with lung involvement in GVHD has been quite promising.

Now we will move quickly, once we see the data, to start a Phase III trial. And that means that currently, we have an IV formulation for axatilimab, so the Phase III would be planned to be run with the IV formulation. Work with our colleagues at Incyte is ongoing for subcutaneous product development. And we anticipate that all of this would converge at the time of data from the Phase III so that we would have a subcu administration form available sort of peri-launch of the Niktimvo or axatilimab, if you will, for IPF.

And so beyond that, again, we are really eager to see where else we can translate that data that we've observed in terms of targeting macrophages and monocytes from this inflammatory and sort of fibrosis aspect. And so we have a whole list of indications that we have in line to follow on, things like scleroderma, interstitial lung disease associated with scleroderma, chronic lung allograft dysfunction and others. So we think there's a little -- quite a bit of promise in terms of axatilimab program.

And so our lineup today is actually really incredible. And so I'm eager to pass this on to Dr. Maher, who currently, he's Professor of Clinical Medicine and Interstitial -- and Director of Interstitial Lung Disease at the Keck Medical School at the University of Southern California. But Dr. Maher is considered to be a global thought leader in the field of interstitial lung disease and has really prioritized the investigation of novel and innovative discoveries in terms of the disease and translating those into the clinical setting and has done so with an incredible track record of that.

And he's been a member of our Steering Committee from the beginning as we established our Phase II study. And so we're really thrilled to have him here and have him participate in this discussion. So with that, I will be passing it on. Now Dr. Maher is not, obviously, in the room, and so we'll be watching his presentation on the screen.

Great. Thank you very much. Hopefully, everyone can hear me and see me. So sorry not to be there in person, but a pleasure to be discussing the importance of the axatilimab program in patients with idiopathic pulmonary fibrosis. And I thought I would just give a little bit of background to bring everyone up to speed on the disease itself and the unmet need before touching on axatilimab itself.

So for those of you not entirely familiar with pulmonary fibrosis, the lung, as we know, is an organ of gas exchange and it's designed as such. We've got, as you can see in the photomicrograph here on the left-hand side, the sort of beautiful laced-like architecture of the lung with each of those little pink bounded spaces being an alveolus where the gas exchange happens. And then on the right-hand side, we've got a cartoon graphic of the human lung and the different regions. So we have the main airways. These then divide about 27 times until you get down to the alveolar space.

And when we talk about interstitial lung disease and pulmonary fibrosis, we are talking about a group of diseases that essentially call scarring and destruction around the wall of alveolar space. Now in the context of axatilimab, which is also being tested in GVHD, the primary abnormality that we see in the lung in patients with GVHD is fibrosis of that terminal airway.

So if you look at the bottom left-hand -- bottom right-hand picture of the little alveolus, in GVHD, the fibrosis happens around the neck of that little airway that joins the alveolus. And in idiopathic pulmonary fibrosis, it happens around the outside.

If we go to the next slide, this is just the picture illustrating what we see in the lungs of patients with fibrotic lung disease. Once idiopathic pulmonary fibrosis develops, we see this, ultimately, architectural destruction of the lung with laying down huge amounts of collagen and fibrotic tissue. And it's that fibrotic tissue and architectural destruction that leads to respiratory failure because the lung no longer works to get oxygen into the body.

Next picture or next slide. So idiopathic pulmonary fibrosis is a disease of older adults, typically affects men in the 60s, about 3/4 of patients are men for whatever reason. It does seem to be of increased incidents in patients who spent a lifetime working in dusty or smoky environment or who have smoked in the past. What we see is the scar tissue, which if you press advance, gets progressively worse over time. And here you go, you don't have to be an expert in interpreting thoracic CTs to see how the texture of the lung changed between those 2 slides. That's the same patient 18 months apart.

And once pulmonary fibrosis develops, it becomes inexorably progressive. And without treatment, the average patient will die about 3 years from onset of symptoms due to respiratory failure.

If we move on to the next slide. This is the current classification scheme for fibrotic lung diseases. I'm not going to go into it in detail. But the reason to put it up is to say that idiopathic pulmonary fibrosis is simply one of many diseases that cause a scarring of the lungs. The reason that we've tended to focus on IPF for clinical trials is that it's both the most common and the most aggressive form of fibrosis that we see in our clinical practice. But about 2/3 of my patients will have other diseases. And in recent times, we've seen the use of antifibrotic drugs effectively across the full range of diseases, not just IPF. So there's a real opportunity to make a difference across a much broader range of patients, and you've already heard scleroderma ILD mentioned as a potential opportunity in the future. That's certainly another example of a disease group where we see fibrosis as an important and life-threatening complication.

Next slide. So I'm not going to go into this slide in detail. This is just describing the pathogenesis of pulmonary fibrosis. But suffice to say that over the last 10, 15 years, we've made huge strides in understanding the disease. We do ourselves a disservice by calling it idiopathic and suggesting we don't know the cause. In reality, it's a disease of aging that arises in genetically susceptible individuals after a lifetime of damage to the lung. Once the process develops, what we see is activation of pathways involved in the normal wound healing response. And importantly, once the disease is up and running, we see activation of multiple cell types in the lung, including epithelium, fibroblast endothelium and, importantly, from the perspective of axatilimab, the inflammatory cells within the lung.

If we go on to the next slide. Now over the last 15 years, we have seen an evolution in the treatment landscape. In 2014, we had the approval of pirfenidone and nintedanib. And then after a barren spell of negative trials, we saw nerandomilast, a PDE4 inhibitor, approved last year. In the last 12 months, we've seen positive results from the TETON trial of inhaled treprostinil, and we're currently awaiting readout from the Phase III admilparant trial of the LPA receptor 1 antagonist from BMS. And then hopefully, we've got the axatilimab as a hopefully successful treatment in the future.

Now if we go to the next slide. Although it's been important having treatments available and although those treatments have almost certainly improved survival for patients with pulmonary fibrosis, the reality is that despite having had pirfenidone and nintedanib for a decade, my patients are still dying from respiratory failure. So we might have delayed death from the disease, but we certainly haven't come close to preventing it.

And the graph on the right is a work that we did with patients on long-term antifibrotic therapy, that essentially estimates that, even with treatment, patients with pulmonary fibrosis are losing 10 to 15 years of life expectancy due to the disease itself. And so a huge unmet need remains.

And if we go to the next slide. And not only that, the drugs that we've had up until now, pirfenidone and nintedanib have had challenges with tolerability, that's actually led to a very low uptake in their use in the United States. The graph on the left was work that was done with the Optum insurance database showing that only about 25% of patients were being offered antifibrotic therapy. And a lot of the reason that larger numbers weren't being offered treatment was because of concerns about side effects and tolerability in a slightly older population.

And then the graph on the right just shows the discontinuation rates with nintedanib and pirfenidone, which approach 50% at 1 year. So we have drugs that physicians were reluctant to use and when they did use them, patients struggle to stay on them. So again, speaking to the huge unmet need.

If we go to the next slide. This was work that my group did when I was back in London. Essentially, we had an interest in the macrophage-monocyte axis in driving the disease. Worth remembering that our lung is our only internal organ that is exposed to the outside environment. We're breathing in air, which brings with it pollution, viruses, bacteria into our body. So we have a highly developed immune system within the lung. And the central cell that provides immune surveillance is the macrophage. Now we're born with macrophages in our lung and there is a population of macrophages that never goes anywhere near the bone marrow, spends its whole lifetime in our lung and replicates there.

But when we get infection, we are reliant on bone marrow derived monocytes that traffic through the bloodstream into the lung, and then differentiate into alveolar macrophage like cells to provide additional immune support in moments of infection. And the bone marrow derived and the lung-derived alveolar macrophages have slightly different phenotypes.

The work we did originally was just to look at how those change over aging. And as we get older, more of our monocytes are coming from our bloodstream. Those monocytes have a different phenotype or the ones that are resident in the lung. And importantly, in people who develop IPF, what we see is an exaggerated form of aging with an ever-increasing number of the monocytes in the lung coming from the bloodstream, and those monocytes then having an increasingly profibrotic phenotype when we assess them based on their cell surface characteristics.

And then on the right-hand side was work we did looking specifically at CSF-1R. If we look in the lungs of patients, we find elevated levels of CSF-1R in IPF patients. The higher the levels, the worse, the prognosis for that individual, the more rapidly progressive their disease. And on the far right-hand side is a photo micrograph, you can perhaps pick out the macrophages which are the cells with a little brown rim around them. And that brown rim is just indicating where the CSF-1R is located, which is on the vast majority of the macrophages in the fibrotic lung.

Next. And then this was additional work. This was work done by a group in Stanford, just showing that circulating monocytes, so the precursor cell to the alveolar macrophage are predictive of outcome in patients with pulmonary fibrosis. The more circulated monocytes, the worse the outcome. And we and other groups have subsequently replicated this finding in multiple cohorts, again, just emphasizing the importance of the monocyte macrophage access in driving fibrotic lung disease.

Next. So I'm not going to go into this because you've already heard about it, but mechanism of action of axatilimab is very much to be targeting the macrophage monocytes. I think this is important for a number of reasons. Firstly, because I believe this cell type is intimately involved in driving disease. Secondly, it's not really an axis that's being targeted at the moment, traditionally with antifibrotic drugs, there's been a lot of focus on the interaction between alveolar epithelial cells and fibroblast, but very little focus on the role played by the immune cells, particularly the macrophages within the lung.

Next. So you've heard about some of this data. This was the trial of axatilimab in patients with GVHD. As I've already alluded to, GVHD causes fibrotic complications in the lung, but the fibrosis is different to what we see in IPF. So like I said, in IPF, the fibrosis around the wall of the alveolus causes the lung ultimately to shrink. With GVHD, the fibrosis is around the terminal airway, so it's sort of circumferential fibrosis that squashes the terminal airways shut. And so that causes narrowing of the tubes. It makes it hard for the air to get into the alveolus then for gas exchange to happen.

We increasingly recognize that the mechanisms that drive fibrosis, whether it's in the lung, kidney, liver or whether it's in the alveolar compartment or around the airways, all those mechanisms tend to converge on a set of common pathways. And so for me, it was exciting to see the data from the GVHD study because axatilimab in those patients with lung disease appear to have clear benefits on the lung, suggesting potentially that it's having an antifibrotic effect in that scenario. So about 45% of patients in this study had lung involvement, and not all of them. But of those that did, over half showed a treatment response with the therapeutic dose that's been moved forward into the clinic.

Next slide. I think the other benefit of this trial is it tells us about the tolerability profile of axatilimab, which is excellent, and certainly compares incredibly favorably to the drugs that we have available to us for treating idiopathic pulmonary fibrosis. And I think that's very important because my vision for the future of treatment of pulmonary fibrosis is that we will be using combinations of therapy, and therefore, vitally important that we have combinations that we can use together.

One of the other issues we've tended to see is a lot of drug-drug interactions with the small molecules that we have available to us, for instance, nerandomilast interacts directly with pirfenidone, which leads to reduced drug exposure and reduced efficacy, with axatilimab being a monoclonal antibody. That's certainly not a problem that we anticipate with this program.

Next slide. And then this was data presented in an abstract at ATS just looking more specifically at that group of patients with lung involvement by GVHD in the pivotal trial. And again, just emphasizing the fact that, that 0.3 milligram per kilogram dose was associated with the best lung responses, and that even patients with very severe small airway fibrosis or the patients with the lowest FEV1 values were showing improvements with treatment. And that's impressive because in clinical practice, this is the group of patients that we have always struggled to treat.

So next slide, so you've heard mention of this. This is the MAXPIRe trial. So this is the trial that has been ongoing in patients with idiopathic pulmonary fibrosis. It's a fairly conventional design, dare I say, we've been running IPF trials for 20-plus years now, so we have a fairly good idea of what an appropriate design looks like.

I think a few things to point out. This is a 6-month study. And I think increasingly, we've looked to do 6-month studies at Phase II because that's slightly longer period of time. It gives us confidence both in the efficacy, but also in the safety of the drug. The readout is the same that we use in other trials, change in Forced Vital Capacity. And you can see the numbers, this is a reasonably sized Phase II study that should answer the question definitively one way or the other as to whether axatilimab works in IPF. And as I've said, based on the data that we've seen in GVHD and based on our knowledge of macrophages, I'm certainly very optimistic that we should see a positive result and hopefully move forward to Phase III.

So if my last slide, please. So just in summary, hopefully, I've convinced you IPF is an important disease. It's deadly. I didn't tell you the incidents, but it affects about -- about 1 in every 100 deaths that occurs in Europe and the United States is due to IPF. So although it's considered a rare disease, it really isn't that rare. Nerandomilast is on target to achieve sales of between $3 billion and $5 billion in its first year, which again, I think, speaks to the size of the market.

I've told you about the challenges that we've had with current treatment, the fact that patients still die from respiratory failure despite the availability of antifibrotics. I've told you about the important role of monocytes and macrophages in the disease, and why I think there is translatability of the data that we've seen from the GVHD population with axatilimab and why that gives me great hope and excitement about their IPF program. So thank you very much.

All right. Thank you so much, Dr. Maher. So I guess, we have some time for Q&A.

Faisal Khurshid from Jefferies. One for Dr. Maher, one for the company, please. For Dr. Maher, thank you for explaining the hypothesis for axatilimab and IPF. Could you tell us a little bit about how you see the strength of this hypothesis in Phase II relative to other drugs given that you've been involved with pretty much everything in IPF drug development? And then for the company, can you remind us what the stats powering threshold is for the study and if you're seeing blinded data from the study?

Yes. So I didn't major on the pathogenesis of IPF, but I think there are multiple mechanisms that are activated in the fibrotic lung. So I'm optimistic that several of the programs that are up and running will hopefully lead to effective treatments.

I think if we look to the pulmonary hypertension space as a sort of analogy, what we've seen there over the last decade is the evolution of a very focused combination approach to treatment that, in pulmonary hypertension, where you've got similar complexity of disease mechanisms, sort of true success in improving outcomes for patients with PAH has been driven by combining drugs with different mechanisms.

And so I think it's sort of -- I don't feel there's any contradiction in my -- in the fact that I'm working with multiple companies going after different mechanisms because I think my clinical practice in the future will be combining those. I think given the complexity of disease, I think a lot of those mechanisms are all important. So I think, it's not that I'm saying today that macrophages are important and tomorrow I'm going to say that the Angiotensin II receptor axis is important. I think both -- all of these axes are important. And I think one of the challenges we have preclinically is teasing out how we should be prioritizing the targeting.

I think the advantage that the axatilimab program has is the data from GVHD because I think there is -- I think the insights from GVHD are important in interpreting probability of success in IPF. And I think that distinguishes it from other programs where, once you sort of put all the Phase III programs to one side, everything that's currently at Phase II, we're essentially waiting on data. So at the moment, we have to weigh all of those Phase II programs relatively equally. And any differences that we might interpret between them are really based on preclinical science that we know has a poor track record of predicting efficacy in the clinic.

So I think for me, the biggest reason for optimism is that effect that we've seen in GVHD, and my belief that fibrosis, whether it's sort of circumferential airway fibrosis or IPF, have a lot of similar overlapping mechanisms. And that's what gives me true reason for being optimistic.

And related to the second part of the question, I don't know, Nick, if you wanted to...

You want to cover...

I just don't know if we've disclosed this.

Oh, okay. I mean I can talk a little bit. I mean, firstly, the study is blind. So we have no access to the data. It's an ongoing randomized placebo-controlled study. So as we guided towards data availability in Q4. So we don't know.

We have talked a little about the primary endpoint in the study enrolled well. It was targeted around about 135 patients, actually overenrolled because of the momentum and enthusiasm to enroll into the study. So we had over 140 patients. So it's very well powered to detect what we would consider a clinically meaningful difference in forced vital capacity, which is the primary endpoint of the study. We'll obviously look at the FVC. We will also look at the percent reduction or improvement in FVC compared to controlled.

Given all of the historical data or recently reported out data, I should say, for other agents in this disease, we have indicated that something in the order of 30% to 40% would be a very meaningful and clinically relevant improvement. But we will look at the totality of the data. We'll look at the absolute difference in FVC. We'll look at the percentage difference. We'll look at all of the other markers.

As Dr. Maher just outlined, we're very encouraged by what we anticipate to be a very tolerable profile and we're also very encouraged by the ability of the drug to combine. We think it will make a particularly suitable drug to be used in combination given the other approved agents because it has a very differentiated mechanism of action.

So broadly, that's what we expect from the FVC and the -- both in terms of the absolute mls difference, 30 to 40 mls, and also the percent difference. And we think that that would give us a positive proof of concept which would take us into Phase III.

And we are planning for success. I mean we're planning for a positive outcome. That means that we are able to front-load some of the considerations that Peter was talking about in terms of taking an IV into Phase III, relevant regulatory household consultations and all of the other things that you would need to do to accelerate the start of a Phase III because we're excited about the opportunity and the unmet need. And if we do get a positive outcome from the Phase II, which we'll report in Q4, we want to be able to start a Phase III as quickly as we possibly can.

Phil Nadeau from TD Cowen. A question for Dr. Maher on the point that Nick just made. Can you discuss how you will evaluate the results from the Phase II trial to give you confidence that the Phase III is going to succeed? As you noted, IPF has been an area where there's been a lot of failures and promising compounds haven't succeeded in Phase III. So what will you look at in the Phase II data yourself? Is the 30 to 40-milliliter improvement, that's statistically significant? Is that enough to give you confidence that a Phase III is going to succeed? Or do you look for concordance between the primary secondaries? Just give us some flavor of what would get you excited and give you confidence in the pivotal?

Yes, and this is certainly has been one of the challenges in IPF is how to interpret these sorts of studies. I think I would say where there have been failures, I think most of those failures have been due either to a failure of study conduct, overenthusiastic interpretation of data without applying appropriate statistical testing to account for outliers, or just trying to run before people can walk.

So for instance, with the Galapagos autotaxin program, we went from a 23-patient study to 1,500 patients. And so just from a drug development perspective, the probability of success was always going to be lower. If we look at things like the [ FibroGen or the Pentraxins ] programs, I think there were issues with the way that the statistical analyses were done a Phase II that led people to overestimate the likelihood of success of Phase III.

So I think what will be important is looking at the handling of data and the statistical plan for this, is going to use contemporary approaches that have been used at Phase III, so the sort of mixed-effects models type, which take a much better way of handling missing data and outliers. And so primarily, I think the biggest challenge we have is that we are really only left with the FVC data as the data that we can rely on for decision-making. Because in a study of this size, FVC has sufficient power to show us difference between groups, other clinical endpoints don't. So in a 6-month study, we don't expect much mortality, we don't expect much hospitalization. We don't really expect to see meaningful changes in symptoms either in the placebo group or the active therapy group. And so it does leave us leaning heavily on FVC in terms of decision-making.

However, in my opinion, every program that has been built on a robust FVC-based Phase II set of data has subsequently gone on to succeed at Phase III. So I think with this design, if we do see an FVC difference, then I think the probability of success in Phase III is high.

And then to sort of answer the question that you didn't quite ask, which is a 30 to 40 ml difference in important? And I would say it is. The FDA's belief is very much that FVC is a surrogate for survival. And certainly, the FDA have been very consistent in approving drugs that show any FVC benefit compared to placebo. So I think if we saw a 30 to 40 ml difference, which would equate to somewhere between a 30% to 50% relative reduction in the slowing of FVC decline. I think that would be a highly approvable drug that would compete well with existing therapies and anticipated future therapies.

Just a quick one, Nick. This is Salim Syed from Mizuho. I know you mentioned you're blinded to the data, but do you have access to the blinded data? Have you taken a look at it?

No. No. The only thing we can say, obviously, from a demographics perspective, that the patient population enrolled mirrors very much the patient population in the recent FIBRONEER studies in terms of the breakdown of who had antifibrotics, which ones, and who didn't. So...

And that's very consistent with recently reported Phase IIIs, which is encouraging. It's a very representative population. The one thing I would just add is that there has been a safety management committee, DMC, overviewing the study, and they have had access to unblinded data to ensure safety throughout. And not surprisingly given we know the profile of axatilimab really quite know -- well known, it's an improved agent at that dose. No concerns with respect to safety. But otherwise, the study remains blinded to us until we report out in Q4.

This is Joyce Zhou here for Anupam Rama from JPMorgan. Maybe just a question for Dr. Maher first. What are your thoughts on Niktimvo's potential subcu every 2-week profile as you think about its role as a combination partner in the future as opposed to maybe some of the other therapies that are also being developed, another oral, also inhaled therapies?

And then for the company, I think in the past, you've said you only need one pivotal trial in IPF for registration. If you could just confirm that that's still the case.

Yes. So to answer that question, I think in a world of GLP-1s, everyone has become incredibly comfortable with subcu dosing, both on the sort of medical side of the fence and on the patient side of the fence. We also have experience in the pulmonary space of using biologics for the treatment of asthma. And again, we've not encountered any major challenges with subcu dosing. In fact, many patients with asthma prefer the subcu dosing to daily inhaled treatment. So I think a sort of every 2 weeks subcu will actually be quite attractive to patients and a number of people who don't want to use the treatment because of fears over self-injection will be very small. So I actually think it's a positive for the drug.

And as to the single study requirement and such, we can just go based on precedent with the recent approval of Jascayd, which was based on the FIBRONEER study, one study for IPF. So we believe we would have a similar opportunity.

And just quickly to note, I mean the FDA say that they used Boehringer's Phase II trial as the supporting study, and there are a lot of similarities between MAXPIRe and the Phase II study that Boehringer ran, which was actually a 3-month study with a similar number of patients and actually use the Bayesian analysis approach to augment a slightly small placebo group. So MAXPIRe will provide the same supporting data that BI were in a position to submit with their submission package for nerandomilast.

Yigal Nochomovitz at Citi. One for Dr. Maher and then one for the company. I was just wondering, Dr. Maher, if you could comment broadly on the potential for axatilimab in terms of disease modification relative to the classic agents like pirfenidone and nintedanib as well as some of the newer ones that have then come to market?

And then for the company, with regard to the stratification, I know the study mentions by background therapy. I'm wondering if you are enrolling all smokers or if there's some other consideration with regard to smoking status to provide a stratification there between arms.

So to answer the disease modification question, I think one of the big challenges we've had with IPF is historically is that the patients we see in our clinical practice, even patients who are considered to have relatively mild symptoms, have already lost more than 50% of their lung to fibrosis. And so by the time we initiate treatment, the lung is pretty damaged and destroyed. And I think the opportunity for true disease modification has been lost.

What we're increasingly focused on as a field is trying to identify patients early, ideally before they have symptoms, where they still have a lot of normal lung tissue. And in those cases, we think we have a much better opportunity for disease modification.

The reason we haven't really focused on doing that in the last decade is because pirfenidone and nintedanib have been so poorly tolerated. As I've shown you, it's been a struggle to get patients who are symptomatic with the disease to take those drugs. And therefore, there was no enthusiasm to try and go into earlier patients and achieve true disease modification. But I think with a drug like axatilimab where we anticipate that it should be incredibly well tolerated as a biologic therapy, that will really open the door to going after earlier disease and, therefore, trying to achieve disease modification.

And I think in all honestly, we're not going to see disease modification in the MAXPIRe study, because those patients have relatively advanced disease. But I do think it's an opportunity for the future.

And as for the stratification factors, I don't think smoking was, I think, a consideration.

Three strata for background fibrotics or none. Most of the patients were on antifibrotic. And if I recall, I think that was the only stratification, but not smoking.

It's about the trivial numbers of patients smoked with the disease. Unlike emphysema, where about 1/3 of patients after diagnosis are still smoking. In IPF, it's single-digit percentages. So it's normally about 3% or 4% of patients are smokers. And for instance, in the FIBRONEER program, those patients were allowed to be included and there was no observable difference in their outcome or response to therapy. So I don't think smoking is an important confounder for an IPF study.

Adam from B. Riley again. So given that the primary endpoint is annualized FVC decline over 26 weeks, a question for Dr. Maher here, I'm wondering if you think that 26 weeks is long enough for what appears to be a macrophage-directed mechanism to separate on the FVC. And if so, could you give some insight regarding what you think would be a clinically meaningful effect size as opposed to statistical?

So yes, I think it should be enough. I mean, these are highly activated cells that are producing large quantities of pro-fibrotic, pro-inflammatory mediators. There are a number of diseases that are very specifically macrophage-driven, and we know in those the disease tends to evolve and progress rapidly. So I think the target itself is responsive. So there's every reason to believe that 26 weeks is more than enough to see efficacy of axatilimab. And I think that the GVHD data essentially speaks to that as well.

What is a clinically meaningful difference? As I've already alluded to, the FDA viewpoint, it's very much that this is a continuous variable that is predictive of survival. And certainly, the regulatory point of view is that any difference is important. And one can look to the FDA approval of nintedanib for scleroderma patients where the agency approved the label extension based on a 41-milliliter delta.

I think to convince people in clinical practice, one is probably looking to see a magnitude of benefit that is similar to the existing drugs. And again, if we use nerandomilast as an example, that's already been embraced by the pulmonary community now that we've had access to it for 9 months, that essentially led to a 32% relative reduction in FVC decline compared to placebo. And that's been enough for very widespread use. So if we use that as the margin for what my colleagues believe to be clinically meaningful, then we're looking at about 60 mls over 12 months. And therefore, the 30 to 40 mls that you've heard mention today over 6 months is in that ballpark. If we can exceed that, then clearly, that would be even better. But I think that is a reasonable minimum standard to aim for.

And I would just reiterate, you can look at the AGAVE results from the GVHD study. And so symptom relief was seen generally in the first month or 2, and then the majority of responses happen within the first 3 cycles or first 3 months. So that was actually one of the sort of basis for us actually choosing a 26-week endpoint.

I think we're good to move on. Thank you.

All right. Thank you so much. Thank you, Dr. Maher.

Thank you, Dr. Maher. Thank you, Peter. So it's my great privilege to introduce our next topic, which is around expanding our pipeline into EGFR-mutated non-small cell lung cancer with SNDX-4321. This is an exciting and new area for us. And just to introduce this topic before I introduce our next speaker, I just want to take a step back for a moment and introduce the concept of allosteric inhibition, which may not be familiar to all of you.

But allosteric inhibitors are actually increasingly reshaping the standard of care in difficult-to-treat cancers. This isn't a new concept in oncology. I think the first allosteric inhibitor to be actually approved and subsequently become a blockbuster drug was trametinib in the treatment of melanoma. And that was followed by asciminib in chronic myeloid leukemia. And today, we're going to talk about SNDX-4321.

And the exciting thing about allosteric inhibitors is they really present a novel and differentiated way to target receptors expressed on tumor cells. Allosteric inhibitors actually bind to the nonactive sites rather than the ATP binding or catalytic sites on the tyrosine kinase receptor. And essentially, by binding to that allosteric site, they actually induce a conformational change that locks the kinase into its inactive site.

So it's a very alternative and differentiated approach to the typical catalytic binding ATP tyrosine kinase that we hear so much about. And these allosteric approaches can modulate kinase activity with very high specificity, which you'll hear more about, which really optimizes the on-target efficacy whilst reducing off-target toxicity, which is obviously particularly important with EGFR inhibitors, which we're going to talk about today.

So our ambition is to address significant unmet needs in EGFR-mutant non-small cell lung cancer leveraging this novel approach. Now this is a very competitive space, currently approved in investigational drugs, however, primarily target the EGFR ATP binding site.

So common third-generation approved EGFR inhibitors, like erlotinib as the standard of care -- I'm sorry, like osimertinib as the standard of care. They actually give reduced benefits for patients with some subtypes of the EGFR mutations such as L858R, patients that have brain metastases or any other atypical activating mutations.

And the next wave of fourth generational investigation EGFR inhibitors just target further the resistance mutations that form in the ATP binding site. And so you get smaller and smaller subsets of the EGFR receptor, such as the C797S resistance mutation, which is one of the common resistance mutations to osimertinib. There are other approaches being developed in the clinic, such as bispecific antibodies and antibody drug conjugates. However, these are IV administered drugs, and they also come with a significant burden of toxicity.

So our approach with SNDX-4321 is differentiated from that and really has the potential to be a first-in-class, again, an area where we have a proven track record of bringing innovative science to the clinic and progressing it with innovative development programs. And 4321 is a mutant-selective allosteric EGFR inhibitor, which allows potentially for double drugging. And double drugging is a little bit like a double log. This is a drug that is potentially particularly well suited to a combination with osimertinib that may actually enhance the efficacy and delay resistance down that EGFR target. It has very high selectivity, as you will hear, and this supports both its combinability and tolerability. And as I've said, has both first and best-in-class potential as we are anticipating leading in this space.

It has a very broad therapeutic window expected from our IND informing work. And it does, of course, have the benefit of being orally administered. And so it would be a very attractive combination for a combination approach with osimertinib.

So it now gives me great pleasure to introduce our next speaker, Dr. Michael Eck, MD, PhD, who is a leading cancer researcher at the Dana-Farber Cancer Institute and also a Professor at the Harvard Medical School. For well over a decade now, he has been pioneering the development of an allosteric approach to EGFR inhibition. And we're delighted to have him here with us today to discuss his work on developing 4321 and the potential for this new approach in EGFR-mutated non-small cell lung cancer. Dr. Eck?

Thanks very much, Nick. And delighted to be here and really excited to have Syndax picking up the torch to take this molecule forward. I should disclose that I am a consultant to Syndax, and as a co-developer and inventor of 4321 and related technologies that the Dana-Farber has licensed to Syndax and in line to receive licensing, royalty, milestone income, et cetera. And I can confirm that Syndax licensed it under very favorable terms for Syndax.

Also, before I start, I just want to say that I hope to be back to that clean-shaven, smiling face soon. I had an accident on my bike a couple of weeks ago and ended up with a broken nose and a couple of broken teeth and not quite put back together yet, but will be soon.

So what's 4321? We've developed it in my lab in close collaboration with colleagues at Dana-Farber over the last several years, in particular, Pasi Jänne, thoracic Oncologist; David Scott and Nathanael Gray, Medicinal Chemists. And as Nick very nicely introduced, it binds in an allosteric site that's distinct from the ATP binding pocket. It's adjacent to it, but completely separate, and can actually co-bind to the same receptor molecule at the same time as certain other ATP competitive inhibitors, including osimertinib, that allows this double drugging approach.

My colleagues and I have published over the years increasingly potent allosteric inhibitors, starting with EAA 045 and then, more recently, JBJ 0963. But I want to say that we haven't yet published in the academic literature on 4321. It's a structurally distinct molecule built on a different chemical scaffold that addresses some of the issues with the prior compounds, particularly much improved PK, brain penetrance, addresses an issue that the prior compounds had with chemical stability.

And also I want to add that really developed specifically for L858R mutant non-small cell lung cancer, which is, I'll show you, is a very large patient population with a very significant unmet need.

So we think 4321 has the potential to change the treatment paradigm for at least a subset of EGFR mutant non-small cell lung cancer. The compound has excellent selectivity. It's orally bioavailable. As I said, it's brain penetrant. I'll show you data demonstrating efficacy in multiple tumor models, both as a single agent and in combination with osimertinib. It's active in an intracranial model.

We think that the allosteric mechanism has multiple benefits. This ability to co-bind with osimertinib, enabling double drugging, which we think could enhance efficacy, delay emergence of resistance. Improved selectivity for wild type. As many of you will know, inhibition of wild-type EGFR is a dose-limiting toxicity of EGFR TKIs. With the allosteric approach, we think we're, if not entirely, almost entirely avoiding that liability. And as a single agent, because of its unique binding site, it can address on-target resistance to osimertinib in patients who progress after frontline therapy with osimertinib.

So as I'm sure all of you are aware, lung cancer is a very big problem. About 200,000 people newly diagnosed annually in the United States with non-small cell lung cancer. About 1/3 of non-small cell lung cancer is due to mutations in EGFR. The most common mutations by far are the so-called exon 19 deletions in the L858R point mutations. L858R accounts for 30% to 40% of EGFR-mutant lung cancer. The Del 19s about 40% to 50%. Atypical mutations including compound mutations that occurred together with exon 19 and L858R, which are referred to as the classical mutations, account for up to 20%.

The standard of care for treatment now is osimertinib with or without chemotherapy. This is, for the classical mutations, the exon 19 deletions and the L858R mutations. And while osimertinib, which is a third-generation drug along with its predecessors for second-generation agents have really transformed the standard of care. There's very significant unmet needs that remain. In particular, as I'll show you, for the patients with the L858R mutations with CNS disease and with the atypical mutants as well as resistance to osi.

So just an outline of what I'll run through in terms of unmet needs and the way in which we think 4321 will address them. So point one, L858R patients have poorer outcomes than those with exon 19 deletions. Actually, L858R patients don't do any better with osimertinib than they did with first-generation EGFR TKIs. It's much better tolerated, it's a very good drug, but it doesn't increase overall survival in the L858R patients, in contrast to the Del 19s.

4321, very active as a single agent and in combination with osi in this model. Probably come as no surprise that patients with CNS metastases fare worse than those who don't have it. 4321 is brain penetrant, as I'll show you, is efficacious in an intracranial model.

Patients with atypical mutations have poorer outcomes. And we think that we've developed it and really focused on L858R, it turns out it has activity in at least a subset of the atypical mutations, we think will have potentially benefit for those patients as well or at least a subset of them.

And because of its distinct binding site, 4321 will have activity against patients who develop resistance to osimertinib due to further on target mutations in the receptor itself, including not just C797S but other mutations in the ATP site, that confer osimertinib resistance.

So to the difference in efficacy of osimertinib in the L858R versus exon 19 deletion. So from the FLAURA2 study, you can see breaking things out between Del 19s and L858Rs that overall survival at 48 months is 47% with osi without chemo and 56% with. That compares with L858R patient population where 48-month survival is only 31% with osi as a single agent, a bit better at 38% when adding chemotherapy to osimertinib.

Point two, patients with CNS metastases fare worse than those without. And I'm realizing that I've got the wrong fare here. Obviously, that should be F-A-R-E. Anyway, without CNS metastases, 48% overall survival at 48 months without chemo, osi plus chemo gets us to 57%. And the patients with CNS disease at the time of diagnosis, only 31% make it to that 48-month mark with osi alone or 39% with osi and chemo. And I should say that the data here aren't broken out by L858R and exon 19 deletions, but some smaller studies that have looked at that, so that, as you might expect, sort of the double whammy of LR and CNS disease leads to a poor survival and poorer prognosis. And it's not rare by any means to have CNS spread already at the time of diagnosis. About 40% of patients will already have CNS metastases and many more will go on to develop it in the course of treatment.

Patients with atypical activating mutations also have a shorter time to treatment failure and shorter overall survival. These are figures from John Heymach's lab paper a few years ago. They've plotted the frequency of atypical mutations. And as you can see, there are very many of them that are low frequency and scattered around the kinase domain, but a few of them are fairly prevalent. The G719X is about 11%, L861Q, for example, between 5% and 6%.

And as compared with the classical mutations, exon 19 deletions, L858R, atypical patients have a significantly shorter time to treatment failure. And I think this is not just osimertinib in this figure, it's any generation of EGFR TKI. The difference would be more striking if we were looking just at third gen.

And on target mutations in the receptor are a significant cause of resistance to osimertinib. As many of you will know, many ways to get resistant, so-called bypass mutations or amplification of the MET receptor that don't have anything to do with EGFR itself, but a significant fraction of resistance is due to further mutations in EGFR. When osimertinib is used in the second line, as much as 20% of resistance arises from on-target mutations. C797S is the most common. That's the residue that osimertinib forms its irreversible covalent bond with, but also other mutations in the ATP site, L718, L792, G796 and others. When osi is used in the front line on target resistance is a bit less common, but up to 12% with essentially many of the same resistance mutations emerging.

So more about 4321. As we've introduced, it's a mutant selective and potent allosteric inhibitor, has negligible activity against wild-type EGFR. The experiment in the lower left here is a xenograft study with A431 cells. It's driven by over-expressed wild-type EGFR. Whereas EGFR inhibitor afatinib leads to tumor stasis, here, as you see in green. 4321 has essentially no activity, no difference from vehicle control here.

It's active against L858R with or without common resistance mutations to osi. On the lower right, you see Ba/F3 cell data comparing 4321 and osimertinib in L858R Ba/F3 model, similar activity to osimertinib. But on the far right, you see the introduction of the C797S mutation confers profound resistance to osimertinib but doesn't affect the potency of 4321.

We've also seen activity against a subset of the atypical mutations, in particular, L861Q, one of the more common atypical variance that I pointed out a moment ago.

Just want to reemphasize that it has no activity essentially against exon 19 deletions or exon 20 insertions. So as far as the allosteric is concerned, those might as well be a different disease.

4321 is highly brain penetrant. As we see here, it's effective in this intracranial xenograft model. This is an H1975 model with a dual subcutaneous and intracranial implant, with the intracranial implant red out bioluminescence. You see on the left that even a low dose of 4321 leads to tumor regressions comparable to those seen with osimertinib. And on the intracranial side, on the right, you see, at the 25 mg per kg level, tumor regressions that look a bit better than those we see at osimertinib with a similar milligram per kilogram dose.

And 4321 is very active as a single agent in patient derived xenograft model. So LUN439 is an L858R mutant non-small cell lung cancer model. We see here dose-dependent tumor regressions at 5, 15 or 50 mg per kg of 4321. I don't know what happened to the lines through there. But anyway, you get the idea.

Though it's very active as a single agent, as I've shown you, we think that the more significant opportunity and the bigger unmet need could be addressed with combination therapy, with, for example, osimertinib. And the allosteric approach really recommends itself as a combination agent because of its distinct binding site outside the ATP site. We expect it to have both essentially orthogonal resistance mechanisms and orthogonal toxicity profile, which makes it ideal as a combination agent.

Also the potential for co-binding with ATP site inhibitors, including osimertinib. They have crystal structures that show how the allosteric can co-bind at the same time to the receptor with osimertinib. It's also very clean across the kinome, as you see in this kinome scan data on the right, essentially only hitting the EGFR branch of the kinase family tree.

We've done in vivo efficacy studies that show a combination benefit of combining 4321 with osimertinib, particularly notable in seeing delayed tumor regrowth. And this is the H1975 model, again, with the L858R/T790M genotype. The mice in this study were dosed for 15 days, then monitored for regrowth. And I think you can appreciate that as compared with osimertinib as a single agent in red, 4321 as a single agent in purple, that the combination in green significantly delays regrowth. And we saw also improved survival in the combination treatment arm. I have to say the combination, very well tolerated, no increased body weight losses compared with osimertinib alone in the combination arm.

So just to wrap up, very much excited about 4321. It's a completely novel approach, well differentiated from what the rest of the world is doing, crowding around the ATP site with fourth-gen inhibitors, addresses a very large unmet need that's about half of the size of the osimertinib patient population. Osimertinib is now, I think, about a $7 billion a year drug for AstraZeneca. We think huge opportunity here for 4321 to improve outcomes for a large fraction of those patients.

Highly active as a single agent. But again, it's this combination with osi that we think is really the larger opportunity, the bigger unmet need. Its allosteric properties make it, as I said, the ideal combination partner. And also CNS penetrants addresses the very large unmet need from the additional morbidity and mortality that accrues to patients who have that. Also see an important indication here in the atypical mutants, including L861Q.

So I'll stop there and pass the baton back to Nick.

Thanks very much, Mike. Thank you for that very nice overview, Dr. Eck. It was very nice. I was actually at AstraZeneca for over a decade during the development of gefitinib and then osimertinib. I was Head of Clinical Development there and have had close collaborations with the Dana-Farber, with Dr. Eck and colleagues, for Pasi Jänne, for over 20 years and really want to recognize their world leadership in the research on EGFR. And I'm extremely excited about this next chapter of targeting the EGFR receptor, which really does present, I think, an innovative and differentiated approach from many of the approaches that are currently out there.

So I want to touch briefly on what we're doing with this science. This is something that we have been working on now for a few years in collaboration with Dr. Eck and collaborators at Dana-Farber. And we are ready to complete our IND-enabling studies quite soon now. Our intent is to have the IND filed by the end of this year, which is extraordinarily exciting. The profile looks very encouraging. And that will enable us to initiate a Phase I trial in patients essentially with building on the science that Dr. Eck presented, L858R or other atypical mutations who have progressed after an EGFR tyrosine kinase inhibitor, most likely osimertinib in 2027. And we will evaluate also a combination with osimertinib ultimately in frontline non-small cell lung cancer for patients with susceptible EGFR mutations. We think that combination of approaches presents a very attractive opportunity for these 2 drugs to be combined together.

One of the attractive and, I would say, innovative aspects of taking on a clinical development program like this is it does allow us to demonstrate monotherapy activity very soon after getting in the clinic. Our expectation, unlike many drugs, is that we would see monotherapy activity and that, that would declare itself quite quickly in a Phase I experiment. So we would hope to be able to report activity by targeting this allosteric receptor, which would be the first time that's been reported in non-small cell lung cancer quite early on, and then transition, quite quickly, having demonstrated monotherapy activity to a combination with osimertinib in TKI refractory patients with the intent of pivoting to the front line very quickly.

So it's an innovative and accelerated development program with an IND-ready to file at year-end. And we are anticipating being in the clinic in 2027.

So on that, I will open up for questions on nonsmall cell lung cancer.

Andres Maldonado from HCW. Just a quick question on kind of the broad thesis and theory on allosteric targeting. Some allosteric binding targets have been described as transient and almost heterogeneous in nature. Can you comment on, once the mutation is garnered, how heterogeneous is that pocket or homogenous is that pocket? And what that told you about the residence time of the molecule you needed to make to target? And more importantly, when you're -- when you looked at the binding for osimertinib and any other ATP competitive inhibitors, are you binding at the same KD with 4321 as compared to monotherapy binding?

So take the first part of the question first. So the allosteric site is a site that's essentially opened up or created by the L858R mutation and other similarly-acting mutations. And you can think of the allosteric as a prosthetic, if you will, that sort of replaces what L858R or L858, excuse me, is normally doing to keep the kinase turned off. So there's a key helix called the C-helix that moves in and out in EGFR when it's turned off and on. Out is off, in is on.

And there's a loop flanking L858, that's in the wild-type receptor keeping that C-helix propped out and off. With an arginine mutation there, can't do that anymore, and it opens up this pocket then the allosteric can then bind in. So the confirmation that the allosteric is stabilizing is actually a very native-like off-state of the receptor, one that it normally wants to adopt but can't with the mutation. And so we're restoring that ability.

We've done quite a bit of studies with the JBJ series compounds on differences in how binding of one agent affects the other, comparing osimertinib and other ATP site-directed agents with binding of the allosteric. And the JBJ series compounds very dramatically increase the affinity for osimertinib and vice versa. Having osimertinib there increases the affinity for the allosteric.

With 4321, that effect is very muted. So very modest, if any, effect on one for binding of the other. Pretty much neutral co-binding. It was initially kind of sad about that. But then I -- then we realized that the same thing was applying with wild-type EGFR. So now I feel very reassured that one drug is not affecting the potency of the other per se in a binding affinity sort of sense.

Brad Canino with Guggenheim again. On the expectation for monotherapy activity, I guess, I want to split that between the 2 subgroups, because we've all seen examples of next-generation drugs getting responses in atypical patients, largely because osi wasn't optimized for that group, but it was for L858R. So what patient molecular characteristics do you expect to respond if they're L858R and pretreated with osimertinib to respond to monotherapy 4321? And are you recruiting just the C797S resistant population? Like if they have off-target resistance, should we still expect a salvage response from this new drug from you guys?

Yes, I can start. I think obviously, the sweet spot is on target resistance due to mutations in EGFR, and not just C797S, but the other ATP site mutations that you saw on that slide. I think that's one differentiator from fourth gens. The fourth gens in general have been developed to overcome C797S, but not those other ATP site mutations. So could expect a larger response rate with the allosteric that has been seen with some fourth gens because of the ability to cover a broader spectrum of those on-target mutations.

And with respect to other mechanisms of resistance, never say never, but I don't see an obvious reason to expect the allosteric to work when it's not -- when resistance is not due to on-target mutation. So I'll let Nick talk about patient selection.

Yes. And Brad, the way we're thinking about this is reflective of that science, in terms of the CDP. And what we do know is that we wouldn't be expecting activity in the exon 19 or 20 mutations because they don't have the presence of the allosteric inhibitor. So initially, we will exclude exon 19, exon 20.

And then obviously, the drug was developed specifically for L858R mutations, but we actually think the activity could be broader than that, including some of those common resistance mutations that are characterized by osimertinib either refractoriness or resistance. So we'll have a relatively broad population at the beginning of the Phase I, excluding exon 19, exon 20. And then I think as we progress into the Phase I and we begin to see activity, we'll be able to delineate more clearly where the allosteric benefit is most pronounced.

And I think whatever the expectations for monotherapy activity and given the preclinical data that you just saw, our expectation is you would see monotherapy activity, but I think it's also particularly exciting in the concept of being able to double drug. This is a particularly complementary approach for all the reasons that we just discussed to combine with osimertinib, which really would anchor the receptor in an inactive state. So that would also be an important part of our initial Phase I development.

This is Kevin back online for Corinne from Goldman Sachs. Just wanted to follow up on that in terms of just the total package of efficacy that you want to see to give you confidence in the frontline combination. And then specifically on tolerability too, what are you looking for that could give you confidence in that frontline combination in terms of tolerability as well?

Well, we're very encouraged by the profile that you just saw and the lack of activity against the wild-type receptor that tends to be the dose-limiting toxicity. I mean broadly from our IND informing studies, we're not really seeing any obvious sort of maximum tolerated dose or dose-limiting toxicities as we go into the IND-informing studies in the animal experiments, which is encouraging. So we think you should be able to combine quite easily with osimertinib without seeing significant overlapping toxicities. So that's the first thing to say.

I think in terms of what you'd expect to see in terms of efficacy, our expectation is to be able to dose escalate quite quickly into a full therapeutic dose. We would probably want to dose quite high, again, because we have a broad therapeutic threshold, we're not anticipating a lot of activity against wild-type EGFR or any other significant toxicity. So we wanted dose quite high in order to be able to make sure that we are targeting some of those atypical mutations.

I think any activity that we see in a resistant or refractory population to osimertinib as a monotherapy is going to be very exciting. And we were talking about this last night. So I think that will, in and of itself, seeing monotherapy activity in this area of high unmet need will be exciting. We will then transition into the combination of patients that have become refractory. And again, we'll look for additive or potentially even synergistic activity when we combine with osimertinib.

So we'll see how the Phase I's progress, but our expectation again is if we're going to see a clinical signal, we'll see it quite quickly, anticipated with monotherapy activity. And we'll be excited to see that. And we think we'll be able to generate those data quite quickly.

And again, we have a -- as I said, we have recently hired some outstanding leaders in the development of lung cancer and we have great collaborations, including with Dana-Farber, but other leading institutions in both the U.S. and in Asia, where, obviously, the prevalence of EGFR-mutations is a little higher. And so we'll have fantastic collaborators to lead this Phase I experiment and really guide us through it as we generate data and see what activity we're getting. And we're excited about that.

Yigal Nochomovitz from Citi. I was just curious you talked about the atypical mutations. Is that including the so-called PACC mutations, the PACC mutations, which some people refer to synonymously with atypical? Or is it different? And how many of these atypical mutations have actually been tested? Because the list is quite long, I believe there's 70 or 80 of them. And would you enroll all of them potentially in the Phase I, certain ones?

That's a great question. Do you want to start, Mike?

I can comment. I can't keep which ones are PACC and which ones aren't straight. You can thank John Heymach for that. But we've tested a few in depth and published on them with the earlier allosteric with the JBJ compound. We've done less at the Dana-Farber with 4321, but have done, I think, I can say, an animal study in L861Q, where we see very clear efficacy. We've looked at some of the other more common ones also and seen activity. But I think, Peter, you may want to comment further?

Yes, we've continued some of the work from the lab there, and as you say, actually quite a few of them. So we've been working our way down the list, and the majority are responding, obviously, at different potencies. But we think we'll be able to, because our idea is that we can dose high, that we don't see wild-type EGFR as dose limiting, at least preclinically and hopefully clinically. So it will allow us to cover the broad range of these atypical or PACC mutations. I think they're overlapping. There's certainly going to be a few that aren't responsive, but the majority we've tested so far are responsive.

And we -- that was factored into our consideration around the CDP, rather than actively select because the list is complex and long, we thought we'd deselect and then we'll learn about activity just simply by deselecting those patients where you really wouldn't expect activity because of the lack of the allosteric inhibitor. So we'll include everybody apart from the exon 19/20s, and then we'll see.

I would just add it's a fairly complex space. Many of these are also occurring in tandem together with classical mutations. So that's another area I think that it's very important. It broadens the potential indication.

And just one follow-up. I don't know, I may have missed it. But is it a covalent or non-covalent? I wasn't clear.

It's non-covalent. It's reversible.

Faisal Khurshid from Jefferies. If you don't mind, I just want to ask a bigger picture question of how did you arrive at in-licensing this asset? Like were you looking to get into this area specifically? Was it based on asset availability or something else? And should we expect further BD from you guys?

Maybe I'll take the question, and Nick, you could follow on. So Nick mentioned his deep relationship, Peter's deep relationships with Farber. Obviously, this is an area of high unmet need. The opportunity to be first, best in class, we keep the bar very high. And business development, we've been talking about that for some time now. Looking for differentiated assets that we could take forward with the expertise that we have and really make a difference and generate proof of concept quickly, right? And so this sort of lends perfectly to what we were looking for in oncology. And so that was sort of the genesis of it all. And I don't know, Nick, if you want to talk anything else about that.

No, I think that's it. I mean, I think it's just another example all of the type of opportunity from our collaborations with these institutes that just fits very well with our model of development, which is translating great science, taking it into clinic and generating a signal quickly and then hopefully progressing from there. So it's just a particularly good fit. It's a precision approach, which we're very focused on. And it's really a sweet spot, I would say, for us as an R&D organization, as a company to pursue this type of approach. So we're very excited about bringing into the clinic next year and hopefully validating the nice preclinical models that you heard about today.

And I'd just say in terms of future business development, it's how we built the company, right? So we've been able to in-license or acquire assets and do quite well with them. And we expect this to be another one that we'll take forward.

Will there be others? We hope so. We hope to do more, keep the bar high. But we're now focused on a very nice book of work that we have in front of us. And we will do everything we can to be successful there. But business development is always something that we think about actively.

With that, let's close. Thank you.

All right. I'm charged with taking us home here. So first of all, I just want to thank all of our speakers today, wonderful job, our collaborators in the room and online. Thank you for all the questions that you've had, and the attention today to what we're presenting.

So just to recap on where we are as a company. We're in a terrific position with what I'd say a full pipeline blockbuster opportunities now, building on what we've created with Niktimvo and Revuforj. We look to expand those franchises, leverage our world-class capabilities and really drive this deep pipeline of opportunities, milestones. And data will be emerging not only this year but next year and the year after for sure.

Solid financial footing, we've taken care of that in terms of capitalizing the company through profitability. So we are in a very good position to drive growth and succeed.

Just a little bit of a snapshot on where we are with all of this opportunity. So we talked about having blockbuster opportunity now in acute leukemia, in GVHD, in IPF, in myelofibrosis and, of course, lung cancer. So 5 areas of potential growth.

When you think about Revuforj, really getting to the front line first, expand the use and the opportunity, we'll have -- and we have had all year data emerging in frontline maintenance, real world. So we'll have many data sets that will continue to emerge at medical conferences, and we'll publish on new areas like NUP98 in the -- at the end of the year.

Myelofibrosis, of course, we're generating data with the consortium. We'll be starting that and hopefully have data next year. And that will be an important precursor to what we do with our next-generation menin compound in '27.

Of course, in chronic GVHD for Niktimvo, 2 big trials reading out in the coming months and year. We have axatilimab combination with ruxolitinib in the fourth quarter, and we have the steroid combination next year. So very important opportunities for expansion in chronic GVHD. And of course, IPF, big opportunity we heard about it today, the MAXPIRe trial reading out in the fourth quarter, and we're excited about that.

And then lastly, of course, the EGFR compound, will be in the clinic by the end of this year. We think this will be a very swift path to proof of concept, initiating that trial in early '27 and having data in early '28. So lots in front of us.

Two Phase II readouts this year, multiple revumenib readouts in acute leukemia and certainly beyond that. And then 4 assets in the clinic in 2027. So chock-full of good opportunities.

So I want to say thank you again to all of you for joining us. I want to thank our collaborators. I want to thank the wonderful people who work at Syndax who make this possible, some of whom have made this possible today, bringing this presentation to you all. And of course, patients who make this all possible. Thank you. We look forward to continuing the dialogue. We'll see many of you, of course, in the fall, but -- and on our earnings call coming up. But thank you for being here today and giving us your attention. Have a great day, everyone.

Hello, and welcome to the 2026 Annual Meeting of Stockholders of Syndax Pharmaceuticals Inc. Please note that today's meeting is being recorded. [Operator Instructions] It is now my pleasure to turn today's meeting over to Dennis Podlesak, Chairman of the Board of Directors of Syndax. Mr. Podlesak, the floor is yours.

Thank you. Yes, good morning. I am Dennis Podlesak, Chairman of Syndax Pharmaceuticals. And it's my pleasure to welcome you to the Syndax Pharmaceuticals 2026 Stockholders Meeting.

Before I call the meeting to order, I'd like to introduce to you the members of the Board and the executive team who are with us today. The other members of the Board are Michael Metzger, our CEO; Marty Huber; Jennifer Jarrett; Keith Katkin; Pierre Legault and Aleksandra Rizo. The officers of the company on this virtual meeting are Luke Albrecht, our General Counsel, Keith Goldan, our Chief Financial Officer. And I'd also like to introduce Jeff Kirkland and [ Tinik Caporo, ] representatives of Deloitte & Touche, the company's auditors, who are available to respond to appropriate questions.

With that, I'll call the meeting to order. The meeting will now officially start. We'll proceed with the formal business of the meeting as set forth in your notice of the annual meeting and proxy statement. After the formal part of our meeting, we'll give you an opportunity to ask any questions you may have.

I'd like to turn the meeting over now to Michael Metzger and Luke Albrecht.

Thank you, Dennis. Will the Secretary please report at this time with respect to the mailing of the notice of the meeting and the stockholders list?

I have a complete list of the stockholders of record of the company's common stock on April 21, 2026, the record date for this meeting. I also have an affidavit certifying that on April 30, 2026, a notice of Annual Meeting of Stockholders of the company was deposited in the United States mail to all stockholders of record.

At this time, I would like to introduce Sue Nelson of Computershare. I'm appointing Ms. Nelson to act as the Inspector of Election at this meeting. Ms. Nelson has taken and subscribed to customary oath of office to execute her duties with strict impartiality. We will file this oath with the records of the meeting. Her function is to decide upon the qualification of voters, accept their votes and when balloting on all matters is complete, to tally the final votes.

Will the Secretary please report at this time with respect to the existence of a quorum?

I have been informed by the Inspector of Election, the proxies have been preliminarily received for 66,797,451 of the 88,595,948 shares of common stock outstanding on the record date, representing approximately 75% of the total number of outstanding shares. This constitutes a quorum for the meeting today, and we may now carry out the official business of the meeting. If there are any additional proxies to be submitted to the Inspector of Election, please do so at this time.

We will now proceed with the formal business of this meeting. There are five proposals to be considered by the stockholders at this meeting.

Time is now 12:04 on June 10, 2026, and the polls are now open for voting on all matters to be presented. The polls will be closed to voting after we go through the matters to be voted on.

The first item of business is the election of two Class I directors to serve until the 2029 Annual Meeting and until their successors are elected. The nominees for Class I directors are Pierre Legault and Michael Metzger. Are there any questions?

The second item of business is the approval on an advisory basis of the compensation of our named executive officers as disclosed in our proxy statement. Are there any questions?

The third item of business today is the ratification of the selection by the Audit Committee of the Board of Directors of Deloitte & Touche LLP as the independent auditors of the company for the fiscal year ending 2026. Are there any questions?

The fourth item of business today is the approval of the Syndax Pharmaceuticals, Inc. 2026 Equity Incentive Plan. Are there any questions?

The last item of business today is the approval of the Syndax Pharmaceuticals 2026 employee stock option purchase plan. Are there any questions?

That was the final proposal for today's meeting. The Secretary will now describe the voting procedures.

Voting is by proxy and via online ballot. You do not need to vote if you've already sent in your signed proxy, or if you have submitted your proxy during this meeting. If there is anyone in attendance whether or not you already submitted a proxy, who now wants to vote, please submit your ballot via the internet. Each share of common stock is entitled to 1 vote.

The time is now 12:06 and the polls are now closed for voting.

May we have the results of the voting?

The preliminary report of the Inspector of Election covering the proposals presented at this meeting is as follows: The proposal to elect Mr. Legault; and Mr. Metzger as Class I Directors of the company is carried with each director receiving votes from a majority of the shares voting. The proposal to approve on an advisory basis, the compensation of our named executive officers as disclosed in our proxy statement, is carried with only over 94% voting in favor. The appointment of Deloitte & Touche as independent auditors for the fiscal year ending 2026 is ratified with over 99% voting in favor. The proposal to approve the Syndax Pharmaceuticals 2026 Equity Incentive Plan, as disclosed in our proxy statement, is carried with over 56% voting in favor. Lastly, the proposal to approve the Syndax Pharmaceuticals 2026 Employee Stock Purchase Plan as disclosed in our proxy statement is carried with over 99% voting in favor. We expect to report our preliminary voting results or if available to us on a timely basis, our final voting results on a current report on Form 8-K to be filed with the SEC within four business days after the end of this meeting. If not earlier reported, we expect to report our final voting results in an amendment to our Form 8-K within four business days after the final results are known to us.

This concludes the formal portion of today's meeting.

The meeting is adjourned. At this time, we would like to take any questions you might have for us.

Michael, I will check to see if there are any stockholder questions submitted.

There are no questions.

Operator?

This concludes the meeting. You may now disconnect.

All right. Good afternoon, everyone, thanks again for joining us at the Goldman Sachs Global Healthcare Conference. We're thrilled to have Michael Metzger; and Keith Goldan, Chief Executive and Chief Financial Officer for Syndax here with us this afternoon. And maybe we'll just kick it off some high-level questions.

First, how do you think about the core competencies of Syndax. And how does that inform kind of your strategic priorities for the business over the near term?

First of all, thank you, Corrine for inviting us here today, great opportunity to be in front of this audience. So Syndax is in a great position as a company. You mentioned our core competencies. We've been able to bring two drugs all the way through development and get them approved and certainly launched them in the last year plus has been very successful for the company. That kind of informs our core competencies. I would highlight R&D and the ability to translate early science into products of meeting and bringing them all the way through development.

So the R&D capabilities of Syndax are quite strong, gotten more robust over time. So that is something we lean on significantly to advance our medicines and really differentiate in the marketplace. And then, of course, the commercialization competency within hem today, we think is differentiating for us as we've advanced both of our medicines and they're both hem medicines to bring them to as many patients as possible. So I think those are core competencies that allow us to advance the business and really drive differentiation over time. So I would highlight those as really important.

Maybe more temporarily, we're currently in the middle of a pretty busy clinical data period between ASCO and EHA. Could You speak to the key themes you hope doctors and investors take away from the presentations you have at those two conferences.

Absolutely. And it is an exciting time for us as we've been meaningfully represented at all of the conferences most recently at ASCO and then at EHA this coming week, where we have multiple presentations, both oral and poster presentations for both of our medicines. I'd highlight for Revuforj the significant data in combination with standard of care agents that ESA and in COVI, also chemotherapy, 7+3 uses both in relapsed/refractory and in newly diagnosed patients as we're running pivotal trials in newly diagnosed patients, we have a whole slew of data coming in both real world and controlled trials and single-arm trials that help inform and derisk these combinations.

I think that's extremely important as we continue to build the business. Physicians get comfortable with using the drug both on label and potentially off-label and really solidify our leadership as the [ men ] of choice for many years to come. also highlight the maintenance data that has become increasingly important, specifically around the KMT2A population for revenue Forge, where patients are getting in higher. Increasing amounts to transplant, which is a great outcome for patients.

And then with Revuforj, you have the opportunity to go back on the maintenance capacity and that has become an important growth driver for the business. The data that we're seeing in the real world and around many of the centers that we're working with, suggests that patients could do quite well in maintenance. We saw this at ASCO in an oral presentation where a subset of patients, KMT2A/MPM1 and now MIF98, which is another important lesion that is able to be treated with Revuforj.

We've seen that patients get maintenance and can stay on as a landmark analysis in that trial 2 years of 90%. So that's a sea change versus what you've been able to see before the advent of Revuforj. So I think these are the themes, combination data treating patients earlier, the outcomes there, why it's meaningful to treat them, bring them to transplant and then also give the maintenance. That's what we're hoping to highlight.

All right. One more temporal question, then we're going to come back to all the clinical and commercial pieces. You recently did this convert -- announced it about a week ago. Maybe talk about that in the context of your overall kind of like financial strategy and funding the business. What does that allow you to do?

Sure. Maybe I'll start and I'll pass it to Keith. The convert is an opportunistic inbound from fundamental investors, we believe are important to our business going forward. So low cost of capital for us relative to anything we've seen Keith outline the terms of it. But essentially, it gives us an opportunity to fund beyond our current business. And we have a pipeline that's emerging. We'll talk about that at our upcoming R&D Day. We're excited about these assets.

We need to invest in them. We want to invest and we want to move them quickly ahead. We have a track record of success, as you mentioned, early bringing assets in, developing them optimally and moving as quickly as we can. I think that is a use of the proceeds as well as for IPF. Beyond this trial that we're running a positive study in IPF will lead to future development and expense and we want to have the resources available to us to exploit that opportunity. So those are sort of the uses, maybe, Keith, you describe...

Yes. I mean I'd begin by saying that it was opportunistic. The deal came to us. It was unsolicited inbound by a fundamental investor that want to anchor in the deal that specifically wanted to participate in the growth of the company through a convert, it was historically low cost of capital for us. It was -- the deal was done at 2.25%, up 35%. And it's a nice addition to our capital structure, which is right now comprised mainly of just equity as well as the synthetic royalty that we sold on Nektimvo to Royalty Pharma. So it's a nice complement to the overall capital structure and use of proceeds like Michael said.

Okay. So maybe digging in on the commercial side, you have Revuforj now approved in relapsed/refractory AML in both the KMT2A and PM1. But if we start with KMT2A. Could you talk about like the patient journey, where they see revenue forge today, kind of what portion of patients are getting that therapy, where they could and where that could kind of go in terms of going to transplant, coming back to maintenance, et cetera.

Yes, it's a very important advance for patients. I mentioned it earlier. KMT2A patients are generally younger than NPM1 patients, for example. When I say younger, a lot of children, average HNR pivotal trial was about -- so the goal for those patients who hadn't really had a medicine before that was impactful for their disease, certainly not one directed at two. was to get them to remission, which our drug does. About 2/3 of the patients in our pivotal trial got to a complete remission and then get them to transplant. And you treat them for about 2 to 3 months, you bring them to transplant.

And then the paradigm is after they've gotten through their engraftment period where their bone marrow repopulates you can put them back on Revuforj to continue treatment and keep them in remission. And right now, what we're seeing, we had about 25% in our clinical trial going to transplant, which is a big difference versus what they've historically had before Revuforj and now in the real world, as we reported in our last quarter, we're at about 50% of patients going to transplant. So about 70% of our patients are treated either second or third line, so that's earlier than they were in the clinical trials drives them to higher response rates and ability to get to more transplantation.

And then now what we're seeing patients coming back about 45% of the patients who go to transplant come back for maintenance. We expect that number to grow. We expect it to grow because physicians tell us they want to do it universally. They believe that this is an important impact on patients. We also have seen it in the data, starting to see some real-world data suggesting higher rates of maintenance. And so we will expect that -- we expect that to go to somewhere in the neighborhood of 70% to 80% of the patients going on to maintenance at steady state. So that's the paradigm and that we expect will be a big driver for the business going forward.

With those kind of in mind, you've said that 6 to 12 months should be like the expected duration of therapy, but that's a pretty big window. What do you need to see that narrow that? And where could it go over time?

Certainly, it could go 6 to 12 is a wide window. First year on the market, we saw average duration of therapy in the range to 6-month range that was due to the fact that you had you didn't have the impact of maintenance longer term, right? So you only had 12 months in the market, you didn't have the opportunity for patients to go through their engraftment period and go back on and have the impact of maintenance.

Second year, we said somewhere in the 6- to 12-month range. We now know about call it, 50%, 45% of the patients are going on to maintenance. We expect that number to grow meaningfully over time. That will drive the duration of therapy, 6 to 12 months. Could it go longer in the future? Yes. I mean physicians have told us they intend to give in the neighborhood of 12 to 24 months of maintenance on average. And so we need that time to build through the 6 to 12 months in the second year, but we do think it's realistic.

You think about where you are, like maybe you could mark-to-market from when you launch this product in KMT2AR to today, I guess, how are you tracking in terms of the metrics that you cared about at the time, whether it's like market share or percentage going on to transplant or maintenance, et cetera, versus your expectations?

Well, we're certainly tracking with expectations, maybe even exceeding expectations. You penetrated about -- it's a 2,000-patient incidents for KMT2A in the U.S. So we penetrated about 50%, approaching 50% in year 1, which sounds very high, and it is very high. There's really nothing indicated for KMT2A and standard of care is not effective, as I mentioned. So that 50%, we believe, could grow to 80% market share. That's about as high as you see in a target for a targeted therapy. So that's essentially where we expect it to go. How long it will take to get there. Probably in the next year to 2 years, we expect to be there.

Okay. The more recent approval for Revuforj was in relapsed/refractory in NPM1 AML. And maybe you could just start by characterizing kind of the competitive position in Revuforj in that patient population where patients have more options.

They do have more options. So NPM1 is a larger patient population, roughly 4,500 patients in the relapsed/refractory setting. They have co-mutation. So NPM1 is a driver mutation. They are often mutated about 85% of the patients have some other mutations. Some are actionable, some are not.

I'll mention two: One is IDH1 or 2 there are medicines approved for those two mutations; There's also FLT3, which has some two different drugs approved for FLT3. So physicians, when they're thinking about treating NPM1 patients often will reach for standard of care medicine in addition to Revuforj.

And so that could impact when they actually give a meta inhibitor, such as Revuforj in the treatment of a patient with NPM1. We do expect to have a dominant share the data that we've put out so far is quite significant, stacks up well against any competition. So efficacy is the most important driver of choice for physicians why they would use our drug over another drug.

Our drug has the highest level of efficacy in the category. The drug is very well tolerated. There's a lot of history now. Use of the drug, same physicians are actually treating KMT2A and NPM1. So the expertise and the experience, I should say, treating patients with both now, even preceding the approval in NPM1, we had some utilization off-label for NPM1.

So physicians are used to using the drug are comfortable with the profile. The efficacy is strong, as I mentioned. It can be used as monotherapy now in combination. We're seeing about 40% of use in combination with drugs like Ven/ASA. So there's a big body of evidence that the drug is effective. And I would say that the safety is well chronicled. The drug is easily tolerated. Safety is well managed and we understand it well. So physicians are, in turn, kind of feeling very comfortable with the profile compared to what else they have to utilize for these patients.

Between the two, you've put out like a $2 million or so kind of peak sales opportunity estimate for the drug. Now that you're on the market, have you learned anything that would shift that expectation?

Well, I think the drug is a -- we feel like it's effective, as I said, monotherapy and in combination and the ability to treat patients in combination will drive utilization earlier. When we mentioned the total addressable market, we're talking about treating the absolute most patients you can in the category. So in order to do that, you need to be able to treat them earlier. And I think using the drug in combination will impact that. I think that is one potential learning as well as the fact that I would say for NPM1, historically, there have not been a lot of transplants.

We don't expect there to be as many transplants as there are in KMT2A. However, that we are seeing patients getting transplanted that or NPM1 specifically on Revuforj so that's sort of an upside that we see. We're excited about that.

Another kind of source of potential upside is the data you started highlighting with the NUC-98 population. Can you expand on the size of the opportunity and the Revuforj could play there?

Right. So it's another lesion. So when we discovered that NPM1 was an area of interest, it was based on the fact that there's an overlapping gene signature with KMT2A, the [ Hoxnee ] signature, upregulation of Hoxnee is another such lesion where there's upregulation enough Hoxnee drug has been showing up some of our data sets, and it's exciting to see the impact on that specific lesion. We'll have more data at EHA to highlight that presentation specifically around DIP98,so I would look out for that. It's an important area, and we're learning that as it used to be thought of is it more of a pediatric indication.

It's an area where we're seeing adult patients actually show up with 98 as well. And what we've heard from experts is that it could be as large as 5% of AML overall. No overlap with KMT2A or NPM1. So there's no cross co-mutation relative to NPM1. So that's a discrete patient population that could add meaningfully to what we're doing, both in relapsed/refractory disease as well as front line. So again, it's what we would expect as amended inhibitors, we expect to be discovered to be able to be used in other lesions, not just the three that we've been talking about, but potentially more in the future as we track that Hoxnee signature.

And in terms of the development strategy to make sure physicians understand they can use it there and that they do what kind of like investment you're talking about and making sure that, that gets educated, et cetera?

Well, we have some investigator-initiated work. We also have some real-world data that we're putting together. So we'll continue to put that data out at conferences and potentially have a strategy to get it into guidelines, which would be impactful for physicians.

Okay. Beyond the relapsed/refractory patient populations we've just been talking about. You also have clinical efforts in the frontline setting. Maybe as you look at the front line, how do you think about the pockets of unmet need and how Revuforj kind of might be able to satisfy those.

Yes, certainly. The unmet need is probably the highest in the unfit population. So there's unfit and fit within AML. Fit is generally patients who can withstand high-dose chemotherapy and unfit are generally older patients who do not take the same regimen of chemotherapy. They generally get Ven/ASA. Ven/ASA is approved and is now actually very impactful for patients. And it's thought that maybe even patients who are fit for chemotherapy might be better off with taking Ven/ASA. That's an emerging thesis, some data at ASH this year that suggests that, that could be the case, a lower impact regimen from a chemo perspective. So the area of highest unmet need in the front line is certainly the unfit patient population.

And so our data so far is the most robust in combination with Ven/ASA. We've been able to show impact on CR rate well beyond the doublet in Phase I/II trial called BD AML trial. We continue to update that data. And we have overall survival as an important readout in that trial towards the end of this year. So that's an important supportive data set. We are running a pivotal trial in the frontline to get the drug to as many patients as possible as quickly as possible. And that's -- it's called the EVOLVE trial.

Maybe you could double-click on that a little bit in terms of what we expect to see from a clinical data generation perspective over the next 12 to 24 months in the frontline setting.

Right? So we're enrolling this 400 to 500 patient trial called EVOLVE. It's a randomized trial on top of standard of care, Ven/ASA. CR-it's dual primary end point, independently powered so you can win on either CR is the accelerated approval endpoint. OS is the confirmatory endpoint. And that trial is up and running with the global registration trial. So it's up and running now. We expect to open several hundred sites around the world and enroll the patients over the next year.

So that's the time line. We have given guidance on when we expect to finish that enrollment exactly. But it's something where we started first. We expect to be first to frontline, and I think this is the trial that will likely get there beyond before others. The second trial is the REVEAL trial in the FIT patient population, similarly sized with an accelerated approval endpoint as well as event-free survival as the other endpoint confirmatory endpoint. But both of these trials up and running enrolling patients globally and on plan to get there first.

You mentioned BEAT AML, and I think you anticipate having some update that program as well this year. How should we think about benchmarks from BEAT AML and how they might translate into our confidence in the frontline strategy?

So the VIALE-A is the -- was the approval trial for Ven/ASA alone. And that is, I think, widely accepted as the benchmark with a CR rate in the 30% range, 30% to 40% range as well as overall survival in the high 14 around 14.5 months in that range. what we're looking to do is improve upon both. And so far, BEAT AML has shown us on a CR rate, we're at close to 70%, so almost double we're seeing with Ven/ASA alone.

And overall survival on a very immature look at 7 months, we were out to about 15 months already pacing a little have where Ven/ASA alone. We do expect to do a mature look at the data at the end of the year, which will be many more months of follow-up, bigger data set. So that's of interest to us as well. We think we'll add meaningfully to the overall survival piece of the puzzle here, which should portend well for derisking the EVOLVE trial.

Okay. And how should we think about the market opportunity in the frontline setting relative to the other -- you know.

Relapse. Yes, so the newly diagnosed setting, about 9,000 patients between the fit and unfit patient population. It's about 55-45 split between patients who are fit for chemotherapy versus patients who are not fit for chemotherapy. And so that opportunity, if you think about it as, call it, we like to think about it as a $5 billion plus setting in the sense that you have 9,000 patients at roughly 40,000 to 50,000 a month for the drug, WAC pricing and patients staying on for likely 12 to 24 months is what we expect in the frontline setting. That's the calculation you get to that kind of total addressable market of about $5 billion.

And maybe just last week some before we talk about Nick tempo, but how do you think about the competitive landscape in frontline versus the competitive landscape that you like are currently situated in?

Well, we were the first to get the drug approved in KMT2A and NPM1 and I expect that we'll be first to front line as well. We started first. We have the most data there. Physicians are extremely enthusiastic. We're working with the best groups in the world to get those trials up and running and enrolled. So I think we have a very good setup to be first. And I think the profile that we've shown to date with the combination has really shown us up to be as pretty much as good as you can get. And so -- we feel very encouraged by the data. We feel encouraged by our position and we'll have a dominant share once we get there. But I think it's important to be there first, and that's what we're set up to do.

Okay. Nektimvo was approved in August '24, and it's a partner product with Insight. Maybe you could just talk about kind of again mark-to-market eye in the launch to date and compare for your expectations in chronic graft versus host disease.

So Nektimvo was approved in third line plus chronic GVHD. As you all know, it launched in February of 25 in the first 11 months on the market, did $152 million in sales. close competitors, the product called REZUROCK, which was also approved in third-line GVHD a couple of years prior, and we outpaced what they were able to do in their first 12 months by a nice margin in terms of sales, in terms of patients treated. So that's usually not how it goes. Usually, order of entry, you have some step down off of the prior drug that has been approved, and that was not the case with us.

So I would say it surpassed our expectations in the first year. The product is very well accepted by physicians at this point. So it's very broadly covered not only by payers, but physicians are writing the product. And that's because the efficacy is probably the best they've seen in the category for heavily pretreated patients to see that kind of level of efficacy and tolerability is really encouraging. So physicians are warming to the product, we've seen about 50% penetration in fourth line, about 1/3 of patients in third line, so growing meaningfully.

And so that has been a nice start for Nektimvo, we do expect it to grow meaningfully from here as we continue to penetrate frontline and waiting on combination trials. We have an important combination reading out in the fourth quarter of this year. That could drop utilization really open up Nektimvo frontline opportunity for additional growth.

Okay. Since you just mentioned that, I guess, could you talk about the broader development strategy for Nektimvo in the context of GVHD, including the subcutaneous product that's in development.

Sure. So we -- you mentioned subcu, subcu right now, the product is an IV dose every 2 weeks or potentially once a month as well. Physicians have the opportunity to do that. The product, we believe, will grow meaningfully once we have combination data in -- with frontline or I should say, other agents that are approved standard of care.

So ruxolitinib, Jakafi is approved in second line, steroids are approved in first line. So we have trials combining with both. At the end of this year, in fourth quarter, we'll have data on a very interesting Phase II trial where we combined with ruxolitinib. We also have a rux arm in that trial and a steroid arm in that trial. Seeing the components will be pretty revealing in terms of what we can do, can we improve upon the standard of care, rux alone or steroid alone.

In that population, again, newly diagnosed patients. So I think that's a very important trial in the fourth quarter. We're also running a pivotal trial, in combination with steroids. Steroids are effective, but you tend not to want to use them too long. They have some difficult side effects, tolerability gets a little challenging as well. So you want to be able to use steroids early on in the treatment course but turn them on them off and the ability to combine with axatilimab or Nektimvo and really keep efficacy at a high rate. While safety and tolerability keeps pace.

I think that's the name of the game, eliminate steroids from that regimen over time. that pivotal trial will read out in early 2028. So these are the key trials that we're launching in order to -- or carrying on in order to really solidify our position and build our position in chronic GVHD. And you mentioned subcu. Subcu is a nice add-on potentially for GVHD and even for other indications such as IPF, we are running an important trial in the ability to give the drug perhaps once a month as the subcu could open up some opportunities for us within that paradigm.

Okay. Maybe in the interest of time, I want to shift to the IPF trial, so thank you for the segue. In terms of the data updates that we're going to get later this year, I guess, could you remind us of the trial design in terms of patient inclusion, exclusion criteria? And you're just confident that this Phase II will be representative and derisking a registrational program.

That's exactly the setup. The setup this is a randomized trial, 2:1 on top of standard of care. So patients can receive pirfenidone or nictetinib as background therapy, we will stratify for those patient segments. It's a 26-week endpoint. A good test of the medicine over a period of time, which we think translates well into a 52-week potential extrapolation of that data. the trial is -- as I said, it's 135 patients. So it's, again, randomized. 135 patients. We actually overenrolled it a bit.

So it's about 145 patients well powered to show at least a mild difference in decline between the placebo arm and the active arm. And this is a -- so this is the endpoint of FVC and if you want to be able to kind of extrapolate to that Phase III. So we believe that this will be a good test. It's well powered to show a meaningful effect on FVC. We'll look at a variety of secondary measures as well. DLCO and quality of life measures. So this has the opportunity if the drug works well in this category to be a fantastic add-on as a therapy that doesn't have drug-drug interactions it's an antibody. So it could combine very nicely with other standard of care agents and we'll be testing on top of standard of care.

So for us, we feel like this is a very precise and well-conducted Phase II proof of positive trial.

One of the questions we get is what the level of confidence is that 6 months is enough time to see separation between patients that are on the treatment arm versus patients who are not. What is your kind of level of confidence that you will? And that you've enrolled the right patients to kind of see that separation?

Well, 26 weeks, if you look at the trials that have done -- that have been positive in those products that have gone on to prove themselves on the 52-week endpoint in larger pivotal trials. You look at the curves at 26 weeks, and they separate and they stay separate. So I think based on what we've observed from other trials, should be able to have a good result and have a durable result by the 26-week time point. So we feel quite confident in that. And it's not true of trials that were run on the 12-week end points.

So that's what kind of drove us to power it up use a dose that we feel very comfortable with, which is the 0.3 milligram dose and stick to the 26-week end point. we're including patients, as I said, they are stable on background therapy. So they have to have some respiratory -- meaningful respiratory function, but have frank disease. So we're looking at adding to what standard of care is and obviously staying on therapy is going to be important. So you want to have enough fitness where you can test the disease -- test the medicine in those patients, but not lose patients because of -- they're too sick to participate.

IPF is also like a very busy clinical indication right now in terms of competitive agents. How do you think about the fit of this drug and mechanism of action relative to some of the other ones in the category right now?

So the mechanism is its CSF1R inhibitor. So CSF1, as we know, in GVHD is upregulated and affects the disease causing macrophage. So similar in IPF where you see upregulation of CSF1 and actually having high rate high levels of CSF1 is a negative prognostic factor for disease and progression in IPF. So I think there's a -- we feel a commonality of if you can impact the disease-causing macrophages by down-regulating CSF1, you have an opportunity to impact both fibrosis and inflammation.

And so that is a new mechanism, different cell type than anybody else is kind of targeting within IPF. And so if we have the opportunity to show this in this trial where we impact the disease, it will be the first time CSF1 has been able to show those types of effects, excuse me. And as I mentioned, have a potential combination with other standard of care agents that impact other cells.

Okay. And then just remind us because this is a partnered asset, how did the economics and decision-making work between you and your partner in Insight?

Yes. Do you want to talk about that?

Sure. So we have the asset is partnered with Insight for all indications. So for research and development purposes, for any indication in the U.S. Insight pays 55%. We pay 45%. So we get advantaged economics there. But then commercially, for any indication, it's a 50-50 profit split defined as net product revenue, which insight books, less cost of sales, less advertising and promotion gets you to a net product contribution. And that split 50-50, we pick up the 50% on our P&L as collaboration revenue.

And in terms of the decision-making around the IPF program, what does that look like pending positive data later this year?

Well, both parties will have a decision to make. We do these things together, but we also have independent decisions. And if one party wants to go forward, they can without the other. But most likely, with a positive result we expect both parties to participate together in funding the trials and finishing development.

And what does the registrational study look like in IPF? And kind of could you give us a sense for time lines there as well?

Well, we haven't guided on time lines is a little premature. Trial design will have something to do with the result that we see in Phase II. And I mean specifically around the number of patients that we're going to need to include in the trial. It will likely be on trial. We'll use this trial as a supporting trial for the package for approval. And it will be the standard end points, 52 weeks, FVC, secondary endpoints as well.

So it will look a lot like what others have done. I don't think we're looking to blaze a new trail on a pivotal trial really kind of carry through what we learned and recapitulate a lot of that in -- from the Phase II into Phase III.

Okay. You highlighted the R&D Day earlier, I guess what should we be focused on as we head into that event?

Look, I think the R&D Day is our first opportunity to do this. We had announced through the R&D announcement that we have an early pipeline now that we are excited to talk about. It's getting to that stage, and it will require some investment. We talked about the converter earlier, and that's one of the uses of proceeds to beyond '26 to really accelerate the early pipeline, new science, on strategy, precision medicine within oncology. Those are the themes.

And we're very excited about these opportunities. We'll also talk about IP and GVHD and some of our ongoing work with Revuforj as well talk about frontline. And so it's an opportunity for us to really put in perspective all of the R&D work with some emphasis on some of the new projects that we're working on.

So obviously, all of that is kind of internal, at least already internal. How do you think about kind of the broader business development opportunity and capital allocation as you have a little bit more cash on the balance sheet, shifting to profitability over the intermediate term?

Look, profitability is something we can do with the existing cash that we have on the balance sheet. None of our expense guidance has changed. We feel like we are driving the profitability to both products really contribute to that. significantly, and we'll get there reasonably soon. I think the new cash is a really important piece of the puzzle from a standpoint of growth right? So new products in the pipeline as well as some of these adjacent opportunities, IPF being one of them, where we need to be able to invest in those opportunities alone.

I think BD fits in from the standpoint of we're always interested in looking at new opportunities, but we're very disciplined, keep a very high bar. We have some additional flexibility, but I wouldn't conclude that we're going to go spend a lot of money on new business development. I think we feel very confident in what we're working on today and what we're bringing through, and we'll talk a little bit more about that at the R&D Day.

Beautiful. Well, with that, I guess we'll see you guys in July. And thank you so much for joining us for those of us who joined this year and online.

Great. Thanks, Corrine.

Good day, everyone, and welcome to the Syndax First Quarter 2026 Earnings Conference Call. Today's call is being recorded. [Operator Instructions] At this time, I would like to turn the call over to Sharon Klahre, Head of Investor Relations at Syndax Pharmaceuticals.

Great. Thank you, operator. Welcome, and thank you all for joining us today for a review of Syndax's First Quarter 2026 Financial and Operating Results. I'm 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; Steve Closter, Chief Commercial Officer; Dr. Nick Botwood, Head of R&D and Chief Medical Officer; and Keith Goldan, Chief Financial 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 2. Before we begin, I'd like to remind you that any statements made during this 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 Factors 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 made represent our views as of today, April 30th, 2026, only.

A replay of this call will be available on the company's website, www.syndax.com, following its completion.

And with that, I'm pleased to turn the call over to Michael Metzger, Chief Executive Officer of Syndax.

Thank you, Sharon. Good afternoon, everyone, and thank you for joining us. Starting with Slide 3. In the first quarter, we continue to make strong progress advancing our commercial objectives and pipeline programs designed to unlock the full potential of our first 2 medicines.

On the commercial front, we delivered over $100 million in combined sales of Revuforj and Niktimvo, underscoring robust demand for both medicines and advancing the company towards profitability.

Revuforj net revenue totaled $49 million in the first quarter, highlighting our leadership position in menin inhibition and strong adoption across both indications. Revuforj net revenue grew by double digits quarter-over-quarter, primarily driven by new NPM1 patients. Adoption in NPM1 has been strong and growing steadily since Revuforj was added to the NCCN guidelines for relapsed/refractory NPM1 mutated AML in September of 2025, followed by the FDA approval of our expanded label in October of 2025.

We are the leaders in the relapsed/refractory space in both NPM1 and KMT2A and well positioned to drive further growth and unmatched efficacy data and expanding prescriber base, excellent payer coverage and multiple evolving treatment dynamics that should ultimately extend the average duration of therapy, including a growing number of KMT2A patients proceeding to transplant after receiving Revuforj.

Notably, recent analysis indicates that Revuforj is enabling nearly half of KMT2A patients to receive a potentially curative stem cell transplant, a significant increase from our prior estimates of 33%. This growing transplant rate gives patients the best chance for durable remissions ultimately driving longer term -- longer treatment durations as an increasing number of patients return to therapy post-transplant.

This step change compared to the 25% transplant rate we observed in our clinical trial aligns with what we have expected as Revuforj is used earlier in the treatment paradigm and often in combination with other therapies in the real world.

The pool of patients on Revuforj post-transplant is expanding each quarter, although that growth continues to be obscured by the large number going to transplant. While the robust transplant rate seen with Revuforj has a short-term impact on the business, it is, first and foremost, a very positive outcome for patients and will translate into durable and sustainable growth as an increasing number of patients return to therapy. This is an important and unique growth driver of our KMT2A business.

Turning to Niktimvo and chronic graft versus host disease or GVHD. Niktimvo delivered $55 million in net revenue in the first quarter. This result reflects consistent new patient starts, partially offset by natural attrition among the large cohort of predominantly later-line patients, who started Niktimvo during the first quarter of launch last year. Notably, the same dynamic was also seen during the same period of the launch of REZUROCK as well as other rare disease therapies.

Looking ahead, we expect strong growth with multiple drivers supporting the business, including a broad prescriber base and increasing uptake in the third line, which should extend the average duration of therapy.

Turning to our pipeline, we've made excellent progress advancing the programs that will fuel the next phase of growth for the company, including our pivotal frontline trials of revumenib. We are well positioned to be the first to get a menin inhibitor approved in frontline AML with strong global site activation and patient enrollment underway in our pivotal trials.

We will continue to expand the body of evidence supporting our medicines with multiple important data readouts anticipated in the second quarter and throughout the year. Similar to past years, we will have a major presence at ASCO, EHA and ASH with new data from multiple studies of Revuforj across the acute leukemia treatment continuum, including new maintenance data, which will be highlighted in an oral session at ASCO.

These upcoming data sets will continue to advance our leadership in menin inhibition and highlight Revuforj's best-in-class profile across multiple acute leukemia subtypes and settings.

We are also nearing 2 potentially transformative Niktimvo readouts in the fourth quarter, including Phase II data in idiopathic pulmonary fibrosis, or IPF, and in newly diagnosed chronic GVHD patients treated with Niktimvo plus Jakafi. Data from these trials could further unlock Niktimvo's multibillion-dollar potential in chronic GVHD, IPF and beyond.

From a position of strength, we are delivering long-term and sustainable growth and advancing innovative treatments that can significantly improve the lives of patients. We have a world-class R&D and commercial organization with a proven track record of delivering breakthrough medicines to patients.

We have 2 products poised for future label expansion, important upcoming data readouts and the expertise necessary to continue delivering innovative medicines. We are well funded to invest in the successful commercialization and further development of Revuforj and Niktimvo and on our way to reaching profitability with growing revenue and a stable expense outlook.

I'll now turn the call over to Steve to discuss our commercial results in more detail. Steve?

Thank you, Michael. Starting with Revuforj on Slide 4. Revuforj is now a little over a year into launch, and by any measure, it has been an exceptional commercial success with net revenue now annualizing at nearly $200 million. We continue to track well above launch benchmarks set by other AML therapies and expect to continue to outpace other drugs and redefine success in this space.

Two factors underpin our conviction, our ability to target a substantially larger population and other mutation-directed AML therapies and multiple treatment patterns that are expected to extend the average treatment.

In the first quarter, we delivered approximately $49 million in Revuforj net revenue and double-digit quarter-over-quarter growth across all key metrics, including net revenue, total prescriptions and new patient starts. Two drivers of our business, new patient starts and patients returning to therapy post-transplant and both are building nicely.

We added about 330 new patients in the first quarter, up approximately 10% compared to last quarter, with the growth driven by new NPM1 patients. New patient starts have increased even more significantly compared to the 200 to 250 patients we were adding per quarter prior to the expansion of the Revuforj label to include patients 1 year and older with relapsed/refractory NPM1 mutated AML.

We've continued to gain momentum and reach new highs, demonstrating the durability of Revuforj's strong market position even with the launch of a second menin inhibitor approved for adult NPM1 patients.

Early indicators suggest at least 40% of new starts in the first quarter were NPM1 patients, up significantly from 10% of new patients prior to the NCCN guideline update in September of 2025. Between the NPM1 patients who started in the first quarter and those continuing on therapy from prior months, we estimate NPM1 accounted for at least 30% of the $49 million in net revenue.

We're positioned to be the market leader in NPM1 with the strongest clinical profile. In recent market research, HCPs who treat our target population ranked efficacy as the most important factor in their treatment decision, followed by safety and tolerability, availability of long-term efficacy data, personal experience with the drug and inclusion in clinical guidelines.

Notably, more HCPs strongly favored Revuforj over the other approved menin inhibitor on the top 5 most important factors as well as nearly all other factors, including ease of access, drug-to-drug interactions, fear or KOL endorsement, ease of administration, flexible dosing to name a few.

Turning to Slide 5. We have a strong foundation to support the continued expansion of our KMT2A and NPM1 business, including a world-class team with excellent customer relationships and favorable listings in the NCCN guidelines, the most influential guidelines for clinicians as well as payers.

Our already robust prescriber base has continued to expand following our approval in NPM1, including our activation of Tier 1 and Tier 2 accounts, the highest volume centers in the U.S. who treat 2/3 of our target population. Over 85% of these accounts have now ordered, up from 70% prior to the label expansion.

The total number of accounts that have ordered has also increased quarter-over-quarter and is now well over 500 accounts, reflecting growing adoption in centers of all sizes, including community practices. Our growing prescriber base reflects physicians' enthusiasm to use Revuforj for their NPM1 patients and positions us to drive further penetration in both indications.

We also have nearly perfect payer coverage and physicians can access the menin inhibitor they prefer without any meaningful barriers. Revuforj's formulary coverage stands at 97% of all covered lives, including all commercially covered lives, Medicare and Medicaid, a coverage position that leads the class.

We have engaged and educated payers extensively, and they recognize the value of Revuforj and its status as the only menin inhibitor approved for multiple acute leukemia subtypes.

While the class leader in NPM1 will be determined by HCP preference, not price or recommendations from payers, I will note that payers understand the 2 menin inhibitors are priced at parity with Revuforj actually costing less for the large percentage of patients on CYP3A4 inhibitors.

This was made clear in a recently updated IPD analytics monograph, which no longer suggests use of menin inhibitor over another based on price alone, clearing up a point that had led to temporary confusion among a small handful of plans representing less than 1% of all covered lives.

Turning to Slide 6 and the multiple factors that will drive further Revuforj growth. The first is our continued expansion into relapsed/refractory NPM1 mutated AML. Of the 4,500 patient annual incident population, we estimate that less than 10% of patients have received a menin inhibitor, highlighting the substantial opportunity for further growth.

Compared to KMT2A, where we saw a steep uptake curve due to the lack of other approved therapies, we expect our NPM1 business will build over time because there are other options that physicians may consider for this population, depending on their co-mutations, for example.

With 2x to 2.5x as many NPM1 patients as KMT2A patients, we expect NPM1 will become a major component of our business over time. With strong physician support and unmatched efficacy data in a disease, where efficacy is the most important attribute to physicians, we expect to have dominant market share in NPM1 and KMT2A.

The second factor is the growing number of KMT2A patients who are proceeding to transplant after receiving Revuforj and then returning to therapy post-transplant. As Michael noted, the transplant rate has been building over time with recent analysis indicating that nearly half of KMT2A patients are proceeding to transplant after receiving Revuforj. Around 45% have restarted after pausing treatment for 1 to 2 quarters, a percentage we expect will grow over time.

While the pool of patients in Revuforj post-transplant is expanding, that growth continues to be obscured by the large number going to transplant each quarter. Importantly, we expect to observe a meaningful step-up in post-transplant use after leading institutions report on their experience using revumenib as maintenance in the second quarter.

Long term, we expect up to 70% to 80% of transplanted patients will ultimately be put back on therapy for 1 to 2 years based on our clinical trial experience and feedback directly from physicians.

The third factor is use of Revuforj in early lines of treatment and in combination with other therapies. Claims data show about 70% of use in the second and third line, even as we've added more NPM1 patients to our next. This is encouraging because when patients are treated earlier, you expect to see higher response rates, longer durations of response and more patients proceeding to transplant as we now see playing out.

Claims data also show about 40% combination use. While Revuforj is approved and promoted as a monotherapy, the significant combination use highlights physicians' comfort with the Revuforj profile, and that could extend treatment durations.

All these evolving treatment patterns will drive an increase in the average treatment duration, especially the growing number of KMT2A patients proceeding to transplant and then returning to therapy. This group of patients is already approaching 9 months of therapy on average with this duration expected to meaningfully increase over time.

We are confident in our ability to continue building a sustainable business with our first 2 indications for Revuforj, which together represent a $2 billion-plus market opportunity, as shown on Slide 7.

Turning to Niktimvo on Slide 8. Building on an excellent launch year, Niktimvo delivered $55 million in net revenue in the first quarter of 2026 and is now annualizing at over $200 million. In the first quarter, about 5,000 infusions were administered and approximately 300 new patients started even with severe weather impacting patient access to infusion drugs in the first quarter.

Performance this quarter reflects strong and consistent new patient starts and solid persistency, partially offset by natural attrition among the large cohort of predominantly later-line patients, who started Niktimvo during the first quarter of last year.

This dynamic was also seen at a similar point in the REZUROCK launch, a drug which reached $500 million in annual U.S. net sales within the first 4 years of launch in the same indication. All indicators of demand suggest we will resume growth next quarter as we continue to steadily add new less advanced patients.

Turning to Slide 9. The fundamentals of our Niktimvo business remains strong with multiple drivers for continued growth. The first is continued adoption in the fourth line and growing usage in the third line.

Within 1 year of launch, Niktimvo has captured 32% of the third line plus market with the majority of use in the fourth line and increasing uptake in the third line as providers gain experience. As the patient mix shifts more towards third-line patients with less advanced disease, we expect this will extend the average treatment duration.

Second, this is a chronic disease with the potential for patients to stay on therapy for long periods. Of the patients who started Niktimvo at launch in the first quarter of last year, 60% to 70% remained on therapy in the first quarter of this year, highlighting the potential for extended durations of therapy, especially as our patient mix shifts more towards third-line patients. Our clinical trial experience shows the duration of therapy can be measured in years for a meaningful proportion of patients.

Third, Niktimvo has a broad and productive prescriber base and strong commercial synergies for both Syndax and Incyte. Virtually every bone marrow transplant center in the U.S. has prescribed Niktimvo and all have become repeat customers. Physician feedback is very positive.

They continue to report strong activity in multiple organs with particularly notable results observed in patients with lung and skin fibrosis, some of the most challenging to treat manifestations of the disease. All these drivers put us in a strong position to expand our impact third line plus chronic GVHD, the $2 billion U.S. market opportunity, as you can see on Slide 10.

In summary, our quarterly results underscore the strong demand for Revuforj and Niktimvo and the substantial commercial opportunities we have with both products. We have the right medicines, the right team and the right strategies to continue delivering for patients and driving strong and sustainable growth..

With that, I'll hand the call to Nick to discuss our development programs.

Thank you, Steve. Starting with revumenib on Slide 11. We've made significant progress advancing our pivotal frontline trials and our integrated evidence generation plan designed to establish revumenib as the menin inhibitor of choice across the acute leukemia treatment continuum.

I'd like to highlight a few key points. First, we're focused on advancing enrollment in our pivotal frontline trials, which have the potential to support additional FDA approvals and the registration of revumenib outside the U.S. We are well positioned to be the first to deliver pivotal frontline data for a menin inhibitor.

Global site activations and patient enrollment are well underway in these trials, which were informed by a robust body of clinical evidence, allowing optimization of endpoint assumptions and other aspects of the study design.

We've also been able to leverage the strong relationships we've built with leading investigators and patient advocacy groups around the world through our work pioneering this new class of therapy. To support these collaborations and rapid enrollment, we have a team of highly qualified and well-connected MSLs located in key geographies, including Asia, fully focused on revumenib.

As a reminder, EVOLVE 2 is the Phase III trial of revumenib plus venetoclax and azacitidine in newly diagnosed unfit NPM1 or KMT2A AML patients. This trial conducted in partnership with the highly regarded HOVON network, was the first pivotal frontline trial of a menin inhibitor to begin enrolling patients. EVOLVE has dual primary endpoints of complete remission and overall survival, both in the NPM1 population to support the potential for accelerated and full approval, respectively.

REVEAL is the Phase III trial of revumenib plus intensive chemotherapy in newly diagnosed fit NPM1 patients, including adults and children 12 years of age and older. REVEAL also has dual primary endpoints of MRD-negative CR and event-free survival to support the potential for accelerated and full approval, respectively.

In the FIT KMT2A population, we are pursuing a novel and differentiated approach. In addition to generating further data in combination with intensive chemotherapy in partnership with the National Cancer Institute, we are progressing the RAVEN trial with leading clinical researchers. RAVEN is a Phase II trial of revumenib plus ven/aza in newly diagnosed KMT2A patients who would be considered fit for intensive chemotherapy.

The design of RAVEN is supported by the strong activity observed with revumenib plus VEN HMA in KMT2A patients and growing physician interest in moving from 7+3 intensive chemotherapy backbones to more tolerable VEN HMA backbones.

The second point I would like to highlight is that we will continue to advance our scientific leadership in menin inhibition with a major presence at key medical meetings, including at least 15 revumenib abstracts accepted for presentation at ASCO or EHA. The volume and breadth of the data we will present underscore physicians' interest and commitment to revumenib with its differentiated profile and strong activity across multiple genetic subtypes.

I'd like to highlight now some of the key data sets we expect to report in the second quarter of 2026. First, we expect new real-world evidence with revumenib. This data set will build on the first real-world evidence that another group, Moffitt Cancer Center presented for revumenib and the therapeutic class at ASH last year. Moffitt reported a 77% overall response rate and 75% MRD negativity rate among relapsed/refractory NPM1 and KMT2A and NUP98 acute leukemia patients who primarily received revumenib as part of combination therapy.

In addition to showing compelling clinical activity, revumenib was well tolerated as a monotherapy and in combination with standard of care therapies. We also expect new post-transplant maintenance data, including a data set accepted for oral presentation at ASCO. These will be important data sets given physicians growing interest in using revumenib post-transplant.

The upcoming data will build on retrospective data presented by MD Anderson at ASH last year from 10 pediatric KMT2A or NUP98 rearranged patients. They reported that revumenib was well tolerated in the post-transplant setting with encouraging early efficacy. Notably, all patients were alive and 90% were relapse-free at a median follow-up of 19 months.

Additionally, we expect updated data from our Phase I trial of revumenib plus intensive chemotherapy in newly diagnosed NPM1, KMT2A or NUP98 AML. You will first see an abstract with a data cutoff that is similar to the preliminary 708 data we presented at ASH last year, showing high rates of response and MRD negativity, along with a favorable safety profile. Data with longer follow-up will be presented at the meeting.

We also anticipate updated data from the relapsed/refractory cohort in the SAVE trial of revumenib plus venetoclax and decitabine/cedazuridine in NPM1, KMT2A or NUP98 acute leukemias. This update will build on the compelling data previously reported from SAVE, which shows overall response and MRD negativity rates above 80% in heavily pretreated patients.

And finally, we expect additional relapsed/refractory NUP98 rearrange data from our AUGMENT-101 trial and expanded access program. NUP98 rearrangements, which are found in up to 5% of AML cases are associated with a poor prognosis and high unmet need with no approved targeted therapies.

Last year, at EHA, we presented the first and only data to our knowledge showing compelling activity with a menin inhibitor in NUP98 patients. This data was met with strong enthusiasm by clinicians, and we are already seeing academic centers treating relapsed/refractory NUP98 patients with revumenib, underscoring the benefit of having one menin inhibitor with activity across multiple subtypes.

NUP98 is one of several subtypes associated with acute leukemias associated with upregulation of HOX genes that may be sensitive to revumenib. Altogether, more than 50% of AML patients may have a genetic alteration, which is susceptible to revumenib.

The body of evidence supporting revumenib will continue to grow throughout 2026 with additional data expected in the second half of the year, including an update from the BEAT-AML trial of revumenib plus ven/aza in newly diagnosed NPM1 or KMT2A AML. We also expect an update from a Phase I trial of revumenib plus gilteritinib in relapsed/refractory patients with a FLT3 mutation and an alteration associated with HOX overexpression.

Early data presented at ASH last year showed the combination appeared tolerable with early signs of efficacy supporting continued evaluation. For the subset of relapsed/refractory NPM1 patients with FLT3 co-mutations, menin plus FLT3 inhibitor combo is one of several potential options that physicians may consider depending on patient-specific facts.

I'd now like to turn to axatilimab development on Slide 12. This will be an important year with 2 upcoming data readouts. We are now expecting top line data from the Phase II trial of axatilimab plus ruxolitinib in the fourth quarter, a time line which pulled in due to faster-than-anticipated accrual. The data from this trial could inform the potential for axatilimab in earlier lines of chronic GVHD and potentially pave the way to a steroid-sparing approach.

We also expect top line data from our Phase II MAXPIRe IPF trial in the fourth quarter. Earlier this year, we completed enrollment and actually exceeded our original enrollment target of 135 patients due to the number of patients put into screening as we near the end of enrollment.

This speaks to investigator enthusiasm for axatilimab and the desire for new treatment options in IPF. Given the high interest in this program, I will highlight the evidence supporting the scientific rationale for CSF1R inhibition and outline the trial design.

Moving to Slide 13. Significant evidence points to CSF1-dependent monocyte-derived alveolar macrophages as a promising new target in IPF. These cells are believed to play a key role in driving lung fibrosis.

Multiple studies implicate the CSF1R pathway in IPF and provide strong mechanistic rationale for our program. For instance, high CSF1R levels are observed in IPF patients versus healthy controls and higher levels of CSF1R and monocytes predict shorter survival among IPF patients.

Turning to Slide 14, axatilimab is an IgG4 monoclonal antibody, which is optimized for diseases with an inflammatory and fibrotic component. It binds to the CSF1 receptor on the surface of monocytes and macrophages, preventing their activation by CSF1 and IL-34. This reduces the levels of circulating pro-fibrotic and pro-inflammatory monocytes and monocyte-derived macrophages and inhibits the activity of these pathogenic macrophages in tissues.

Based on these observations, axatilimab has the potential to make a more pronounced impact on the fibrotic process by targeting pathways that sit upstream of the pathways engaged by currently available IPF therapies.

The IPF program is supported by the remarkable activity observed with axatilimab in chronic graft-versus-host disease. Responses were observed across all organ studies, including organs with fibrotic manifestations of the disease, such as the lung and skin.

Among patients with lung involvement, who received axatilimab at the dose we are studying in MAXPIRe, nearly 50% achieved a lung response and over 90% reported improvements in shortness of breath at rest. These data, together with the strong mechanistic rationale are driving strong physician support for axatilimab's potential in IPF.

Slide 15 shows the design of MAXPIRe, a Phase II randomized, double-blind, placebo-controlled trial of axatilimab in approximately 135 IPF patients. This is a well-designed trial that has the potential to provide robust proof-of-concept data for axatilimab in IPF to inform a registrational program.

The inclusion criteria is similar to other recent IPF trials. Background antifibrotic therapy is allowed but not required. And the primary endpoint is the annualized rate of decline in forced vital capacity or FVC measured at 26 weeks.

In summary, we have a data-rich period ahead and are laser-focused on executing our pivotal programs. We are just starting to demonstrate our ability to translate promising science into novel medicines for patients with hard-to-treat diseases.

With that, I will hand the call to Keith to discuss our financials.

Thank you, Nick. Earlier this afternoon, we reported detailed first quarter 2026 financial results on our Form 10-Q, and I'll now highlight a few key points on Slide 16.

Total revenue for the first quarter was $64.9 million, up 224% over the same period last year. Demand for Revuforj remains strong with $48.9 million in net revenue, up 144% from the same period last year. We achieved these results even with typical first quarter dynamics, including severe winter storms, which had a transient impact on both products in February and a growing number of KMT2A patients temporarily pausing Revuforj to proceed to transplant.

Inventory levels remain within the 2- to 3-week range we have previously guided. We expect continued growth over the coming quarters as adoption in NPM1 increases and the average duration of therapy extends as Revuforj is used earlier in the treatment journey and the number of patients on therapy post-transplant continues to build.

Now I want to turn to Niktimvo, which continues to be an important cash flow contributor to Syndax with our 50% share of the net commercial profit totaling $15.9 million in collaboration revenue in the first quarter. The collaboration revenue that we reported was 29% of the Niktimvo product revenue reported by Incyte within the range of 25% to 30% that we've been guiding to.

Our collaboration revenue for the first quarter is a significant step-up from the $0.2 million in collaboration loss we reported from the first 2 months of sales of Niktimvo in the first quarter of 2025.

We continue to expect our Niktimvo margin contribution, defined as the collaboration revenue recorded by the company as a percentage of Niktimvo net sales to be in the 25% to 30% range in the near term and increase longer term, as sales grow, while much of the expense base stays largely fixed. We anticipate continued growth throughout the year as Niktimvo is increasingly used in the third line and duration of therapy extends.

With regard to expenses, guidance remains at total R&D plus SG&A expenses in 2026 of approximately $400 million, excluding the impact of $50 million in estimated non-cash stock compensation expense.

We are well funded to continue investing in our commercial and development priorities with $352.1 million in cash, cash equivalents and marketable securities as of March 31st, 2026.

With this robust balance sheet, growing revenue from 2 medicines and stable expenses, we are on our way to reaching profitability.

With that, I will hand the call to Michael for closing remarks.

Thank you, Keith. Looking ahead, we are focused on driving revenue growth and delivering on the milestones shown on Slide 17, which will fuel further innovation and support value creation.

We are in a strong position with multiple near and long-term growth drivers supporting both of our medicines. Revuforj is poised for further growth as we expand into NPM1 and continue to penetrate the KMT2A market, a segment where Revuforj is the only approved therapy.

A growing number of KMT2A patients are proceeding to transplant, outpacing our near-term expectations and returning to therapy post-transplant, which will extend the average treatment duration and drive durable and sustainable growth.

With the broadest label and best efficacy profile of menin class, we have the unique opportunity to cement Revuforj as the menin inhibitor of choice in relapsed/refractory disease and ultimately be the first to frontline, unlocking a $5 billion-plus market opportunity.

Niktimvo continues to be a meaningful contributor to our bottom line. We have ample opportunity for further growth in our first indication as our patient mix evolves and important readouts later this year in frontline chronic GVHD and IPF that could open transformational multibillion-dollar markets in the near term.

I will close by thanking everyone who has made it possible for us to deliver breakthroughs for patients, especially the individuals and clinicians who have chosen to participate in our clinical trials as well as our dedicated Syndax team and the long-term investors.

With that, I would like to open the call for questions. Operator?

[Operator Instructions] The first question is from Anupam Rama from JPMorgan.

Just a quick one on Revuforj. I know that later this quarter, you're going to have data from that multicentral real-world study that you're going to -- that you highlighted in your opening comments. What should we be looking for in that presentation beyond what we learned in that Moffitt study that you highlighted? I'm looking for data points that might help us understand how physicians are using the product and how we should think about extrapolating to the revenue trajectory of the product moving forward? And will this real-world study include both the KMT2A and NPM1 experience?

Anupam, thanks for the question. Very important new data coming. So we're excited about that, and I'll pass it to Nick to give you a little bit more detail.

Yes. Thank you. I'm not going to talk about the data specifically, but I'll give you a flavor of the things to look for as you would anticipate in these types of data set. I mean one is we're expecting broad coverage across the genetic subtypes, including NUP98. As previously seen, what we're seeing in the real world is extensive use in combinations of therapy. That's clearly not part of our current indication. But given the data we've generated, we know that physicians like to use it in combination in earlier lines of therapy.

I think the other things I would say to look out for is the number of patients that are progressing to transplant because of those catalysts and factors for that, the number of patients that are able to get to transplant, I think that will be an important data point to look for.

And then, of course, the ability to get patients on to maintenance. Now that's not, again, something we are promoting on, but it's an important part of patient care. Physicians are wanting to do it. We want to provide data and we are observing it in the real world. So those are the things I'd be looking out for as we generate more real-world evidence.

The next question is from Corinne Jenkins from Goldman Sachs.

Maybe quickly from us, is there a way that you can kind of help us quantify the headwind to revenue or patients you're facing in a given quarter at 50% of the KMT2A population is going to transplant, recognizing that, that normalizes once you reach a steady state of KMT2A penetration?

And maybe on that note as well, I think you commented at the end of 4Q, you were at about 50% penetration in the KMT2A market. Is there an update on that front as well?

Yes. Thanks, Corinne, for the question. So I'm going to hand it over to Steve. Maybe I'll handle the second part of the question first, which is sort of the state of the KMT2A market, which is certainly growing. We had gotten to roughly approaching 50% penetrated on an incidence population of about 2,000 patients last year, and we continue to see that progressing.

Certainly, the impact on maintenance is a big growth driver for that business. We do think we'll get nicely north of 50% this year, but I do believe that the maintenance piece is such a considerable part of what grows in the future as more patients are now going to transplant with about 50% of patients going to transplant and right around that number coming back.

But I think that's likely to grow considerably in the coming year or so, and that's driven by what we hear from physicians and all the data that will be coming out. Nick mentioned some should help that with that growth rate. But that's KMT2A, a very healthy piece of our business, but maybe I'll turn it over to Steve for the other.

Yes. I think it was the same question around KMT2A. I think the first part of the question was just headwinds and maybe that's around bringing patients back in that post-transplant setting. I think what we've looked and some of the numbers we've updated this quarter using claims data when we look back and we realize there's a greater percentage going to transplant and this increasing number coming back post-transplant.

The way to think about it is average is probably 3 to 4 months to get patients back. But the longer run market, we realize there's patients that may be 6 months or more off treatment from that transplant to when they get back on. So the timing is going to be important. We've seen that grow as an important piece of our business. It's a little slower to build than it would be just bringing new patients in, which is driving the business right now on the NPM1 side.

So in terms of that -- because it all lands on duration of treatment, which is something we've seen extend and particularly, I think we have this in our notes, the patients that do come back, particularly those that start in the first 7 months of launch, they're already at 9 months and longer in terms of duration of treatment. And that will extend, and there will be more folks in that group over time, which is why we expect the duration of treatment to grow considerably over 2026.

The next question is from Phil Nadeau from TD Cowen.

Two from us, one commercial and one on the pipeline. In terms of the NPM1 penetration, what do you think is gating for increasing that penetration? Is it simply time line market? Or are there data sets that could be important, such as the FLT3 combo data that's expected later this year? That's first.

And then second, on the pipeline, the data you present from lung involvement in cGVHD is very impressive. What is the time course of the responses in GVHD? Is 26-week duration likely to be sufficient in IPF?

Great. Thanks, Phil, for the question. So the first question related to sort of what's gating relative to the growth of NPM1. Maybe I'll turn it over to Steve to make a comment there and maybe to Nick for the pipeline question.

Yes. NPM1, it's -- clearly, we're at the front end of that population, Phil. So there's a lot more patients to grab. I think when you think about our own business, there's been step-ups in the business, and it really began for us in that Q3 time frame, right? At the end of September, we got NCCN guidelines and then obviously, the full indication for the fourth quarter.

So we've seen big step-ups in our own business, roughly in the 250 range in Q3 in new patients, a big step-up in Q4, another step-up in Q1, our averages. We're looking at 330 new patients in the quarter. So that will build. It's a different market. KMT2A was obviously our launch, lots of patients came in.

There's [indiscernible] the standard of care, patients have no other options. We know for NPM1, they do. There is FLT3 commutation. So it's a little bit more complex. The patient tends to be older. We're not going to see as much likely transplant and then restarts in that population. So we're going to give it time and the time to peak will just be a little bit longer in the NPM1 population relative to KMT2A.

Yes. I'll just add that the profile that we're showing for NPM1 is best-in-class. I think we feel very confident physicians tell us that time and again that we have, as Steve said in his remarks, broad advantages across the profile. So we feel very confident that we'll continue to build that market, build that business to have dominant share over time.

Now the next question was related to IPF, and I'll turn it over to Nick to.

Yes. Thank you, Phil. Happy to take that question. So first thing I'd say this is a very robust and statistically rigorous proof-of-concept study in IPF, and we're very confident in the 26-week endpoint. There have actually been some other previous pots that have even looked at 12 weeks. We think 26 weeks is a very good compromise in terms of it being too short, but enough time to be able to detect a difference.

We actually annualize that. We'll report annualized rates of FVC decline using standard FDA-approved models for modeling that out to 52 weeks. So this will be a very rigorous proof of concept to inform a Phase III program.

And if you look at previous Phase III studies, if you actually look at the graphs for separation, you see very clear separation by week 26. So we're confident that 26 weeks will be sufficient to detect the difference and inform a Phase III.

The next question is for (sic) [ from ] Brad Canino from Guggenheim.

Just following on the previous question on the transplant maintenance dynamic continue to be more of a temporary headwind for now. My question is really simply, when will this start to flip to a tailwind? It sounds like there's 2 levers now. You're pointing to flat quarterly patient starts, so you're refilling the population. But how much higher than a 50% transplant rate can even be possible in this population? Are you topped out there and now you can grow that maintenance restart?

And then are you confident in that 6-ish month now wait to the restart for maintenance? Or could that even extend to be patients starting 7, 8, 9 months later and push out the time to that start of the tailwind as well? Separately, it looks like you lost about 14 points of year-over-year growth due to gross to net. Is there a chance that reverses back later this year and it gets worse? Or should we think about that being a neutral effect for the rest of the year?

Brad, thanks for the questions. So I think you're right about the maintenance dynamic is today is a bit of a headwind. I mean, obviously, a great opportunity for patients, many more going to transplant. It's far exceeded our expectations. You've probably heard us talk about the fact that maintenance could -- or rather transplant could get as high as 50% and that's essentially where we're at.

So I think that happened a little bit faster than we expected. But that's probably where it will be. I don't expect it to be much higher than 50%. So I do think that has sort of topped out. We will ultimately see. But that's point number one.

Point number two is the effect on restarting and how long we're going to need to wait until that really becomes a big factor. We have talked to many physicians. Obviously, the work that we've done seems to indicate that we'll get to 70% to 80% of patients restarting maintenance. And we've seen that accelerate as every quarter has gone by.

So I think that's an important milestone or important bogey for us. Whether that takes another quarter, 2 quarters, a year, we'll see. We ultimately think that's where we'll be at steady state. So that will be an important driver of growth as we go forward here, and that's the dynamic we see playing out.

We do see patients, as Steve mentioned, that over a 6-month period of time as you wait to come back and engraftment for maintenance, it's a little bit longer than we expected. We are picking up patients now in the claims that it's not 3, 4 months of engraftment and restart. It's more like 5, 6 months, maybe even longer. So that -- again, that is a piece of this. I don't think that's the vast majority of patients. I think that's some of the patients.

So again, we do expect in future quarters to start to see some of the compounding effect as we sort of peaked at our 50% transplant rate, and then we'll have more patients coming back. So that's the dynamic to look forward to.

Maybe, Keith, do you want to talk about gross to net?

Yes. Brad, with respect to the gross to net, I would just say, not sure exactly of your math, but I would say that we've consistently guided since we launched that we expect gross to nets to settle in the 20% to 25% range. We're still squarely within that range, and I'm not changing our guidance at this time.

We did see what I would call typical 1Q seasonality impacts on the gross to net just due to the high deductible -- mostly due to the high deductible commercial resets and the Part D donut hole, but the impact was still landed us within the guided range.

The next question is from Stephen Willey from Stifel.

This is [ Josh ] on for Steve. Do you think that the data from the Phase II axa/rux combo trial would be sufficient to potentially support a compendia listing for frontline GVHD? And then how do you think data from this trial will serve to inform or derisk, if at all, the Phase III trial looking at axa in combo with steroids in the frontline setting?

Thanks, Josh. Good question. So let me turn it over to Nick to handle both of those, I think.

Yes. I think it's a well-designed study and a very interesting hypothesis that you might be able to avoid steroids in the frontline setting. So this is a potential steroid setting approach. It's 120 patients, about 40 patients per arm and it's basically -- I mean, it's a noncomparative randomized study, but really the benchmark for this is about a 40% response rate using standard NIH criteria at around 6 months.

So if you see a meaningful improvement on that, let's say, 60%, which is kind of aligned where the study would be, I think that could not only inform clinical practice, but potentially also compendia listing just because of the morbidity associated with long-term dexamethasone.

We will also look at a number of other clinically meaningful endpoints in that study like the time to actually have to reintroduce steroids. And if you can really delay that again, I think clinically, that's significant. The duration of response and time to events or other endpoints. And I think when we look at the totality of those, it will be very informative to both the practice and compendia and could inform future registrational studies.

The dexamethasone combination Phase III study that you mentioned is a different hypothesis. This is where axatilimab can actually add to dexamethasone. So it's a slightly different hypothesis, and that could offer an alternative standard of care. They have quite complementary mechanisms of actions, and that is a typical Phase III study.

The next question is from Faisal Khurshid from Jefferies.

This is [indiscernible] for Faisal. Want to follow up on the progress in the first-line AML Phase III trials. Where do you see yourself relative to the competition there? And maybe a little bit more on EVOLVE-2 and how you see that stacking up in?

Thanks, [indiscernible]. So let me first comment and then I'll let Nick make other comments. The progress on the trials, we're doing quite well. I think as Nick remarked in his written remarks, we have -- this is a period of standing up our trial, standing up sites, enrolling patients, everything is on track and going quite well. So we feel we are going to be first to front line. We feel confident in everything that we're doing to execute against our time lines. And so everything is on track. And I'll turn it to Nick maybe more about EVOLVE.

Yes. Thanks [indiscernible[. This is -- I mean, simply, this is one of the highest focuses for my team. It's a very high priority and we're spending a lot of time on this, and we have 2 different approaches, EVOLVE-2. Again, this was the first study to start enrolling. So it's been enrolling now for nearly a year.

We're working with HOVON, which is giving us a fantastic network of sites across U.S., and we are also now entering sites in the U.S., making a lot of progress with site activations and indeed patient enrollment.

In fact some of the metrics around patients per site per month are actually somewhat in excess of what we modeled, and that's quite exciting because I think it speaks to the physicians' enthusiasm and the support of the HOVON group to enroll this study.

So because we've generated such a body of evidence with ven/aza, we actually feel very confident in the design and some of the statistical assumptions of that study. And it's moving along very nicely, and our expectation is to be first with a readout for that trial.

Likewise, REVEAL, we've made a lot of progress. As you know, we recently confirmed the dose of 160, 270 in combination with intensive chemotherapy, which is great. We're working with a leading CRO internationally.

We're busy setting up sites in Asia and activating sites. And again, we're running very much to track. So we're feeling very confident about that study as well and more on that to come. But no, the teams are feeling confident and we're in a good place.

The next question is from Mayank Mamtani from B. Riley.

Congrats on the progress. A lot going on for you guys. Just any chance you are able to share the absolute number of patients launched to date that have returned post-transplant? And on the 300 new patients added intra-quarter, if you can give any color on the mix, NPM1 and KMT2A versus what we saw in the prior quarter? And if anything on the NPM1 you can share on duration and co-mutation yields relative to what you had maybe initially expected last quarter, that would be great to hear. And then I have a follow-up.

Yes, Mayank, thank you for the question. So on the absolute number of patients, I think maybe I'll ask Steve to make a comment if we have that data.

We can estimate. We don't have exact numbers, but I would share right now. We know we've treated 1,400 patients roughly from launch to date now, break it down by KMT2A and NPM1 patients. So it's probably at least 200 at this point we'll come back -- so we will come back with that.

Yes. I mean, look, I think part of what the challenge of breaking down KMT2A versus NPM1 is it doesn't work like that in claims. So you have to make some certain estimates. So that's a little bit trickier.

Your question about co-mutations was what percent of patients have co-mutations, I think that was my interpretation of your question. I think broadly speaking, NPM1, a high degree, 85% of patients have co-mutations -- about half of those have FLT3 mutations. So we're running trials to look at combinations and things like that in terms of the FLT3 population.

Other patients have IDH inhibitor -- IDH mutations as well. So it breaks down in a multifaceted population of patients that you have to deal with combinations or with -- in some cases, we use venetoclax and azacitidine to combine our drug with in order to handle all of that. So I think that's the extent of the co-mutation question. So we'll leave it there for now.

Duration [indiscernible] Michael duration of NPM1.

Yes, thanks. So duration, I mean, we had talked about duration of NPM1 over time being in the roughly 7 to 9-month range. I think it's early days to look at and have a duration calculation specifically for NPM1. We had talked a little bit more about the KMT2A population and how that's kind of coming together with the impact of more patients going to transplant and returning for maintenance.

And as Steve mentioned in his remarks, patients who have actually received a transplant and have gone on to maintenance are on average up to 9 months and counting. So that's a very positive forward indicator of where that business is going.

And I can think that NPM1 is certainly tracking with patients staying on drug for multiple months. Some will get transplant, most will not. And so that will be an impact -- a factor in how duration ultimately plays out. But we expect patients to do quite well and be on drug for months.

And on the axa plus rux study, the Phase II time line got pushed up. Is the Phase III steroid study that Nick, you just mentioned, is that also tracking ahead of plan? I believe you've said early 2028 readout. If you can clarify that.

Yes. No, that time line is the same. Nothing's moved out. They're independent of one another. As Nick mentioned in the trials are different trials, and they have different -- everything is different about them. So no, I wouldn't assume that time line has changed.

The next question is from Etzer Darout from Barclays.

Maybe if you could just provide any color, commentary or even guidepost on 2026 revenue guidance? And then any color as well or commentary on commercial dynamics with this different NMP1 call points with ziftomenib on the market? Anything you can provide there would be great as well.

Sure. Thanks for the question. So first, maybe I'll turn to Keith on how we're approaching revenue guidance, which is going to be easy to answer.

Sorry, we don't provide revenue guidance. We're early in the launch of NPM1. There's competition out there. So probably wouldn't be responsible for us to go out and give guidance at this point.

Right. And then anything on the commercial dynamics between us and our competitor, I think that was the genesis of the question there. Steve?

Yes. I mean, dynamics we can share. Competition is always good for us to be at our best. But I think importantly, menins are exciting. Lots of physicians are interested. awareness is there. It's an obvious path in KMT2A. We've done very well and met and probably exceeded physician and patient expectations.

The NPM1 patient is different. I think you can see by the nature of these calls, there's co-mutations. It will build differently over time. So we think it's a good thing that there's another menin player in the market, raising awareness, finding a place for menins.

We've shared -- and Michael shared thoughts on just our profile, how physicians think about it. We've got a better profile than NPM1. So anything that's done on behalf of the class will have benefit to us as the market leader in NPM1 and in KMT2A. So we'll see how it rolls over the coming months, but we think it's a good thing, and we think ultimately, we'll benefit from it.

And I'd just say that NPM1 is a very considerable piece of our business. It's growing. We feel very good about our competitive position. Steve's organization is essentially built us into the market leader, and we expect to continue to build that piece of the business competition or no competition.

The next question is from David Dai from UBS.

Just on the Niktimvo IPF, what levels of investigator or payer interest are you seeing today in Niktimvo's antifibrotic potential? And how might positive IPF change -- positive IPF data change the commercial opportunity long term?

Thanks for your questions, David. So 2 questions related to Niktimvo. One, payer interest around IPF. I think that was the first question. Steve, would you have a comment on that?

I really don't -- I mean, this is handled -- we know there's interest. There's clearly unmet need. The drugs that are there don't work incredibly well. So you're going to see payer interest serving that population. Work it's generally done by Incyte handle that piece.

What I would just add is that, I mean, this remains an area of high unmet need. It's poorly served by currently approved therapies. I mean there are 3, maybe 4 therapies approved. None of them are very satisfactory. The survival and prognosis of these patients is very poor. And no drug to date has really impacted the natural history of the disease. So there really is a great need for a drug that could potentially impact the natural history of the disease, and that's the hope with axatilimab that it might be able to do that.

From an investigator and physician perspective, the support we've had from investigators and their desire to contribute in a potential Phase III is very high, which I think speaks to their interest in a novel and differentiated approach to the treatment of IPF. So we're feeling very good about that.

And as you know, the market opportunity here is quite large. We're talking about 150,000 patients or thereabouts in the U.S. And that's -- this is a new -- would be a new mechanism for this disease. If we're able to show in this trial meaningful impact on the efficacy endpoints and safety as well, we'll, I think, have a very interesting and compelling proposition in IPF to serve patients. So it could be sort of, I'd call it, a game changer relative to market size.

I think GVHD is considerable as we've laid out. We think we have a very compelling proposition in GVHD alone. Once you add in IPF, it's obviously a completely different size of opportunity in the U.S. for us to get involved. So excited about that.

The next question is from Yigal Nochomovitz from Citi.

On RAVEN, I had a question. If that study, that Phase II looks good, would you then consider a Phase III given the regulatory pathway is a little less well worked out relative to what you're doing with REVEAL ND? That's my first question.

And then I was also interested, you mentioned that you're guiding to 50% to transplant up from the 33%, but then you're still restarting about 70% to 80% on Revuforj. I'm just wondering if why that number was staying the same, if you're increasing the number going to transplant, I thought perhaps maybe you'd get even more restarting, but maybe that's not the right logic. So just curious how you think about that part too.

Yes. Thanks, Yigal. Let me just clarify on the second question. So we had said that we're getting to about 50% patients transplanted. That was correct. What we expect to target is 70%, 80% of patients to come back. Not everybody will come back for maintenance, but the vast majority we expect to get to that point.

Right now, we're not there yet, right? So we're kind of approaching half of the patients coming back for maintenance. That number will grow. It will grow based on our confidence from the data that we've put together, which -- some of which will be presented in the coming weeks at some of the medical conferences.

We've heard from physicians -- this is what they expect, expect to put patients back on maintenance. They feel very strongly about that. So this is what we expect will happen, and we feel very confident in that over time, but we're not quite there yet. So that's the dynamic we're experiencing. It's great for patients, many more going to transplant. The funnel -- the actual funnel of patients who are available for maintenance is expanding. And so that's all very positive driver of business going forward.

And the second question related to RAVEN, and I'll turn it to Nick.

Yes, I'm happy to take that question. And we're excited about this hypothesis because this is a bit of innovation in an area where patients could potentially get an alternative and better tolerated approach.

These patients would normally get intensive chemotherapy in order to try to get to transplant. And the hypothesis here is by giving them ven/aza and revumenib, you can get these fit KMT2A patients, many of them quite young to transplant without all of the morbidities.

Now in terms of its intent, clearly, that's a high -- an area of high unmet need. We haven't talked about the specifics of the study design yet. But clearly, a compelling result that you get high rates of transplant and good outcomes with a much more -- much better tolerated regimen would certainly be informing clinical practice potentially guidelines, and we would even be thinking about how would that support a registrational approach given the totality of the data we're going to be generating in the frontline setting. So more on that to come, but we think it's a very differentiated and innovative approach to this patient population.

The next question is from Jason Zemansky of Bank of America.

Congrats on the progress. Two, if we may. I wanted to return to the subject of Revuforj access. There was some discussion last year in the community that some plans were requiring step edits through one menin inhibitor. You mentioned there was some confusion over the relative cost of Revuforj. I was curious as to whether or not this was related? And can you speak to whether or not you're seeing any step edits throughout the universe?

And I guess secondarily, you mentioned that about 45% of KMT2A patients were resuming therapy post-transplant. I think last quarter, you cited a range of 40% to 45% of patients. Just curious what kind of gets you through that barrier of, I guess, 45%? Is this a case of sort of fast adopters and very cautious adopters? And really what's it take to get more of those docs on board?

Thanks, Jason. Good question. So let me start with your question about access, which I'll turn to Steve and he can address.

Yes. So as you know, the access is great, 97% across both indications, not only a high number, but it did it very quickly. So plans have been reimbursing Revuforj since the launch. So your point about step edits, and I did mention this in my comments, there's literally 3 plans that have step edits in place, and it's really restricted just to the 270-milligram dose. It's not a lot of patients. It's less than 1% of the overall.

And some of that came about on the monograph, which I also referenced in my prepared comments. Monograph that came out later part of 2025 and just had some incorrect information and made some assumptions just based on dosing that if you were to exclusively prescribe the 270 dose, you would have a higher WACC than the other menin competitor. We know that, that is not the case. In fact, most patients, 75% to 80% of them are not on that dose. So the WACC ends up being lower, about 15% to 20% lower than our competitor at the one dose that they have.

So since the monograph has been adjusted, they've corrected the fact base. They have removed the guidance on a step through our competitor at that dose and the recommendation is no longer there, plus they updated it for other reasons, clinical, nonclinical. So the information is there.

So the step that is in place is practically ineffective and physicians get to choose what they want to. So there's -- according to our information, there's not one patient that has had to walk through a step for Revuforj to date, and we don't expect that to continue moving forward.

Thanks, Steve. And I guess the second question relates to maintenance and how do you increase maintenance beyond the 45%. I'll just remind you that we've actually increased the use of maintenance throughout last year. So you saw it kind of go from about 1/3 of patients all the way up to 45%. It is steadily increasing.

But we do, as I said earlier, that data and real-world evidence will ultimately drive it. And we have a robust strategy in place to deliver to get to this steady state 70% to 80% point, which will happen at some point in the future.

We don't -- we can't predict exactly when I was a little off on my 50% prediction. I thought that would happen later and it happened more quickly. So we are very bullish on the fact that we will get there.

And all the data that we have coming out, and we're very focused on this should help physicians think through how best to dose patients and at what interval. And they're just -- some are very cautious about patients coming back from transplant, as you can expect, their engraftment period varies by patient. and physicians want to make sure that count recovery is well underway and that they're managing patients really effectively. So we help them with that, where there's lots of data that's coming out and ultimately, getting to that 70%, 80% should be quite achievable. So thank you.

[Operator Instructions] The next question is from Salim Syed from Mizuho.

Congrats on the quarter, guys and progress. I guess 2 from us. One on just MAXPIRe and then just the other one on the Revuforj chart you provided on Slide 4. On MAXPIRe, Nick, can you maybe remind us -- it's a robust study, but could you remind us what you're powered to show at the 26-week time point? I presume the powering was done on the 26-week and not the 52-week that you plan to model to. And then what the variability or standard deviation you're assuming on the primary endpoint? That's question one.

And then question two, just on Revuforj. I guess like one of the dynamics here, it looks like from this chart, which I thought was super helpful here. It looks like on KMT2A, you guys actually like maxed out sort of at this 200 new patients per quarter pretty quick. Are you anticipating the same sort of dynamic on NPM1 to max out with new patients per quarter within, I guess, like maybe 3 quarters here or so, 4 quarters? And what would be the underlying dynamic why you would max out so quickly?

Do want to answer the -- Nick.

Yes, Salim, thank you for the question on [ MAXPIRe too ], it's a good question. And what I would say is [indiscernible] specific -- statistical assumptions, but I would say it's a very well-powered study. So we plan to recruit 135 patients. We're actually slightly overenrolled because of the physician support. So we over enrolled by about 10 patients -- it's a 2:1 randomized study with an FVC primary endpoint, and it is well powered. And we'll look at an annualized rate, and we'll use the standard statistical modeling to report at the annualized rate.

Rather than what is powered for, what I would suggest to you is what we would want to see because we're actually looking for a fairly significant difference in order to inform a Phase III design. We're not looking for small incremental differences.

So in terms of the rate of decline, somewhere in the region of a 40% improvement in terms of the reduction in the rate of decline would be really meaningful. And that's the kind of -- based on historical controls, the sort of figures looking at the totality of the data we want to be looking at to inform a Phase III. And the study is well powered to be able to show that type of difference. So we'll let it read out and look forward to reporting those data in the fourth quarter.

And Selim, I think to your second question about dynamics on Revuforj, I'll just simply say that when you think about KMT2A and NPM1, we have not maxed out. I think KMT2A is continuing to grow, as I mentioned earlier, is this population of about 2,000 patients. These are -- so it's a rare disease. You need to find the patients. And I think we are getting as many as are available.

We are the only menin in that space. We have the best profile and physicians are recognizing that the drug works very well for these patients. So we expect to continue to build that market share well beyond what we're at. And every quarter is going to be a little bit different, but I feel very confident about that.

And then NPM1, same thing. There's no -- it's a much bigger market. As you know, it's about 2x to 2.5x the size of KMT2A and the opportunity there is large. So we expect to cover the whole universe and get as many patients as possible. This should continue to grow.

In NPM1, it's all about new patients. And then in KMT2A, it's about adding incremental patients quarter-over-quarter, new patient starts. But I would say the increase in maintenance is a -- in transplant, as we talked about in maintenance is going to be a big driver of growth for that segment as well.

I guess my question is more at the rate that they're coming in and it looks like that's what's not -- they are not the number of total patients, but the rate that they're coming it seems pretty consistent here [indiscernible].

Yes. We talked about a consistent rate of new adds, right? So we're not -- it's I wouldn't say we haven't -- we'll continue to penetrate and build. It will be a steady new rate of patients coming for KMT2A, NPM1 should be slightly different, larger market and new patient starts will be more -- certainly in the early stages of launch be more dramatic. But I think the businesses and the way the business actually accrue revenue are slightly different as we talked about.

Our final question today is from the line of Andres Maldonado from H.C. Wainwright.

Congrats on the progress. Just 2 quick ones for me. First, a quick follow-up on axatilimab in IPF. I guess, could you provide a little bit more color on how we should be thinking about the Phase II readout as primarily an all-comer [ ESC ] study? Or is there a biological subgroup such that patients with maybe more monocyte/maybe macrophage-driven inflammation, where you expect to break out just based upon the fact that the CSFR1 mechanism is stronger there?

And then maybe an underlying question for Revuforj. I guess as we look at the NUP98 kind of opportunity, I guess, what would you need to see clinically to treat this distinct expansion opportunity rather than just a scientifically interesting, but commercially smaller subset?

Andres, thank you very much for the questions. I'm going to let Nick get into the IPF question.

Yes, it's a very interesting and relevant question. Of course, we'll analyze the intent-to-treat population. Our expectation is that we'll see a benefit across all comers. These patients are treated on a background of antifibrotics. So we have stratified for by the type of antifibrotic they're on, whether it's nintedanib [indiscernible] or no antifibrotics. So we will look at that, and we'll look at those subgroups.

But given that we know about patients that have high levels of monocytes and high levels of CSF1R, we are expecting that this populate and that, that is correlated with a poor prognosis in IPF, we are expecting that the -- the benefit would be seen across the intent-to-treat population. So that would be our expectation and what we would be planning to do with the Phase III. But certainly, we will look at subgroups accepting in a smallish Phase II, it's difficult to tease out differences in subgroups.

And I'm happy to talk a little bit about NUP98, [ while it's just a start ]. Just from a clinical perspective, we have, as you already know, presented data on a small subset of NUP98, where we showed that 3 out of 5 patients had a form of morphological remission, which was very encouraging.

We are planning to present additional data this year. I mean, biologically, it makes complete sense for these patients with NUP98r that they should benefit from Revuforj. We've seen that across the spectrum. And as we plan to publish further data this year, certainly, considerations for submitting for the consideration of NCCN guidelines would be something we would be thinking about. So that's the plan based on the data we've seen for this subset.

And we probably estimate it to be somewhere around 5% of the baseline of AML. So it's not an insignificant subset and clearly an area of high unmet need because these patients tend not to do very well.

Yes. I think that's -- as Nick said, 5%, I think it's an under -- it seems to be somewhat an underdiagnosed area. We hear this from physicians regularly now that Revuforj could be a good option for them. We've been following the HOX/MEIS signature, gene signature, which has kind of yielded NPM1 and now NUP98 and there may be other subsets.

So the ability to expand even beyond, call it, 50% of AML is potentially possible. And we feel like we're on the cutting edge to make this part of -- hopefully part of the portfolio. So we'll follow up on that, but thanks for the question.

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. Thank you all. We appreciate everyone tuning in today to discuss our recent progress and the exciting milestones ahead. We look forward to seeing many of you at the upcoming ASCO and EHA medical conferences and of course, several investor conferences in the second quarter as well. With that, have a great evening, everyone.

Hello, again, everyone. My name is Etzer Darout. I'm one of the Senior Biotech analysts at Barclays. It's my pleasure to have Syndax Pharmaceuticals with us for our next fireside chat. With me today, I have Michael Metzger, Chief Executive Officer; Keith Goldan, Chief Financial Officer; and Nick Botwood Chief Medical Officer. Thank you, gentlemen, for joining me.

Maybe Michael, just to kick us off for those less familiar with the story, maybe just provide an overview of Syndax and then we can jump into Q&A.

Sure, happy to do so. Etzer, thank you for having us. Thank you to Barclays for kind invitation. Syndax is now a commercial-stage organization, a company focused in oncology, two leading products, one for acute AML and ALL in specific subsets, KMT2A, acute leukemia for adults and pediatrics as well as NPM1 acute leukemia. So these are, together, they cover about 50% of the market for acute leukemia, and that's a real step change in terms of what you can target as a modality.

So these are a menin inhibitor to remind people the class of drugs. We are leading the class in terms of being first to market, also have best-in-class profile. So really important setup. We launched the drug in late '24, had a banner year last year in terms of sales, product is growing very nicely through the fourth quarter and into this year. So we're excited about the forward. We have lots of development to do with the medicine and well positioned for success.

And now, next, we have Niktimvo, which is for chronic GVHD. And another new mechanism for these patients is indicated in third line plus patients and it's a CSF-1R inhibitor for which introduces something new to the market in terms of being both an anti-inflammatory and antifibrotic agents broad profile, and also off to a terrific start. We launched that product in early '25 in less than a year, $152 million in sales, growing very nicely in the fourth quarter as well.

So two growth products within the hematology/oncology space and the leading position in order to take advantage of what comes next, which is development for both molecules and excited to be here today to talk about that.

Great. And on the market sort of experience that you've had so far with Revuforj, you've talked about the duration of therapy. Obviously, this is a driver for all indications in terms of being able to sort of drive revenue. And you've indicated perhaps longer duration in 2026 versus 2025. What are the key leading indicators that you could point to that would help you to again, add the metric for how that's doing and whether or not you can reach sort of that longer duration of therapy goal?

This medicine has become quickly the standard of care for patients who have KMT2A acute leukemia. Now we have a new indication with NPM1 launching at the end of last year. So this will, we believe Revuforj will be the standard of care for NPM1 in relapsed/refractory disease as well.

Key to both opportunities, of course, is to treat as many patients as possible to do that, you need to treat them as early as possible because it is a very serious illness. And so treating them second and third line, we've seen the majority of our patients get treated there relative to where they were treated in clinical trials, which was mostly fourth and later lines, which is customary of how clinical trials go. But now in commercial practice, we see second, third line.

We expect that to continue to build. So even the vast majority of patients from here will be treated in second line for both indications. And so that will allow for patients to get to transplant, stay on drug longer, ultimately do better. And when you bring them back for the key to -- at least for KMT2A is to bring these patients to transplant many of them are very young. And so you want to be able to bring them to transplant and then put them on maintenance therapy. That maintenance therapy is a key component to duration of response, and we've seen patients out 3 years on our therapy.

So that will be a key part of how this builds over time, and we did talk about 4 to 6 months of an average duration in year 1, where you have fewer patients being able to experience maintenance because it takes some time to go through your transplant process. and then come back for subsequent therapy. So we expect that to build in 2026 and beyond. In '25, it was 4 to 6 months. And in '26, we think it will be in the 6 to 12 months once you factor in the impact of maintenance.

So we're off to a very good start in that regard. But that -- I think treating them earlier is a key component to that and obviously, getting them to transplant.

Right. And obviously, another question is competition as more menin inhibitors entered the space. And I think with any drug, as more competitors enter the space, physicians now have to kind of triage the decision tree in terms of who gets what. And I guess as you speak to physicians, how are they thinking about Revuforj? And then where are the touch points that you think are going to be important or critical to continue to drive uptake of a Revuforj?

So we have a wonderful commercial and medical organization who cover the entire universe of physicians. We've had the best data. Our label covers all of the indications adults pediatrics, AML, ALL with regard to Revuforj, now NPM1 as well as KMT2A. So we have the broadest label with the best efficacy in the class the ability to bring the medicine to as many physicians as possible and support broadly with new data, right, bringing combination data, real-world data.

We've been able to do that throughout '25, and we expect to be doing that again and even more significantly in '26. That will allow us to give physicians the full flavor of how they can use it as both monotherapy and also in combination. And then, of course, you need to carry through and really create that partnership with physicians, which we've done so well in the first year, you have the ability to get them the drug in 4 days. The drug is completely covered from a payer perspective and quickly. So we were we're in a very good position to deliver on the promise of the drug by actually delivering it to the patients. And so we're in a great place in order to continue to be the product of choice for physicians as they come across any patient in any particular situation.

Great. And maybe a question for Keith. Obviously, capital allocation across the commercial platform is important, but also sort of thinking about how to leverage that spending versus that of the pipeline? And just maybe how you're thinking about supporting beyond commercial story, right? And then, obviously, being able to allocate enough resources to the pipeline.

Yes. I mean one of the fortunate pieces of our business model is that we do not perform discovery research. Both of our assets, Revuforj and Niktimvo were both in-license and it allows us to keep our operating expenses controllable and relatively low.

So we've made a commitment to keep our OpEx flat this year at $400 million for SG&A plus R&D. That's consistent with last year. And that still allows us to fully invest in maintaining our leadership position in the menin inhibition space. Co-promote Niktimvo with our partners at Incyte and also maintain our leadership position in the race to the front line in combination for both products really.

The one of the reasons we're able to do that is because unlike any biopharma or SMID-cap that I know of our size, we were able to capitalize on two successful launches, and both are quickly contributing really nice gross margins that helped to offset the burn in commercial and in R&D.

Great. And maybe some of the combo use that you talked about previously, it seems to us that -- I mean, at least anecdotally from the information that you're giving us that the combination is combo friendly, if you will. Maybe what features you're seeing with Revuforj in combination use that are again, advancing this, it seems that sort of ramping up of the combination use of the drug.

Yes, for sure. I'll let Nick address the combinations have obviously been very exciting.

Thank you, Etzer. Thank you for the invitation, it's nice to be here. Revuforj is obviously approved as a monotherapy. But interestingly, we're seeing a lot of uptake and use outside of its currently approved indication in combination. And obviously, we're not promoting in that setting. But I think what we're learning is that there is a clear physician desire to use the drug in combination. We have reported in real-world evidence last year that interestingly, from Moffitt Florida Cancer Center. Actually 80% of the patients that were treated in a combination, either a combination with ven/aza or a single-agent combination agents.

So it's clearly an attractive proposition for physicians and patients. And I think the reason that they want to do that is if a patient is felt they can tolerate it, then you do get higher response rates, upwards of a 70% or 80% response rate as opposed to around the 50% response rate for monotherapy. So it's a desirable thing to do.

Now what makes Revuforj particularly attractive as a combination therapy. The first thing is that we have now established across a variety of different standards of care that you can combine at the currently approved dose. So we've established that it's tolerable and you don't really get any incremental toxicity by combining them when it's carefully managed according to current guidelines. And that's, I think, the first consideration that you can combine safely and at the currently approved dose.

The second is that, as I've said, you get these response rates, but you also get these really deep responses. So we've reported that in those patients that respond, whether they're being treated with Ven or ven/aza or an as combination or an even intensive chemotherapy combination. They get very profound reduction in the minimal residual disease. A lot of these patients become MRD negative, and that allows a greater number for these patients to get to transplant.

So these are attractive features. It's also, I think, helpful that in terms of drug-drug interactions, we have a very clear dose modulation for patients on CYP3A4. That's actually very helpful because it allows for leveling out PK exposure. But importantly, you don't need to make any kind of adjustment for patients on antacids or PPIs, which are very common concomitant medications for these patients getting potentially a chemotherapy combination. So I think that the experience that physicians now have in the real world, the fact we've been on the market for as long as we have has really supported that use in combination makes it an attractive option.

And as you think about combinations, we also think about earlier line use of Revuforj. Think about like the must wins and as you're executing on your front line plans, we hear about MRD negativity, event-free survival, transplant, getting the patients to transplant. What do you view as kind of the key wins, if you will, as you think about the endpoints that we should be paying attention to as the data starts to roll out in those frontline.

No thanks. It's an important question. I mean the first thing I'd say is it's got to be safe in combination. We're always focused on safety and make sure the patients are well managed in clinical trials. And we've now established across, in fact, four Phase Ib studies. So our own 708 study, which was a combination with intensive chemotherapy, a study with the NCI and then two studies, SAVE and BEAT AML, respectively, with Ven and our hypomethylating agent that the drug can be combined safely at recommended doses with the appropriate monitoring and guidance. So that's the first consideration.

So we'll ensure both rapid enrollment in the first-line studies, but also that the studies enroll with high quality and a focus on safety. And then in terms of endpoints, I think there are a number of endpoints that are important, and we've built these into the Phase III. One of the endpoints that's becoming increasingly thought about and utilized is the concept of complete response rate or in the instance of patients treated with intensive chemotherapy complete response rate with MRD negativity, which is kind of probably the most stringent criteria that you've eradicated disease. And there is increasingly evolving body of evidence that supports. If you can get a patient into a complete response or in the case of fit patients and CR with MRD negativity, that's going to correlate very well with time to event endpoints.

The gold standard, of course, for all of these frontline studies is to improve the survival, actually improve the outcome for these patients hope that they will live better and longer lives. And that's the endpoint that we have built into our unfit study because we believe it's achievable.

And we have generated very encouraging survival data already from our BEAT AML study. Even though the follow-up was really very immature, we've shown over 15 months median overall survival, which compares really somewhat favorably with historical controls, if you accept those studies have a much longer follow-up. And we anticipate updating those data later in the year.

And then the other endpoint that we'll look at, which again is an important endpoint is event-free survival. So this is again a surrogate and you would expect it to track with overall survival. But in the setting of patients that are fit for intensive chemotherapy demonstrating a survival benefit is quite difficult, simply because it takes a long time. And we'll look at it. But the dual primary endpoint of that study is event-free survival. So this is how we're approaching it in our frontline program.

And the fit KMT2A study, I guess the RAVEN study, you opt for the lower intensity approach versus sort of high-intensive induction. What's the clinical bar there that you think you need to achieve so that instead of, "Oh, well, this is just a less toxic combination" versus truly one that could be a new standard of care? How are you thinking about the bar there?

Yes, I'm excited about this study, and it's a very nice complement to our pivotal program because we want to continue to innovate and lead. And I think overall, we've presented the most compelling data in combinations for KMT2A. And based on, if you will, the kind of the evolving approach to how these patients are being treated, we felt that this was a very important, as I say, complement to our pivotal program that could generate data that might inform clinical practice and offer a differentiated option to patients that are fit and would otherwise get intensive chemotherapy.

So Etzer, to your question specifically, the idea of this study is for patients who are fit with KMT2A. As Michael said, these tend to be a younger fitter population. The idea is to get them to transplant. But maybe be able to get them to transplant with less of the morbidity and toxicities associated with giving them intensive chemotherapy. There was a nice study at the plenary session at ASH last year from Amir Fathi, the PARADIGM study that suggested that this might be a reasonable approach. Our hypothesis is that if you add revumenib, you may get even more patients to transplant.

Now the proportion of patients that get transplant in that setting is quite high already. It's probably 70% or so. We will compare it in an innovative way to sort of baseline of how many patients are getting to transplant to see if at the very least, we can replicate or maybe even improve the number of patients getting to transplant, reduce the amount of toxicity. And then we'll track the number of patients that are then able to go on to maintenance. And ultimately, as we were speaking about earlier, what the event-free survival looks like.

So these are the criteria that will go into that study, and we really think it could be a really meaningful study for patients and offer a viable, better tolerated therapy with equally good or potentially even better outcomes.

Great. Myelofibrosis, I think, is an interesting opportunity. You've previously highlighted some encouraging preclinical data around the role menin inhibitors could play in this space? And I guess how are you thinking about the decision points, how to more maybe when to more aggressively pursue myelofibrosis versus the investments you're obviously making in AML?

Sure. Yes. And maybe the first thing to say, I mean, these are very exciting data that we generated in collaboration with John Crispino in his lab they got best of ASH. Clearly, a lot of interest in the hypothesis of menin and the role of megakaryocytes and its role in myeloproliferative neoplasia. So we're really building on that. I mean, these are early days from a clinical perspective. We haven't announced our clinical trial program, but we will be announcing that this year, and we'll be working with some of the leading cancer centers and consortium treating MF because of the interest that's been generated by these data with revumenib. And the fact everybody is very familiar with revumenib as a leader in the menin space.

So we'll talk about the studies. But what I can share with you is that we will be looking, obviously, at monotherapy initially to see if we can replicate the preclinical findings, the in vivo or the in vitro data that was generated both as a monotherapy, but also interestingly in combination with a JAK inhibitor. And there's a lot of innovation in how you inhibit JAK and why the combination should be synergistic. And so our clinical program will include, obviously, initially patients with relapsed MF but moving rapidly into a more frontline population in combination with current standards of care and potentially other novel targeted therapies because there's a lot of innovation in this space.

And then we'll be looking at a series of classical endpoints we'll be looking if we can improve the symptomatology associated with MF. So [ hardness ], anemia, weight gain, we'll be looking at splenomegaly and whether we can reduce the splenic volume reduction 35. And then ultimately, more disease-modifying measures like aberrant allele frequency. So we'll look at JAK2 alleles. We'll look at bone marrow fibrosis scores to see if we're really modifying the disease. And based on the preclinical findings, we feel pretty confident this could potentially be a very interesting life cycle management opportunity and bring a new treatment option for patients with MF.

Great. Maybe spend a few minutes on Niktimvo in the remaining time. I think it's fair to say that, that drug has continued to surprise to the upside. And -- maybe just initially, where you're seeing the drug really work best? I mean you think about different patients with GVHD, order involvement, inflammatory heavy fibrosis heavy patients? Where are you seeing sort of where that drug is working best?

Yes. So this is mostly used now in the fourth line, as I think the first year, we penetrated fourth line well. We're starting to see great uptake in the third line about 20% as of last quarter. So we think this has a lot of growth in the relapsed/refractory setting. And certainly, we're developing it. We have trials ongoing one pivotal, one Phase II trial in combination with Jakafi and also with steroids. So we'll have a lot of data coming on the use in combination. But as a monotherapy, we've been really making great headway in terms of bringing this to patients.

But I think two areas that seem to be a focus for potentially even using it earlier would be the lung manifestations that we see with GVHD, chronic GVHD which the drug has demonstrated very good ability to reverse inflammation and fibrosis in those patients. And so we've done some work on Bronchiolitis Obliterans Syndrome and syndrome, which we published, which shows this effect. And that's been potentially an area of focus. And of course, the sclerotic skin that can be very difficult to treat as well in GVHD, the drug as well. in those patients, too.

So it has a very profound effect across all the different organ manifestations. But I think in particular, those types of patients seem to be a choice for physicians that they would go into use axatilimab product.

Great. And Incyte running new combination programs with rux with steroids. I think 2027, 2028 time frame for readouts. I mean what defines success for the trials. When you think about response rates, deeper multi-organ responses, steroid sparring other areas. Where do you think -- how should we predefine success in those studies?

Yes. Maybe just say firstly, that these are very important studies in the life cycle of axatilimab in GVHD and really position us very strongly to move axatilimab potentially into earlier lines of therapy. And based on the activity we've seen and the data Michael was talking about, we feel quite confident when you combine them, there's a very high probability that these studies will be favorable and successful.

Now in terms of what specifically, we'll look at, they're slightly different in terms of their design. We have a study that's in combination with current standard of care, which is dexamethasone. And this is, frankly, an unsatisfactory standard of care. Patients have to receive high intensity dexamethasone initially, either intravenously or orally and then they have a tailored response to dexamethasone over sometimes several months, but sometimes it can be out to 18 months. And there are significant sequela of treating patients long-term.

So we have a combination study with axatilamab combined with dexamethasone, which will have a primary endpoint of event-free survival. So the hope is we're going to actually improve the efficacy. The mechanisms are quite complementary in terms of their impact on the immune system. Dexamethasone obviously has widespread, but it's predominantly, I would say, anti autoimmune through action on the T cells. Whereas axatilamab is more targeted down to kind of monocytes to monocyte-derived macrophages. So those potentially are quite complementary, which may offer a nice option.

So we'll look at event-free survival, but we'll also look at whether it's actually possible to tailor patients off of their steroids sooner, which will be a huge win for patients because of all of the morbidity associated with long-term dexamethasone.

And then the Phase II study, which is a 3-arm study is a very interesting concept because -- it has three arms, one of which is with Jakafi alone. And then it asks the question does axatilimab at to JAK inhibition and so you get a kind of contribution question addressed. And then you asked the question, well, does that combination actually offer an alternative to having to give steroids at all? Now that has a standard response rate criteria that you can assess response quite quickly at day 28 in GVHD to know whether patients are responding or not. And that's an attractive option to potentially move in terms of guiding clinical practice, axatilamab into a frontline setting.

Great. Maybe a couple of questions on IPF. Obviously, it's very topical, folks who want to get a sense around bar and other questions. But maybe first question, assuming Phase II success. How should we think about potential Phase III design of that study? And as well as what potential role could we see a subcutaneous formulation play in the development of IPF and how we should think about a potential subcu coming online?

So yes, very excited about this Phase II study called MAXPIRe, which will read out second half of this year. I think given the totality of the science, we have a high degree of confidence it may read out favorably. We set the bench quite high in terms of what we'd like to see. That will guide the design of the Phase III to your point. We are planning for success. I mean we're doing as much as we can to expedite the start of a Phase III study, should the study read out favorably.

Obviously, it's a double-blind placebo-controlled study. So we have no insights to how it will read. But given the totality of the evidence, we're optimistic. So we are planning for success. The Phase III, as you say, the assumption is we would start a Phase III with a subcu formulation. We do have a subcu formulation in development.

The size, powering and the design of the Phase III is obviously not finalized, it will be somewhat dependent on what we see in the Phase II. So more on that to come. But our expectation and ambition would be to if a favorable outcome to start the Phase III as quickly as we can.

And you've outlined the cost sharing expectations around with Incyte assuming the Phase II study works. Have you talked about specifics around decision rights, funding responsibilities and the like around that, again, assuming success with the Phase II?

Yes we have very established ways of operating with Incyte within our agreement and cost sharing 55% for them, 45% for us for U.S. development. So that's all well understood. In terms of going forward, assuming a positive trial, we would assume that we would go forward in working together on the IPF indication, and that means everything from subcu development to Phase III to funding. So there's a lot of work to do, and we expect to be doing it with our partner under the confines of our existing agreement.

Great. Looks like we're up on our time. Michael, Nick, Keith, thank you so much for your time, and thank you for our listeners for their participation. We'll talk again soon.

Thanks.

Thank you.

Thank you.

Good day, everyone, and welcome to the Syndax Fourth Quarter 2025 Earnings Conference Call. Today's call is being recorded. [Operator Instructions].

At this time, I would 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 Fourth Quarter and Full Year 2025 Financial and Operating Results. I'm 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; Steve Closter, Chief Commercial Officer; Dr. Nick Botwood, Head of R&D and Chief Medical Officer; and Keith Goldan, Chief Financial 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 2. Before we begin, I'd like to remind you that any statements made during this 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 Factors section in the company's most recent Form 10-K as well as other reports filed with the SEC. Any forward-looking statements made represent our views as of today, February 2026 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. Good afternoon, everyone, and thank you for joining us. Starting with Slide 3. I'm pleased to share our fourth quarter and full year financial results following a transformational year that positions Syndax for continued growth in 2026 and beyond. In 2025, we demonstrated the exceptional strength of our commercial and R&D capabilities, successfully launching 2 first and best-in-class medicines and achieving our third FDA approval within the span of approximately 1 year. 2025 was a remarkable year for Syndax, and we have only just started to unlock the potential of our first 2 medicines.

Let's dive into our commercial results for Revuforj. In the first full year of sales, we generated robust top line results, delivering $125 million in Revuforj net revenue in 2025 and further solidifying our leadership in menin inhibition. Notably, we ended the fourth quarter with 38% growth in Revuforj net revenue and 35% growth in prescription quarter-over-quarter, showing strong demand and momentum heading into 2026. Two main factors drove this impressive increase in demand. First, continued growth in our KMT2A business as the number of patients on therapy post-transplant begins to meaningfully stack. Second, growing uptake in relapsed/refractory NPM1 mutated AML following the FDA's approval of our expanded label at the end of October.

Our launch into NPM1 is off to an excellent start, building on the solid foundation we established through our launch in KMT2A, including a robust prescriber base that has extensive experience and comfort using Revuforj. We are confident we will win in NPM1 with a best-in-class product profile, including the broadest label and unmatched efficacy data, together with strong customer relationships and excellent market access.

Turning to Niktimvo and chronic graft-versus-host disease or GVHD. Fourth quarter results were strong with a 22% increase in Niktimvo net revenue quarter-over-quarter. This continued growth reflects a steady stream of new patient starts and a high percentage of patients staying on therapy. Niktimvo net revenue for 2025 reached $152 million in the first 11 months of launch, tracking ahead of the 1-year benchmark set by Sanofi's REZUROCK, which reached $500 million in annual U.S. net sales within the first 4 years of launch in the same indication. Niktimvo's outperformance highlights its unique ability to address both fibrosis and inflammation. As we expected, Niktimvo contributed significantly to our bottom line in 2025. Our 50% share of the Niktimvo product contribution totaled $42 million in collaboration revenue to Syndax in 2025. As Niktimvo sales continue to ramp, while much of the expenses -- the expense base stayed largely fixed, we expect to retain an even larger proportion of Niktimvo revenue over time.

Altogether, Syndax revenue reached $172 million in 2025. Achieving this result in our first year as a commercial company underscores the significant unmet needs we are addressing and our ability to execute at the highest level. We remain confident in the continued success of both launches supported by multiple growth drivers that Steve will discuss shortly. Importantly, we remain well funded to continue investing in our strategic priorities to fuel the next phase of growth. This includes advancing our life cycle and frontline programs to expand our patient impact and unlock more than $10 billion in total addressable market opportunity.

On the clinical development front, we made significant progress advancing our pipeline in 2025 and recent months. In addition to achieving a second FDA approval for Revuforj, we were also the first company to initiate enrollment in a pivotal frontline trial of a menin inhibitor, positioning Syndax to be the first to frontline. We also delivered the first real-world evidence for a menin inhibitor, among many other achievements that advance our scientific leadership and the body of evidence supporting our medicines. More recently, we completed enrollment in MAXPIRe, a robust Phase II trial of axatilimab in idiopathic pulmonary fibrosis, or IPF, a disease with high unmet need, which affects a large patient population. This trial has the potential to demonstrate axatilimab's utility in IPF and provide further rationale for its mechanism in a disease -- in a number of diseases with similar manifestations.

We've made remarkable strides advancing our mission and building Syndax into a leading oncology company with 2 successful commercial launches gaining momentum, important upcoming data readouts and multiple exciting opportunities for label expansions, we are positioned to make a major impact on patient care and deliver long-term and sustained growth.

With that, I will turn the call over to Steve to discuss our commercial progress in more detail. Steve?

Thank you, Michael. Starting on Slide 4. Now as Michael noted, we reported strong results from our launch of Revuforj. In the first full year of the launch, we delivered $124.8 million in Revuforj net revenue, well above launch benchmarks set by other AML therapies, even though KMT2A translocations are less prevalent than some other targetable mutations in AML. As we enter year 2, we expect to continue to outpace other therapies and redefine success in this space. Our conviction is supported by our recent label expansion, which enables us to now target a substantially larger population than other AML therapies as well as multiple dynamics that are expected to meaningfully extend treatment durations.

In the fourth quarter, demand for Revuforj accelerated throughout the quarter, resulting in $44.2 million in Revuforj net revenue, up 38% from the prior quarter. New patient starts were up about 20%, driven primarily by uptake in NPM1, bringing us to approximately 1,050 patients treated commercially since launch. With the vast majority being KMT2A patients, we approach 50% penetration of the KMT2A incident population within the first year of launch, which really is an outstanding result. Total prescriptions were up approximately 35% from the prior quarter. The increase was driven by new NPM1 patients and continued growth in KMT2A as the pool of patients on therapy post-transplant expands. The percentage of Tier 1 and Tier 2 accounts that have ordered Revuforj also increased in the fourth quarter with more than 80% of these accounts now activated, up from 70% in the third quarter.

In addition to an increase in the number of the largest academic centers ordering, the overall number of accounts ordering also increased, reflecting growing uptake in academic centers of all sizes and community practices. The growth in our prescriber base following the label expansion reflects physicians' enthusiasm to prescribe Revuforj to their NPM1 patients and positions us to drive further penetration in both NPM1 and KMT2A.

Turning to Slide 5. There are multiple factors that will drive continued Revuforj growth in the near term. The first driver is growing uptake of Revuforj in relapsed/refractory NPM1 mutated AML, our second indication, which triples the size of our annual addressable patient population to a total of 6,500 patients. Our launch into NPM1 is off to a fantastic start, building on our broad and growing prescriber base and excellent market access coverage. Physicians are enthusiastic about our data in NPM1 and the results they've seen with Revuforj in their patients. Like we achieved in KMT2A, we rapidly established reimbursement in NPM1 with formulary coverage now complete at 97% of all lives covered just 4 months after approval well ahead of typical industry time lines.

Regarding our ramp in NPM1, we began to meaningfully add new NPM1 patients following the addition of Revuforj to the NCCN guidelines for relapsed/refractory NPM1 mutated AML towards the end of September. The latest available data suggests we exited the third quarter with NPM1 patients representing about 20% of our new patient starts. That's up from our original estimate of approximately 10% across the third quarter. Now while data are still maturing, early indicators suggest that at least 30% of new starts in the fourth quarter were, in fact, NPM1 patients.

Looking ahead, we will continue to expand our NPM1 business and are confident we will capture dominant market share and further cement our leadership position in menin inhibition. Our confidence is underpinned by our unmatched efficacy data, excellent customer relationships and a growing body of clinical data that differentiates Revuforj, including real-world evidence. The second driver is the robust transplant rate in KMT2A and growing use of revumenib post-transplant. We estimate that approximately 1/3 of KMT2A patients treated with Revuforj have proceeded to a stem cell transplant with physicians putting their patients back on Revuforj after a 3- to 4-month pause for engraftment. And the latest claims data suggests that approximately 40% to 45% of these patients have now restarted Revuforj, and that's up from 35% to 40% reported last quarter.

We expect this percentage will continue to increase as more patients complete the engraftment period and additional data is reported by leading institutions that are building experience with Revuforj in the post-transplant setting. Based on what we observed in our clinical trials and feedback from physicians, we expect patients could stay on therapy for 1 to 2 years post-transplant, given the high risk of relapse and the favorable tolerability of Revuforj. The third driver is continued use of Revuforj in early lines of treatment and growing use in combination with other therapies. Claims data show that approximately 70% of usage is in the second and third line among patients treated for active disease. This is important because when patients are treated earlier, you expect to see higher response rates, longer durations of response and a higher percentage of patients proceeding to transplant.

Claims data also show about 40% of usage in combination with other therapies, and that's up from 33% in the third quarter. While Revuforj is approved and promoted as a monotherapy, the growing combination use highlights physicians' comfort with the Revuforj profile and could extend treatment durations. All these evolving treatment dynamics have an important impact on the average duration of therapy. In 2025, the first full year of the launch, the average treatment duration was in the 4- to 6-month range. As treatment patterns continue to mature in the second year of the launch, we expect this to extend to 6 to 12 months. We have everything we need to continue building a sustainable business with our first 2 indications for Revuforj, which together represents a $2 billion-plus market opportunity, as you can see on Slide 6.

Turning to Niktimvo on Slide 7. The fourth quarter was another strong quarter for Niktimvo with $56 million in net revenue, up 22% from the prior quarter. 2025 net revenue reached $151.6 million, surpassing first year launch benchmarks set by REZUROCK. From the start of the launch through the end of the fourth quarter, approximately 13,500 infusions have been administered to more than 1,400 patients. We continue to receive excellent feedback from HCPs on the rapid and durable impact they are seeing with Niktimvo on fibrosis and inflammation across organ systems.

Turning to Slide 8. There are multiple drivers for continued Niktimvo growth in 2026. First, continued adoption in the fourth line and growing usage in the third line. In the first 11 months of the launch, we estimate that we captured approximately 20% of the third line plus chronic GVHD market. While this is excellent progress, we still have significant room to continue growing and bringing the benefits of Niktimvo to more patients. Second, this is a chronic disease with the potential for patients to stay on therapy for long durations. Persistency rates are high, with approximately 60% to 70% of patients who started Niktimvo in the first quarter of 2025 remaining on therapy at month 10.

Our clinical trial experience shows that the duration of therapy can be measured in years for a meaningful proportion of patients. Third, we have a robust prescriber base, and Niktimvo has strong commercial synergies for both Syndax and Incyte. 90% of bone marrow transplant centers in the U.S. have prescribed Niktimvo with all centers placing repeat orders year-to-date. With multiple drivers for further growth, we are well positioned to expand our impact in third-line plus chronic GVHD, a $2 billion U.S. market opportunity as shown on Slide 9.

In summary, we've made tremendous progress in our first year as a commercial company. We successfully delivered 2 novel medicines to thousands of patients and advanced the company towards profitability in the process. This is just the start of the impact we can make for patients with Revuforj and Niktimvo.

With that, I'll hand the call over to Nick to talk about our pipeline.

It's a pleasure to be on the call today to discuss the important milestones ahead and update on our pipeline. So if you turn to Slide #10, we're laser-focused on executing the programs that will characterize the full therapeutic potential of our medicines. Starting with revumenib. We are advancing an integrated evidence generation plan to rapidly deliver practice-changing data across the acute leukemia spectrum as well as leading global registration programs in the newly diagnosed setting.

Some of the key trials are shown on this slide, and I would like to highlight a few key points. First, global enrollment is underway in our pivotal frontline trials of revumenib, and we are positioned to be first to the frontline with pivotal data. Importantly, our frontline strategy is supported by compelling Phase I/II data showing high rates of response, MRD negativity and favorable tolerability with revumenib in combination with low or high-intensity chemotherapy regimens. Among the patients who are eligible or unfit for intensive chemotherapy, enrollment is underway in EVOLVE-2. This is a Phase III trial of revumenib in combination with venetoclax and azacitidine or ven/aza newly diagnosed NPM1 or KMT2A patients.

EVOLVE-2 has dual primary endpoints of complete remission and overall survival based on the NPM1 population to support the potential for accelerated and full approval, respectively. In the fit NPM1 population, enrollment is underway in REVEAL, the Phase III trial of revumenib in combination with intensive chemotherapy. REVEAL has dual primary endpoints of MRD-negative CR and event-free survival to support the potential for accelerated approval and full approval, respectively. In the fit KMT2A population, we are pursuing a novel approach. In addition to generating further data with intensive chemotherapy, we are progressing the RAVEN trial in collaboration with clinicians at the forefront of menin clinical research. This innovative Phase II trial will evaluate revumenib in combination with ven/aza in newly diagnosed KMT2A patients who would be considered fit for intensive chemotherapy. This trial builds on the strong activity observed with revumenib in combination with venetoclax and hypomethylating agent in KMT2A patients.

RAVEN has the potential to advance the standard of care for fit KMT2A patients if the efficacy outcomes are similar or superior to what is typically seen with intensive chemotherapy combinations, but without the associated toxicity. The second point I'll highlight is that 2026 will be another year in which Syndax will demonstrate a strong presence and scientific leadership at every major medical meeting in our field. Specifically, we expect to report additional data from the ongoing Phase Ib/II trials of revumenib combinations in the frontline setting, including an update from the BEAT AML trial in the second half of the year. We also look forward to additional data presentations on the clinical use of revumenib in the post-transplant maintenance setting, an area of growing scientific interest as well as further real-world evidence collaborating with leading institutions across the United States.

At last year's ASH, we saw the first of what we expect will be a growing body of data from centers looking at outcomes with revumenib in a post-transplant maintenance setting. Investigators from MD Anderson presented real-world data from 10 pediatric patients with KMT2A or NUP98r acute leukemia who received revumenib as maintenance after their stem cell transplant. They reported that revumenib was well tolerated with encouraging early efficacy. At a median follow-up of 19 months, all the patients were alive and 90% were relapse-free. Also at ASH, investigators from the City of Hope presented the design of a Phase I trial evaluating the safety and preliminary efficacy of revumenib given as maintenance for 2 years post-transplant in adult and pediatric patients with NPM1 or KMT2A acute leukemia. This trial and others will provide important data to inform future research and clinical practice.

With over a year of commercial use, we and our collaborators are well positioned to deliver impactful real-world evidence supporting revumenib clinical use. Investigators from Moffitt Cancer Center presented the first real-world evidence for revumenib and the menin therapeutic class at ASH. Their data showed an overall response rate of 77% and MRD negativity rate of 75% among patients with relapsed/refractory NPM1, KMT2A, NUP98r acute leukemia who received primarily revumenib as part of a combination therapy.

This usage highlights the clinical value of having a therapy with activity across multiple genetic subtypes, a differentiating feature of revumenib's profile as well as physicians' comfort combining revumenib with standard of care therapies. They also reported patients proceeding to stem cell transplant and the majority resuming revumenib post-transplant. In addition to observing excellent clinical activity overall, revumenib was well tolerated. We expect Moffitt to report further data this year as well as other centers with extensive experience using revumenib in clinical practice. These will be important data sets that help -- that further help to differentiate the breadth of revumenib use and provide practice-informing data to physicians.

Turning now to axatilimab, I'll highlight 2 key points. First, in partnership with Incyte, we are working to expand axatilimab's impact in chronic GVHD with 2 ongoing trials in newly diagnosed patients. One of these trials is a Phase III of axatilimab in combination with corticosteroids with top line data expected in early 2028. The other is a Phase II trial of axatilimab in combination with ruxolitinib with top line data expected in early 2027. Second, we continue to make progress advancing the development of axatilimab beyond chronic GVHD. Earlier this year, we completed enrollment in our Phase II trial of axatilimab in idiopathic pulmonary fibrosis, or IPF, and are on track for top line data in the fourth quarter of 2026. Given the high interest in our IPF program, I will review some of the key evidence supporting this program and outline the Phase II MAXPIRe trial design.

So turning to Slide 11. Monocytes and monocyte-derived macrophages are a promising target in IPF. A growing body of evidence supports that circulating monocytes migrate to the lung and become pro-fibrotic inflammatory alveolar macrophages, which drive the fibrotic process. Research has shown that these monocyte-derived profibrotic macrophages are CSF-1 dependent. Axatilimab is an IgG4 monoclonal antibody, which was specifically optimized for diseases with an inflammatory and fibrotic component. It blocks a specific extracellular domain on the CSF-1 receptor on the surface of monocytes and macrophages, preventing their activation by CSF-1 and interestingly, IL-34. This reduces the levels of circulating pro-fibrotic and pro-inflammatory monocytes and monocyte-derived macrophages and therefore, inhibits the activity of pathogenic macrophages in tissues. By targeting B cells, axatilimab has the potential to provide a more pronounced impact on the fibrotic process than other therapies that target alternate pathways.

Slide 12 outlines the multiple lines of evidence that support the potential for axatilimab in IPF. Firstly, it has been shown that higher monocyte levels are associated with shorter overall survival in IPF and other fibrotic diseases. In addition, preclinical bleomycin mouse models of IPF show reduction in lung fibrosis with CSF1R inhibition. Most notably, we observed remarkable antifibrotic activity with axatilimab in chronic GVHD patients. Responses were observed across all organ studies, including organs with fibrotic manifestations of the disease, such as the lung and skin. Among patients with lung involvement who received axatilimab at the dose we are studying in our IPF trial, nearly 50% achieved a lung response and over 90% reported improvements in shortness of breath at rest. Leading experts in IPF with whom we have consulted, including some who are also participating in the trial are enthusiastic about axatilimab's mechanism, the compelling results in chronic GVHD and its potential in IPF.

Slide 13 shows the design of the MAXPIRe, a Phase II randomized, double-blind, placebo-controlled trial of axatilimab in approximately 135 patients with IPF. The inclusion criteria are similar to other recently reported IPF trials. The primary endpoint is the annualized rate of decline in forced vital capacity or FVC measured at 26 weeks. This is a well-designed Phase II trial that has the potential to provide robust proof-of-concept data for axatilimab in IPF to inform a pivotal registrational program. We have an exciting year ahead as we continue to pioneer the broad development of menin and CSF1R inhibition 2 mechanisms that hold tremendous promise for patients.

With that, I will hand the call to Keith to discuss the financials.

Thank you, Nick. Earlier this afternoon, we reported detailed fourth quarter and full year 2025 financial results and I'll highlight just a few key points on Slide 14. Total revenue for 2025 was an impressive $172.4 million, consisting of $124.8 million in Revuforj net revenue, $42.4 million of Niktimvo collaboration revenue and $5.1 million in milestones and royalties. In the fourth quarter, Revuforj net revenue increased by 38% compared to the third quarter. This growth was driven by demand as inventory levels remained within the 2- to 3-week range we previously guided to. We expect continued growth over the coming quarters with the fourth quarter approval in NPM1 and an increasing average duration of therapy in KMT2A patients.

Turning to Niktimvo. It was a meaningful cash flow contributor to Syndax in 2025. From the $151.6 million in 2025 Niktimvo net revenue reported by our partner, Syndax recorded $42.4 million in collaboration revenue after deducting the cost of sales and commercial expenses. We expect the Niktimvo margin contribution, defined as collaboration revenue recorded by Syndax as a percentage of Niktimvo net sales to be in the 25% to 30% range in the near term and increase longer term as sales grow while much of the expense base stays largely fixed. We expect continued robust sales growth given the high unmet need Niktimvo is addressing and the potential for patients to stay on therapy for extended durations.

As previewed at the JPMorgan Conference in January, we expect 2026 expenses to be stable compared to 2025. We have guided to total R&D plus SG&A expenses in 2026 of approximately $400 million, excluding the impact of $50 million in estimated noncash stock compensation expense. And we expect expenses throughout the year to be relatively flat quarter-to-quarter.

Turning to the balance sheet. We are well funded to continue investing in our commercial and development priorities with $394 million in cash, equivalents and marketable securities at the end of 2025. With a robust balance sheet, growing revenue from 2 medicines and stable expenses, we expect to reach profitability without the need for additional capital.

With that, I will hand the call to Michael for closing remarks.

Thank you, Keith. 2025 was a landmark year for Syndax in which we solidified our scientific and commercial leadership. Looking ahead, we are laser-focused on driving revenue growth and delivering on the clinical milestones shown on Slide 15 that will fuel further innovation and value creation. We are in an excellent position to deliver on our commercial objectives with multiple drivers for near- and long-term growth of both medicines. Demand for Revuforj is accelerating as we expand into a second larger patient population and the number of patients on therapy post-transplant begins to stack.

Revuforj is uniquely positioned to be the menin inhibitor of choice in the relapsed/refractory setting and the first menin inhibitor approved in the front line, unlocking a $5 billion-plus market opportunity. Niktimvo is annualizing at over $200 million and is a meaningful contributor to our bottom line within the first 11 months of launch. We have ample opportunity for further growth in our first indication and trials are underway in frontline chronic GVHD and IPF that could be -- could open transformational multibillion-dollar markets for Niktimvo.

I will close by expressing my deep gratitude to the patients in our trials, our dedicated Syndax team, collaborators and long-term investors. Their unwavering support has made it possible for us to advance our mission at this -- to this point and continues to power Syndax's long-term success.

And with that, I would like to open the call for questions. Operator?

[Operator Instructions] Our first question will come from Anupam Rama with JPMorgan.

This is Priyanka on for Anupam. So last month at the JPMorgan Healthcare Conference, it was noted that usage in the KMT2A maintenance setting post-transplant was in the 30% to 40% range. Today, we're seeing about 40% to 45% having resumed treatment post-transplant. So what factors are driving the increase in such a short time?

Priyanka, thanks for the question. Look, the growth in KMT2A has been fantastic. And I think the post-transplant maintenance has been a big factor in the growth here. And we're talking about patients that are going to transplant right now at about 1/3 of patients going to transplant and then more patients continue to come back for maintenance. And so that is a growing phenomenon, and we've gone from 35% to 40% and now 40% to 45%. So it's continuing to step up quarter after quarter. And that's what we would expect. We would expect this to continue to grow, get us to even a higher watermark. This is something physicians want to do and believe in, and we're seeing the results quarter-over-quarter.

Your next question will come from Corinne Johnson with Goldman Sachs.

You mentioned that about 30% of patient starts are coming from NPM1 in terms of like the early data reads through this quarter. I guess, what do you think that should be at steady state? And then maybe separately, you obviously completed that enrollment in the IPF study. But could you remind us what you're looking for in order to determine a go-forward decision on that indication? And how does that decision get made between you and your partner Incyte?

Great. Thanks, Corinne, for the question. So maybe the first part, I'm going to make a comment and turn it over to Steve. Right about now 30% plus NPM1 as a percentage of new patient starts. We do expect that to grow. I mean we're off to a fantastic start. We have best profile really anchored by efficacy and great tolerability. Physician awareness is high. So we're feeling that, that number will grow meaningfully throughout this year. And Steve, I don't know if you make any other comments.

I mean the only thing to add is we've seen a progression of this. We know in previous quarters, it was a much lower percentage, the NCCN guidelines. We talk about third quarter, which is probably closer to 20% new patient starts, Corinne. So 30% is our best estimate based on the data we have. It is going to go up meaningfully. We know the NPM1 population is larger than the KMT2A population. So it will likely pretty quickly go to 50-50. In the end, it's going to be more NPM1 patients simply because there's more out there. But to reiterate what Michael said, we love the start. We love the reaction we've gotten in the fourth quarter. We haven't had a full quarter yet of promotion. We're seeing more accounts prescribed. Formulary access is, as I mentioned on my prepared comments, at 97% that's just a couple of quarters -- a couple of months in, the same as it is on KMT2A. So in a great spot, a lot of momentum at the end of the year carrying over into January.

Great. And Corinne, your second question related to IPF. I'm going to let Nick make some comments about what will essentially put us in a good position come the readout on IPF, Nick.

Yes. And first, I would just say it's a very well-designed and robust Phase II study. So it will give us a clear proof of concept that will inform. And we'll obviously look for both statistical significance, but also clinical relevance against historical controls. The primary endpoint of the study is forced vital capacity or FVC. In terms of absolute measures, just based on what we've seen from recent studies, something of the order of 40 mls difference at the 26-week primary endpoint annualized to about 80 to 100 ml when you analyze that out. Or if you benchmark it against Fibrnir, which showed across its 2 dose levels, a relative difference of about 23% to 38% something in excess of 40% would be both statistically significant and clinically meaningful.

But we are really looking for some sort of incremental change that would be extremely competitive versus currently approved standards of care. And based on all of the preclinical and clinical data that I went through in the prepared comments, we're feeling really quite confident in both the design and the outcome of this currently double-blind, placebo-controlled study that we hope to read out at the end of this year. So those are the sort of benchmarks we'll be looking for.

Yes. And lastly, I'd add that I think you had a question about our partner and how do we make the decision to go forward beyond the data. But I would just say that our -- both us and our partner are eagerly awaiting the results of this trial, and we're in a great position to elect to go forward. And I expect that upon a positive result, both Syndax and Incyte will work together on the rest of the program, Phase III and launching that.

Your next question will come from Claire Dong with Jefferies.

So just kind of a follow-up question on the IPF trial. Let's say, if it reads out positively in the fourth quarter, can you talk about what's the fastest and realistic path to a pivotal trial and eventual approval? And then if the data is positive, how are you thinking about the next indication? And what criteria are you using to prioritize for the next indication?

Thanks for the question. I'll just make a comment and turn it over to Nick. Look, we would be as expeditious as possible in designing the next trial and executing on that. We haven't guided yet in terms of time lines for the next trial, but obviously, this would be a very important result for the franchise. And so we look to start a trial very quickly. Nick?

Yes. And just a few additional considerations. One is that we would be planning a Phase III with a subcu regimen. We have a subcu regimen of axatilimab in development. We feel that, that would be an important element of a future Phase III and approval. Based on the robustness of the Phase II design, we are only anticipating the need for one pivotal Phase III in IPF. We feel that would be sufficient to confirm what we see in proof of concept, assuming the study is positive. And obviously, our intent is to have Phase III enabled for as soon as we possibly can after the end of Phase II. So we are planning for success, all of the enabling work that we can do ahead of time we are doing whilst we await that signal. So we haven't guided, as Michael says, to the start of the Phase III, but those would be some considerations. The one other point I would make, of course, is that we'll have a very good statistical sense of the margin of benefit, which allows us to power Phase III appropriately, and I hope quite aggressively on the basis that we're really looking for a step change in clinical benefit.

Your next question will come from Josh Bowen with Guggenheim.

This is Josh on for Brad. So as you guys continue to capture patients earlier on in the disease course, you have more patients on combinations and more making maintenance, should we think about the overall contribution of each of those components to the trajectory towards that 6 to 12 months duration range you guys are noting for 2026?

Josh, thanks for the question. As you noted, combination use is growing. So we're seeing about 40% of our patients, and that's up from prior quarters, about 40% of our patients treated in combination, which is a great sign that we're treating them also earlier in the treatment regimen, which, of course, as was noted in, I think Nick's comments or Steve's comments, as you treat patients earlier, they tend to do better and stay on drug longer, and that's a recipe for success. Combinations allow that to be possible. So we do believe that, that number will grow over time. But of course, monotherapy is the basis of our approvals and how we're anticipating the drug will continue to be used as well. So a big part of our future. But as you approach frontline, that's really where combinations are going to become even more important. And we have, of course, the most data in the field around combinations at this point, and the drug has been very well tolerated and also showing great efficacy. So we're in a particularly good spot there.

Your next question will come from Phil Nadeau with TD Cowen.

Congrats on the progress. Two from us. So first, in terms of maintenance therapy, I think we're hearing at ASH that there was some question on the appropriate dose of Revuforj in maintenance. It seems like with use increasing, maybe those questions are subsiding. So are physicians comfortable with what dose they should be using in maintenance? And then second, on the strategy for moving Revuforj into newly diagnosed fit KMT2A patients, you talk about that a little bit more? It seems like you're betting on the Revuforj plus ven/aza trial. Is that a little risky in that intensive chemotherapy seems to be the standard of care today. So why not do a registration trial in combination with IC?

Yes, Phil, thanks for the question. First part of the question was related to maintenance therapy and our physicians now comfortable with the dose, given that maintenance use is increasing, I would say, yes, right? That's an easy one to answer. And I do think that we've done a lot in the field to look at real-world data and other publications in order to support the use of maintenance. And I think the specific dose has come up as a question, and we're trying to answer that, and we'll continue to answer that. Nick, you might want to comment on that.

Yes No, thanks, Phil. And actually, we had a trial in progress, you may recall at ASH last year from Dr. Ball, City of Hope. We hope that data to read out this year. This is a Phase Ib/II study actually looking at the optimizing the dose in the maintenance setting. It's dose escalating, we should be able to report that out. Currently, the standard dosing for maintenance is the same as our approved dose and indeed, it is the same dose that we take in combination with either ven/aza or intensive chemotherapy, which is the 160, 270 dose. Of course, physicians are allowed to dose modify as they need to, to manage any cytopenias in the maintenance setting. But I think that Phase Ib will be informative when it reads out in terms of the optimization of dose and maintenance. But that's where we stand with that. And then maybe I jump to fit KMT2A. Why don't you handle it.

So Phil, the thinking with RAVEN, and firstly, we -- I would say that we have by far the broadest data set with KMT2A in combination with both intensive chemotherapy and HMA regimens. And it was really the basis of the compelling nature of those data that we set out our program in the front line that really includes all of the areas. So recall that we have a randomized study planned in collaboration with the NCI, which will be with intensive chemotherapy for the KMT2A. And we think that's a very valuable collaboration building on their Phase I experience. As you know, we reported data from Phase I with the NCI at ASH. So that will be happening. Recall, of course, that KMT2A patients are included also in our EVOLVE-2 study. The primary endpoint is powered for NPM1 because, of course, for unfit patients, NPM1 is the predominant population, but KMT2A patients will be included, and we will be doing a sensitivity analysis that includes KMT2A.

And then really based on the evolving or changing perhaps clinical practice for fit KMT2A, we really wanted to innovate and felt we were in a good position to do that, working with leading academic centers. And there was some interest in combining with ven/aza even for fit patients to reduce morbidity because we really believe you will be able to get those patients to transplant in the same way as you would with intensive chemotherapy, but perhaps without all of the associated morbidity and toxicity that you might get from an IC plus menin combination. So that is an innovative approach that we really feel could move the standard of care forward, and that's what we are focused on, and we really want to continue to innovate with the thought leaders in this space.

Maybe just a follow-up. So could the NCI trial or EVOLVE-2 result in a label for first-line in combination with IC?

Yes. It's very much data dependent. I mean those could be practice informing, guideline informing or potentially label informing. It's going to depend on the outcome. It's going to depend a little on the patient population. So it will depend. We have, as I say, a broad program, including KMT2A, and it will depend on what we see.

Your next question will come from Stephen Wiley with Stifel.

I guess it looks like Niktimvo's sequential growth here in 4Q hasn't really slowed that much relative to 3Q, which seems to be a bit interesting for a second mover IV drug. So what anecdotes are you seeing? And are you thinking any differently about how long you might be able to see double-digit sequential growth for this franchise? And then I just have a follow-up.

Stephen, thanks for the question. Yes, we agree Niktimvo is off to a -- it's had a great first 11 months exceeding benchmarks, and we see continued growth into this year for sure. So we're feeling quite good about quarter-over-quarter. But Steve, do you want to make something?

Yes. Great question, and the drug is off to a great start. I think the reason why it's serving unmet need that hits what hallmarks of the disease with fibrosis and inflammation, you've got an account base that there's not that many BMT centers in the country. Nearly all of them are writing and the effort that we have against it between Incyte and Syndax is pretty tight, but these are priority accounts and we support them, and we're seeing good dynamics, not just in new patients, but also in terms of persistency. So this is how these brands grow. There's a wide swath of patients at launch and then the goal is to bring in as many new patients as possible on a monthly basis, and we're consistently doing that. So it's going to feed itself and the product is going to perform as expected. We'll start to see durations increase. It's not uncommon for ultimately patients to be on for not months, but years. So those are the dynamics we'll see at play. So I would expect to see steady growth, if not increasing in the near future.

Okay. And then I know you and Incyte made a presentation. I think it was at ATS last year, looking specifically at Niktimvo and BOS chronic graft versus host disease for AGAVE. And just wondering if you can talk a little bit about the biological similarities and dissimilarities between that indication and IPF. Is one more fibrotic? Is one more inflammatory than the other? I'm just trying to think about how that data set should bode for translation into IPF.

Yes, excellent question. Thank you, Steve. I'm going to turn it over to Nick.

Yes. Actually, there's a lot of underpinning similarities in terms of the biology. I mean both are associated with both inflammation and fibrotic changes. Both of them are associated with increased numbers of circulating monocytes and macrophages. So whilst as you rightly point out, GVHD, pulmonary manifestations tend to be more obstructive in their pattern. You get a more restrictive pattern in IPF. We feel a high degree of confidence that what we saw in those bronchiolitis obliterans syndrome, pulmonary manifestations of GvHD is quite a good analog for IPF. We've also seen axatilimab cause really quite remarkable reductions in inflammatory cytokines like TNF, TGF-beta, IL-10, et cetera, which is also very encouraging.

Interestingly, there are some recent publications, Blood 2025 for some of the currently approved drugs in IPF that have shown activity in GVHD as well. And that kind of cross reference does suggest that there are some common underlying pathologies, which we believe is the case that gives us a lot of confidence that what we've seen both preclinically and clinically with axatilimab will translate very well into IPF.

Your next question will come from Mayank Mamtani with B. Riley.

Congrats on the progress. Maybe I can stay on the IPF topic, if I may. So you are testing the lower dose here, at least relative to the 1 mg per kg GVHD trial. So maybe just comment on what you have seen in the dose response maybe from the AGAVE study before. And I also noticed you stratified by pirfenidone or nintedanib exposed patients. So how you expect to have sort of that powering between the 2 stratification? And is the Phase III trial also potentially going to be 26 weeks versus maybe the 52 weeks you usually see in IPF?

Yes. Go ahead, Nick.

So maybe start with the last one first. So a planned Phase III would have a standard FDA and other regulatory authority endpoint at 52 weeks. That would be the standard. So that's straightforward. We've annualized our Phase II, which is an accepted methodology, and we have a very robust statistical model for doing that. That's the first question. Your second question related to dose.

Dose response.

The dose response, yes, sorry. Yes, this is actually very good because we had a very clear dose exploration in the AGAVE study where we explored 3 different doses and clearly showed that the lower dose 0.3 mg per kg was the most well tolerated, but also interestingly the most effective. And that applied equally in the patients that had bronchiolitis obliterans syndrome, which we've actually presented those data, where if you look at the 0.3 mg per kg, nearly 50% of the patients actually had a response using standard NIH criteria and 90% of those patients at the lowest dose had an improvement in their symptoms at rest, which is very encouraging. So we feel pretty confident that the dose that was approved for GVHD is the appropriate dose to be testing in IPF as well.

Your next question will come from Etzer Darout with Barclays.

Just quickly going back to an earlier comment. Just wondered what you're seeing with regard to the most common combo agents being used currently? And then also exiting sort of the quarter, what average duration of therapy are you seeing? And how does it differ in NPM1 patients versus KMT2A patients?

Yes, Etzer. Thanks for the question. So first, the combination agent, I think it's -- we're being used in combination with ven/aza probably most often. We're seeing with other combination agents as well. IC is another, obviously, with chemotherapy. So -- but I think we'll start to see that expand as time goes on. But right now, I would say the majority of the combination use is more often with ven/aza. Then in terms of average duration of therapy, I think we talked about 2025 would be in the 4- to 6-month range for rev, and that's squarely where we were. So I think we're not going to comment on this year yet. We're in this quarter, but we're encouraged by what we're seeing. We said that would extend to 6 to 12 months, and we feel good about that as well. So I think that's the average duration of therapy. Was there a third question?

Your next question will come from David Dai with UBS.

Perhaps on the quarter. So we're a little bit encouraged to see the post-transplantation maintenance use increased to 40% to 45%. So what do you think would be a reasonable percentage at steady state? And then just on the IPF, axatilimab, how should we think about the competitive landscape, especially given that we have Tyvaso as well as Insmed, TPIP, both are inhalation. How do you think axatilimab could differentiate among the competitors?

Thanks, David, for the question. So first, in terms of increased -- the movement in increased post-transplant maintenance, now at 40% to 45%, up from 35% to 40%. So that was last quarter. Look, I think this is -- it's a great question, where could this go? We would expect this number to meaningfully increase over quarters. And so could be 70%, 80% of patients based on what physicians tell us, they want to put all their patients back on maintenance. However, we know that there are extenuating circumstances where some patients won't be able to go on maintenance. But we expect somewhere in the order of 70%, 80% of patients could go back on maintenance in this setting. And that's obviously a sea change. Nothing has ever been able to -- no drugs have been able to accomplish that, certainly for KMT2A patients. NPM1 patients will receive less -- fewer transplants and of course, in turn, less maintenance as well. But overall, that would be a very meaningful change for these patients. And then in terms of IPF, Nick?

Yes. I mean I think the first thing to say is that, I mean, IPF remains an area of high unmet need. The benchmark is not very high, and we have optimism that axatilimab may actually bring a degree of disease modification, delaying early inflammation, potentially preventing fibrosis, maybe even reversing fibrosis, which you'll see. We have some evidence from certainly wound healing that there seems to be some reversal of both inflammation and some of the fibrosis you see in some of the sclerotic changes of the skin. So the bench is not very high. Most of the currently approved standards of care just delay the deterioration in FVC to an extent. We have to recognize as well, axatilimab has a very unique mechanism of action. It's really targeting the macrophages as we talked about, most of the other agents are targeting fibroblasts. So that brings a very differentiated profile.

And then as I mentioned, if we -- as we plan for the Phase III, we would be planning for a subcu regimen. It would be Q2 or Q4 potentially based on the data we generated. Some of the other currently approved agents are quite difficult to prescribe inhalation, sometimes 4 puffs 3 times a day, I mean, they're quite onerous for patients. So we think a subcu regimen in Q2 or Q4 could be really quite competitive in terms of its profile. So I think those are the things which would differentiate us at the end of Phase II with a positive signal.

Your next question will come from Yigal Nochomovitz from Citigroup.

I just had a question on the real-world dynamics. So the combo use of 40% and the 70% second line or higher, are those percentages sort of steadily growing? Or do you see that as relatively stable for the time being until you generate evidence from those settings in the clinical trials?

Thanks, Yigal, for the question. So look, I think it's very encouraging what we're seeing in the real world. And I think the combo use 40%, I would -- we would expect that to grow, right? And then in terms of -- Nick, do you want to comment on that?

Well, I would just say that we will be presenting some updates from the real-world data we presented at ASH at Moffitt through this year and also some further real-world series from other leading academic centers across the U.S. And what I can say is that the trend from those centers at least is that there is a desire to use it in combination because we've seen a higher response rate in CR/CRh. And for physicians and patients that can tolerate a combination, there is a desire to give them a combination because of those increased response rates. And I think as we generate more data and we present more experience from the real world, that will drive increased use because of those better outcomes. And we've also established it's very tolerable to give in combination.

Okay. And just one follow-up. Is it fair to assume that those metrics, the 40% and 70% are roughly similar across KMT2A and NPM1 or are there any notable differences there?

In terms of combination, I think we're about the same. I think we would think they would be the same. 70%, it could be very high relative to how many patients go back on from transplant, yes, similar.

Your next question will come from Salim Syed with Mizuho.

A couple from us. Just one, I appreciate the commentary on the 30% of your new starts are NPM1. Could you help us just reconcile that from a share perspective? So if every 10 NPM1 patients coming into the funnel eligible for menin how many are you getting versus current right? Do you have any sense or any idea of what your share is there? And then just on the additional data that we'll be getting this year kind of related to Yigal's question, could you help us quantify what you think the halo effect might be in terms of uptake once you present that data for revumenib?

Great. Thanks. So maybe the first question, I'll turn to Steve about the market share dynamics.

Yes, Salim, thanks for the question. This is things we'll look at over time. It's going to take us a little bit of time to parse that out. So it's just too early to know. I mean our data points are the same ones you have, which is what they provided as sales volume last year, which we know was on the low side. Some of that's by stocking. Some of that presumably is demand, but it's very small. I mean that we do know. Physicians have a choice, and we know that they're going to pick Revuforj based on the profile, the dynamics, the experience, formulary access and use they've had in this NPM1 patient population. So our focus is on broadening the patient population for Revuforj to the biggest number of patients as possible regardless of a competitor or not.

And your second question, Salim, just maybe restate it, if you don't mind.

Yes, sure. Just kind of related to Yigal's question. Just when we got this additional data that you plan on presenting for Revuforj this year and some of the combination data, just sort of how you're quantifying the halo effect you can see commercially in terms of uptake?

Very important. I mean, look, we're continuing to pursue lots of collaborations. We have -- we talked about Beat AML. We talked about SAVE. We talked about several of these real-world evidence trials that we're generating with combinations, both in the fit and unfit settings. All of that, how we use the drug, maintenance, all of that is exceptionally important when it comes to utilization, whether we have indications there or not. And that will build as we get to the front line. We're enrolling very significant frontline trials. We expect to be first to frontline, and we'll have all the data supporting that with potential -- a potential for guidelines even before we get to frontline. So we have a very robust plan and as you say, a halo, which should accrue to us as we are the leaders here in this space.

Your final question will come from Jason Zemansky with Bank of America.

Congrats on the quarter. Just a quick -- 2 quick follow-ups, if I may, for me. In terms of your growth in NPM1 patients, can you -- or do you have a sense of how much of that represents a bolus of patients prior to the approval? And then I guess, secondarily, given that your competitor has been on the market just for a few months, can you at least qualitatively comment on whether or not you've seen an impact at all on your prescribing?

Yes. Jason, thanks for the questions. So maybe I'll let Steve address this question about growth in NPM1, kind of where we started and where we've kind of found ourselves. And then I'll come back to your competitor question in the end.

Yes, Jason. So in terms of bolus of patients, which you can see at launches of drugs, we certainly saw it at the launch of initially with KMT2A, there's this broad selection of patients that are on market that are available. And I think the best analogy I have for Revuforj, if you can consider KMT2A and the launch of the drug, it's a car to stop light, light turns green, you go with NPM1, it's a little different. You're kind of on an on-ramp getting on a highway and you're accelerating. So there's not going to be as pronounced of an effect on NPM1, meaning we've already captured some patients, and we know that an elevation of 10% in prior quarters of NPM1 use within Revuforj that accelerated in Q3 up to probably around 20%, and we're at least at 30%. So that's the ramp. I will say this, the number of new patients, we were pleased with what we saw. We continue to see that momentum roll into the first quarter of '26. So I feel like we're in a good spot.

Yes. And I'd just add relative to competition, look, we feel we have -- we're in a -- as Steve said, we're in a fantastic place. I can't say we felt much of an impact. We had a great fourth quarter relative to our competitor, what their sales were. So we expect, honestly, to dominate this space. We have a superior product profile, and I expect we'll have superior execution. So we're, again, going into the year with very strong enthusiasm about what we can achieve, and we're in a fantastic spot.

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.

Well, thank you all, and we appreciate everyone tuning in today to discuss our recent progress and the exciting milestones ahead. We look forward to seeing many of you at the upcoming conferences, TD Cowen, Jefferies, Leerink and Barclays. And so with that, have a great evening, everyone, and thanks for tuning in.

Okay. We'll go ahead and get started. Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, Priyanka Grover, Rati Pinhe and Joyce Zhouo.

Our next presenting company is Syndax and presenting on behalf of the company, we have CEO, Michael Metzger. Michael?

Thank you, Anupam. Nice to see everybody. Thanks for joining us. Thank you to JPMorgan for the invitation to present today. It's a pleasure to be here. Pleasure to see all of you.

Let's get started. So a reminder, today, I'm going to be making some forward-looking statements, and we'll jump right in here. So 2025 was a transformational year for the company. We've transitioned successfully to a commercial stage oncology company with the launch of Revuforj and Niktimvo, 2 first and best-in-class medicines with great promise for patients. And we've really proven that we've been able to deliver for patients, 3 FDA approvals in the span of about 14 months and a very strong launch for 2 drugs. Really our bed-to-bed side -- sorry, bench to bedside in about 4 years, which is sort of unprecedented speed, really shows the depth and commitment of our team to generate fantastic products, and we're here. So we've generated really strong results, and we'll talk about that today.

We have a lot of momentum going into 2026. We're on the road to profitability with growing revenue and stable expenses. And we have about $400 million on the balance sheet of which to really execute on all of our goals. We have 2 products in front of us that are not only approved, but we have very large market opportunities and differentiated product profiles in order to execute long term and the commitment to maximize value.

So let's start with Revuforj. Revuforj is the first and only menin inhibitor to be approved in multiple acute leukemia subtypes. It was first approved by the FDA in 2024 in November for relapsed/refractory acute leukemia with a KMT2A translocation. And the second indication, most recently in November of '25 for relapsed/refractory NPM1 mutation. I'll remind you, this is a disease of acute leukemia. These are perhaps some of the worst prognosis that you can have as a patient. So there's a very high unmet need and urgency to treat. And this is the market backdrop. So current Revuforj indications unlock perhaps a $2 billion total addressable market in the relapsed/refractory acute leukemia setting, 6,500 patients between the 2 subtypes. And as you approach the front line, you add -- get to about 9,000 patients. So an even bigger opportunity, really unlocking about $5 billion total addressable market.

We have a comprehensive clinical development program underway to unlock this total opportunity. And what's unusual about menin inhibition and specifically Revuforj is we're addressing about 50% of the acute leukemia AML market with a targeted therapy. I'll say it again, a targeted therapy, so we can select the patients that we can treat. And these patients through the use of transplantation, we can drive very high rates of response, drive patients to transplant and then put them back on for maintenance treatment. That elongates the time on therapy, keeping patients in remission for months, if not years. That extends the size of this market and changes it from a, what you'd call a niche AML market to a very, very significant one as $5 billion plus suggests. So we talk about Revuforj in terms of being really well positioned for success with a best-in-class profile and first-mover advantage. So best-in-class profile.

We have unmatched efficacy with our drug compared to other competitors in the class. And this is an efficacy-driven market. That means that physicians are, first and foremost, concerned with getting their patients to a response, a deep and durable response. And our drug allows that to be accomplished most often. It's been approved in multiple subtypes, as I mentioned. So AML, ALL, adult, pediatrics, we cover all the subtypes. This also allows for patients to be dosed individually. So we have different dosage forms that allow different amounts that can be dialed in by the physician, and the drug is extremely well tolerated. And it can be used concomitantly with other medicines. So physicians are not only using this as a monotherapy where it's approved, but they're also thinking about how to use it in combination. And our drug has shown itself to be well tolerated and effective with other drugs.

And also in the scheme of what other drugs patients are receiving, such as gastric acid-reducing agents, our drug does not have an effect on those agents. So it's a best-in-class profile, highest efficacy, really well tolerated and really is dialed in for the patient and physicians have recognized that. And we have first-mover advantage. So we were the first to be approved menin inhibitor. And so we have now a year plus on the market with robust and growing prescriber base.

It means a lot to be in front of physicians and working with them for a year. They become very comfortable with your drug. They prescribe it to their patients. And if they have good results, they tend to come back and prescribe it again. And that's, in fact, exactly what we're seeing with Revuforj in its first year. So we've built a competitive immunity and really an excellent, excellent trusted relationship with physicians.

We have really excellent market access. So we've been able to bring the drug to patient bedside in 4 days or less. That's industry best, and our reimbursement from payers is at a very high rate. It sits at about 97%, 98% for payers within KMT2A, and it's building exceptionally fast in a new indication for NPM1 as well. So we are making excellent progress not only to get the drug to patients but actually get it paid for in its first few months on the market.

And as I said, we are a trusted partner to HCPs. We put the patient first. We do everything we can in order to bring the drug to patients and physicians recognize that. And so when they're looking for something for their patients to treat them effectively and quickly, they come to us, and we deliver.

All right. So let's talk a little bit about our performance. We were -- I'm privileged to be able to preannounce our results as of today for the quarter and for the full year for Revuforj. The strong launch really underscores the exceptional product profile we have and really the wonderful execution of this team. So in fourth quarter of this year, $44 million in preliminary net revenue. That's up 38% from the last quarter.

I mean, put it a little bit in perspective, the last quarter grew at about 25%. We're now growing at 38%. So tremendous growth from a revenue perspective, which you would expect with a new indication and the dynamics around KMT2A. We've really built on -- and I'll also mention that the sales are really driven by demand. So demand is where you'd like to see growth, and we have that with the launch of this new indication as well as what we're seeing with KMT2A.

Inventory is stable, 2 to 3 weeks, and that's what we've guided to historically. It remains the same for this quarter. We've really built on what we've done. We have a lot of momentum, and we've built on what we've done with KMT2A. The launch of NPM1 is off to a fantastic start. And I would say it's driven also by the fact that physicians have great knowledge of the product. They've been using it for a year. Some of that use has been in NPM1, not on label, but it has built their confidence and understanding of how to utilize the drug. And they're very well aware, and we're welcoming when we sat with them at ASH this year and showed them the data. They were excited about the label, excited about bringing this to their patients. So that built a lot of momentum as we go into the fourth quarter. And you can see it here.

It really accrues in the TRxs where we had 35% quarter-over-quarter growth from last quarter. And for the full year, $125 million in full year revenue. And if you put that in perspective, this really surpasses all the benchmarks that we've seen for other AML therapies in the category, and it's not even really close. So we expect this to be a continued acceleration in demand and growth throughout 2026, and we have the team to execute on that.

So let's talk about some of the evolving clinical practice patterns that we see that we believe will help to grow the brand into 2026 and beyond. So first of all, there are really 3 things. First, I'll mention movement to earlier lines of therapy. Patients are being treated and physicians have said this from the beginning, they're treating them in the second line and third line primarily. So the majority of our patients are being treated earlier.

Why is that important? It's important because if you treat them earlier, they tend to have a higher rate of response. They do better, they stay on drug longer, have an opportunity even to be transplant. So it really drives -- the earlier treatment drives the utility of the drug. And we've also seen physicians give the drug in combination. It's a growing phenomenon. That's what they told us they wanted to do. As you move towards the front line, those are combinations with drugs like venetoclax as well as chemotherapy, and we're starting to see that use build. This all accrues to longer duration of therapy.

Second key point, we're building this transplant rate in KMT2A. Historically, KMT2A patients in the third line have about a 5% chance of being transplanted. In our clinical trial, we were about 25% transplanted. We're now at about 1/3 transplanted. We expect that number could go to 50% or higher. That would be an incredible result for these patients who have perhaps the worst prognosis in AML.

What that is usually followed by is post-transplant maintenance. Physicians told us from the beginning that they wanted to put them on long-term maintenance, a year to 2 year of maintenance. And that is precisely what we're seeing.

In the last quarter, we were able to see about 35% to 40% of patients going on post-transplant maintenance. Again, that drives the duration of therapy and really is good for patients. And then third, is this new indication. We've tripled the patient population by getting NPM1 approved. So we have really growing adoption. We see it in the TRxs growing adoption in NPM1. We have best-in-class profile in NPM1 as well as KMT2A. That will help us drive the brand. So these are 3 phenomenons that we think are very important to the growth of the brand in 2026 and beyond.

So let's talk about the future. So we've been first in a lot of things in the menin space. We are the first to clinically validate the menin inhibition. We were the first to get an FDA approval for a menin inhibitor with Revuforj in KMT2A. We were the first to receive an FDA approval in NPM1 relapsed/refractory AML. So we've done a lot of things first. We have a lot of momentum. We are -- we have a fantastic plan, and I'll tell you a little bit about that in a second. We have a great clinical development plan to drive utilization and get approval in the front line, and we have tremendous momentum to get there.

So let me tell you a little bit about our plans. So we're advancing the broadest data generation plan to rapidly deliver practice-changing Revuforj evidence and support global registrations. And there's a lot of trials on here, and I'll just hit some of the highlights on subsequent slides. But it's really a plan to generate a robust and differentiated body of evidence supporting Revuforj.

So let me start first with the relapsed/refractory piece of the business. We had AUGMENT-101, you're familiar with it because it yielded 2 approvals for both KMT2A and NPM1. That trial continues to pay dividends as we continue to look at that data. We also have combo trials that are coming through with practice-informing data. We presented 13 abstracts at ASH this year, one being the SAVE trial, which is in newly diagnosed patients. We've also had data in relapsed/refractory setting in combination. So these types of data will be really, really important to enable the physicians to choose what kind of combination and which kind of patients they want to treat their patients with.

Next is the maintenance and MRD relapse setting. This is a -- we have a robust data generation plan underway in collaboration with some of the leading academics and cancer centers in the country and around the world to really look at maintenance and look at MRD relapse as important uses of the drug in the future.

And then lastly, I'll talk about frontline. A lot of focus on frontline for us in the coming year. Encouraging data, which we've seen from -- in both the fit and unfit setting in combination. We highlighted Beat AML and the SAVE data, which I just mentioned, which are both for patients who are fit and unfit for chemotherapy. These are the next big frontiers for us as we unlock the largest opportunity. The EVOLVE and REVEAL trials, these are pivotal trials that are underway as of this year, 2025 -- last year 2025, and 2026, we'll accelerate that. And importantly, they have endpoints to support potential accelerated approval as well as full approval.

And then last, I'll mention the RAVEN trial, which is a highly innovative trial that's planned in fit KMT2A. This is a trial looking at venetoclax plus azacitidine plus our drug in patients who are usually fit for chemotherapy. The idea here is to be able to give them a less onerous regimen where we could have fantastic results and efficacy, but also spare the toxicity that you often encounter with high-dose chemotherapy. So a very innovative approach and robust to not only get to frontline and be the first to frontline, but also to fill in data in the near term over the next few years in these other settings.

All right. So let's switch gears and move on to Niktimvo. So this is our second drug. Niktimvo is poised to deliver on the promise of CSF1R inhibition in chronic GVHD and beyond. It's the first and only CSF1R blocking antibody to be FDA approved in the third line plus GVHD setting. Importantly, as a novel mechanism of action, affects the macrophage and monocyte and has an important impact on the inflammatory and fibrotic aspects of the disease. So physicians feel there's an unmet medical need in this category, and we're able to fill it with a new drug that has just excellent promise.

The feedback since the launch of this drug has been extremely strong. We've been hearing from physicians that it really fulfills on the need to impact various organs that are impacted from GVHD. And so this brings to bear all the things that we had hoped for a new agent in this category. Trials are underway in the first line to really unlock the opportunity in chronic GVHD and in other indications such as IPF, a very large opportunity, which I'll mention in a minute.

So just to look at the market where we are today, 6,500 patients currently treated in third line plus GVHD. It's about a $2 billion total addressable market for us in that indication. The opportunity is to expand to frontline where you really unlock larger amount of patients. We're talking 15,000 to 17,000 patients once you get to frontline worldwide, it could be significantly larger than that. And beyond just GVHD, we have this opportunity in IPF, as I mentioned, larger opportunity, 150,000 patients in the U.S. suffering from idiopathic pulmonary fibrosis and in need of new therapy.

So again, I'll mention the results that we highlighted this morning in our press release. Very strong results for Niktimvo, really underscoring the importance of this novel medicine to patients and certainly to us. Niktimvo generated $56 million in preliminary fourth quarter 2025 net revenue. That's 22% up from the last quarter and $152 million in preliminary full year 2025 net revenue. The company expects to share -- expects its share, which is 50%. We do have a collaboration with Incyte. We book about 50% of the net profit, which equates to about 25% to 30% of Niktimvo net revenue.

Niktimvo net sales are annualizing at greater than $200 million. It's not even its first full year of launch. It's about 11 months of launch. So this also really blows away other benchmarks in the category when you think about another drug, Sanofi's drug, REZUROCK is in their first year, did about $136 million, and we are already well surpassing that. So the contribution to Syndax is expected to grow materially as we move beyond what we've done this year and continue to penetrate, and it's a very important drug for the portfolio, as you can see.

So there are multiple drivers to continued Niktimvo growth in 2026. rapid adoption into the fourth line, that's primarily where we're penetrating today and growing utilization in the third line for GVHD. Second, I'd say patients are staying on therapy for a long time. This is not a drug they take for a month or 2. This is a drug they could take for years. We've seen it in our clinical trial where patients are staying on for multiple years, and we're seeing it play out that way in commercial as well. So you have patients from launch. Most of the patients from launch are still on therapy, which is remarkable. So that will build over time. It has a stacking effect in terms of building the brand. And so we expect that to continue.

And then last, I'll say that we have a very solid prescriber base, 90% of the U.S. bone marrow transplant centers are already prescribing. So again, very healthy set up for us as we grow the brand into 2026 and beyond. And of course, we have a very robust clinical development plan underway to drive growth. Chronic GVHD, 2 trials primarily. One is the Phase II trial, axatilimab plus ruxolitinib, otherwise known as Jakafi. Top line data is expected in this trial in the early part of 2027. And then a pivotal trial for AXA plus corticosteroids, top line data expected in early 2028.

And then I'll turn our attention to the idiopathic pulmonary fibrosis trial, MAXPIRe, the Phase II trial, AXA plus with standard of care. We are running that trial at a 26-week randomized, double-blind, placebo-controlled, multicenter primary trial with primary endpoint being a change in FVC and the top line data is expected in the second half of 2026, and we're excited about that result. Really, if that result is a positive result for the brand, it could be transformational.

So let's talk about 2026 priorities and anticipated milestones. So I would say that we've really accomplished everything that we set out to do in 2025. And that's not easy to say often. So we feel really, really terrific about what we've been able to accomplish, and we have a lot of momentum going into 2026.

So let me talk about a few of the milestones in '26 as we really are focused on generating value based on focused development and data generation in our pipeline. That's how you get the most out of these 2 very impressive drugs. So first, I'll say we're going to report top line Phase II axatilimab data in the second half of '26. Of course, I mentioned that just recently, just a minute ago. We're advancing our global enrollment in a pivotal first-line trial for Revuforj in fit and unfit patients. We're going to advance both of those and be focused there. We're going to continue to publish and present industry-leading clinical data, including revumenib data in frontline and the maintenance setting.

We're initiating this RAVEN trial, which is that innovative trial I mentioned for fit KMT2A patients. And we're going to initiate a proof-of-principle trial in a clinical trial with revumenib in myelofibrosis, a new area that we've had some data and very exciting data that was recently published at ASH this year. We're going to follow up on that. So with that, these are our anticipated milestones.

We feel like we have a tremendous amount of momentum going into 2026. I've never been more excited as a leader of a company to have the people at Syndax who are so dedicated and passionate about what we do. We brought 2 fantastic medicines to patients, and we've done it in record time. And now it's time to really build the opportunity and build tremendous value for shareholders and patients alike.

So with that, I'll turn it over to Anupam for questions. Thank you so much.

Thank you, Michael. I'll ask the first couple of questions, but there's going to be an opportunity for folks in the audience to ask a question as well. So feel free to do that. I was wondering, Michael, if you could put into context this first year of launch with Revuforj as it compares tracking relative to like historical analogs.

Yes. I mentioned a little bit of it in our -- in my talk. Look, this has been a year where we started fast, we ended fast. There really hasn't been any let up. Both brands have surpassed what we've seen with other analogs.

In AML, the closest analog did about $80 million. gilteritinib in its first year, we did $125 million. So it's not just the sales, though, it's scripts, new patients, it's formulary coverage is everything across the board. So it's execution. It's the drug profile, but it's also execution of this team. So very proud of that. And likewise, for Niktimvo, I mentioned our competitor who's also approved in third line, 136 in their first year. We did 152. Again, addressing more patients, patients are staying on longer. We're really doing something different in the category and hopefully better for patients, but that's what I'm most proud of, and I think it speaks to what we've been able to accomplish with these profiles.

I know you just launched NPM1, but what are you looking to learn in the next, let's call it, 2 to 3 quarters or a year where you might get comfortable in giving some sort of guidance to the Street in terms of what we should expect?

Yes. No, it's a new launch. And the way we think about it at least it's KMT2A, we have about a year of experience. We have NPM1. It's a bigger patient population, some different dynamics in terms of transplant, in terms of having a competitor. There are other factors. And so I think we need a little bit of time to sort through how that all kind of comes together. What's clear to us is we have a larger market opportunity.

We have a best profile. We are extremely well positioned to execute, and we're going to dominate this space. So it's not a matter of if, it's a matter of when, and we'll talk a little bit about as we go probably into -- when we get into the year, give more specific metrics on how we're building share and things like that. But now it's a little bit early to do it. I think we're -- based on the sales that you saw today, first quarter -- sorry, fourth quarter of this year, $44 million, up 38% versus last quarter, just speaks to the uptake that we're seeing in NPM1 and truly what we're seeing with KMT2A as patients come back on therapy in the maintenance capacity.

Maybe just then focusing in on KMT2A. I think on the third quarter, you've been talking last year about getting 50% penetration by the end of the year. Like where did you fall relative to that kind of commentary as well as now looking to 2026, how do we think about penetrating market?

Yes. We were pretty steadfast that we would get to about 50% penetrated in KMT2A. I'll remind you, there's nothing approved for KMT2A. We're -- standard of care also doesn't work very well. So patients are really in need of new therapies. So we're able to deliver that. And when you have that kind of dynamic, you have fast uptake. And so we've been able to penetrate about 50% of the KMT2A market. That's about 2,000 patients in incidents. So every year, unfortunately, for patients, you have about another 2,000 that you have to treat. So we will continue to penetrate beyond the 50%.

We've seen targeted therapies get -- some of the best have gotten up to 90% of a targeted market, and we think we can accomplish that over time. So that's the goal. We want to really penetrate as much as possible. And there's really nothing in our way to hold us from achieving that. So that's a continuing story, but we've gotten to where we wanted to get this year. Next year, we'll continue to push.

And then on NPM1, it's -- I know it's early.

It is.

But any anecdotal commentary you can have about the NPM1 market, what you're seeing? There is a competitor like you mentioned in the space.

Yes. We're seeing -- I mean the profile is really well received. I mentioned it in my remarks. We went to ASH. We had lots of really impressive meetings with physicians. They're very well aware of what this drug does in KMT2A and NPM1 is a growing understanding, but a lot of these physicians are already using the drug. They were using it before approval.

Now this is a real moment of excitement where they see the full opportunity in front of them. They can present or they can bring this to patients on label, they can combine it with other drugs. We're providing them with data beyond just monotherapy data to support their utilization. So the enthusiasm is real and the momentum we see is a result of that. So those are early days, but when they see best-in-class profile, they want the highest rate of efficacy. They want a well-tolerated agent. It covers all the subtypes. We're talking about KMT2A and NPM1.

We're specifically asking about NPM1, but adults and pediatrics, that's meaningful to them. They can bring the product -- one product to their patients. And so that's the momentum, that's the coverage, and that's what they tell us when we talk to them about how they plan to use the drug. So yes, we do have a competitor. You asked another competitor. Competition is good, right? It builds awareness in this marketplace. But we have, we think, a competitive advantage, not only being first, but having the best profile. So we think we'll dominate this category, no doubt.

Questions from the audience? Yes.

Congratulations. I have a question about Niktimvo which -- for chronic GVHD. I think you mentioned that you frequently give it -- sure. I think that you mentioned that you frequently give it over a period of time.

Yes.

Do you see continued response? Or do you see some of the organ systems failing to respond or becoming resistant to that therapy, which has happened with other kinds of therapy like this?

It has happened with other therapies. I think our experience thus far has been somewhat unique in the sense that we had -- in our clinical trial, our pivotal trial, we had the highest rate of response. And it's a little tricky how they score these responses in GVHD, as you probably know, it's multi-organ. You can't depreciate in any one organ, or you lose your response. So you really have to maintain a multi-organ response metric for a period -- a long period of time. And that's challenging.

We've been able to do that, and that's why we can be confident that patients are benefiting. And I think the key marker for benefit is are they staying on drug? Are they -- are physicians keeping them on drug? We dose patients every 2 weeks with an IV or every -- or once a month. And so we have a dose every 2 weeks that's approved, and we've shown data that allows patients to stay on -- go on for once a month. So I mean, what we've seen so far in the commercial practice is about 70%, 80% of patients are still on drug from launch. So we're talking about 11 months.

We expect, and we've seen in our clinical trials, patients on for 3 years plus, like a lot of patients. We're talking about a very high portion of the patients on for many years. So that's, I think, the proof here. I mean if they're not benefiting, physicians are going to take them off therapy. And that's the unfortunate thing in GVHD where patients tend -- they go on therapy, they need therapy, and then they lose satisfaction with those therapies because they stop working, become resistant, what have you. So they need new therapy.

We're offering something new with a new mechanism of action that enables that. So, so far, we've -- it's been going quite well. It's supported by the clinical data that we have generated, and we expect that to manifest in the real world as well.

Questions from the audience? So on Niktimvo, you alluded to that ASH presentation, which I thought was pretty interesting on the monthly dose versus the every 2-week dose. Where is the monthly dose in the treatment paradigm? You obviously have the label for every other week, but the docs seem open to using it in certain situations.

They are open to it. We explored it in our pivotal trial. It's not in the label. But what I can say is that we've had data, we followed up with data. We presented that at ASH, very supportive of a monthly dose. It's essentially the same dose that we give every 3 weeks that's approved, just twice as much, right? So it seems to be safe and effective. It's up to the physician. But so far, it's a convenient dose, and it's something that they're starting to use more regularly in clinical practice.

And then in terms of line of therapy for Niktimvo, are you -- where are you, third, fourth? Are you seeing any movement into second?

We are. I think primarily, we're penetrating fourth line as a new agent in this category. It's approved for third line plus. I think the majority of use is in fourth line, which is a great place to start. There's high unmet need, and there are plenty of patients to start there. We're also seeing use in third line. So we expect that to build in 2026 as we penetrate more fourth line, third line. And we are seeing some second line. Jakafi is approved there, so that's standard of care.

I think what will drive utilization in earlier lines is, of course, combination data, and we're generating that in our clinical trials. I mentioned them in our -- in my talk. Those will read out over time. But I think physicians are very keen to combine this new mechanism with an existing mechanism to generate better responses in this disease. So that will build over time. So today, it's mostly third and fourth line, but I think over time, that will build up to second line.

So this IPF data has come pretty quick, yes.

Yes.

So maybe you could walk us through what gives you confidence mechanistically on IPF and then -- and how you think about kind of FVC as a win scenario, FEV, right?

Right. FVC. Yes.

FVC, yes?

So this is -- this will be a new mechanism of action. CSF1R inhibition affects specifically the macrophage and monocytes, which sit at the nexus between inflammation and fibrosis. And so by downregulating, not eliminating it, but downregulating monocytes and macrophages, you can really have a controlling impact on fibrosis as well as inflammation. We see that in GVHD. We published some data in Lung Obliterans Syndrome, which is a subset of GVHD, has similar pathophysiology to what we see in IPF. And so that gives us a lot of confidence.

You see these profound effects on patients who have lung disease where we've measured FVC, and we've seen improvements in FVC, not even a slowing of decline of FVC that we see with the drugs in IPF that are currently approved. So we feel like we can make a big -- potentially a big impact in this disease. The drug was actually first developed preclinically as an IPF drug. We moved into other indications that we have very compelling preclinical data in IPF that support not only what we've done -- by what we've done in GVHD, but also what the clinical data tells us specifically about the mechanism of action. So we have a great deal of confidence.

We've designed a fantastic trial. The team has put something together that we think is very robust, 135-patient trial, looking at the endpoint of FVC on 26 weeks on top of standard of care. So this is as close as you're going to get to a pivotal trial design, and we feel that this will give us a really good indicator of whether this drug will work in IPF. And we're not cutting any -- creating any shortcuts here. This is a really important readout for us in the second half of the year.

Any final questions from the audience? Thank you, Michael.

Great. Thank you very much.

Good morning, everyone. So thanks for joining today. We're excited to be here at ASH. Really exciting agenda today to walk through. And I'll start by making some opening remarks, and then we'll turn it over to our 4 esteemed thought leaders and PIs on our clinical trials. We're excited to have them here today, and I'll introduce them.

So these are the doctors, who have been working on our trials and helping us advance our programs for quite some time and making a difference for patients. First, in order, Dr. DeFilipp at MGH. So here we are at [indiscernible]. Right. So we'll start off with Dr. DeFilipp. He's the Director of Bone Marrow Transplant Clinical Research at MGH. He'll talk about the latest data in chronic GVHD that we're presenting here today this weekend. And then Nick is going to lead us in a panel discussion with him where we'll be able to ask questions. There will be Q&A from the audience as well. And then we'll turn it to Revuforj where we'll have Dr. Sallman kick us off in looking at an overview of the treatment paradigm for acute leukemia, and he'll present the first-of-its-kind real-world evidence for menin inhibitor. Dr Sallman as you know, is at Moffitt Cancer Center. And then we'll move on to Dr. Jabbour. He'll talk about our post-transplant maintenance data and save results from the frontline AML trial.

Dr. Jabbour is from MD Anderson as well. And then we'll talk about intensive chemotherapy combinations with Dr. Swoboda from Tampa General. That's very interesting frontline newly diagnosed patients in the [ fit ] setting, and we'll talk about all of that data with him. Then it will turn to the development program. We have an extensive -- as you know, a very extensive development program. Nick Botwood, our CMO and Head of R&D, who will walk through our program in detail for both programs for both Niktimvo and for Revuforj and talk to you a little bit how we expect to be building them into the leading franchises. So a lot to go on, and then we'll circle up our panel after that. We'll get all of our physicians back up on the stage, and we'll ask Q&A, we'll address questions. So a lot to do, really extensive agenda, and we're thrilled that you're here to join us for this.

All right. So some opening remarks, and just kick things off, we'll start with the fact that since last year, in the last 15 months, we have really made quite a difference and quite good progress in terms of building our business, a sustainable growth engine based on 2 fantastic products, Niktimvo and Revuforj addressing $10 billion in total addressable market. Niktimvo, as you know, for chronic GVHD indicated in third line plus Revuforj for acute leukemia, a very broad profile now indicated not only for KMT2A, but also for NPM1. We've gotten off to an exceptional start in terms of our product launches for both of these products in 2025, both exceeding industry benchmarks and resetting what we think is possible in terms of AML and as well as in GVHD.

Syndax, as you know, made this transition as a company to a commercial organization and with 2 big products contributing to revenue over the next handful of years in a meaningful way as well as having stable expenses, which we've guided to, we will be on the road to profitability and feel quite confident that we'll reach that in the next few years as we build these multibillion-dollar franchises. So off to a great start with 2 first and best-in-class medicines.

So as usual, ASH is a big event for us. And this year is no different. In fact, sort of a step change in terms of the activity and what we've been able to do on the scientific front, 23 presentations across both Revuforj and Niktimvo, 3 oral presentations for Revuforj, 9 poster presentations, Niktimvo, 3 oral presentations, 8 poster presentations. So a lot on the scientific front, really showing the breadth of each of the programs for Revuforj. In particular, you see the extent of frontline data, combination data, what we can do in the maintenance setting. We'll talk about some of these things today, highlighting the just broad profile that we have for this agent and why we believe it will be not only first but also best-in-class for many years.

Niktimvo also showcasing what we've been able to do in GVHD and where we think the product will go. And in addition, where we think we can take it outside of chronic GVHD into areas like IPF, very exciting. So it's not only been our advances on the scientific front here at ASH, which we showcased, we've also had great presence from our commercial and medical teams who have been engaging with HCPs extensively, more than 100 meetings with physicians, educational opportunities as well, both advisory boards and med aid. So the teams have been extensively involved with physicians. The booth has been -- we've gotten a lot of great comments on our booth had a great traffic, seeing what people bring. We're engaging constantly. Just the feedback has been fantastic about our products and what we've been able to do certainly over the last few years and we've really expanded our portfolio.

All right. Sorry, slides are taking a minute to advance. All right. So we're now on Slide 7. So Revuforj is positioned for long-term growth and success in menin inhibition, as I mentioned, first and only menin inhibitor FDA approved for multiple acute leukemia subtypes in adults and children 1 year or older. So a very broad set of opportunities for us as we've added a second indication in NPM1 as of October. These 2 indications really together represent a $2 billion-plus opportunity, 6,500 patients in the relapsed/refractory setting alone. We have a very broad program, an important program to get this to newly diagnosed patients. We'll talk about some of that data today. And it's exciting because it unlocks the opportunity for more than $5 billion in total addressable market. That plan is well underway and we've initiated trials into the frontline setting with the opportunity to register globally.

So it is a best-in-class profile. We have unmatched efficacy across multiple patient subtypes, both in monotherapy and in combination. It's well tolerated with clear flexible dosing. So we have opportunity for physicians to use it and dial it in specifically for their patients. It can be used concomitantly with other commonly used drugs, including gastric acid reducing agents such as PPIs. So it enables physicians to really utilize it in all of their patients, KMT2A and NPM1 in the relapsed/refractory setting. As you know, we do have first-mover advantage.

We were able to launch this drug ahead of any competition. What's important about that is we've really built experience and trust with the physician community, 1,000 patients treated across commercial and clinical trial experience is very meaningful. We think track record of delivering for patients is equally meaningful. The fact that we can deliver quickly and really work closely with physicians, we are excited to be able to do that as a company, and it's very, very important to us. Excellent formulary coverage, the ability to get the drug paid for and in the hands of the physicians quickly, as I mentioned, super important.

So Revuforj, really the profile underscores the exceptional product profile underscores the demand here and the opportunity here is seen in some of our launch metrics. To date, since launch, $88 million as of the third quarter in terms of net revenue. really exceeding all other analogs in AML, even with about 1/3 of the patients of KMT2A pausing treatment to go to stem cell transplants. It's actually a very important metric that we've been watching closely, a high percentage of patients going to transplant and a high percentage of patients starting to come back from transplant and go on maintenance treatment. As of the third quarter, 25% growth in total prescriptions and new patient starts over 2020 over the second quarter, about 750 patients -- new patients treated since launch. And we're on track to treat about 1,000 KMT2A patients by year-end. That's 50% penetration of the 2,000 incidence market, very impressive for -- we believe, for a first year of launch into any population, let alone one that is an orphan disease.

Building the usage, as I mentioned, in post-transplant maintenance, with KMT2A patients, we want to be able to have patients go to transplant, and we hope that they are in remission for a long time with the addition of maintenance that can be possible. And we believe physicians are very interested in doing this with their patients. Meaningful inflection in demand. We've seen this in the quarter that we're in currently as we start to see patients being -- NPM1 patients being treated and other patients continue to be treated with the drug as we expand into a second indication. So it's a -- we think a meaningful inflection in terms of our growth going into the new year.

All right, Niktimvo. So Niktimvo is poised to deliver on what we believe is a very important unmet need in chronic GVHD. It's the first and only CSF-1R blocking antibody to be FDA approved in the third line plus. It offers a new mechanism of action. It addresses both inflammation and fibrosis. So it is offering something new for patients. The responses that we've seen to this drug have been rapid. Patients are getting on therapy, and they're responding quickly. They're also getting durable and durable responses across organ systems as we've seen in our clinical trial. And this is a big market opportunity as well. It's about $2 billion of U.S. total addressable market in the third line plus.

The opportunity here is to, of course, expand that to frontline, and we are doing trials in combination with Jakafi and steroids to get there. There's tremendous synergy with what we're doing here with Revuforj in terms of sales. We have our commercial organization carrying both products. We're calling on the same audience for both of these products. It's very unusual, and you see that in a company that is launching into a new market to have 2 products and 2 synergistic ones at that.

The trials, as I mentioned, trials are underway in both chronic GVHD to get to frontline as well as very importantly, IPF, which will read out next year and be the first adjacency for us outside of chronic GVHD and a big opportunity as well. So the product has done exceptionally well, $96 million since launch in net sales, product mainly being used in fourth line. We are penetrating third line as well. About 80% of the patients who have started treatment have remained on treatment. So there's great persistency, about 1,100 new patient starts since launch. So Niktimvo sales are annualizing about $200 million within the first 8 months of launch. Again, tremendous results for a new product with a new mechanism of action. Interestingly, the product has been profitable to Syndax since the first quarter of its launch, first full quarter of its launch. And we expect this to grow meaningfully in terms of the margins. The margin should expand for the product as we go forward.

And I mentioned earlier the great synergy that we've seen with Revuforj. First year sales are tracking with another product that we mentioned in the category that is indicated for third line that's doing about $550 million in its third year of launch since launch, and we believe that's sort of a low watermark for what we can achieve for Niktimvo in this category. So we are really making a difference with this product as well. The 2 together give us the opportunity, as I said, to get to a really important inflection point, profitability and growth over the next few years, and we're in a great position to execute.

So with that, I'm going to turn the mic over to Dr. DeFilipp, who is here, and I'll let him take over. Thank you so much.

All right. Good morning, everyone. Thanks for having me. So we're going to just spend a little time talking about chronic GVHD, Niktimvo or axatilimab, set the stage a little bit about what's going on and kind of where future directions look like. So I think most people are probably somewhat familiar with chronic GVHD, but it's the major immunologic complication after allogeneic transplant, which is a potentially curative therapy for a number of different hematological malignancies. Historically, up to 50% of patients who undergo a transplant will end up developing chronic GVHD, which is a multi-organ disease, and it's characterized by inflammation and fibrosis. So typically, the earlier manifestations of the disease are more inflammatory, but the harder to treat and later kind of more morbid manifestations of the disease are fibrotic. And as such, it remains a major complication in terms of morbidity and mortality for our patient population.

And one of the things that we've known about with chronic GVHD for many years now is that once people develop more involved disease and they kind of get on this treatment train, they often require systemic treatment for a prolonged period of time along the lines of a number of years. And this is an area where axatilimab, I think, is a valuable tool for us as clinicians because as has been mentioned, it has a novel mechanism of action through CSF-1 inhibition in that it is able to address both inflammation and fibrosis. So I think it makes a lot of sense using it potentially definitely in the later stages of disease, but then also potentially earlier. And as I always talk to my colleagues about, we get -- we always want to like place these manifestations in buckets and say this is only fibrosis or this is only inflammation. But often what we're dealing with clinically is a mix of different mechanisms and pathologies.

So axatilimab is FDA approved for the treatment of chronic GVHD in the third line and beyond based on the AGAVE-201 study. And here on the left, you can see the FDA-approved dose of 0.3 milligrams per kilogram every 2 weeks, had a 74% overall response rate, and this is the approved dose that we use. So one theme, I would say, coming out like at this time, now it's FDA approved and we've had the drug for maybe about a year. Now people are asking the questions well, how long can I treat my patients and keep -- can I keep my patients on axatilimab safely for a longer period of time? And maybe what's the best way or what options do I have to do that? So understanding some nuance in the trial. On the trial, if you had a patient who was being treated and they were responding and they had a sustained response after a period of time, you were able to continue and maintain the dose intensity of this approved dose, but by giving it a little less frequently.

So instead of giving it 0.3 milligrams per kilogram every 2 weeks, you're able to give it 0.6 milligrams per kilogram to give it every 4 weeks. So you're essentially maintaining the same dose intensity, but you allow patients to maybe continue the treatment with once a month infusions instead of every 2-week infusions, which I think is an important consideration in our patient population. Typically, a chronic GVHD patient is coming to the clinic at most once a month. So if you want to be able to just get over some of the logistics, make it a little easier for them, this is a potentially a favorable approach. So there was an abstract that was presented here at ASH, looking at within this group of 80 patients who are on the FDA-approved dose in the trial, about 1/4 of them actually made this transition, right? They made this transition and started getting the once monthly dosing.

And you can see here, if you look at this group of 19 patients, they got about 7 months of therapy here while they were getting it every 2 weeks, but they actually got almost 20 months of their therapy on the once a month. So what information can we gather from this?

And essentially, here -- so this is the safety profile. And I think the main emphasis here is just that the once-a-month dose really seems to be a safe alternative and a potentially useful option for us clinically. When you're looking at these data here and you're just looking at incidents, just one note, you may say, hey, after the switch, the numbers look a little higher, but you have to remember, you're looking at 20 months of potential time versus only about 7 months. So our interpretation, though, is that there's no real new safety concern or signal about keeping your patients on axatilimab for a longer period of time. And I think that, that is a good thing to see and know because this is something that I think a lot of people will want to do clinically.

So on that similar theme of just longer follow-up of patients on trial. So there was a -- there is going to be a poster this evening at 6:00. This is just longer-term follow-up of the patients from AGAVE-201, and it just highlights that they were able to kind of maintain long-term benefit. So this doesn't only look at the FDA approved dose of 0.3 mg per kg, but it looks at all dose levels. And you can see here the median duration of therapy is now almost closer to 3 years, so longer than what was published with the initial data from AGAVE. The types of adverse events are the types of things that you would typically see in patients who have chronic GVHD who are on therapy, upper respiratory infections, things like that. But there really was not any new sign of anything concerning. And I think, again, emphasizes that this is a tolerable medication that can be maintained in these patients for a longer period of time.

So the other thing I really want to emphasize today is kind of like where things are moving forward. So there's a lot more data that's going to be coming out, I guess, in the upcoming months or the upcoming year, just secondary analyses that are underway looking at more patient cohorts from AGAVE-201. But I think the next phase of what we're moving to as a field is if we have these highly effective and safe agents, can we potentially change the trajectory of these patients' chronic GVHD by moving these agents into the frontline. And do we have to go down that same route that these patients will be on treatment for years and years? Or can we potentially vastly improve or even resolve some of their chronic GVHD issues by being a little more aggressive in the upfront setting.

And hand-in-hand with that is can we potentially get away from using steroids, which carry their own side effects and not really disease specific. So this is one trial looking at this. And there's a poster this evening again that goes over here some prespecified interim safety analysis. So the way this trial is working is if you have a patient who has newly dosed chronic GVHD, they get randomized into 1 of 3 treatment cohorts. One you can see here is in the yellow is axatilimab in combination with ruxolitinib, but no steroids. The middle and the green is ruxolitinib alone with no steroids and then the corticosteroids kind of standard of care arm.

And what you can see here in this early interim safety analysis is that it really does seem that both non-steroid approaches seem to be safe. There are no patients who have come off of treatment in terms of patient withdrawal. You can see it is an open-label study, so you have to kind of keep it and it's early, but there's insufficient response to treatment. You actually don't see any of those. And when it comes to axa and ruxo or rux, although there are those patients with steroids and the safety profile, again, looks promising.

So this trial continues to enroll. It's total and here is 120 patients, and this is obviously just the first 45, but definitely one approach into moving into the front line. So the other approach to moving into the front line is a little more traditional in this Phase III trial of axatilimab, at least not yet replacing steroids, but asking if we keep steroids on, but we add, again, axatilimab as an effective and safe agent, could we potentially get better improvement in the front line, may be able to taper steroids down and maybe have less side effects. So this is going to be a large 240-patient study. This is an international trial with many sites in the U.S. and also outside the U.S., where the primary endpoint will be event-free survival endpoint approximately 6 months into treatment.

So in conclusion, right, we have data now that shows that we can continue our axatilimab treatment and give it in once every 4 weeks dose at 0.6 mg per kg every day. And with this, patients have been able to stay on treatment for long periods of time, which is a lot of potentially clinical benefit for us as clinicians. We have long-term safety data, again, just, I think, giving us more confidence that our ability to keep people on axatilimab. Some of those patients had been on it close to 3 years. And then we have upfront trials that I think everybody in the field is really excited about and what it can do for our patient population.

So with that, we'll go to questions and answers, I guess. Thank you so much.

So thank you, Dr. DeFilipp, that's a very nice overview of the data. I'm Nick Botwood, I'm the Head of R&D and CMO at Syndax. I had a few questions that we would love to ask. In addition to this nice overview, you're obviously a very experienced practitioner post-transplant. I'd love to just hear a little bit about your own experience in the clinic with axatilimab.

Yes. So we've had a lot of experience with axatilimab through the trials and now commercially. We've had it available at our centers since March. And I think all of the clinicians feel very comfortable in using axatilimab for our patients. As was kind of hinted to, I think, a little bit earlier, although it is approved in third line and beyond, probably the first patients were using it in clinically is probably in the fourth line as many of these patients already gotten third-line therapy. And I think our experiences have been good. I think one question always comes up is the logistics of an IV infusion, which, yes, for some patients is maybe not preferable either due to their preference or some logistics. But interesting, I would say that there are some patients who are really just not interested in taking more pills, and they're very happy to potentially get an IV infusion rather than looking at the daily burden of more medications from that perspective.

We have seen some early responses, but I think the other thing to keep in mind is one theme I think we see across all different chronic GVHD manifestations and therapeutics is that sometimes those fibrotic manifestations do take a little bit longer to respond. So sometimes you just have to kind of keep going if you're going after like lung disease or you're going after more involved skin disease, it does take a little bit longer. But because of the safety profile, especially at the FDA-approved dose, that's something that's quite feasible.

It's a very interesting point. And what is your sense generally just from your own experience in terms of that duration of therapy? I mean, given that time to resolution of some of those fibrotic symptoms, I mean, what has been your experience? Do you find it's been reasonably well tolerated or...

Yes. No, it is well tolerated. But like my personal opinion is if you have more advanced fibrotic sclerotic type disease, as long as the drug is well tolerated, I would give it at least 6 months. And that's not necessarily specific to Niktimvo. I would -- but that's just my general feeling for these types of drugs is that like if you're going to commit now -- yes, you have to make sure the patient is tolerating the medication well, but you need to be able to give them sufficient time. These types of manifestations, they didn't develop overnight. They're not going to go away overnight.

And you had some experience with patients on long term as well. You presented some very nice data of a cohort of patients out 3 years plus if you had that experience.

Yes. I mean I've had -- as participants who were on the trial, I had -- clearly had one patient that I remember who we had on for over a year, who had a lot of benefit in their skin disease.

Maybe just going back to biology for a minute. It's a conceptually very interesting mechanism, CSF-1R antibody. Maybe just share a little bit about what it is that perhaps differentiates that particular approach and target than some of the other available therapies for this particular disease. What is it that you find attractive on a sort of biological mechanistic basis?

Yes. So I mean -- so there have been a few different pathways that have been looked at, right? There's JAK inhibition, there's ROCK inhibition. Some of these are -- they all kind of address inflammation. Some of them may also cover fibrosis. But I think the ability of CSF-1 inhibition to target the macrophage and I think -- which is an important cellular group of cells that are involved in the tissues. I think there's interesting kind of preclinical data that continues to come out now saying that this is one of the key cells that we want to address in order to be able to limit the development of that cause more morbid forms of chronic GVHD. So having a drug that directly targets it, I think, is something that's very attractive.

It's really nice. It's very nice. So we have -- you presented some preliminary data on our frontline study and also highlighted our Phase III study in combination with dexamethasone. What is it that excites you about the potential with those combinations to move into those earlier lines and frontline therapies? And which of the approaches do you find particularly attractive and exciting?

So frontline -- so in general, as I kind of mentioned before, I think frontline is really where the field wants to move. This is where we as clinicians want to go. People don't like feeling obligated like they have to go through first line with steroids and like kind of sit on their hands waiting to give the drug that they actually want to get. So I think there's a lot of buy-in from the community that this is the way to go. As I also mentioned a little bit before, this -- I think it's very compelling this concept of maybe changing the trajectory of a chronic GVHD kind of experience post-transplant, like if we're able to target some of these other pathways in a more specific way early on, can we change kind of the course of the disease.

And I think one thing along those lines that I've always felt to be a compelling question that I'm hoping that we'll see a readout of from these trials is if you give a medication that has an antifibrotic mechanism of action early on in the patient's course before they have any fibrotic symptoms, could you potentially prevent those symptoms from developing rather than saying, "Oh, I'm only going to think of an antifibrotic medication once I see fibrosis because I think preventing it may be a lot more effective than trying to always treat it.

Yes. No, doctor that's very -- very exciting. Thank you for that. I think in the interest of time, I'm sure there's a lot of questions from the audience. We are going to invite you back for a panel discussion at the end. But I think in the interest of time, we'll hold the panel, we'll hold the questions until the panel, and we'll move to our next speaker. So thank you, and we'll have an opportunity for more Q&A in a bit.

And on that note, I'm happy to introduce our next speaker, and that is going to be -- that's the wrong slide, I believe. I don't know what happened. I believe we're going to have Dr. Sallman come and present his experience of real-world evidence and an overview of the treatment of leukemia. So if we could go back to Dr. Sallman's slides, I should welcome him to the podium. Welcome.

Perfect. Good morning. It's really, really great to be here and really working with Syndax over this past year. Clearly, we have the first agent, both for KMT2A and NPM1 mutant patients. So really initially, immediately post-label approval, we were utilizing it in multiple settings. And I hope kind of some of the slides that I'll show you really highlight how rapidly the field is changing. Again, this is even early post approval, even when it was only for KMT2A. But to essentially set the line, of course, we have frontline therapy, relapsed/refractory. I think one clear message is it doesn't really matter what type of mutation that you have. As soon as you have relapsed disease, outcomes are really uniformly poor across any molecular subset, including NPM1. I think sometimes just messaging, hey, NPM1 mutations are always good. And this is really not the case. Again, in relapsed/refractory, median overall survivals of around 6 months. And there are other groups.

So for example, patients over the age of 60 don't do well even from frontline-based therapy. Some of this is based on co-mutation, secondary type acute myeloid leukemia. In general, our major goal right now is to cure an increasing number of these patients. And so many patients will ultimately be bridged to stem cell transplant. Of course, in KMT2A, this is really a universal standard, if at all possible. And even in NPM1, again, patients that are older, patients that may get non-intensive therapy, of course, with the Paradigm HMA/Ven trial yesterday, I think this is an even increasing discussion. And remember from that presentation that patients even with NPM1 were allowed if they were over the age of 60, again, the bulk of the patient population.

I think another thing is that MRD is really guiding us. I think MRD technologies continue to get better and better. And particularly with NPM1, they are by far the most well validated, can be done both in peripheral blood and bone marrow. And essentially, if you have NPM1, majority of time, this will essentially imminently lead to relapse and thus eradicating it, both in the set of intensive and nonintensive therapy is really critical. So you can utilize menin inhibitors definitely in that setting, both as monotherapies and combinations to ultimately get there. Again, just another comment sort of on this fit versus unfit. Again, how we utilize Paradigm, I think maybe we could get some discussion from all of us in the question-and-answer session. But these lines are continuing to blur. There's really not much as a fit or unfit. It's really what is the most optimal and best therapy for our patients.

So I think there's so much data coming out. I think we had the sort of menin education session. I think there was maybe actually 2 of them, but we had ours early Monday morning, and there's 88 slides, all with different response rates, what do all these things. So I think it's just good to rehash this and then maybe highlight what is relevant to patients from that perspective. So of course, for any response, in general, the blast will clear to less than 5%. There is a unicorn called partial remission. This really rarely, if ever, occurs, maybe in early cycles where you have a significant blast reduction in differentiating agents, you can see count recovery, and this is actually full count recovery, so the same as complete remission, but PRs are very rare. But for essentially all the other responses, blast nuclear to less than 5.

For full count recovery, when we say that, that's platelets over 100,000 and neutrophils above 1,000. CRh has been increasingly recognized important. And again, there's not really magic behind it, but it's just the point that you have sort of multi-lineage recovery. All of the severe cytopenias have essentially resolved. So again, these are neutrophils above 500, so outside of the severe range. These are platelets above 50,000. Again, patients can have major surgery. So really, all of the major mortality issues related to the cytopenias of AML are essentially resolved in patients with CRh. In CRi and CRp, there's a lot of heterogeneity in these responses. I mean sometimes they're astronomically close to one or the other. So you could have your platelets of 49 and neutrophils completely normal and sort of fall into that range. CRp is specific to platelets. CRi can be either platelets or neutrophil recovery from that.

Now a lot of people ask what matters. So we know that we're used to CR/CRh for label approvals but when you have your patient in front of you, I actually like to -- because this is really not in the full data set as far as MLFS. So I have a young patient actually post heart transplant, post allo transplant, and we only had fusion panels this past year, relapse after multiple therapies and ended up having a WT1 RAS phenotype, which we now recognize is quite classic for NUP98 rearrangement. So we identified the fusion in that patient. And he's only had blast clearance, but he had extreme amount of extramedullary disease. He was really not even able to get out of the hospital, actually had a hospice discussion. He's only 20-something years old. And that patient actually had great clinical improvement. Now he's not had blood count improvement whatsoever. He gets transfused once to twice a week, but he's 9 months now alive where he would have been dead essentially probably within the month from that back.

So I think sometimes people will say, "Hey, does ORR matter or not? There are clear major instances where MLF is just dramatically impactful. So again, this is the first real-world evidence. And I think it's -- we're going to see increasing numbers and hopefully, both national and international collaborations looking at this because I think we're all -- and we're going to hear from my colleagues in a moment, very excited about combinations and frontline approaches. But how are we managing these patients now? We are all going to be significantly older by the readouts of those trials. So median age is 54. Again, I think a lot of this is very, very similar to the studies. About half of our patients were KMT2A, a little bit less than maybe you would expect with NPM1, and I think we can have some discussion with that a little bit later, heavily pretreated, even a little bit more than some of the trials that have been out there, 4 lines of therapy. You can see we have treated some patients in the frontline setting, but up to 6 lines of therapy.

The vast majority of patients having venetoclax, which we know has an OS typically of sub-4 months in the relapse state and around 1/3 of patients having prior transplant. You can see even in the setting of a newly approved agent, right, we have already rapidly moved to combination therapy with really only single agent being utilized in 3 patients. I really mostly consider this in patients that are relapsed, frail, clearly not transplant candidates. And again, we can talk more about the combination setting in a moment. So these are our efficacy data. Again, it's a very heterogeneous group, and we have very granular data on the next slide as far as swimmer plot.

But the overall response rate is the majority of patients. And the composite complete response rate now, particularly in combination therapy, is almost 2/3 of patients. Again, especially in relapse, I think you'll get a little bit more composite CR than CR/CRh. And again, many times, this is really equally meaningful, particularly in that setting. You can see in patients that did achieve response. And I would say at our institution for NPM1, we always do flow and deep molecular, about 10 of the negative 4 to 10 of the negative 5, I would say, is the sensitivity at our institution.

For KMT2A, we're utilizing flow, although hopefully, we'll be able to incorporate molecular MRD in the not-distant future. So 3/4 of those patients achieving response. And then 4 patients were bridged to transplant. I wouldn't focus on the percentage of patients. You got to remember multiple patients in this cohort were not eligible either based on comorbidities or age from that perspective. Two patients were able to get to second transplant. And I'd just like to highlight, this is an extremely rare thing. And even for patients that get to second transplant, often their outcomes are extremely dismal. Our patients, and I'll highlight one of them in a moment, are doing very well. I do think about 3/4 of patients are ultimately going to go on maintenance. I think there's always going to be a potential patient with engraftment issues, comorbidity issues, GVHD, et cetera, that may not ultimately be able to go on, but I think this is reflective even though a small number.

So again, you'll have this slide. I think many came to our poster the other night as well. So again, a lot of data. And again, what we're excited about in partnering with Syndax from that perspective is we essentially hope to update these data sets several times per year. So we're going to continue to evolve how our outcomes responses, efficacy in different settings. So again, the median time, very similar to clinical data was 1 month, time to best response of 2 months. I would like to highlight and Dr. Jabbour and I have talked a lot about this as well as Dr. [indiscernible] and a couple of others, that CNS relapse is a real challenge in KMT2A. So in the past, these patients were never alive. But now that these patients are live and deep durable remissions, I'd like to highlight actually the patient on the very top, who was actually originally on a study, then essentially bridged over to commercial maintenance.

Again, this patient was post second transplant 1 year out was in still an MRD-negative complete remission and had a pretty florid extramedullary relapse. We've treated him with definitive craniospinal irradiation. He remains on revumenib and it's doing fine. But we've now incorporated sort of standard intrathecal prophylaxis ideally before transplant, potentially after transplant in select settings. How many to do? We don't know. Maybe we'll do 4. But I think we're relatively universal maintenance is going to be a key consideration.

I think, again, a lot of this has been in combination. So far, when we've utilized it in frontline, we've not had a patient relapse and choosing the right Venetoclax dose is quite critical. Again, we can comment on that a little bit later. We have been able to have sort of MRD erasing therapy as monotherapy, although I may try more combination approaches in the near future in that setting. Again, relapse has been quite rare with these combination approaches. Again, follow-up is really critical. We've not met any median for PFS or OS across any setting, but again, small numbers, and we need longer follow-up.

Again, safety is obviously quite critical and giving revumenib is really easy. You can have QT prolongation, but this is really never an issue. This is really an annoyance as sometimes drugs are launched, I think similar to Ivosidenib. The biggest issue is really first cycle with particularly electrolyte issues. So almost everybody will have a concurrent electrolyte disturbance. You can see we did have 3 patients, but no patients have come off. Now DS was in 2 -- one patient, I'd say, was complicated. It was on sort of a dual IDH plus menin inhibitor. And again, patients rapidly resolved with corticosteroid. I would say combination therapy, I don't really think that DS occurs in that setting. Some patients can get interruptions. These are often very brief. And only we had one patient that had a dose adjustment related to cytopenia. And I believe that patient was in the post-transplant. Again, patients are alive and doing quite well from that perspective.

So I think with that, I can turn it over to Dr. Jabbour, who's going to talk about revumenib more specifically and post-transplant and probably some other data from the MD Anderson.

Thank you, David. Good morning, everybody. I'm very grateful to be here with you this morning. I flew from Houston last night and the rain tropical like Houston. So transplant and KMT2A-rearranged disease, I think there's a limit how much we can do with transplant. We can -- I can get the slide moving. Okay. We can increase the intensity of the conditioning, but we get to a limit where we cannot proceed any further. We know KMT2A-rearranged disease are really bad patients. And even you transplant them, the outcome is really poor. And here, when I'm sharing the data from MD Anderson about 10 patients, where you can make a difference is by implementing a good maintenance strategy. You've heard from Dr. Sallman about induction, about offering revumenib or other combinations, but that is not the whole game. If we go for transplant because our aim is to go for transplant is to try to offer treatment post-transplant because, as I said, we cannot increase anymore the intensity of the conditioning.

Here, our experience from 10 patients at MD Anderson pediatric experience at my institution. Median age being 10, we get up to 18. These are patients who are really bad to treat. Among them, 8 came to KMT2A Rearranged disease and 2 NUP98-rearranged rearrangement. They failed transplant. Half of them had 2 transplant already. So they have a patient population really bad. And here, I urge you not to compare like numbers to numbers. I get calls from investors or other tell me what do you think about this one and this one? You have to put it in context. You have a patient who failed already 2 prior transplantation. These are not patients coming frontline to get one drug. They were treated with mainly revumenib-based therapy, be it on a clinical trials or compassionate or even some of them in combination in a safe trial that I will share with you in the next few slides.

Good thing about it, this patient responded. And then before transplant, all were MRD negative. So yes, you want CR. Yes, you want CRP, you want whatever. But the key factor is, if you get transplant, somebody in MRD-negative situation, you're going to get the best long-term outcome. And I feel transplant is a big investment. If you're going to invest into transplant, try to get your patient transplant in the best shape possible because your outcome post-transplant is determined by the depth of the response you have before going into transplant. And here, we have patients who did respond well, thanks to the menin inhibitors and in particular, revumenib here.

So the study was designed to offer 12 cycles of 12 months of therapy. Of course, you have to wait for engraftment. You have patients who failed prior transplant, and therefore, this is tricky here because these patients have a very frail graft. And the earliest you can start therapy is when the [indiscernible] are above certain level and they engraft. And therefore, median to start was around 3 months. But the good thing is these patients did get mostly -- most of them get the whole duration of treatment. Median was 11 months. And some of them, one patient decided to stay beyond the duration of therapy offered by the investigator. Now there were bumps. Of course, there were bumps. Myelosuppression, yes, it is an issue. You have to keep in mind, these patients are on multiple medications.

They are on tacrolimus, they are on GVHD prophylaxis. They have 2 transplants and there are frail numbers. And yes, the place can drop below 50. And yes, we can hold therapy, but that is not unusual for such a population where whatever you give them, they want to drop their count. The good thing about it, they were able -- we were able to hold therapy, decrease the dose and resume therapy in certain patients were able to reescalate back to the normal dose and 90% of the patients remain free of relapse.

To put this in context, the median survival is only 4 months for these patients and less. And if you give them a transplant, still you don't improve much their outcome. Therefore, having 90% at 1 year post-transplant doing well, that is something very promising. And I think today in my practice, from the day the drug was approved, I must confess, I always off-label. I go for transplant, I do it post transplant. I try to eradicate minimal disease, and this is a proof here in 10 patients where you can give them good maintenance therapy, they are MRD negative and you reach a success story. So I think that is really, really promising at a median of 19 months, you have all patients alive and only one patient relapse. This is really encouraging piece of evidence reflecting the activity of the drug.

How about adverse events? As I mentioned, these are patients heavily pretreated. They had only 2 prior transplantation. Therefore, seeing thrombocytopenias, this is not unusual but very manageable. And here, we have only 3 patients who had grade 3 thrombocytopenias. Grade 2, Grade 1 are irrelevant in the practice of transplant in patients who failed multiple therapies. And yet, among these patients, that did not lead to treatment discontinuation. In contrast, we had to hold, resume at a lower dose and reescalate whenever possible. Therefore, I think the adverse event profile are highly manageable. No patient had to stop the drug because of adverse events. And therefore, I think this data support the use of maintenance drug post-transplantation, be it within the label. I never read the label. By the way, I must confess, I do not read the label or eventually in the prospective trials to be proven, and I know there's ongoing trials to address this point as well.

So very encouraging evidence of the activity of revumenib post-transplant as a major strategy. Now here will come where the money is, correct? The save life of people. And I think this acronym is really interesting. And I want to give credit to my colleague, Dr. Issa who was closely at MD Anderson and we brainstorm every single day. Yes, we have a drug approved. I think the research and the benefit start after an approval. I don't care how narrow the label is, but I wanted to be on the market. And by having a drug on the market, I can have research done. I can optimize the use of the drug. And as of today and every single day we want to optimize the use of these menin inhibitors, in particular today, revumenib. So we designed a trial combining based on evidence that there's synergy between BCL2 inhibition and menin inhibition as a triplet of HMA oral formulation, venetoclax BCL2 inhibitors and revumenib, and we explore different dose level. And of course, we explore the combination with or without azoles to make dose adjustment.

The study was first open for relapsed/refractory disease. I won't share it with you today, but let me refresh your memories and remind you, the response rate is double of what you can get in a single-agent drug. The survival is double of what you can get with single-agent drug. So very encouraging. Furthermore, with the combination, we did not see evidence of resistance on mNPM1, which quite reassuring as well that you can give the drug at the long run without any concerns. Now when you go for a triplet, you must adjust the dose of the treatment. And I know this is confusing because the label of HMA/Ven tells you to give the Ven for 28 days in induction and [ purchase ] thereafter, and we know we cannot go this way in a combination.

Therefore, what we did in Houston, we said we do bone marrow on day 13, and we will hold on day 14. And then later on, we amended even for revumenib to avoid myelosuppression. If somebody is in a marrow remission, we get 21 days of rev during the induction and 28 days subsequently, but then we adjust the dose of Ven 14 days and less. And by doing so, to avoid any excessive myelosuppression that can be encountered. Again, we adjust based on azoles interaction.

And finally, we offer maintenance therapy post-transplantation for a duration of at least 1 year. So my colleague showed the data yesterday on -- from the SAVE update on 21 patients. We enrolled 14 patients with NPM1 and 7 patients with KMT2A rearranged disease. I'd like to highlight a few features here. Look at the median age of this patient, 70 median age of this patient. A few years ago, this patient was sent to Hawaii to spend whatever left of their life, not to be treated, median of 73 with NPM1 range going up to 83, again, defining fitness of these patients. These patients are getting therapy today and responding as I will show you later. median age for the KMT2A rearranged disease up to 77, so younger population.

Second feature, very important, look at the co-mutations because somebody may ask me how this will compare to HMA/Ven. I want to ask this question right away upfront. We cannot compare apples-to-apples here because look at the co-mutations. These patients have multiple bad mutations among them, FLT3, NRAS/KRAS. And we know from the [indiscernible], these patients do not do well. And finally, we have around 40% of the patients having MDS-associated mutations. So the patient population treated here are really hard to treat. And therefore, we have to put the results in the context as I showed you here, and I'll come back to this when I go on more data.

Side effect, I hate to show this slide first, but here's how it is because when I hit my patient, I don't look for safety, I look for efficacy first because no matter how safe the drug, if it's not effective, you can offer holy water. better than treatment. Nonetheless, Dr. Sallman highlighted the QT prolongation. I never care about it. And I was surprised when Syndax team told me about QT prolongation with these cancer patients, QT prolongation becomes so irrelevant. We have so many drug-drug interactions. We give Zofran left and right. We give quinolones for everybody who had a pulse. And therefore, having QT prolongation, this is less -- the least of my concern, particularly that were all grade 1 and 2. We did not have in our SAVE trial, a single patient having QT prolongation. This is one.

Second issue you want to ask me about is differentiation syndrome. Yes, it can be seen. But when you give a combination, it's less of relevance. But I keep a low threshold for it to implement high steroid whenever I see it mainly in somebody with hyperleukocytosis and monoblastic leukemias as was seen in the patients here, but none of them was grade 4 and above.

We had zero fatality from this. and this is highly manageable. By -- when you give the chemotherapy, you're going to get the tumor burden lower. And then you're going to give the rev, I think this in a combination, it's less of a relevance, but I want you to keep that in mind to implement to have a low threshold to implement therapy whenever it's needed. So overall, from this combination, nothing was of a particular interest, especially during the induction. Now I'll tell you more information in a subsequent slide.

Look at the efficacy, objective response rate, overall, 86%, in NPM1 was 86% and it is same, very high response rate. And the CR/CRh is at 79%. This is way higher than what you expect with the Aza-Ven alone. So if your primary endpoint is CR, CRh or objective response rate, we are meeting our endpoint. The combination is delivering an optimal -- leading to optimal response rate, and that is how the randomized trials [indiscernible] a plus or minus menin inhibitors revumenib are being designed or other menin inhibitors. So in a CR/CRh, we are meeting our primary endpoint.

Early that, yes, we had 2 patients unfortunately passed away at the beginning, I want to go more granular on these patients. Remember, it's an AML, and we have patients up to age of 83 with the co-mutations. They are really bad patients and tough to treat. And we're learning how to optimize our supportive care and we have to optimize adjustment of the dose of the drug in order to avoid this kind of events. Losing one patient is bad. I'm not underestimating it, but we need to learn how to optimize our supportive care and how to deliver this combination. As Dr. Sallman mentioned, all these patients went on to achieve an MRD negativity. And we're testing MRD by flow, and we have an asset I will show you next with NGS that can allow us to go 10 to minus 5 and eradicate the disease before we go for transplant or other strategies.

So we're using [ Invivoscribe ] asset at MD Anderson, and we're able to assess the NGS MRD negativity in this patient population. The numbers are small, but 80% within 2 cycles became MRD negative by NGS. Why it's important? It's important because if you look at the right side, there are 2 patients who did not get into MRD negativity by NGS, and these 2 patients unfortunately relapse. So I think moving forward, as we do in other leukemias, having MRD negativity at a very low level, it's critical. And what we're doing is, we're comparing historical data with aza-ven alone versus aza-ven rev to tease out the activity of revumenib in MRD situation. And I think this is where the drug should be used because if we're able to eradicate minimal disease, we deliver safer drug, less of a complication and a better outcome.

Okay. Here, the survival overall, follow-up is still 9 months. It's a short follow-up. The median survival has not been reached. And so the median event-free survival at 1 year, it was 57% 12-month survival and 50% for EFS. Then I'm showing you the data by genotype, NPM1 and KMT2A rearranged disease. In neither one, the median has been reached and the 12 months survival is 53% for the NPM1 and 69% survival for KMT2A rearranged disease. So very promising numbers despite very bad population enrolled from the beginning.

Here I want to go into more granularity and show you what you call the swimmer plot that everybody loves. I think sometimes it's complicated to read for people who are busy and do not see the small details like myself, the white whatever is MRD negativity seen. But I want to highlight the patients who really did not do well, unfortunately. First of all, 1/3 of the patients, despite their age, you might remember, it's 7 years old people went on to receive transplantation.

So we've heard Dr. [indiscernible] in the session during HMA/Ven, but I'm not saying HMA will be offered for all-comers. But I'm saying for bad genotype, if your goal is to go for transplant, such a combination is a good combination to get you into MRD negativity and to get you for transplantation. And we've seen patients having remission durable. Now we've seen 3 relapses. I want to focus mainly in 2 patients with NPM1 mutation because the patients have a really bad disease. One of them, for example, patient #67 wasn't compliant, did not take the medication, missed half of the dose of revumenib and yet they had KRAS, SRSF2, TET2 trisomy 9 and monocytic differentiation.

So this patient is really with any treatment available today will not do well. And the second patient, multiple mutations, 74 NPM1 [indiscernible] disease, FLT3, BCOR, DNMT3A, TET2, so multiple mutations, and these are patients known not to do well. So if I want to move forward, I can be more selective and enroll patients with easy disease to treat and yet lead to great results. But that does not reflect the real-world data, that real-world evidence what we need to accomplish and do. This is why this patient did not do well. So we still have work to do, how we can optimize the combination to deliver a more efficacious therapy for these patients. Nonetheless, again, I would like to highlight MRD negativity was seen in the vast majority of these patients by flow and by NGS.

And finally, for the KMT2A-rearranged disease, we had one relapse. But that is expected as well for this patient population, very hard to treat. So in conclusion, I think the SAVE results are really, really encouraging. The triplet is leading to what we expect, the hypothesis we put upfront, we are meeting our endpoint, high response rate in both NPM1 and KMT2Ar disease with the larger samples to confirm the findings. However, one last word of cautious. I think we still need to optimize the combination NPM1.

KMT2Ar disease we're doing great. In NPM1, we cannot afford any toxicities. We need to optimize supportive care. We need to optimize maybe the schedule of the drug, not to give it continuously, be careful with the [ vein. ] And finally, my own experience, I'd like to hear from my panelists as well, I think oral decitabine is more myelosuppressive than the IV formulation, even though they will get the label equivalently. We know, for example, in a triplet of FLT3 inhibitors, oral decitabine and HMA -- and that we show at ASH here, we have a lot of myelosuppression, too. So therefore, we need to optimize supportive care in order and optimize the schedule of the drug in order to deliver safe treatment at the long run. But I'm very happy to be here. I'm happy being in a time of history where we're making difference and making cancer histories in the MD Anderson [ logo ]. Thank you very much.

Going to ask Dr. Swoboda to come up, share the experience of another important combination with intensive chemotherapy. Dr. Swoboda?

Thank you guys for inviting me to give this talk. I'm an investigator on the 708 study, and I'm really excited to go through some of the granular details of this clinical trial. And so as probably everyone already knows here, the 708 study is a combination of intensive chemotherapy with revumenib in the frontline setting, and it's an early Phase I clinical trial. It focuses on 3 different populations: KMT2A, which obviously AUGMENT-101 clearly focused on.

NUP98r, which I think is an extremely important subset of patients. We've seen from early data with revumenib that, that population that we were able to achieve some CRs. It's a really refractory patient population. And even though there's only a little bit of data in that setting, I think it's actually in real-life practice, an area that needs a lot of exploration and study. And then NPM1, and it's important to highlight one of the key components of the NPM1 subset. So initially on the 708 study, FDA mandated ultimately an inclusion of only high-risk NPM1 patients.

And so that was NPM1 plus a chromosomal or molecular change that based on the ELN -2022 classification. And then as of June 26, 2025, that was -- the protocol was then amended to include all NPM1 patients. So as we work through the data, it really reflects that change over time and the dose levels also reflect that update in the protocol. And so there's -- the dose level 1 is below our dose of what we see in AUGMENT-101 at the 220 and 110 dose. And then the dose level 2 is sort of our standard dosing revumenib at 270 and 160, it completed the dose escalation and now moving on to sort of the dose expansion cohort.

So what did this patient profile look like? So since -- as you can see in the dose level 1, the majority of patients were KMT2A, and they also were a much younger population. It was majority being a female population, otherwise, overall very fit population. As we expanded into dose level 2, as I said, we broaden the expansion of that NPM1 cohort. The age ultimately increased where the median age was around 57 in the dose level 2 cohort. And the -- it started to shift where now the majority of patients are NPM1 mutant. And so this is just looking at some of the safety data, and I think it's important to walk through. I think the most important part is 0 differentiation syndrome was seen in the combination of intensive chemotherapy.

Outside of that, like Dr. Jabbour was talking through, QTc is something that we don't really necessarily worry too much about. We monitor it, but we don't really worry about it in clinical practice. But it still is extremely encouraging that there was only one grade 3 QTc event and the rest were relatively low grade. Of the one Grade 3, that patient did discontinue off the drug. However, they were able to achieve a response and have maintained and ultimately moved to transplant.

And so the dose reductions were relatively low, about 6% in the overall patient population and discontinuation was about 13%. One of the patients was due to an intracranial hemorrhage probably related to low platelet count. The other was a QTc prolongation and there was another infection patient. So things that you would honestly expect when you're treating these KMT2A, where to remember, they tend to be a very proliferative disease, oftentimes come in very sick. And so it's not unexpected with intensive chemotherapy that you might see some combinations even with standard 7+3 chemotherapy.

And so something that was really encouraging. We worry about this a lot with FLT3 inhibitors is myelosuppression. And so even though we added revumenib in combination with 7+3 chemotherapy, there wasn't a significant increase in myelosuppression compared to what we would standardly see with 7+3 alone in this patient population. So the time to neutrophil count recovery was around 29 days as early as 19 to 35. And then similarly, platelet count recovery was around 28 days, which is sort of what you would expect in this patient population and even increasing the dose to the dose level 2 did not change that parameters as far as recovery, which is encouraging and helpful for investigators.

So we focused on a couple of swimmers plots previously. I think it's really important to highlight in this swimmers plot that the data is still maturing. And so I would say a lot of the not as promising data from what we're seeing in the 708 study is really just a reflection of we haven't given enough time to make the appropriate assessments. As Dr. Sallman was walking through response, thinking about a CR or a CRi, a lot of times, we just need to give more time for the patients to recover their counts.

And as an investigator, when you do a bone marrow, you might initially have a patient that is MLFS if you do it at day 28. But if you give it time oftentimes in this study, we have 2 weeks, so up to day 42 to assess the counts, patients will go into a CRi or even a CR. And so as you can see in the dose level 1 with a little bit more follow-up, we were able to get 100% response rate in that patient population.

And you can see that patients in that population were able to go -- they were on therapy, proceed with transplant. And now several of those patients have resumed on maintenance post-transplant. There's many patients that have proceeded with transplant, but they really haven't got to the time point. As Dr. Jabbour mentioned, a lot of these patients even in the pediatric population were around day 110. So they haven't got to the point to where we would otherwise initiate maintenance. And so even though we're saying on this slide that it was a 5 out of -- 7 out of 13 of patients proceeded to transplant and of those 4 out of 7 were on post-rev maintenance. I think that's just a reflection of we need to give those other patients a little bit more time, and I imagine the majority of them will end on by maintenance post-transplant.

No relapses were observed so far in this study. And as we show just the final slide with the response rates, keep in mind that several of these patients were less than -- had less than 21 days of rev were less than 28 days on therapy during this data cut. And so overall, I think as that -- like I said earlier, as that data continues to mature, I think the response rates will sort of equal out a little bit better.

And so as you can see, dose level 1 was 100% -- with 100% CR. Importantly, measuring MRD status in this population, is key, and there was 100% MRD in the dose level 1 patient population. This was by multiparameter flow because this was KMT2A patients. It's based on local institution guidelines there. But we don't have a widely available, obviously, MRD target for KMT2A yet.

And so in the dose level 2, we saw a response rate that was slightly lower at the 92.9%. But again, I think some of this just reflects needing to have more mature data in that patient population. Also moving into an NPM1 group, the response rates are going to be a little bit lower and probably will not hit that 100%, but still extremely encouraging data from both patient populations. And when you look at the data combined, I think it's very encouraging. And so overall, the safety of intensive chemotherapy in revumenib is very comparable with what you see with 7+3 alone.

QTc prolongation is infrequent. And I think it's not something that we worry about outside of the context of clinical trials, and we're really able to manage well. Preliminary data suggests great responses in even a high percentage of MRD negativity. And then it provides robust data that's led to the Phase III REVEAL-ND study. And so that will be a very exciting study for the community and one that I think Syndax designed actually very well and in just the NPM1 population. Thank you.

Thank you very much, Dr. Swoboda, for that very nice overview of intensive chemotherapy. So it's my pleasure now just to briefly overview our overarching clinical development program for both Revuforj and Niktimvo at Syndax. And I'd like to focus first on the relapsed/refractory setting. So on the right of the slide here and focus on the AUGMENT-101 study, which was our pivotal study in relapsed/refractory acute myeloid leukemia, which we led to our approvals originally KMT2A disease and then more recently, NPM1, including pediatrics, children above 1 years old and ALL. So a really broad indication now in the USPI supported by AUGMENT-101 in the relapsed/refractory setting.

Now we have a bold and innovatively designed program in the frontline setting. And I'd like to just walk you through how we're thinking about this, let me start with the patients who are considered ineligible for intensive chemotherapy. And this is an exciting and rapidly evolving space as we think about the treatment in the frontline setting. And we want to continue to lead and innovate and make sure that we are bringing forward treatment combinations that are the most suitable and bring the greatest benefit to patients.

So we have generated compelling data with ven/aza combination, ven/aza being the standard of care for patients considered unfit for intensive chemotherapy. We presented at EHA earlier this year data from the BEAT-AML study, Joshua Zeidner study. And then you have heard data today for a combination of ven and an oral hypomethylating agent. Again, absolutely compelling data in both NPM1 and the KMT2A subset. That has led to the evolution of the EVOLVE-2 study, which is a study we're doing in collaboration with HOVON. This is an international study, including a number of sites in the U.S.

This is revumenib added to a backbone of ven/aza. It -- upon it's focused on the NPM1 population, but is also open to randomized patients with KMT2A disease. It opened earlier this year. It was the first study in the frontline setting to randomize a patient with a menin inhibitor, and it is enrolling well. We're actively initiating sites, and we envisage that it will execute extremely well through next year and it has dual primary endpoints, including both overall survival, but also a complete response rate, which we think could serve as a surrogate to support accelerated approval with the potential to bring that therapy to patients sooner.

Let me now turn to patients considered fit for intensive chemotherapy. And you've heard some compelling data this morning from the study 708 of revumenib in combination with intensive chemotherapy. That is also supported by data that we are doing in collaboration with the NCI that will be presented at this congress, which also supports both a very tolerable combination with intensive chemotherapy and a compelling efficacy profile with deep and durable responses and high MRD negativity.

We are also planning to initiate a study based again on the evolving landscape. Many of you will have heard the Plenary session yesterday from Amir Fathi and the potential of ven/aza to be a viable treatment option in order to get patients to transplant. We believe because of the compelling data we have generated with ven/aza, particularly in patients with KMT2A, we are planning a frontline study in combination with ven/aza focused on those patients that have that rare and difficult-to-treat mutation, thinking that, that could be a very attractive and viable alternative option for them.

And then, of course, we have our pivotal REVEAL newly diagnosed patients. This is a randomized controlled study for patients with NPM1 disease on a backbone of 7+3 intensive chemotherapy. It is designed with registrational intent. It has 2 dual primary endpoints, event-free survival and MRD-negative CRBM. And I am pleased to say that we have had our first site opened and we are envisaging enrolling our first patients by the end of the year. It's a large international study with many sites, and we think it will enroll extremely rapidly given the data that we've generated and the momentum we have behind this study.

So of course, this is our core program. We have, in addition, as you can tell from the number of abstracts we have had at ASH, a very broad collaborative program with leading academic sites throughout the world who are generating clinically relevant data to support physicians and patients on this journey.

Let me turn now briefly to axatilimab. And the work that we're doing both in chronic graft-versus-host disease and also other diseases that are characterized by both inflammation and fibrosis. So let me talk first about our frontline programs that Dr. DeFilipp already mentioned earlier, but just to highlight the approach that we're taking, and this is really about a move into earlier lines of therapy.

And the way we're thinking about this is twofold. Firstly, we have a combination to see whether the CSF-1 antibody can actually add to dexamethasone that is a standard of care in frontline chronic graft-versus-host disease. We also have an innovative approach, which is a steroid-sparing approach where you combine axatilimab with Jakafi, and this could potentially offer an alternative for patients in the frontline setting, avoiding them having to have the morbidities associated with steroids.

We're also excited about our randomized Phase II study. This is a proof-of-concept study in idiopathic pulmonary fibrosis. There is a compelling both preclinical and clinical rationale to undertake this study. It's enrolling very well. We anticipate it will be fully enrolled by the end of this year. We're very close now and that we would have data available in the second half of next year. It has an FVC primary endpoint. We think this will serve very well as a registrational informing study if it reads out positively, which we feel quite confident about based on the, as I say, both the compelling preclinical hypothesis and the clinical data we generated in the AGAVE-201 study for patients that, in particular, had pulmonary symptoms.

So that completes a high-level overview of our development program. I would be happy to take any questions on that as well as we enter into our Q&A. We are now going to invite our panelists back up on to the stage for Q&A. So if I could invite our panelists and we will open for questions. But I have a few questions that I'm going to start things off with before we open it to the floor. So if you would please come up. And also, I'm going to ask Michael and Steve to join for questions on our programs.

Perfect. Well, welcome back, everybody, and thank you again for the fabulous overview, and it's very exciting for you all to be able to share the data that we've had at ASH. Maybe I could start just a little bit with clinical practice given we have the benefit of your expertise here. And perhaps a question -- we'll maybe start with Dr. Swoboda.

Given the data that you've presented today, maybe you could just share a little bit about your own clinical experience with Revuforj. Obviously, you work in a very major large institution. I know you have a lot of clinical experience, but maybe just share a little bit about how you're thinking about using it in what settings and what your experience has been?

Yes. Thank you so much. So we had the pleasure to have access to the drug relatively early. And I think there's a lot of areas where we really felt patients could benefit. Remember, in KMT2A patients, it's not that we worry necessarily about the response, but that sustainability of the response and that quick and early relapse. And so I think the first area we actually started to use the drug was post-transplant maintenance. We had patients that had moved to transplant that were KMT2A mutant and then we're coming out post-transplant. And we really wanted to initiate an amount of targeted therapy that would ultimately hopefully reduce the risk of relapse in that setting. And so we put several patients right off the bat on post-transplant maintenance.

As we've got practiced more and accumulated more data, we continue to find areas that we just want to use the drug even outside of what's on the actual label itself. Like David Sallman said, I would say in the -- we had maybe one patient that we've used it as a single agent. The reality is the majority of the -- and outside of the context of post-transplant maintenance. The reality is the rest of the patients in the setting of relapsed or even in the frontline setting, we're using in combinations in all our patients.

Overall, I would say the safety profile has been good, especially pre-transplant. Post-transplant in a maintenance setting, it's sometimes been a little bit challenging, especially if you're starting at a higher dose to do early initiation, which is what we want to do oftentimes. And so we've talked to transplanters and made appropriate dose adjustments, lowering down to the lower dose and then ultimately escalating the dose based on tolerability rather than going the opposite direction in post-transplant maintenance, which is something that we do commonly in FLT3 with gilteritinib in many ways. So we're sort of used to that way of practicing.

Great. And maybe Dr. DeFilipp, you obviously talked about axatilimab, but you have a lot of experience in the post-transplant setting. I think you have also had some experience with revumenib. I don't know if you'd like to just share a little bit about your clinical experience with revumenib...

No, definitely. So as a transplanter, having better AML therapeutics to get patients to transplant is extremely important was highlighted here, getting them not only to transplant, but in transplant in good physical condition, but also in the best remission status possible is extremely important.

But overall, I think as an institution, like we really look at maintenance as being a key tool for us, right? It's almost -- the traditional way of thinking about it is like you threw everything you had at these patients until they got to transplant and then like -- that was like the goal line, right? And now we just have tools to be able to continue more of an individualized approach after transplant. So it's almost like get them into a good remission, pause to get them their transplant, which would be their potentially curative therapy, but then get them back on their disease-specific therapy afterwards.

And we had a case of a patient who was multiply refractory to many lines of therapy, was able to get Revuforj and was able to get into remission, the patient to transplant and actually restarted the maintenance at probably day 14, which was probably a little bit [ bold, ] but I would say that I was quite worried that I felt like the only thing that had worked this patient and we had been anticipating trying to get a transplant so directly.

Now yes, we felt some cytopenias earlier on, but the patient has been able to stay on, continues on is almost a year out and remains unlikely remission. So very happy with our experience.

That's great. And maybe a question for Dr. Sallman or Dr. Jabbour. A lot of interest at this congress about the concept of MRD eradication. Just wondering in clinical practice now, whether you have any reflections on how you think about Revuforj MRD eradication?

Go ahead.

I would say, to me, MRD is really the most important facet of AML care at this point. And I think it's really what's most rapidly evolving the field. Again, I think it's -- not all MRD is created equal, and this can be unique based on differential subsets. But for NPM1, it's extremely important. There's hundreds of published data sets across intensive and nonintensive, essentially if you're positive for the vast majority of relapse and if you're negative, these are patients that maybe even with nonintensive-based therapies are we curing more.

I think how we best eradicate, again, we had even several in our -- Andrew Wei last year presented 8 patients, 3 of 8 cleared, 5 of 8 had significant reductions. So -- and I'd say in our experience, it's been at least half of patients with monotherapy having deep level reductions. What's nice is safety. There is no safety issue with MRD. DS is an impossibility in the setting of MRD. I do think what's the -- it's not a singular time point. So once -- we're checking MRD all the time. And if we're making a change, we're often reassessing all the time. So is single, double or triplet the right for MRD erasing, I think.

But no, any time I see it, I will do something essentially immediately. I think this is -- we are a little bit in the pharmaceutical races for all of these frontline studies. But is adapted approach is best. Obviously, we get Elias opinion in a moment. But if I have a patient, for example, on HMA venetoclax, we know about 4 cycles, you often get your best molecular remission. That's -- if the patient is positive, adding on is also a very -- it's another approach, especially as patients may be on a whole bunch of different trials, placebo, we don't know what's on and what's not. So I think these are critical time points that you can really personalize the patients manage.

That's helpful.

I definitely echo David and everything he said. I think there's nothing called minimal. It's actually measurable. I mean you have NPM1 as a major event in your physiopathology and having detecting minimal disease at this stage, it's the best time to intervene. I don't want to wait for the disease to be flourishing and monoblastic. I want to try to intervene as early as possible. The earlier we intervene, the better the outcome is. In ALL, we have plenty of data, and we have actually MRD as surrogacy for approval. And I hope one day in AML, that will be the same, too.

Dr. Jabbour, just while you have the mic. May I ask you, obviously, yesterday, Amir Fathi presented PARADIGM study at the Plenary session. And I think there's a lot of interest in potentially evolving approaches to getting patients to transplant and standards of care. I just wonder whether you could offer some reflections on how you think that data, I know it's only one day and there's a lot to reflect on, but how do you think that may change the PARADIGM and how we should maybe be thinking about that and as it relates to our program?

Okay. I want to be bold as much as I can. I came to ASH and people ask me, wow, we have a new standard of care for AML. This is not what the aim of the study is. Remember, 3/4 of these patients enrolled were adverse features. Yes, I agree for patients who are bad patients, intensive chemotherapy is not the answer for them. If you can give them a regimen, they can get you into remission without toxicities and go for transplant, that's great. This is what the trial is addressing. But the trial is not saying, hey, guys, if you have an AML, give HMA ven, that is the solution. Because AML is a rare disease. And I don't want to doctor in a committee in Montana or in Spokane or somewhere, no funds for these regions.

Like but you see one AML every other year, they give them HMA ven standard of care. This is not the standard of care. It's a good option for a patient with a poor biology, as David mentioned during his presentation. For these patients, yes, I think MECOM AML, fibrillation AML, intensive chemotherapy will get you nowhere. So get them a regimen that can get them into CR without toxicities and transplant, that is great. And I think we can build on this for this patient population.

That's great. That's great. Maybe Dr. Sallman, just -- do you want to go to the floor. Please, yes, let's do that. Let's open to the floor questions.

David Dai from UBS. Just a couple of questions. One is for the physicians. Maybe just think about there right now 2 menin inhibitors for NPM1, relapsed/refractory NPM1 AML. So I'm just curious, how are you deciding between these 2 drugs? And what are some considerations when you're deciding to choose between these 2?

Maybe I can start with the comment there. So ultimately, we have a lot of experience with revumenib. It's first to market. And so I think having experience with an agent is extremely significant when a new agent is coming on board. You see it across both academic and community practices that it's really hard to ultimately change their practice pattern, especially when efficacy data is relatively similar in that patient population.

The things that are different, QTc prolongation, interaction with drugs, we're very comfortable with managing. So QTc is not an issue, drug-drug interactions, we deal with venetoclax. We're not -- we do this all day, every day with our pharmacists. So in an academic practice where we have specialty pharmacy to help us on these things, it's not things that we generally worry about. However, with zifto, there is the interaction with antacid. The majority of our patients that are getting induction chemotherapy and in the hospital are going to be on a form of antacid.

And I think that is something that kind of will potentially limit our start. So at least in my practice, I don't know how -- outside the context of the clinical trial, I'm really finding a hard time to pick a patient that would maximally benefit from zifto over revuminib. The only patient that I could think of would be someone with significant cardiac toxicity, but I'm curious to what do...

I think the 2 approval are good, but they are not a home run. I mean with the response rate and the survival we have is not amazing. I think the best way to use in my practice is a combination. And we have the SAVE is to go for a triplet and build on it and make the best of it. Toxicities are not an issue. QTc prolongation or DS have to be a low threshold to intervene, but that is not an issue for me. One thing I was asked by your colleagues one day, I said, you going to go buy a car, okay, and you have a car for the same price, you can get hybrid or gas, I want to pay the hybrid. I want to have the NPM1 and KMT2Ar, HSCT both inhibited. That's how I choose. For the same price, why not buying a hybrid?

Clara Dong from Jefferies. So one question on GVHD and one on revu. So for GVHD among the 19 patients who transitioned to a different dosing, what baseline factors help investigators feel more confident that the patient was stable enough for Q4W dosing? And is there any like organ or phenotype for which you will actually discourage Q4W transition?

And then for AML, so from the real-world study -- actually, for SAVE study, can you talk about the timing for patients achieving MRD negativity and since it seems they were achieving early cycles. And that being said, is there a rationale to alleviate venetoclax or decitabine exposure earlier?

Should we start with the Q4?

Yes, chronic GVHD question. So I think there's -- it's going to be really in the eyes of the physician here. On the trial, the patients had to have had a response. And I think one of the things that is always challenging in chronic GVHD studies is how a response is graded on the trial. Sometimes there's a lot of gray area of what that actually means clinically. But I would say that from a clinical eye, you would be looking for someone who had maybe a deeper clinical response that you would then want to move into the every 4-week dosing.

You wouldn't want to take something -- if you really felt like you had more on the table to achieve, you're probably going to keep them on the every 2 week and then go down the 4. But ultimately, when you think about this go to every 4-week option, it's definitely something you can do if a person for some reason, switches to that and they feel like they were doing better on the every 2 week, they can always shift back. It's not like a one directional decision. So I think that it's just a convenience factor and another option that we have as clinicians.

Regarding SAVE, time to MRD remission is around 2 cycles. You get MRD activity. I think the key for the future is how to optimize use of oral decitabine and menin inhibitors. And that is true for all menin inhibitors, whether it's zifto, rev, blexi, [indiscernible], I think we have to be cautious how to give these drugs. And I think if you get into MRD negativity, yes, you can tailor therapy based on response. If I have to repeat the exercise, but SAVE again, I think with 4 days of oral decitabine. The ven in my practice, I never go beyond 14 days in the subsequent courses, even reduced to 7 days, and I give 28 days of menin inhibition and recycle.

Phil Nadeau from TD Cowen. Two questions on revu. First, on post-transplant maintenance. There seems to be a theme both from the presentation and what Dr. Swoboda just said of looking or searching for the correct dose. So how well understood is the dosing PARADIGM in maintenance today? Is there more work to be done there? And maybe the company -- we'd be curious to hear from the company if there's formal work going on?

Then second, in terms of the pivotal trial in first-line KMT2A, could you go into a bit more detail on your plans? I think you just said you're going to do a rev plus ven/aza pivotal. Is that correct? And are you also looking at rev plus intensive chemo in KMT2A?

Should we talk about dosing and maintenance?

Yes. I think right now, there is additional work to be done because I think the reality is most of these KMT2A relapses are early. And so as an investigator, we want to try to get it as early as possible. But you're dealing with a lot of challenges when you're dealing with it in the context of post-transplant maintenance because you're dealing with the immune suppression, the other antibiotics, the cytopenias, GVHD that can often mimic some of the side effects that are consistent with differentiation syndrome.

And so when you try to initiate it early on a high dose, oftentimes you're dealing with cytopenias, you can deal with AKIs. And so if you try to initiate on a lower dose, the only concern there is, are we maximizing efficacy in this patient population? Are we -- especially in that window where we haven't maximized graft-versus leukemia effect because they just got a lot of immune suppression.

And so I think that's the thing. Yes, I think there is additional work that needs to be done to find a dose that is safe and efficacious and how can we initiate it early because like the slide showed, we were at 110 days. I think all the investigators here feel like we need to initiate earlier than that in real-life practice.

Yes. I would just comment. I think one nice thing, we also have 25-milligram tablets, there is actually some additional titration that you can. I think there's differential practices based on azoles. I saw in the pediatrics 100% seem to still be on them. That's not a very common practice, at least in many adult populations. I'd say it's more of an issue that it's a annoying to monitor. We're monitoring the accounts all the times and tweaking. But again, the vast majority of patients are able to stay on. I'm a little bit hit hard and peel back, but you're going to get differential practices. I think this is where the real-world again, nationally and internationally, I think we'll say, hey, this is what may be most optimal. I think from the same point, we need to be a little bit cautious. Is there a right dose that ultimately leads to the right efficacy. So I think the data is too small to answer that question right now.

And Phil, just to answer your question, we do have ongoing work exploring different doses in the maintenance setting. We have an ongoing study and a planned study because we think it's important. And we also have experience of different dosing because of the flexibility that's built in with Revuforj that clinicians can use because for the reasons that we just discussed. And in terms of the frontline studies, I would just say the following that, firstly, we have generated now really compelling data for KMT2A subset, both in relapsed/refractory now in the front line with both intensive chemotherapy. You saw that and also with then HMA combinations. We're very excited about that.

Our plan is to bring data forward for that subgroup of patients as quickly as we possibly can. That is our focus. And by doing that, we have a focus by including KMT2A both in the EVOLVE-2 study with HOVON. They are included in that study. And then we have 2 approaches, one working with the NCI myeloMATCH, where we have a cohort for KMT2A on a background of 7+3.

And we are also planning based on all of the data that's being generated, a combination with ven/aza for KMT2A because we think that could be a viable alternative to try to get those patients to transplant without all of the morbidities of intensive chemo. So it's a really broad program to really try and accelerate data that will support clinical practice, which is important. Do we -- we have time for another question...

This is Jeff from B. Riley. I only have one question for post-transplantation maintenance is the developing standard to treat for fixed duration or treat until MRD resurgence or treat indefinitely if untolerated. What patient factors could guide this choice?

I mean, usually, you cannot give treatment for life -- you don't give treatment for lifetime post transplant, of course. Yes, it will be better by your MRD negativity. Somebody for transplant in MRD-negative situation, you design a program for 1 year or 2, but not beyond that.

If post-transplant, you remain MRD positive, you have to think definitely, maybe not inhibitor alone is good enough option. Usually, you go for maintenance in somebody who is either MRD-negative or MRD-positive barely transplant and you try to get them into MRD negativity. I will do my practice I will do 2 years of maintenance and then stop thereafter.

And I think the re-disease eval at that 2-year time point is important because we learned in morpho, for example, with some patients that were on placebo, they came off they relapse. So I think you always need to reassess the MRD. And I think this is a good question that we're going to continue to learn more about over time. But for right now, I think we're going to copy morpho a couple of years. I think we'll redefine it.

And remember, we -- as a company, no matter how big the company is, you cannot do all trials possible. So that is something we will learn while we're practicing and optimize the use of the drug as we go.

Thank you. We have time for just one more question.

Sure. This is Dara for Steve from Stifel. Two maintenance-related questions. One, could the pool of maintenance eligible patients be larger than CR/CRh that we've seen from monotherapy given that we're learning at this ASH in prior medical meetings that combinations are clearly more effective in relapsed or refractory?

And second question is, what is your respective philosophy around when is the best time to transplant patients? I hear your emphasis on taking the first opportunity to transplant patients safely and also taking the best opportunity to take patients to transplant. Are you feeling like with revumenib, you're picking 1 of the 2?

I think going for transplant in MRD-negative situation is the best way to go. And usually, you can get into this type of response with 2 or 3 cycles. So usually, I see somebody in my clinic, I want to try them for transplant. That will give me 2, 3 months to get them into MRD negativity and go for transplant. In every frontline trial, we have a maintenance component to it, be it 1 year or longer. Again, as Dr. Sallman mentioned, reassess MRD status [indiscernible] therapy and go from there. So in every regimen frontline, rev maintenance is designed to and 2 to 3 cycles to get to MRD negativity and go for transplantation.

I just in frontline, just to emphasize because it's a little bit different in salvage where relapse is even more difficult. I think in frontline, you do have time because there's almost been no report of early relapse across mutations. And we know at least with HMA/ven, double therapy even in NPM1, probably 4 is where we get most patients there. But like you said, if you get there at 2, go at 2, you get there at 3, go there at 3, but you have time to even treat -- even 4 to 6 cycles, probably it wouldn't go that long, but 4 -- up to 4, I think, is very reasonable to achieve that, particularly in frontline where relapse is not that.

And NPM1 in particular, KMT2A is different.

So thank you very much. I'd like to thank all of our panelists for their presentations today. And of course, the ongoing collaboration that we have had for our programs. We have great momentum coming out of ASH. We're excited to have presented such a breadth and deep data set. We are very focused now on executing our programs and think we have very good momentum heading at the end of this year and into 2026. We're excited to bring Revuforj to more patients in need and move into earlier lines of therapy.

Thank you all for your attention today. Of course, I'd like to thank all of the patients and the families without whom none of this research would be possible. So thank you, and I hope you enjoy the rest of the day.

Okay. Well, thanks for joining. Good morning, everyone. I'm David Dai. I'm the biotech analyst here at UBS. Thank you for joining our fireside chat with Syndax Pharmaceuticals. It's a great pleasure to welcome the executive team, have Mike Metzger, Chief Executive Officer; Steven Closter, Chief Commercial Officer; and Nike Botwood, Chief Medical Officer. Thank you, Michael, Steve and Nick. I appreciate you joining us.

Yes. Thanks for having us, David. Always a pleasure to be here with you and UBS team.

That's great. So with that, for someone who are new to this next story, could you give a quick overview of Syndax, your lead programs as well as any kind of overall company strategy?

Sure. First of all, thanks for the introduction. We're at a very exciting point with the company. So Syndax is now a commercial stage company focused on oncology. We have 2 commercial stage assets, which we've developed from the very beginning all the way through now have launched in the last year. We've had gotten off to a fantastic start. Revuforj is our asset in AML and ALL for acute leukemia. First of its kind, first and best-in-class menin inhibitor, selective menin inhibitor, first indicated for KMT2A, acute leukemia, which is about 10% of the overall population of AML and ALL.

And now newly introduced and approved is NPM1, is another large subsegment of the population in adult AML and pediatrics, and that affects about 30% to 35% of AML. So now we have a very broad offering in adults and pediatrics, AML, ALL, KMT2A and NPM1, roughly 40% to 50% of the population, a very large opportunity, about a $5 billion opportunity, which we're exploring. And we have a fantastic -- we're off to a fantastic start there. We'll tell you more about that.

Our second asset is Niktimvo, which is for chronic GVHD, another first-of-its-kind CSF-1R antibody directed at third line plus chronic GVHD patients. We launched that product in February of this year and also off to a fantastic start. Both products are outpacing all the metrics in their respective areas. And so we are very proud of what we've done so far, but we're just getting started.

So the company's strategy is to develop products in oncology, and we've done that successfully now with these 2 products, and we are expanding them. So we're moving quickly into frontline trials to bring them to newly diagnosed patients in combination with standard of care therapy, and that goes for both assets. And beyond that, we'll look to move into additional indications for both of these assets, not only newly diagnosed patients, but for instance, with Niktimvo going into areas such as IPF for patients who have fibrotic disease of the lung. So much to discuss, but we're off to a great start and here to answer your questions.

That's wonderful. Very exciting, a lot of progress and a lot of excitement happening over the next 12 months, too. So maybe let's start with Revuforj for a lead program. It's almost a year into launch in the KMT2A space, and you just launched the NPM1. Maybe just help us understand some of the ramping. How is it going so far? Could you share with us patient also physician feedback and experience on Revuforj so far?

Feedback has been fantastic. I mean we had -- again, we had -- for NPM1, the second indication, we had the opportunity to get the drug into guidelines. So we were able to -- ahead of approval, which is at the end of October, based on published data, we were able to access the guidelines. Our field medical team initiated work with the guidelines and talking to physicians about the new indication. And then we got approval, which was a broad indication for relapsed/refractory disease in both adults and pediatric patients.

So the feedback from physicians has been fantastic. They're eager to put their patients on. The drug is well tolerated and very efficacious. And this is an efficacy-driven market where physicians really are focused on getting their patients into remission as quickly as possible. Our drug does that very well. And so they're excited about this new indication because it extends the population and allows us to really do more with the drug. And so, so far, so good. We're ramping quickly, and we expect to have a good fourth quarter and into next year as well.

Excellent. Excellent. So on KMT2A, right now, more than 750 patients have been treated so far, 1/3 of them have progressed to transplantation. As you're treating more patients, as you mentioned before, and the healthier patients, you can imagine, do you envision more patients would potentially be put on transplantation?

I think the simple answer is absolutely yes. There's no reason to think that with a drug that gets patients to a very robust deep response quickly, and drives more patients to transplant, why physicians wouldn't be apt to transplant more of them and also put them back on therapy. So the opportunity here is not only to drive patients to transplant, but to bring them back in a maintenance capacity and put them on therapy and keep them there in remission for an extended period of time, months, if not longer.

And so we're talking about a year to 2 years potentially of maintenance, which is a very significant driver of this business, specifically for KMT2A patients who have the ability to -- there's younger patient population, more of them are fit for chemotherapy and for transplant. And then you bring them with Revuforj, you bring them back on maintenance, that could be potentially a very long period of time that drives the revenue of that smaller population of patients, about 10% of AML.

For NPM1, they do the same. They do -- this is an older population, but they do transplant them. And so the ability to treat them earlier, patients tend to do better, stay on therapy longer and potentially get maintenance as well. So that's the paradigm that these physicians really would like to pursue. And with a drug like Revuforj, they're able to do it as well as possible.

Got it. Got it. And so one thing you mentioned was that some patients went into maintenance therapy. And so far, we've seen about 30% to 40% -- based on the most recent metric, 30% to 40% of patients were put back on to Revuforj after transplantation. How do you think this number would change over time? And what's your sort of expected percentage at steady state?

It should increase, really 2 factors. One is physician experience, the ability to -- once they put a patient on maintenance, they tend to put them on maintenance again, right? They have a positive experience. And we've heard that from physicians all along that they expect to put their patients on maintenance as much as 70%, 80%, we expect potentially over time could go on maintenance. That's very different than 35% to 40%.

So I do think it's a matter of experience. It's also a matter of time. There's some patients who haven't just been given enough time in our very brief commercial experience to go back on therapy yet. So you got to give them a little bit of time. It takes 3 to 4 months once they have their transplant to engraft. So some of those patients are just starting to get to that period of time where they can go back on. So the 2 factors, time and physician experience, and I think that favors a much higher amount of patients going back to maintenance.

Is there a number in terms of what the steady state maintenance therapy is going to look like?

Well, I said 70%, 80% is a possibility, and we don't know based on our clinical experience, it's at least that high. So we'll see. We'll see what happens. But I do think that the building experience that we have should drive that number up meaningfully.

Okay. That's really good. And tell us a little bit more about those kind of patient journey around that. How quickly do you think these patients can be put on maintenance therapy based on the current experience with respect to patients getting on the CR and MRD-negative CR and then transplantation and then eventually get a maintenance. What's sort of time line look like here?

It's -- look, the time line has been pretty consistent from our clinical experience and now through our commercial experience where you have a patient gets to response rather quickly, first response, about a month, best response, about 2 months, 2 to 3 months, they get their -- at that point, they get their transplant, so they're in remission.

They receive a transplant, and they're going through that engraftment period where it takes time for the bone marrow to come back and fully populate their blood cells. And so you have about 3 to 4 months of time where they're off Revuforj and they're pausing treatment and then they return to maintenance thereafter. So it's from start to resumption of therapy, it's somewhere in the 6-month range where they'll start to get...

Got it. And do you think this number will also change over time too as patients get a little more comfortable with Revuforj, physicians get more comfortable with Revuforj going forward. Do you think this number will evolve over time as well?

Maybe Nick can answer that question.

Well, I think it's a fascinating area actually and the science is evolving. I mean there's increasing data that supports the concept of maintenance after transplant. And I think physicians are getting more familiarity with how to dose. You have to remember that after transplant, patients marrows after engraftment are quite delicate. And so you have to have familiarity with dosing to ensure that the drug is tolerable. So we're gaining a lot of experience now with managing cytopenias. And one of the benefits, I think, of Revuforj is that it does allow a little bit of flexibility in the dosing, and so physicians are getting to know how to do that.

But there's also some quite fascinating science in terms of mechanistically why it might make sense to put a patient back on Revuforj to give that increased chance of event-free survival. We're actually going to -- at ASH, have some quite interesting series of real-world evidence. We promised data coming from our commercial experience now every year of approved and ASH will be the first time we've had the opportunity to present some of that data. Two series, one from Moffitt in Florida, another one from the MD Anderson, interestingly, from the pediatrics Department of MD Anderson that they also have experience in adults. But in that series of about 10 patients that went on to get maintenance after transplant, we have a 1-year event-free survival of 100%.

And that's really encouraging for this pediatric population where normally the relapse rate would be quite high. But on maintenance, all of them tolerated it very well. Patients were able to dose interrupt or even reduce if necessary to manage cytopenias, but to be seeing preliminary efficacy that looks as promising as it does, as those generated continue -- as those data continue to be generated, I think it's just going to increase the desire to have patients back on the Revuforj after transplant. So already, we're beginning to see that and publish it, and that's very exciting.

Yes. And I think another question just around the duration of therapy. I think most investors care about right now. Just help us understand where it is now? And how do you think it's going to evolve after patients or more patients are getting on to maintenance therapy?

Yes. What we've said is this first year of launch, we expect the duration of therapy in the order of 4 to 6 months, and that factors in mostly new patients starting and patients staying on therapy and then dropping off and going to transplant and for a very small portion of the year being able to come back, and we expect that to accelerate in the future years.

So this year, factoring all that in 4 to 6 months average time on therapy for this year and then it extends next year with the introduction of more patients going to transplant coming back for maintenance, probably more in the range of 6 to 12 months next year.

And how do you think the number will evolve over time as well?

It could get longer. I mean I think there's no upper limit to what could happen. I think we're already setting a very high watermark for other therapeutic classes within AML. You haven't seen the ability to extend to maintenance with FLT3 and IDH. You just don't see it as much as you do with KMT2A, for instance, where you have a younger patient population and you have a medicine like Revuforj that drives to remission so quickly and enables the transplant.

So I think this is a very -- this population is specific for this KMT2A and NPM1 for a drug like Revuforj to really impact and drive maintenance. So it's a different capacity than you've seen with any of the other targeted therapies within AML.

Got it. Great. So now you recently got approved for NPM1 patients, but we did see an updated black box warning of [indiscernible]. Maybe just help us understand the decision of the FDA to include or to update the black box warning to include this [indiscernible] case? And how do you think this might impact adoption in NPM1 setting?

I'll just make one comment, and then I'll pass it to Nick. I don't think it will make a difference at all. In fact, this is -- physicians have had fantastic experience prescribing the drug for KMT2A patients and some for NPM1. They've done it off-label. And so this body of experience speaks for itself. We've done extremely well from a sales perspective, but also introducing this new therapy to physicians and they want to use it.

They feel it's well tolerated. This is very much standard of practice for them. They're not doing anything out of the norm to introduce and use Revuforj, and they feel very, very comfortable with it. So our experience speaks for itself.

And maybe I'll pass it to Nick specifically around.

No. Thank you, David. QT prolongation is not new for Revuforj. Frankly, it's not new to prescribing physicians in AML. There are many drugs in the treatment of acute myeloid leukemia that have significant benefit that cause QT prolongation. So physicians have a lot of experience in managing it. It's been a warnings and precautions as we've significantly expanded our use of the drug, both in our clinical trial setting. In the label now, we have a safety data set of nearly 250 patients, and we've exposed many more than that, including commercial and compassionate use. So as we've expanded, we did identify a case of [indiscernible] that met the criteria for a warning.

But the guidance in terms of how you manage QT is exactly the same. You do weekly ECGs, you optimize electrolytes and you make sure patients are well managed. And by doing that, we've really been able to mitigate any potential risk of the clinical consequences of QT prolongation, and that's really important for prescribing physicians. But I think what's really driving this is efficacy in a setting where we're talking about relapsed/refractory AML. These patients have sadly very short life expectancy. What you want to do is you want to get these patients into response, give them a chance of a durable remission and potentially even a transplant.

So that's very much in their mind. I don't think that the management of QT is really a big consideration in the best selection of a first-in-class agent, which has really changed -- transformed, I would say, the standard of care in relapsed/refractory AML. So it's really very well managed and not a concern to prescribing physicians.

Yes. I would just amplify the fact that this is an efficacy-driven market. Physicians care, first and foremost, about what's -- which drug is going to get their patients to remission. And our drug does a fantastic job of that. And relative to any other menin inhibitors potentially coming behind us, I don't think anybody has seen data that is reminiscent of what we've been able to show in monotherapy or even in combination. And it makes the choice quite easy for physicians. They monitor the same way they were monitoring before. So the label doesn't change that.

Got you. Got it. And since the approval, you had a couple of weeks, right, of bringing the field team with the [ updated ] label to physicians. I'm curious how has the feedback from physicians so far? Maybe Steve, you can talk about this, what has been some of the feedback from the physicians on the NPM1, especially on the NPM1 setting, how they're viewing the label and how they're treating patients so far on the ramp?

Yes. Good question, and there's a lot of excitement. We haven't had a lot of time. NCCN guidelines were granted in the third week of September, a little lift there, a little bit more visibility, but awareness is very high, certainly on the condition and certainly on the drug. We talked about the KMT2A launch and the 750 patients that have been on since launch. There's been over 2,200 prescriptions, and that's against an audience that's smaller than most other targeted AML therapies. So it's off to a great start. The drug has done incredibly well. Physicians can easily identify patients.

And the treaters that have used the drug so far, and it's a very broad patient population, there are hundreds of accounts that have had a lot of experience. So there's no challenging -- no challenges to getting patients on therapy. And it's that same treating audience and it's physicians, it's nursing staff, it's distribution, it's pathology within these accounts, that broad experience they have so far with Revuforj, they're going to see NPM1 patients. So that will translate incredibly well. So early days, patient population, as you know, is bigger than KMT2A. We'll be excited to share results at the end of the quarter, but we're off to a great start.

David, I'd maybe just add one thing that familiarity is so important. But also we know that physicians like to use the drug in different settings and in different combinations. And to support that, I mean, obviously, we don't promote in that setting, but to support clinical practice, combinations of drugs is really important. And we're going to have a really outstanding presence at ASH this year. We're excited about that. We're going to have 12 abstracts for revumenib, 23 if you include Niktimvo. So really strong scientific leadership.

Included in that, as I already mentioned, is some real-world evidence. The real-world evidence would suggest that in academic centers like Moffitt, they like to use Revuforj in combinations. That's their choice because they think it gives them a higher chance of getting a patient into response. That's important. And our focus has been ensuring that we're doing the right research, working with the best sensors with the best clinicians to generate data that supports how physicians want to use Revuforj and generate that data. And I think ASH is going to be a testimony to how we're doing with that, more to come. And that's really important that we continue to lead and innovate and provide those data to ensure the best practice.

That's a great segue to start talking about some of the combination strategies you have for Revuforj, especially moving to frontline. So maybe making -- just tell us a little more about some of the strategies and clinical development plans you have for Revuforj in combination with various different therapy standard of care in frontline setting.

I'm incredibly excited about that. I mean, as I said, we transformed the standard of care in relapsed/refractory. Our intent is to continue to lead and be first and transform the standard of care in newly diagnosed patients. That's where we believe we can have the greatest impact, and we can bring more patients potentially even to cure. So it's been a focus of our program throughout. We're going to have some more very important data at ASH.

As we think about developing Revuforj in frontline newly diagnosed patients, clearly, you need to have established data in combination, both to establish tolerability to confirm the dose you want to take forward and also show preliminary efficacy. So if you start perhaps with the unfit population, patients not considered eligible for 7+3 or intensive chemotherapy, that's really been a preliminary focus of our program and we have generated compelling data now from the Beat AML study, and then you'll see some updated data at ASH from the SAVE study, showing really compelling tolerability, but importantly, efficacy in combination with VEN and an HMA, whether that's IV or oral.

And those data gives us and our collaborators very high degree of confidence that we can get a successful Phase III in combination with ven/aza. And we know that ven/aza is increasingly being considered a standard of care, certainly for unfit patients, but potentially even fit patients as an alternative to intensive chemotherapy because of the reduced morbidity. And that's incredibly exciting for us because we've demonstrated such compelling data across NPM1 and KMT2A.

And then when you think about intensive chemotherapy, patients sit for intensive chemotherapy, we're going to update some important data at ASH showing our Phase I data, both with some work we're doing with the NCI and also Syndax sponsored Study 708 that shows, number one, you can combine very effectively with intensive chemotherapy. We have shown that we can combine at the current recommended dose of Revuforj, which is important. That's the dose we'd like to take forward into Phase III, and we'll be confirming that shortly.

But really importantly, compelling activity. We've seen 100% complete response rates in KMT2A and 100% MRD negativity. So when you combine Revuforj with an intensive chemotherapy regimen, you do get both a tolerable regimen, but importantly, really striking activity with very high percentage of patients actually going on to get a stem cell transplant. So we have guided previously that we're planning to start our REVEAL program focusing on 710, which is the NPM1 population by the end of this year, so very soon, and that study is posted on ct.gov.

And then in terms of the KMT2A population, more on that to come, but we're very encouraged by the data we've seen both in combination with intensive chemotherapy and ven/aza for that smaller population. And we really think we're leading in that space because, again, we've seen 100% CR and 100% MRD negativity, which is extremely encouraging.

So very robust plans to get us registrational programs in the front line. And then that is obviously supported again by a variety of collaborative and investigator-driven studies to ensure that we're providing physicians with all the data they need to optimally treat their patients. So a very exciting program as we move into frontline.