Syndax Pharmaceuticals, Inc. (SNDX) Earnings Call Transcript & Summary

Hi, everyone. Just wanted to start everything. We're running a couple minutes behind. But I'm Michael Metzger, the CEO of Syndax. Welcome today to our investor event. It's a great Monday morning for us at ASH, where we've had a great weekend and expect to have a good couple of days to wrap up the meeting. It is, as you know, a really, really important time for the company as we advance 2 of our medicines to hopefully approval very shortly. So, I'm going to provide a short introduction, and we have a host of speakers today who are involved with our program, thought leaders in the space who have done wondrous things for our programs. And so, we'll let them speak to a variety of data that were presented either during the weekend or will be presented in the next day or 2. So, I'll introduce them and let them take the show from there. So, I'd just start with our forward-looking statements. I ask you to refer to our SEC disclosures for more information. So, just as introduction, I think most of -- all of you probably know, we are very near commercialization. The company is in a very unique place to have 2 assets, 2 heme assets that are very focused in the same area. And the opportunity in front of us are very, very significant, potentially 2 best-in-class and first-in-class medicines. You know them both. Revumenib is a novel menin inhibitor, targeting KMT2A and NPM1 acute leukemias. And axatilimab is our first and best-in-class CSF-1R antibody, targeting chronic graft versus host disease. We are on track to -- for revumenib to file the NDA by the end of this year. We're working under RTOR, which gives us a great advantage to work closely with the FDA to file it in a very rapid fashion. The opportunity is, as I said, multi-billion dollars, both in relapsed/refractory and expansion to frontline studies. We'll talk about some of the data today with regard to combinations, which is new and exciting, as well as tomorrow, we'll present at the Plenary -- or the late breaker for our pivotal data. And axatilimab is on track for a BLA submission by the end of this year with our partner, Incyte. Very exciting in its own right. A multi-billion-dollar opportunity in third line GVHD and expanding to earlier lines through combinations. And no need to mention, also these are long-lived franchises. We have patent protection out through 2040. So, this is a franchise both for menin and for axatilimab that will live on for a long time. It has the opportunity to really expand into other indications. So, we did do our planning. I do want to give a shout out to Dr. Wolff. Last night, a great presentation yesterday at the Plenary for axatilimab, which was exciting. And as I mentioned, we have the late breaker tomorrow. Hope everybody can stick around for Tuesday morning. So, what are our goals at ASH? I think lots of companies have different goals. Our goals really are to be here and showcase both of these really important medicines, which we'll be bringing to market, we hope, very soon, and to showcase some of the new data that's emerging in combination, we'll talk about today. Obviously, we're here to partner with the physician community. This does not happen without the help of great physicians to advance these medicines. And so, we're here to help educate on our data and what we're bringing forward and what we will hopefully launch in 2024. And then, obviously, we have these ongoing trials, a lot of work going on for both programs. And so, we look for continued involvement from the physicians to help us enroll our trials and maintain the excitement about both of our medicines. So, with that, I'm going to just announce or introduce our panelists today, a great group of professionals here to help us explain some of this data and walk through the opportunities. So, on my left first is Dr. Vedran Radojcic, who is our Senior Medical Director at Syndax. I give him a call-out because he was a leading investigator at Utah for many years and came to Syndax to lead our program after -- and now, we're at an exciting point in the program. So, we're happy to have him here today to present for us. And also Dr. Daniel Wolff from University of Regensburg, who presented at the Plenary. And then, for revumenib, Dr. Eytan Stein from Memorial Sloan Kettering Cancer Center; Dr. Ghayas Issa from MD Anderson; Joshua Zeidner from North Carolina University -- University of North Carolina, sorry; and Neerav Shukla from Memorial Sloan Kettering Cancer Center. So, a great group today. I'm going to turn the mic over to Vedran, who is going to come up and talk to you first about axatilimab. Thank you.

Sure. Thanks, Michael. Good morning, everybody, and it's a pleasure to have you here to introduce our programs or review our programs and their progress over the years. So, as Michael said, I was a PI on the axatilimab study when I was in my academic role before joining 2.5 years ago. And it was a pleasure to collaborate with my colleagues to execute this trial to fruition that culminated in the Plenary and in the upcoming BLA in the coming days. So, just kind of a brief overview of chronic GVHD. This is a relative niche space in a unique disease area. This is a most common long-term complication of the allogeneic hematopoietic stem cell transplants affects up to 50% of all transplant recipients. Dr. [indiscernible], as the introducer yesterday, did a quite nice summary to provide the background of the volume of the problem. About 50,000 people worldwide and about 15,000 to 20,000 people in the United States suffer from chronic GVHD after they have been most likely cured from their disease. So, this is a very difficult disease to treat. It's characterized by multi-organ involvement. As you can see here, there are 9 organs that are scored for the response in the NIH chronic GVHD consensus. Lot of responses in the different organs are rare. There are particular set of organs that's characterized by difficulty to treat, by difficulty to improve the patient outcome. And many of these organs, including lungs, skin and those that are characterized by fibrotic, continue to pose a tremendous challenge to the treating community as well as the patients. These patients need to be exposed to the prolonged treatment for the very reason that deep and durable responses are uncommon with the currently approved agents. So, current standards of care in chronic GVHD have been unchanged for quite some time when it comes at least to the frontline therapy. So, the corticosteroids are a current frontline standard of care. But majority, large majority of patients, about 60% of them, develop corticosteroid resistance or dependence and need to transition to the next line therapies very quickly. And actually, last few years were quite exciting for the entire chronic GVHD field, not just for the understanding of the disease and biology, but also for the advancements in the new medicines brought to the market for the patient population, which includes Jakafi, IMBRUVICA and REZUROCK in respective treatment lines. These approved agents are small molecule inhibitors that target very specific and focused cellular pathways identified in this disease as essential for certain mechanistic approaches, but they don't target diseases broadly and are characterized by their own shortcomings in terms of tolerability, safety and duration of the use. Approved therapies after steroid failure, nor steroids alone, as highlighted here, are curative. So, there is definitely an unmet need to improve the responses and outcomes of the patients with chronic GVHD. So, CSF-1R pathway is a pivotal pathway in chronic GVHD. CSF-1R controls monocyte and macrophage biology, their development, differentiation, survival and function, and it regulates the key cell that influences multiple different aspects of chronic GVHD development and sustenance. The CSF-1R signaling is critical for development and function of alternatively polarized macrophages, which are always -- often called pro-fibrotic, but they also exert pro-inflammatory functions. In chronic GVHD, these monocytes and macrophages -- these monocytes converting to macrophages, then exert the functions of inducing tissue damage and promoting fibrosis stimulation of the myofibroblasts. Where does the axatilimab come in this story? So, this is -- axa is a monoclonal antibody that targets CSF-1R signaling on monocytes and macrophages. It binds to the receptor, prevents the binding of CSF-1, one of the key ligands, displaces it, which then leads to diminishment of pro-fibrotic macrophage, inflammatory macrophage generation and their diminished function that's detrimental to tissue damage, to fibrosis to patients with chronic GVHD. We have previously reported on our earlier Phase I/II trial, which showed promising results in recurrent similar population that studied in AGAVE, with an overall response rate of 67% in the aggregate patient population. So again, just to illustrate the observed benefit in that study that's carrying forward in the AGAVE that Dr. Wolff will speak to, we have seen tremendous responses in patients who have been considered abandoned and with manifestations, irreversible improvement of sclerotic manifestations that remain a major unaddressed need for this patient subset. When it comes to where that positions axatilimab in the current treatment paradigm, we can kind of try to compare it to the existing agents, to the steroids that are very anti-inflammatory based on our current understanding that come early in the disease. As the disease progresses, this inflammation pattern or part may diminish, but the fibrotic component still continues to go on. Ruxolitinib is primarily anti-inflammatory. Similarly goes for the ROCK2 inhibition with REZUROCK. And we believe that based on our data and more data to come from our studies, that axatilimab has heavy or significant anti-fibrotic and anti-inflammatory contribution because it targets a pivotal cell type that influences multiple different pathophysiologic mechanisms of the disease. So, through CSF-1R inhibition, axatilimab can -- is positioned to address hallmarks of chronic GVHD, both inflammation and fibrosis. So, what does it mean for the drug? I think we think that the drug, based on the results and our experiences and hopefully clinicians' experiences, is that it addresses many of the areas of unmet need. So, as we have shown yesterday, the drug works fast. It works on all the organs across the spectrum. We have reported, and Daniel will speak to as well, complete responses in all the affected organs. This is paralleled with symptomatic improvement in a majority of patients that occurs on a similar chronological order. These responses are durable. And in the end, the drug at the dose of 0.3 milligram per kilo that we are filing on is very safe and tolerable and allows for the long-term use for the disease control. Again, in addition to the compelling clinical profile, unique mechanism of action that's highlighted by the responses to the prior agent -- ongoing responses despite prior agent use, benefits in inflammatory and fibrotic components and consistent results across all patient studies. We do think some of the folks in Twitter sphere have posted that this may be a game changer down the road for the patients with chronic GVHD. So, I will introduce some of the background to the study and then pass it on to Dr. Daniel Wolff. AGAVE-201 was a study designed to test 3 different doses of axatilimab in patients with chronic graft versus host disease after failure of 2 lines of therapy. Inclusion criteria was age 2 years or older, with patients receiving 2 or more prior lines of systemic therapy. Active GVHD was defined by the 2014 NIH Consensus Criteria. Use of standard, let's call, the maintenance medications for these patients, corticosteroids that are usually carried forward from the earlier treatments, calcineurin inhibitors, mTOR inhibitors was allowed but not required. That's reflected in this picture. Importantly, no additional systemic therapy was allowed. In an essence, all patients had to discontinue medications before entering the study treatment, which includes discontinuation of REZUROCK, belomosidil, [ like ] extracorporeal photopheresis and other modalities used in this space, which did pose some risk. In an essence, this allows us to really speak strongly about singular benefit of axatilimab when used as a lone agent in patients with chronic GVHD, and we think that this makes the results even stronger. Primary endpoint was the overall response rates in the first 6 cycles as defined by the 2014 consensus. This was met if the lower bound was 30% or greater. Again, we are strongly believing that this may not be clinically relevant at the current day and age with the different therapies, but we have well exceeded this with the axatilimab results. Clinically meaningful improvement in modified Lee Symptom Scale was a key secondary endpoint with organ-specific response rate, DOR, FFS, OS, and safety additional endpoints on the study. So, just to highlight the patient characteristics, and this is carried forward from the Plenary, highlighting the aggregate data for the patients from all 3 cohorts because the data were so comparable and distinguishable. Typical profile of chronic GVHD patient populations: median age of 53, predominantly male population. Given where the trial was run -- about half of the patient population was accrued in the United States versus mostly Europe -- majority was Caucasian. Very advanced disease, characterized by long time from chronic GVHD diagnosis to randomization, about 4 years. Majority patients with severe disease, more than 4 organs -- 4 or more organs involved in 54. And importantly, number of prior therapies highlights the current day and age paradigm for these patients. 4 as a median. These -- 55% of the patients were refractory to the prior treatment lines, so they did not go in to deepen their response. The drugs -- previous drugs did not work. Prior exposure to currently approved FDA agents was in 85% of the patient population. So, ruxo in 74%; ibrutinib 31%; and belumosudil in 23%. Again, this is even more noteworthy because only 1/2 of the patient population was in the United States where belumosudil was accessible during this period. So, in essence, 40% of our patient populations eligible failed bel. Again, to kind of summarize this data, and kind of potentially contrast to our biggest differentiator vying for the third line treatment is REZUROCK. When comparing to the ROCKstar, patients in AGAVE were more advanced, 4 years from the diagnosis versus 2; similar pattern of organ involvement; more patients with lungs, and as Dr. Wolff pointed yesterday, without any restrictions on the severity of the patients included in the study. We welcomed everybody to reflect the real world treatment that's happening today in the practice, 80% with a severe patient -- with a severe disease, more prior treatment lines, more exposure to the currently approved therapies. And again, what I felt looking at the study is, running the study worldwide in 121 sites, 16 countries and 4 continents really level sets you what you would expect to be seen in the clinical community because you account for the heterogeneity of the clinical practice management. And again, we feel strongly that speaks volumes about the axatilimab potential in the chronic GVHD. And I think at this point, I'm going to pass it to Dr. Daniel Wolff to kind of share the data from AGAVE with you today. Thanks.

Thank you very much. I'm happy to share the data. Maybe one comment why the approach of axatilimab is unique is, in the past, we kind of focused on the player of GVH disease. Now, a colleague framed that the conductor is the target, which makes a big difference, if you know, speaking about football or soccer. Now, the data were kind of striking, given that we treated heavily ill, long failed patients. We got a response rate in the lowest dose with 74% more -- additional 15% were stable on the disease, and the patient fairly quickly responded with a median time of 1.7 months. Given that the patient failed for almost 4 years before, that's a pretty quick relief. And in 60% for the patient, this response was also durable over time. And the most striking issue was that the response rate increased with dose reduction. That was something which struck the community. I will focus now on the dose of 0.3 milligram for the reason that it performed best. Something which already Vedran Radojcic pointed out, there was no predicting failure of treatment. So, regardless of age, only a minority of patients were below the age of 17. Regardless of the number of treatment lines you failed, regardless whether you were treated with an FDA approved agent, including REZUROCK, the response rate didn't change. And that just underlines that this agent behaves somewhat different compared to other interventions. Also, severity didn't play a role. And I already mentioned that the issue that even approved agents failed in a significant proportion of patients. And given what organ responded, we expected some limitation as with our agents, but didn't saw that association. There was hardly no organ which didn't respond, and also organs responded after 4 years of treatment with a complete remission, complete resolution of symptoms. And you could think of that the skin response, which is kind of something which is most impressive for the patient, failed, which was simply not the case. If you ask for symptom assessment, 44% patients had a reduction of the body surface involved and even more patients had an improvement in the skin and joint tightening severity. Why is this the case? It's pretty simple to be explained. Most of the patient had deep sclerosis of bone, heart, skin. And the NIH Consensus Criteria assessing response would require every spot of the body to be resolved with deep sclerosis to call it response. So, even a patient that 95% better, we couldn't score the response, but the patient-reported outcomes tell the story. And as already mentioned, the patients stayed pretty long on treatment with a failure-free survival of 17 months, and only 2 patients in the 0.3 milligram per kilogram cohort died, 1 of progressive GVH disease and 1 also with severe lung disease with a preceding infection. And that just highlights that the trial didn't select for better patients. It just reflected the average patient of -- being treated for years. Symptom burden relief was pretty quick and pretty impressive. If you look, 87% of the patients reported a symptom improvement compared to baseline and a clearly meaningful change, so significantly better was reached with 55% of the patients. And as already mentioned, the skin thickening improved significantly in the vast majority of the patients. And the symptom relief was pretty quick as the response was seen within less than 2 months. The toxicity profile is -- just providing now the toxicity profile for all 3 doses because that was one striking feature of axatilimab. The lowest dose was very well tolerated. Only 6% of the patients had to stop the treatment because of side effects. If you compare this, for instance, to ruxolitinib, there was 30% dropout rate because of side effects. We have only, as already mentioned, one adverse effect-related death in the 0.3 milligram per kilogram cohort, a patient who was severely sick and infected already before. And there were some specific side effects, the periorbital edema, which looks strange, but it's not dangerous, but was hardly seen in the 0.3 milligram per kilo cohort by the increase -- the dose increase. And there is some -- a feature which is not true toxicity, the axatilimab depletes [indiscernible] cells, which clear enzymes out of the blood. And so, those enzymes circulate longer and are detectable at higher level, but that's not toxicity. It's just clearance of those enzymes. But it could impair the validity of the enzymes assessed. To conclude, axatilimab showed responses in all organs treated and in all patient subgroups, including those who [indiscernible], and I mentioned that in the Plenary, [ we would ] have nonreversible changes, and including also lung disease. And there was some rapid symptom improvement in those patients, and only very minority didn't benefit from the treatment. There were no safety concerns in the low-dose cohort. In fact, compared to the others, it was even beneficial or fewer. You have always to state, we didn't compare within the trial with other agents. That's some limitation. It could be used alone or in combination. There are trials [indiscernible] combinatory treatment. And as already mentioned, it was a robust well-powered trial, reflecting the real world. And so, with this trial, we have now established a dose. And the Phase II trial evaluating the combination of Jakafi and axatilimab will start next year, and I'm really eager to recruit patients to that trial. So, thank you very much.

Great. Thank you, Dr. Wolff. Vedran, thank you as well. I'm going to take some -- I'm going to close this section. I'll take a few questions when we get through the end. So just in summary, I think we heard about the incredible monotherapy data, really showcasing the profile of axatilimab. And in summary, the unique mechanism of action really sets it apart from other agents that are approved and used for chronic graft versus host disease. It will be the first agent to target the macrophage-monocyte lineage, which impacts both fibrosis and inflammation. It's a really well-tolerated agent. I think you see the data. It speaks for itself. Low rate of discontinuations really kind of hits home on that fact. Patients seem to not only do well, but stay on therapy for quite some time, which really underpins the incredible opportunity the drug has to impact patients and be a new agent of significance. We mentioned the very strong results, 74% at the 0.3 milligram per kilogram every 2-week dose. 60% of patients still staying on drug at 12 months. And so again, really, I think in patients who have seen this disease for 4-plus years to be able to have that kind of impact speaks volumes about the drug itself. And this is -- I think the point was made by Dr. Wolff. This is enrolling real-world patients. Why is that important? Well, looking across the world, you want to be able to put the drug into physicians' hands and know that they're going to have the impact that they've come to expect in clinical trials. And so, we do think that physicians will adopt the drug and use it once it's approved quite literally. So that's -- in summary, let me talk a little bit about the market, just touch on the fact that the first market that we're going after is chronic graft versus host disease. The drug, when it's approved, will be approved in third line. The overall market is about 14,000, 15,000 patients in the U.S. In the third line setting, it's about 5,000 -- between 5,000 and 6,000 patients. The BLA, we expect it to be submitted by the end of this year with Incyte, our partner. And through expansion, in combination with standard of care agents such as Jakafi, we will hopefully move this into earlier line settings and expand the opportunity to take advantage of the 14,000 to 15,000 patient numbers, as I explained. Beyond the U.S., outside the U.S., it's about a 35,000 patient segment, and we'll look to expand both into the EU, Japan and rest of world through additional work with our partner. And in an exciting way, I think we talk about IPF being a new expansion for the drug. This would be a new mechanism for IPF patients, which we'll introduce in a Phase II study, starting just these last few weeks of the year. So that's an exciting new frontier for the drug as an anti-fibrotic anti-inflammatory mechanism, and we hope potentially to expand into other indications as well. So, axatilimab has a lot in front of it. Hopefully, first, we can see the drug approved in chronic graft versus host disease, but by no means this is the end. This is just the beginning of what we can do with axatilimab, very exciting times. So, with that, maybe I'll pause.

Any questions for either Dr. Wolff for or Dr. Radojcic. Phil, please.

Phil Nadeau from Cowen. During yesterday's session, there was some commentary from the physicians about moving axatilimab forward in the treatment paradigm actually immediately upon the initial approval. Can you talk about the ability for physicians to be reimbursed in an earlier line setting, if it is approved third line? And then more broadly, I guess, what data do you think you need to produce to see more use in earlier lines of therapy?

Yes. Thanks, Phil. Maybe I'll take that question. And certainly, Dr. Wolff, if you can address it as well. Look, I think the question of reimbursement for earlier lines, I think, we have more work to do relative to that. But I think if the physicians are not restricted, they can use the drug as they would see fit. It will be a third line indication. But as I think we've seen with other standard of care agents, they tend to be moving the drug up into earlier lines, depending on what patient is in front of them. And I think the efficacy and the safety of the drug will be pretty impactful in terms of what patients see the drug as early on. And obviously, we're going to look to combine this over time. That's the data that I think you speak to, Phil, the ability to combine it with Jakafi, potentially with steroids, that's the future of this medicine. And so, we'll be running Phase II studies with Incyte come -- starting this year or next year, middle of next year to get at that point. But I think physicians will start to use the drug. And the reimbursement aspect of this, it's hard to say exactly how that will go, but we don't expect that, that will be a barrier for use as patients really need new therapies and they tend to exhaust multiple options that they have. I don't know, Dr. Wolff, do you want to make any comments?

I think I want to comment on 2 sides. One thing is the second -- current second line available treatment, Jakafi has contraindicated a couple of patients, and that could help with reimbursement at the current stage. That's the way -- if you show that you can't use second line, you can go straight to third line. And for the first line trial, me as a physician, I'm really eager to see a steroid-free approach, a combo approach. And if that works, that will be a huge game changer, not only to provide relief for the late-stage patients, but very early on. I think if this is successful, it would just be adopted practice because patients hate steroids.

Yes. Thank you very much. Peter?

Peter Lawson, Barclays. I guess a question really for Dr. Wolff just around the organ involvement and the skin response rates. Do you think those go up as you go into earlier line patients?

For sure because those patients would not have extended sclerosis. But as I already mentioned, that's one side. The other way is the way we document response at current. Actually, the skin was one of the best responding organs. It's just -- if you have a small spot of deep sclerosis on the lower legs, you still can't document that by NIH criteria. And we will have a workshop actually in March to resolve that on a scientific level. But -- so, I wouldn't pay attention to the NIH response rate. I would always regard the patient-reported outcome in the current setting as more important, and that reflects the clinical picture.

Yes. Thank you. Kalpit?

Kalpit Patel, B. Riley. One for the KOL. You noted that there was some anti-fibrotic activity that could be a differentiator for axatilimab. What aspects of the results from this trial suggest better anti-fibrotic activity than belumosudil? And what other decision-making factors would you use to position this drug in the third or fourth line setting?

That's a complicated one, the question. But an easy answer, we had patients in the trial who responded to axatilimab after failure of belumosudil. That [ answers that ] with obviously treating something, a different pathway, which does result in a different outcome. We didn't compare head to head in the same situation, belumosudil and axatilimab. It's hard to say which one is better, that for sure. The side effect profile was hard to say, if you don't combine it within one trial, but at least -- definitely not worse to belumosudil, maybe even better, but that's speculation. So where to position axatilimab against belumosudil is hard to say. It's both third line evaluated. Yes, that's basically very well tolerated.

Can I just add to this? I think the differentiator is really the real world population here. Trial run across the different heterogeneity of the clinical practices, heterogeneity of the agents available with more advanced patient population has failed prior agents really positions -- speaks volumes about the potential for efficacy if used in the similar patient population of belumosudil. When it came to the responses, and I think you can compare directly to Corey Cutler's Blood Paper, the -- what we brought up in the presentation yesterday that Dr. Wolff spoke to, and we can speak to it is that the fibrotic organs did really respond. Esophagus, which is a typical fibrotic organ is there. Skin, with the robustness of the patient-reported and clinician-reported outcomes that don't meet the response criteria on the patient population was 94% sclerotic. Lung responses were close to 50% versus the belumosudil. It's a tremendous -- these are nuances for the very heavily treated patient population, but there are clear pearls in the data that suggests that the drug works differently. And as Daniel pointed out, you hit the main switch. You don't hit one pathway confined to a cell, but you hit the broadly influencing mechanism that's safe. And I think that's the beauty of the drug. You will not make patient more immunosuppressed. We don't see that. But at the same time, you'll be affecting the facets of the disease pathophysiology in the process.

Just to echo, more patients, more advanced patients, more countries involved and consistent responses across the world and across populations.

Maybe time for one more. Brad?

Brad Canino from Stifel. Maybe to Dr. Wolff, just how effective does a frontline combo need to be to beat steroids? And what are you going to be looking for in your initial patients that you put on that will tell you it's on the way to that?

Failure-free survival is a big issue beside toxicity. What happens if you treat someone with steroids, 80% respond initially. We hardly get complete remission. But once you taper the steroids, they flare again. And that's the biggest issue besides the steroid side effects. And the other issue, which just was also mentioned by my colleague is steroids -- because there is hardly any cell which is not affected by steroids. But the community comes increasingly into the conclusion that some of those side effects even may prolong the disease. We know that steroids impair wound healing. That's something which we know for decades. And targeting disease early on with a sufficient failure-free survival, meaning no flare after you stop the treatment, that will be the endpoint. And if this is achieved with even lower [ tox ], that would be a game changer.

Great. Thank you, Dr. Wolff. Thank you for the questions. I think we're going to move on to revumenib. We're going to start with Dr. Stein. He is going to talk a little bit about the acute leukemia. Giving over to you on acute leukemias.

Okay. A crash course on acute leukemia. You're going to learn everything I know in 10 minutes. Let's do it. All right. So, the paradigm for treating acute myeloid leukemia is as follows: first, you want to give a treatment that gets a patient into remission, and then for the majority of patients, you want to send them to an allogeneic stem cell transplant, which will hopefully be curative. And a patient who fails an allogeneic stem cell transplant becomes relapsed and refractory. There are 2 ways to think about doing this. In patients who are well enough to receive and undergo the rigors of intensive chemotherapy, they get intensive chemo. They may get consolidation chemotherapy. That happens at about 20% of patients. Or they go on, in about 80% of patients, to get an allogeneic stem cell transplant. For patients who are unfit for intensive chemotherapy. These patients typically will get a hypomethylating agent with venetoclax. Those patients, some of them will go on to get allogeneic stem cell transplant. Many of these patients who are not candidates for allogeneic stem cell transplant will continue on azacitidine and venetoclax in perpetuity or until the time of relapse more common than perpetuity. The salvage chemotherapy is given or targeted therapies given upon disease relapse. For patients who have specific targetable alterations, so think about a FLT3 mutation, IDH mutation, in our case, an NPM1 mutation or a KMT2A rearrangement, they would get the targeted therapy that is appropriate for their disease. It's important to think about the treatment response criteria in AML because I think this is a source of confusion for doctors and a source of confusion for many other people. It might be a source of confusion for you and you're looking at this. So I'm going to make it very, very simple, okay? There are 2 things you need to get into a complete remission for AML to be called a CR. You need to have eradication of the blast from the bone marrow to less than 5%, and your bone marrow needs to be able to prove that it operates normally again. And a surrogate for operating normally again is that you get normalization of the platelet count and the neutrophil count. So if your platelets go to over 100,000 and your neutrophils go to over 1,000, that is considered a complete remission. All of the other categories are sort of degradations of what the blood counts have done. So if your platelets go to 50,000 and your neutrophils go to 500, but they don't get all the way up to 100,000 or 1,000, we call that complete remission with partial hematologic recovery or CRH. If you get one going above 100,000, the platelets recovering, but not the neutrophils recovering or the neutrophils recovering and the platelets now recovering, that's called the CRI, a CR with incomplete count recovery, and that is a different measure of response, again, less than 5% blast. And finally, if you have clearance of your blasts, but you don't have any recovery of your blood count, that's called a morphologic leukemia-free state. And all together, all the categories together is what constitutes the overall response rate. As a -- okay, so stop looking at this because I know you guys are studying it. I can see that. What -- I don't want you to study because I want you to listen to what I'm about to say. So, as a clinician who is practicing medicine in a relapsed and refractory patient, what I care about is getting those blasts to less than 5% because once those blasts are less than 5%, I'm going to send my patient to an allogeneic stem cell transplant. I'm not necessarily waiting for that patient to achieve a complete remission because why wait? And I worry that maybe the patient may end up relapsing. So, in studies that are done with targeted agents in relapsed and refractory acute myeloid leukemia, sometimes the rate of morphologic leukemia-free states, or CRIs, is elevated over what you might have seen had the doctor decided to wait longer, but no one is waiting longer because you want to get that patient to a transplant as quickly as possible. It's also important to think about measurable residual disease. And this just shows you the depth of the tests that we end up doing and what measurable residual disease is. So MRD simply is that if you have less than 5% blast, which again I told you would be clearance of the blast, it could be a CR, it could be a morphologic leukemia-free state, if you still have molecular evidence or flow cytometric evidence of disease at a very low level, that is called MRD positivity. If you don't have any of that by various methodologies, either MFC, multiparameter flow cytometry, PCR or TPCR, et cetera, et cetera, you can see how sensitive these various tests are. That's called being MRD negative. And being MRD negative, as you might imagine, having no cancer is better than having a little bit of cancer, sort of very, very straightforward. Okay. So again, the treatment goal for patients with relapsed and refractory acute myeloid leukemia is to eliminate leukemia, as I told you, get the blast down to less than 5%. Ideally, you want the patient to be MRD negative. Although it's not a prerequisite to do an allogeneic stem cell transplant for a patient who is transplant eligible, we send them to a transplant because we think that is likely the best way to get them permanently cured. For a patient who is not eligible for an allogeneic stem cell transplant, your goal is to improve their quality of life by avoiding infections, minimizing transfusions, maximizing quality of life, and you do that by keeping them from relapsing with whatever agent you may be giving them. This is just showing you the goals and the methods for allogeneic stem cell transplant. As we talked about, there are a number of steps. You've got to clear the marrow. Then you give conditioning to ablate the marrow and allow engraftment. You give the conditioning regimen. Then you infuse the cells. And we talked about -- you just heard a second ago about all the potential complications. So I'm not going to go through that again. So I think it's important to note that KMT2A rearranged acute leukemia and relapsed NPM1-mutant acute myeloid leukemia really has a very, very poor prognosis. For those of you who have studied up on this, which I'm sure all of you have, you already know that KMT2A is bad. These patients have a life expectancy in third line, as you can see on the bottom, of 2 months or less. So, all of these patients will die without effective therapy. I think what sometimes gets lost is that when you're sort of reading the books about acute myeloid leukemia and you see NPM1, the first thing it says is that it's favorable risk. And then you think to yourself, if it's favorable risk, there aren't going to be that many relapsed and refractory patients, why do you need a drug for this? Well, the fact is that any relapsed acute myeloid leukemia becomes unfavorable risk at the time of relapse because once you've relapsed, you are in a very, very bad category and your life expectancy is very, very low. My colleague who is going to speak in a second, Dr. Ghayas Issa, published a very, very nice retrospective study, looking at the outcomes of patients with NPM1-mutant acute myeloid leukemia who had relapsed, and their median overall survival in third line was just a little over 5 months, which is sort of what you would see not as bad as KMT2A, but what you would see with other types of unfavorable risk acute myeloid leukemia. So, revumenib, you can see sort of the slide here about how revumenib is great. I'm going to tell you, from a clinician's perspective, this is a drug that is exactly what you want in a targeted therapy. It's a drug that really, really has very, very few symptomatic side effects for the patient, very few side effects at all, very few toxicities. And at the same time, it relatively rapidly puts those patients into a remission and keeps those patients in remission without having a very, very long or even much of any period of myelosuppression. The myelosuppression is what gets patients into trouble. This is a differentiation agent really doesn't have any myelosuppression. And if, and I hope revumenib ends up getting approved, I think this is a drug that everyone will reach for in patients with relapsed and refractory KMT2A and relapsed and refractory NPM1-mutant acute leukemia. And with that, I thank you very much. Hopefully, you know everything about leukemia now. And I'm going to pass it on to Dr. Issa.

Hi, everyone. Okay. So I'm going to take you through some of the results of the combination. This is the study we call -- no, this is the AUGMENT-101, sorry, confused with the slides. So the AUGMENT-101 is the single-agent revumenib study that is being presented in the late-breaking abstract. This is what hopefully will lead to approval. So, the Phase I of AUGMENT-101 is what we published in Nature. This was a dose escalation. What's important about the study? I guess the reason why it's in Nature is because we saw high response rate and we saw a CR/CRh rate of 30%, a MRD negative rate of about 80%, and these results are promising. We established a safe dose, and that led us to the pivotal Phase II KMT2A cohort. There's also the NPM1 cohort that's still enrolling. So I'll take you through some of the results. The primary endpoint for the Phase II study is a CR/CRh, which is what we do in targeted agents in the relapse/refractory setting to form some benchmark of efficacy. So this is the summary of the results, and this is the breakdown of the patients that were treated. I would point out to how many are heavily pretreated in this population. There's a large proportion of patients that had already progressed after a stem cell transplant. In fact, 10% of the patients had 2 prior transplants, which is -- and if I talk to my colleagues, essentially, these are patients that were given the option of hospice versus clinical trial, and the clinical trial was their last resort, their best hope. And it's well balanced as far as the distribution of what we expect with KMT2A rearranged leukemias. There's a higher proportion of AML. KMT2A rearranged AML is more common than KMT2A rearranged ALL. And we -- after the -- we went through the study, we established efficacy population and safety population. I'll go through the definitions in [ a little ]. The efficacy population are the patients that had enough follow-up for us to know their response and how to confirm KMT2A, and the safety population is anyone who had revumenib. And this is the summary of the response rate, which is really impressive, especially based on what Dr. Stein had said, the overall response rate was about 60%. The CR/CRh rate met the primary endpoint. In other words, it got us to a response rate that's better than anything we expect if those patients would have received standard therapy. We saw, importantly, an MRD-negative response, just like we saw in the Phase I study. So this indicates the depth of response, just like what Dr. Stein was saying. So it's not simply just working on the surface of the leukemia. It's getting us to deep remission where those leukemia cells are not there. And we even know about data that is not shared here about the cytogenetic abnormality, the KMT2A. So if we track it with the tests that we have, we don't find it in these patients. In other words, these cells are working like we expect. They are turning from leukemia cells into normal cells. It's not just simply reducing the number of cells. Those cells are transforming into normal, a sign of differentiation. That's why we're excited about it. The main side effects that we saw were really minimal. Some patients had nausea. Unlike the Phase I, we saw less QTc prolongation, and there were no severe cases of QTc prolongation. So, in other words, this was a test that we saw in [ EKG ], but it had no consequences on the patients, and it was resolved with dose adjustments whenever we needed it in a small fraction that had QT prolongation. We saw differentiation syndrome. The differentiation syndrome was minimal. We were able to control it with steroids. And all these patients resumed revumenib even -- either never stopped revumenib, or after a dose hold, continued revumenib. So it didn't lead to any discontinuation of revumenib. And that speaks to how comfortable physicians or investigators feel on the study to manage differentiation syndrome and continue treatment. When I need a patient and I tell them about differentiation syndrome, I tell them, in a sense, I would like to see it sometimes because I want to know that the drug is working. If this drug -- when physicians hear about differentiation syndrome, when I first told my colleagues about this drug, they were excited because that meant that the drug works. If we didn't see any signs of differentiation syndrome, we would have been worried. This mirrors what we saw in APL with IDH inhibitors and now revumenib. So this is the results of the NPM1 cohort. But specifically, we're focused on the Phase I. These are patients that were treated in dose escalation and had NPM1. Just like what Dr. Stein was saying, unlike what you expect with NPM1 or when you first read about it that it's favorable, in fact, any relapsed leukemia is bad. And that paper that we did, whenever leukemia has relapsed, the NPM1 status doesn't matter. And if we think about chances of response with NPM1 with any therapy you would give, there's less than 10% chances of CR/CRh and the lines of therapy that we're choosing, so this is already very encouraging. And what I would point out also about the NPM1 patients that were treated is that NPM1 has targeted therapy options, and those patients exhausted all these prior targeted therapy options before getting to revumenib. Everyone that had a FLT3 inhibitor had been treated with multiple FLT3 inhibitors. And despite this, we are seeing encouraging responses that mirrored what we're seeing with KMT2A. So the CR/CRh rate is 36%, the overall response rate is 50%, and everyone who had a CR/CRh had an MRD negative remission, so 100%. And you can see that these responses are durable. These patients whenever they were eligible for transplant, went for transplant and resumed revumenib. So this is also very exciting for us. So in summary, what we're seeing is an overall response rate of 63%. This is based on the pivotal results that will be presented by my colleague, Dr. Aldoss on Tuesday. The CR/CRh rate of 23%, a median duration of response of 6.4 months, which at this line of therapy, this is something we would expect and we still consider very, very meaningful. The MRD negative rate is 70%, and this truly establishes the benefit of revumenib in this -- for this disease that had no other option. We also are presenting this at ASH. This was a poster presented by my colleague, [ Dr. Rosenthal ], about the patients that resumed revumenib post-transplant. And I've had some of these patients. In fact, some of my patients have been now 2 years or 2.5 years since the Phase I study and have resumed revumenib and it's really well tolerated. In fact, my patients get scared when I try to take over the idea of stopping revumenib one day, because this is the one drug that had gotten them to that place. And this shows us that these patients are tolerating the drug well. There are minimal side effects, and these patients had multiple lines of therapy to get to this stage. I can't remember what this one is. So I guess, it's trying to get us to what we would expect with KMT2A rearranged leukemias. If we get a response with KMT2A rearranged leukemias, there's no way that I would wait on a single agent for the patients to progress, especially that I know that I can restart revumenib post-transplant. So just like what Dr. Stein was saying, we may not wait for full count recovery because the importance is to try to prevent anything from what we've learned from prior targeted therapies to get them to a single agent. And then hopefully, revumenib is going to control their leukemia, and we're scared to say cure, but there's a good chance that some of these patients that had the combination of revumenib and transplant will get to cure. And when we move revumenib to early on lines of therapy, I would expect that this would continue to improve. So how would I approach this as a physician? How does -- what does this mean? First of all, what we've shown with revumenib data is that this interaction came to [ AML] as critical. We finally found a target that's very important for KMT2A and NPM1. And we've shown that these responses are durable and important. So now we can move it to the frontline setting. And it's different than anything we use in the current standard of leukemia. So we have multiple options of combinations. I've tried to, in one slide, once put all the combinations and it's like -- feels like 3 rows of things that I could do. So I'm very excited about the multiple mechanisms where we can use revumenib in combination. And then just like what we're seeing in the study, this has the option of maintenance, where we have a pill that's well tolerated that could prevent the risk of leukemia coming back, and that would be the maintenance setting. So the usual sequence of events and drug development that we tested in the relapse/refractory. We [ may test it ] in combination, then we move it to frontline, and then hopefully also we're going to do it in maintenance where we prevent leukemia. So this is the study that I presented on Saturday. We call it SAVE. It made sense when Revumenib was called SNDX-5613. So it's Syndax, Astex, Venetoclax. That's what SAVE stands for. So this is an all-oral combination that would use the backbone, that's a standard in acute leukemia. So an oral decitabine plus venetoclax and we're adding revumenib. This is in the relapsed/refractory setting. This is a Phase I/II study, and we did dose escalation to try to identify the revumenib dose that would be recommended, but we also have signs of efficacy. So the 2 doses of revumenib that were tested are the recommended Phase II dose of revumenib, 163. And the starting dose was 1 dose level below that, but we also know that this is a dose that led to efficacy because if you look at the Phase I study of revumenib, every dose that we tested had response, we didn't exclude any patient in the first assessment of the Phase 1 paper to get responses. Venetoclax was given at day 1 to day 14. So some people might ask, why did I do 14 days venetoclax, standard HMA is longer than that. And that's based on our experience at MD Anderson. We do a lot of these studies. And we found that, in fact, 14 days of venetoclax is sufficient. There are more and more trials now that are going to try to play with a number of days of venetoclax, that's what is showing at ASH. And we may be just giving more venetoclax than we need to. So I thought when I was designing the study since I strongly believed in the preclinical rationale that 14 days of venetoclax would be enough to get us responses. Then I use the standard dose of oral decitabine. So this would be days 1 to 5. This is the summary of the data. So these patients that were enrolled on the study were heavily pretreated. The median lines of therapy was 3, 5 out of the 9 or 6 out of the 9 had a prior -- had progressed after a stem cell transplant, 5 out of the 9 had prior venetoclax treatment. And I had this question in the session like what does it mean prior venetoclax. At MD Anderson, we use venetoclax with everything. So these patients had it as frontline with the first combination, not we don't use 7+3. We use high-dose chemo and venetoclax. And then when they relapse, we give them something else and venetoclax. So these patients have had all the time, venetoclax. And one patient had a prior menin inhibitor. And despite being heavily pretreated, we saw responses in all the patients that were treated. This included 5 patients with KMT2A, 3 patients with NUP98 and 1 patient with NPM1. And importantly, also, we saw count recovery. And I didn't wait for the account recovery to get the transplant. So this means that within the first or second cycle before they went to transplant, they had count recovery. If I had waited 5 out of the 9 patients went to transplant. So if I had waited longer, perhaps more patients would have had better count recovery. So the CR/CRh rate was 44% or 4 out of the 9. And there was the MRD negative rate. So 6 out of the 9 patients had MRD negative by flow cytometry. And also, they had disappearance of either the KMT2A or NUP98 by FISH, which is a test that tells us that the chromosomes are gone. And that also highlights the importance of differentiation. So these cells are turning from leukemia cells and to normal. The expected response rate in this setting with KMT2A based on work we've done at MD Anderson would have been an overall response rate of less than 10%. So this is already by far exceeding what we would have expected with KMT2A rearranged leukemias. This is the summary of the side effect. So as I mentioned, again, this was an oral combination, so all pills. And these were -- the side effects could have been related to any of the drugs that were used. And despite having 3 different pills, the side effects were overall minimal. You may notice the rate of febrile neutropenia or the rate of thrombocytopenia, and this is consistent with what we would expect with venetoclax combinations and relapsed/refractory setting. So when patients are prior treated, their chances of count recovery is less. And when they've had transplant, the chances of count recovery is even less than that. So my colleague today, I think today or tomorrow is presenting the data on Astex then alone. And first of all, you can see that the response rate is nowhere near what we're seeing that tells you that it's not the Astex event portion that leads to responses, but also the rate of febrile neutropenia or the time to count recovery is in fact a little longer than what we see with Astex then revumenib. So this speaks to the safety of this combination and how well it's tolerated. We didn't see any Grade 3 QTc prolongation. And I report 2 cases of differentiation syndrome. But if we stick to the academic definition of the differentiation syndrome, these patients didn't really have it, because they had only one sign of differentiation syndrome. So one patient had increase in their white count, and those cells were normal, so this is differentiation. I just felt like labeling it the differentiation syndrome because I wanted to contrast what happens between single agent and combination. So this patient had no symptoms. That's probably because the combination suppresses whatever cytokines cause the things that may happen with differentiation syndrome. And there's another patient that had bone pain only, but no other signs of differentiation syndrome. And in both cases, the bone pain patient had differentiation syndrome resolve with steroids and the patient that had leukocytosis just controlled their counts with Hydrea, which is what we do, and she continued on with therapy without any issues. And we haven't seen any other safety events beyond what we know about single agent; 2 of the 9 patients resumed revumenib post-transplant One of them has been on it for -- maybe I have a [ swimmer's ] plot, I do. One of them -- so this is the first patient. The letter M is maintenance, the letter T is transplant. So she's been on maintenance for 11 months now, tolerating it well. The second patient has been on it less. I'll point out for example -- another thing that [ Dan ] mentioned in the presentation about patient #2. This was a 12-year old that had a history of a sarcoma and was treated for sarcoma and the chemo for the sarcoma caused her leukemia. And then she had treatment for her leukemia, which was she don't respond to it. So these leukemias are usually resistant, and she was referred to me to get on this study, and she also had extramedullary disease. So she had leukemia on her bone marrow, but she had large lymph nodes in her neck and in our arm that were preventing her from using her arm. And within 1 cycle of therapy, this resolved on a PET scan. So the mass in her arm resolved and her counts fully recovered. So this is a complete response. And then she restarted maintenance and he's been tolerating it well. The one -- there's only one patient that progressed on treatment, and this is a patient with NUP98 rearrangement that had a partial remission. And I think there may be some nuances on NUP98, which is a rare fusion versus KMT2A. All the KMT2A had a response by day 14. We tried to do an early assessment of the bone marrow, and all of them cleared their leukemia within 2 weeks of treatment. So this speaks to the strength of this combination and how well we can clear leukemia. And this is to your left, the breakdown of the treatments received by patients in each of the important categories that I talked about. So this is a small sample size and assessment of survival in a small sample size and a Phase I study is not sometimes something done often in academics. But when I was presenting it to my department, my boss was like, when you don't present that, people are hiding something. That means that they get a response and then they die later, within 2 or 3 cycles of therapy, and that's why we're showing it. Obviously, it may change when we enroll more patients, but this is incredibly promising because we see a tail, these patients not just had a response, they maintain the response. So this speaks to the durability of this therapy. We're going to continue to enroll patients. But for a start, I think this is the best start we can hope for. I'll pass on to Dr. Zeidner.

All right. So we're going to go from saving AML to beating AML. So thanks, everyone, for having me. So Dr. Stein and Issa really presented such remarkable data of this agent in the relapsed/refractory setting. And I'm really pleased to present some of our data in the frontline setting. This is a triplet combination in a Phase I study in collaboration with the Leukemia & Lymphoma Society, which is through this BEAT-AML platform. So this is a Phase I study where we added revumenib in combination with azacitidine and venetoclax for upfront, newly diagnosed unfit AML patients with NPM1 mutations and/or KMT2A rearrangement. And I will say that this data is not presented at this conference, so this is kind of hot off the press, but we wanted to give you kind of a high-level overview of some of the results that we've been seeing since this has been really exciting for us. So Dr. Stein really gave you everything you need to know about AML in a nutshell, but really to give you the context of this combination in the upfront setting because it's obviously our treatment paradigm is very different in frontline compared with relapse/refractory. We know that the standard of care, the paradigm shift in the management of these patients with elderly unfit AML is azacitidine and venetoclax. This has really been a game changer, probably the most impactful advance we've had in this disease in several decades. And this is based on the VIALE-A study, which is summarized here. This is a large randomized Phase III study with a combination of azacitidine and venetoclax led to significantly higher survival response rates compared with azacitidine plus placebo. Now these results are for all-comers. So this -- the VIALE-A study included NPM1 mutations included KMT2A rearrangements, but it was not exclusive to that. And the study actually excluded favorable risk cytogenetics, which we're not going to really talk about today, but it's important to put all that in context. The median overall survival, of course, with azacitidine and venetoclax in the setting is 14.7 months. Again, that's in all-comers. And the average remission rate is 66%, 67%, usually within the first 1, 2 or 3 cycles. Now I will say that any of us who has used this regimen in clinical practice, I argue to everyone in my clinical practice hospital leadership that this is the most complicated regimen in all of cancer. You can see these percentages don't really do justice as to the myelosuppression, the complications that we see in patients that are treated with azacitidine and venetoclax. This is very complicated. It leads to lots of dose modifications and adjustments over time, where actually it's not as consistent of a practice between all of us as far as what we do over time in patients who are treated with this regimen. The one thing I want to point out, however, is that this is kind of an induction and continuation phase this treatment. So you use continuous dose of venetoclax. It's orally, plus azacitidine until you achieve a remission. And then once you achieve some sort of hematologic recovery, as Dr. Stein mentioned, you then continue this regimen indefinitely unless they move on to allogeneic stem cell transplant or relapse or have other complications. So we designed this study through the BEAT-AML platform. This is sponsored by the Leukemia & Lymphoma Society, and we modeled it after the VIALE-A regimen of azacitidine and venetoclax. Venetoclax given continuously until a complete remission is achieved and continuously thereafter after hematologic recovery. This is a Phase I dose escalation study where we added revumenib, again, continuously in combination with azacitidine and venetoclax. We studied 2 dose levels. These are very similar to the dose levels that were studied in a single agent, than the combination arm. We started with 113 milligrams q12 hours, and we ramped up to 163 milligrams of revumenib for every 12 hours. All of these patients needed to be on a strong CYP3A4 inhibitor azole in combination with azacitidine and venetoclax. Now bone marrow biopsies were done after the first cycle, and we did not -- we would hold venetoclax and revumenib in patients who achieved a marrow remission, but did not achieve full hematologic recovery. And if there is evidence of persistent disease after a cycle, we continued treatment for at least cycles 2 and/or 3 until the morphologic remission was obtained. So these agents were then continued indefinitely in a continuation phase, once patients achieve a marrow remission. So we enrolled 7 patients on the first dose level, 6 patients on the second dose level. This is kind of just some of our key characteristics that are summarized here. Median age, let me see -- median age was 73 years. So this is an elderly AML population. We enrolled patients 61 to 85 years old. 31% of patients were over the age of 75. We had a pretty even distribution. Again, this is just NPM1 and/or KMT2A rearrangements in order to be eligible for this study, 62% of patients had an NPM1 mutation and 38% had a KMT2A rearrangement. Again, small numbers here, 13 patients have enrolled to-date. So we're super excited because we have seen a complete remission or a composite remission in all 13 patients who have enrolled on this study to-date. You could see the breakdown between both dose levels here of 113 milligrams and 163 milligrams q12 hours, again, a distribution of NPM1 or KMT2A rearrangement. All of these remissions occurred within the first 1 or 2 cycles, the majority actually occurring within the first cycle. And you can see -- and you can see that these remissions are real remissions. There's only 2 patients who actually had a CRI; 11 out of the 13 patients were either a CR/CRh, most of them were full CRs. And importantly, when we looked at flow cytometric MRD through a central assay, 12 of the 13 patients achieved an MRD-negative flow cytometry state. The only patient that did not -- didn't have actually viable cells to do the assay. So it's not that they had persistent disease. We just didn't know that they were negative. In contrast to the other studies that you heard about, this is a population that sort of by definition, is less transplant eligible. These are elderly AML patients, most of whom are not candidates to undergo an allogeneic stem cell transplant, although in the few that are, our goal is to get these patients to an allogeneic stem cell transplant. And you can see here 2 patients did undergo an allogeneic stem cell transplant, but that was in part because these patients, by and large, are not candidates for allogeneic stem cell transplants. This is early. We do have one relapse patient to date. But so far, no other relapses in the other 12 patients. So we just wanted to give you kind of a high-level summary of some of the safety data that we've seen to-date. It's been quite remarkable that giving azacitidine and venetoclax continuously plus a third agent, revumenib continuously, we really did not see significant cytopenias or toxicities that we were actually anxious about when we designed the study. In all the 13 patients, we had 1 hematologic dose-limiting toxicity. That was actually at the first dose level of 113 milligrams, where a patient achieved a marrow remission after the first cycle and did not recover their platelets above 50 by 42 days from the start of the cycle. And so, that 2-week delay where the cycles continue every 28 days, if there was not a platelet recovery above 50 or an ANC above 0.5, the patients had to come off protocol based on the way we designed the study. That was the only patient. Every other patient achieved marrow recovery in order to continue on continuation therapy after achieving a remission. So that was the only hematologic DLT we've seen. The cytopenias have been manageable. And to be honest, not really outside of what we would expect to see with azacitidine and venetoclax without a third agent. We did see differentiation syndrome and QTc prolongation. I would say quite similarly to what we've seen in some of the other studies. There was only 1 grade 3 differentiation syndrome and 1 grade 3 QTcF prolongation respectively, both -- in both instances, revumenib was temporarily held and then restarted at the same dose without actually -- without dose reductions. And most of the other grading here were quite self-limiting and was not clinically significant. Really no other safety issues that we've seen outside of the known reported toxicities for Aza/Ven. We've cleared the DLT window. This is a Phase I dose escalation study. So really, the primary objective is to establish the safe dose here of revumenib in combination with azacitidine venetoclax. We're now expanding given the lack of DLTs that we've seen at both dose levels to get a better kind of assessment of the clinical activity of this regimen. And we're really looking forward to presenting this in a more detailed fashion in an upcoming meeting. But I think really remarkable data and now hopefully moving this agent sort of into the frontline setting where we're seeing, I think, quite impressive results, both from a safety, tolerability and activity standpoint. So thank you. I think, that's it.

Thank you so much. Dr. Shukla. Yes. God ahead, thanks.

I'm Neerav Shukla, I'm a Pediatric Oncologist at MSK. For those of you who may not know much about children with acute leukemia, it's the biology, the genomics of acute leukemia for children is quite different than adults. So many of the targets in adults that have had approvals for drugs such as IDH are not relevant for children. They just don't get those mutations. But KMT2A is very different. KMT2A is very much a pediatric rearrangement. It's enriched for extremely young children. So 25% of AML -- children with AML have KMT2A rearrangements and more than 50% is kids diagnosed under the age of 2. In terms of ALL in which we care 90-plus-percent of our children, there's one population where most of them die. And that's infant ALL, children diagnosed under the age of 1, and over 80% of those patients have KMT2A rearrangement. So if I had to pick a single target that we need to solve in pediatric acute leukemia, it's KMT2A rearrangement. So on behalf of the pediatric community and the pediatric patients really want to thank Syndax for being forward-thinking enough to include children early on in the development of this drug. So unlike our adult colleagues, we tend to be quite aggressive with our patients in terms of intensive chemotherapy. So in the pediatric community, we're quite interested in combining novel agents with intensive chemotherapy backbones. So I'll tell you a little bit about the AUGMENT-102 study, which is revumenib combined with a pretty traditional intensive chemotherapy backbone called FLA, which is a combination of fludarabine and cytarabine. And this is for patients with relapsed/refractory NPM,1 NUP98 rearrangements or KMT2A-rearranged AML. As shown here, there are 2 dose levels. There's dose level -- the first dose level, which was 113 q12, and then the highest dose level dos level 1, which is the monotherapy dose with a strong [ CYP3A4 ] inhibitor. The regimen is intensive chemotherapy with fludarabine, cytarabine for 5 days and then continuous revumenib. So this is just to show that the FLA backbone alone shows high levels of hematologic toxicity. It's expected when we give FLA chemotherapy that our patient counts are going to go down every single time, right? That's just part of the backbone. So this is just some data both the pediatric regimen on the left in an adult regimen on the right, just showing the extent of cytopenias with FLA alone. So of course, we'd expect cytopenias when combining revumenib and FLA. So these are some demographics and some results. So even though this study was open to patients of all ages, it primarily accrued pediatric patients. There have been 15 patients accrued in dose level 1 and dose level 2. You can see the demographics on the left. The median age for the first dose level was 20. But for dose level 2 was 4. And many of these patients are actually initially diagnosed in infancy. A high number of median prior therapies as shown there. The majority of patients at AML. There was a single patient with ALL. And the majority of patients had KMT2A rearrangements with 1 patient with NPM1 and 1 patient with NUP98. We have some -- in terms of the efficacy, of the 15 patients, you could see that there was 1 patient out of 3 in dose level 1 at a CRc and 4 out of 12 in dose 2, which is quite encouraging. We would only expect about a 10% overall response rate. And over 50% of these patients had already received FLA chemotherapy in some sense prior to this. So we really know that it's the revumenib driving the responses in these patients. And then on the right, you can see the safety summary. Again, these are the same numbers we would expect to see with FLA alone. So I think the important thing to get out of this is that, we're definitely seeing an efficacy signal in a heavily pretreated group of patients with the safety summary that we would expect basically with FLA alone. So we're very excited to have a Phase II trial, an international trial that I'm going to help lead that has been developed and hopefully, will open very soon as well as an infant ALL trial to the Children's Oncology Group, which has just opened, I believe, 2 weeks ago. So we're very interested about this combination of FLA and revumenib for children look forward to future efficacy studies. The Phase I trial here has demonstrated safety in a very heavily pretreated group of patients. As I mentioned before, 50% of patients in the trial had already received FLA, and we still saw a 33% CRc rate, which exceeded the expected rate in this heavily pretreated group of children. Data from expansion cohorts to support the RP2D are expected in early 2024. And as I mentioned before, based on these results, we have several Phase II trials that are underway. I'll end there and take any questions. Thanks.

Thank you. So thank you to all the physicians for joining us and walking us through the data, great presentations and representation of our program. Just a few words in closing here, and then we'll take Q&A to close out. So I think we heard a lot about revumenib as both a monotherapy and a combination agent for the first time today. We know that these are deep durable remissions that we're seeing in patients in a variety of settings, both KMT2A and NPM1. Now we have pivotal data and hopefully a package that will go to the agency in the next short while here and get the drug approved next year. In combination, I think it's early days for the combination, but I think we've been able to show some pretty remarkable data that speaks to not only can you combine the drug safely, but you can do it effectively. And so, we'll be following up with additional trials, but it really unlocks what we'd like to say, unlocks the opportunity for revumenib to be not only the first, but best-in-class medicine for patients with KMT2A and NPM1. And just to touch on the market opportunity. I think we all have become accustomed to the fact that this is -- we're starting with relapsed/refractory disease, as you typically do. On the lower left, we think this addresses somewhere north of 5,000 patients and could be a market opportunity approaching $2 billion. As you move the drug up line and some of that data obviously supports doing so, you could approach a much larger market opportunity for patients that have KMT2A and NPM1 in combination with standard of care agents. So in summary, it's obviously a very unique opportunity for a targeted agent in AML and ALL where we have a pretty big impact across about 40% of patients with both of these types of disease. And with that, I would like to thank everybody for being here today and everything that the physicians have done to really advance our program, and we'd like to take some questions from the audience. Yes. Anupam, thank you.

Anupam Rama, JPMorgan. A question for Dr. Stein and Dr. Issa, both of you seem very comfortable using revumenib in a post-transplant setting. Maybe for perspective, you can give us a sense of how long you've had the longest patients on maintenance therapy post transplant?

2.5 years a patient I shared [ with, a patient ] I treated with NPM, and is shared with another colleague in Lithuania, and she is doing great.

Yes, I have a similar, I don't know if it's 2.5 years, but it's over a year.

Michael Schmidt with Guggenheim. Perhaps one for Michael. What else do you need to see for the Ven/Aza combination, before you're comfortable to start a randomized Phase III, I think the data looks very impressive, obviously, from BEAT and from SAVE-AML.

Thanks, Michael, for the question. We are confident. I mean it's -- again, it's not enough patients to confirm the RP2D yet, and I think that's the next step. So we'll have that completed hopefully in the -- we haven't set a date for it yet, but it's enrolling nicely, so we should be able to get that completed and start our pivotal frontline program in '24 as well. So we have -- there's nothing really holding us back. In fact, it's actually very encouraging that we have this data. It's now just having what we need to do to confirm the RP2 as an expansion. Thank you, Michael.

George Farmer from Scotiabank. My question is about differentiation syndrome, 2 parts. Firstly, this notion that background therapy can potentially blunt the effects of DS. I think Dr. Issa, you kind of showed that, however, in the BEAT study, it didn't appear to be the case. Maybe you guys could speak to that, #1. And #2, the grade 5 events that some of the competitors had experienced, that has not been the case with revumenib. What do you think is going on there? Does it have to do with relative potency? Is there something else about the drugs?

Dr. Zeidner, do you want to address the BEAT?

Yes. I would say we've had 13 patients. So I think the confidence interval is so wide. I mean, we've seen differentiation syndrome, whether it's lower or blunted with the addition of azacitidine and venetoclax compared with single agent. I think time will tell. I will say that we, as a field, are so attuned to this that we're probably labeling more differentiation syndrome than what really is, and that's kind of to Dr. Issa point as well. The one on our study that was grade 3, I think, was clearly DS, but how many of the grade 1s and 2s are really DS versus other similar symptomatology but not true DS is hard to know. These were self-limited. I can't really speak to whether it's going to be overall lower with the addition of Aza/Ven. These are also frontline patients. So these patients typically tumor-lysis and other complications are more severe in the front line compared with relapsed/refractory.

I think the second question, maybe Dr. Issa.

Yes, it's a tough one. I don't know why potency would lead to more DS, but not more response. So I haven't solved it in my head.

A question on moving into the earlier lines of therapy, whether it's frontline or maintenance, what endpoints do you think you'll have to look at? Is overall survival the only endpoint that could support approval? Or are there other endpoints like MRD negativity that could lead to a registration?

You weren't addressing that to anybody in particular, but maybe I'll ask Dr. Stein, to can answer that.

You gave me the tough question. I mean think about -- if you think about other targeted agents in the frontline setting, understanding that these were single agents, ivosidenib, the IDH1 inhibitor got an approval in the frontline setting as a single agent based on 30 -- I think, it was 32 patients or something like that. So it's not for a group of patients who have a very, very poor outcome. It's not beyond thought that you may be able to get an accelerated approval based on a relatively small number of patients showing very, very high response rates. But I think that's a discussion with the agency.

Thank you. I see Brad has a hand, oh Jason, please? Hi.

Jason Zemansky from BofA. Congrats on the data. Maybe a question on SAVE. For the 2 patients who dropped therapy, any insights into what happened there? It looks like one was a NUP89, but the other was in NPM1. Anything there that would be prognosticative in terms of what happened?

So the NUP98 patients progressed. But again, so NUP98 is susceptible to menin inhibition, but there may be nuances on how NUP98 responds versus KMT2A response. And that patient had 2 transplants and -- sorry, had multiple lines of therapy. She had one transplant. The second patient is complicated, and I still can't wrap my mind around what happened with him. I'm starting to understand a little bit more. I didn't present it. He had HEP E, which I don't know why, and then had hemochromatosis, which is likely because he's so heavily pretreated that he has so many transfusions that affected his liver. In both instances, I don't think it's related to revumenib or any of the therapies that were given. So it's a bit of an odd case.

Thanks, Dr. Issa. Brad?

Brad Canino from Stifel again. Can I just quickly pull all 4 of the leukemia doctors here with one question of what proportion of patients that you got to transplant from a response from revumenib, would you try to put back on revumenib maintenance?

I would say all. And the patients who don't want to go to transplant if I don't restart the revumenib, they feel anxious because it's the one drug that helped them respond.

[indiscernible]

The safety profile is so strong that I think all of us would want to try to restart it post to maximize the benefit of transplant.

I agree. Yes, I agree. Although I will say in our study, we actually do not allow maintenance on the BEAT-AML platform. Once they go to a transplant, they're off protocol therapy. But absolutely, I mean if I had access to this agent, I would 100% continue post transplant.

Great. Thank you. Kalpit?

One for the AML study. I know, you mentioned that the myelosuppression rates were pretty similar to what you would see with Ven/Aza, but was there a sense of difference in dose modifications or dose reductions with the triplet versus the doublet historically?

So the challenge with the BEAT-AML study is that we actually dosed venetoclax based on the package insert of venetoclax and based on the VIALE-A study results. But in clinical practice, many of us are dose adjusting, get -- reducing the duration of venetoclax really early. Sometimes even as Dr. Issa pointed out at MD Anderson and other sites may not even do 28 days continuously for the first cycle. But then after patients get a remission, most of us are reducing the duration of venetoclax in clinical practice. On this study, we've -- since we modeled the package insert and the approved label of venetoclax, everyone stays on venetoclax continuously without any dose adjustments unless there is more than one hematologic toxicity that occurs in between a cycle. And that hematologics have a grade 4 thrombocytopenia, grade 4 neutropenia, which has to delay their subsequent therapy, if that happens twice, and that's based on the package insert, then you start reducing the duration of venetoclax. So that is to say that starting cycles 2, 3 and 4, once patients achieve remission, they stay on venetoclax 28 days continuously plus the revumenib. And even with that, we still didn't see -- it's early, but we did not see significant cytopenias that you would expect outside even the norm of Aza/Ven. And I wonder if even there's less hematologic toxicity because revumenib is so active in clearing leukemic cells.

Thank you.

Peter Lawson, Barclays. I guess, another kind of poll question for the physicians just based around resistance mutations and whether you had kind of -- the idea of potentially switching menin inhibitors if that [ starts appearing ]?

Yes, maybe I'll give it to Eytan.

I mean yes, I mean there's no -- we don't know anything really about resistance mutations with the other agents that have been presented. There was some data presented on resistance by the company -- well at EHA about Ziftomenib, but I think that data is corrupted in many, many ways, which I'm happy to talk about afterwards. But -- so since we don't know whether the other agents are effective in patients who have these resistance mutations, I wouldn't switch. I mean, certainly, if they were effective then you would switch, so.

Thank you. Any other questions?

I had to step out for a second. Just on the maintenance question, I was just wondering, what's your strategy there? Would you just keep them on indefinitely? Or would you do a fixed-type maintenance even if they didn't relapse? Or how would you approach that? Because that's obviously an important question in terms of duration and thinking about the economic proposition for the drug.

I don't know the answer. I chose 1 year as a fixed duration on SAVE, but I don't know the right answer. [Indiscernible]

Yes. I would echo me as a transplant that for sure, 1 year, maybe even longer.

Yes. We're doing the same with peds. So we're looking at 1 year, although there's many of us who wondered if we should go longer, at least 1 year.

Sure. Sorry.

Actually, I just had one follow-up because on the Q&A last night, you talked about the reason for the inverse dose response. Can you just review that again? Because like what was the -- was it because the CSF1 ligand was going up in response, and therefore, that was causing competition effect? [Indiscernible]

Yes. One, the most likely explanation is if you deplete monocytes and macrophages prolonged, the age and the CSF-1 is just not binding any longer to any receptor and accumulates. And once the monocyte we generate, we just kicked by an overload of CSF1. So kind of you get the opposite end of the regeneration, that in which impairs response. If you just give low dose, you don't cause this access of CSF-1. That data we can show directly. And then, you have not this access. The other issue, as you may, at higher doses, even deplete our bi-standard population, which you don't want to deplete. So that's a common frame I would also add in [ cancer agencies ], just destroying is not a good idea, regulating is the key.

So just to add to this, correct, the sustained elevation, this is -- this is our current interpretation of the data we have. More work is going on to analyze the translational samples collected in the study. But CSF1 is sustainably elevated with a prolonged elevated dosing for prolonged periods of time. And it really mimics the observations with CSF1 steady elevations in other inflammatory states. So that may pan out for chronic GVHD for other indications where axatilimab would be targeted may operate differently based on the baseline characteristics. To be fully determined, but right now, this is our working hypothesis.

Joel Beatty from Baird. For the post-transplant setting for revumenib, do you anticipate that payers will cover that setting? And if so, what data will they base it on? Or would that data could be generated to help support that decision?

Yes. I think maybe I'll take the question. I think it's -- certainly, we've heard and from the physicians who are working with these patients and their families that the first way to think about it is, can you keep them on drug and can you actually keep them in remission, right? And I think that's what we're talking about in terms of maintenance. Paying for it is something that does routinely happen with other agents as they start to put them back on drug for extended periods of time. These are very fragile patients, high risk of relapse. And so, the risk benefit of putting them back on is certainly in favor of doing so, and payers, I think, see that as something that they need to cover. Again, these are small populations of patients, and at this stage of life where there's comorbidity, time in hospital, lots of other treatments and going on, keeping them on an oral pill and free of their cancer is obviously the first order of business. So I think we expect that this will be routinely paid for, but it's something that we'll see in the commercialization of the drug, assuming it's approved. [ Alan? ]

One question for the [indiscernible]. One question for the clinicians. Just in terms of NMP1 relapse, they talk about how they're likely to think about treating with our co-mutations in those patients. And then for the company, where do you stand in terms of looking in that setting, combinations with FLT3 and other drugs that are targeting what may be the co-mutations?

Right. Maybe I'll handle the second question first. So it is on -- as you heard today, there's a lot we can do with this drug, right? And so the priorities, of course, are Ven/Aza combination with revumenib as well as with chemotherapy, and we're starting those pivotal trials next year. So those are our priorities. We do have other combinations that we intend to work on FLT3 being one of them, whether it's a study sponsored by investigators or by the company or a combination thereof, that's to be determined. But there are multiple combinations we'll pursue in order to get this drug as broadly available as possible and some evidence that it works in combination with things like FLT3, which is important. And sorry, Alan, your second question I answered -- oh, your first question?

It's about what happened? How they're likely to treat -- they like to treat co-mutation in the relapse setting...

Great. Yes. Unlike KMT2A, NPM1 has co-mutations with FLT3 and IDH. So there are options. But the way I would approach it is that NPM1 is a founding event in the leukemia development, whereas FLT3 is a later event and treatment with a menin inhibitor should take care of the founding event and also effect, in fact, FLT3 expression. We showed that in the Phase I study. So I'm very excited about menin inhibitors. I would think it's one of the things that I would jump on for NPM1. We still need data to see what happens versus FLT3 or IDH.

And I'll just add one quick thing. In the relapsed/refractory setting, about half of FLT3-positive NPM1-mutated patients will lose their FLT3 mutation at relapse if they're treated upfront with a FLT3 inhibitor in combination with chemo. So many of these NPM1 mutated patients, even if they're co-mutated at relapse were going to be reaching for menin inhibitors, because they may not have other targeted options.

Thank you. Dr. Shukla?

Yes. And just for Pediatrics, NUP98 is actually 12% to 15% of relapses. We're finding it more and more that we're doing more molecular and those are often co-mutated with FLT3 and we have data that targeting FLT3 doesn't really matter, as Dr. Issa, said the founding NUP98, that matters. So sometimes we find the commutations, it's actually still not worth targeting.

Yes. Thank you. So I think we're running late. So I do want to thank everybody for coming today. It's a great work by all of our physician colleagues. Thank you for all your commentary and for participating in making our drugs what they are. Thank you all for your interest in Syndax and supporting us, and we'll take questions as we go here, but exciting days for the company. Thank you so much.