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

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.