Good morning, everyone. I think we're going to try to get started. 7:01.
All right, so thanks for joining today. We're excited to be here at ASH. Really exciting agenda today to walk through, and we'll start by making some opening remarks, and then we'll turn it over to our four 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. I'll actually advance the slides here. Sorry, it's a little delayed here, so here we are at the agenda. 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 or 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'll 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 looking at an overview of the treatment paradigm for acute leukemia. And he'll present the first-of-its-kind real-world evidence for a 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 we'll talk about intensive chemotherapy combinations with Dr. Swoboda from Tampa General. That's some very interesting frontline newly diagnosed patients in the fit setting. And we'll talk about all of that data with him. Then it'll turn to the development program.
We have an extensive, as you know, very extensive development program. Nick Botwood, our CMO and Head of R&D, will walk through our program in detail for both programs, for both Niktimvo and for Revuforj, and talk to you a little bit about how we expect to be building them into 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. Let me 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 two fantastic products, Niktimvo and Revuforj, addressing $10 billion in total addressable market. Niktimvo, as you know, for chronic GVHD, indicated in the third line, plus Revuforj for acute leukemia, 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 two 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 multi-billion-dollar franchises. So, off to a great start with two 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 in the scientific front: 23 presentations across both Revuforj and Niktimvo, three oral presentations for Revuforj, nine poster presentations, Niktimvo three oral presentations, eight 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'll 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.
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 ed. 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 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, we've really expanded our portfolio. All right. Sorry, slides are taking a minute to advance. All right. So we're now on slide seven. 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 one 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 two indications really together represent $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. 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 the 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 the 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 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 a third of the patients of KMT2A pausing treatment to go to stem cell transplants. 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 new patients treated since launch, and we're on track to treat about 1,000 KMT2A patients by year, and that's 50% penetration of the 2,000 incidence market. Very impressive, 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 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 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 responses across organ systems as we've seen in our clinical trial.
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. 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 that you see that in a company that is launching into a new market to have two products and two 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 we'll 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 eight months of launch, getting 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.
We expect this to grow meaningfully in terms of the margins. The margins 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 two 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.
Just give it a shot. Yeah.
All right. Good morning, everyone. Thanks for having me. So we're going to just spend a little time talking about chronic GVHD and Niktimvo or axatilimab. We'll set the stage a little bit about what's going on and kind of what 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.
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 always want to 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. 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 mg per kg every two weeks had a 74% overall response rate. And this is the approved dose that we use.
One theme I would say coming out at this time, now that it's FDA approved and we've had the drug for maybe about a year, people are asking the questions, "Well, how long can I treat my patients and 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?" 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 mg per kg every two weeks, you're able to give it 0.6 mg per kg, but give it every four 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 two-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 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 a quarter of them actually made this transition.
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 seven months of therapy here while they were getting it every two 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, let's see 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 incidence, 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 seven months.
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. 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. On that similar theme of just longer follow-up of patients on trial, there is going to be a poster this evening at 6:00 P.M. This is just longer-term follow-up of the patients from AGAVE- 201. It just highlights that they were able to kind of maintain long-term benefits. This doesn't only look at the FDA-approved dose of 0.3 mg per kg, but it looks at all dose levels.
You can see here the median duration of therapy is now almost closer to three 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. There really was not any new sign of anything concerning. I think, again, emphasizes that this is a tolerable medication that can be maintained in these patients for a longer period of time. The other thing I really want to emphasize today is kind of like where things are moving forward. There's a lot more data that's going to be coming out, my guess, in the upcoming months or the upcoming year, just secondary analyses that are underway looking at more patient cohorts from AGAVE-201 .
I think the next phase of where 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 front line? 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 are 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 pre-specified interim safety analysis.
The way this trial is working is if you have a patient who has newly diagnosed chronic GVHD, they get randomized into one of three treatment cohorts. One you can see here 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 is 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.
When it comes to axa and rux or rux, although there are those patients with steroids, and the safety profile, again, looks promising. This trial continues to enroll. It's a total N here is 120 patients. This is obviously just the first 45, but definitely one approach into moving into the front line. 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, maybe able to taper steroids down, maybe have less side effects? 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 an event-free survival endpoint approximately six months into treatment. In conclusion, we have data now that shows that we can continue our axatilimab treatment and give it in the once-every-four-weeks dose at 0.6 mg per kg every day. 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 three years. Then we have upfront trials that I think everybody in the field is really excited about and what it could do for our patient population.
So with that, we'll go to questions and answers, I guess. Thank you so much.
Yeah. Good. So thank you, Dr. A very nice overview of the data. I'm Nick Botwood. I'm the Head of R&D and CMO at Syndax. I've 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. Love to just hear a little bit about your own experience in the clinic with axatilimab.
Yeah. Yeah. Yeah. So we've had a lot of experience with axatilimab through the trials and now commercially. We've had it available at our center 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 we're using it in clinically is probably in the fourth line, as many of these patients are 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, it 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 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.
That is 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 for resolution of some of those fibrotic symptoms, I mean, what has been your experience? Do you find it's been reasonably well tolerated or?
Yeah. No, it is well tolerated. But 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 six months. And that's not necessarily specific to Niktimvo, but that's just my general feeling for these types of drugs is that if you're going to commit now, yeah, you have to make sure the patient's tolerating a 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've had some experience with patients on long-term as well? You presented some very nice data of a cohort of patients out three years plus. Have you had that experience?
Yeah. I mean, I've had, as participants who were on the trial, I 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?
Yeah. 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, 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.
Yeah. It's really nice. It's very nice. So you presented some preliminary data on a 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 kind of sit on their hands waiting to give a drug that they actually want to give. 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, I think it's very compelling, this concept of maybe changing the trajectory of a chronic GVHD kind of experience post-transplant. 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.
Yeah. No, doctor , that's 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 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 shall welcome him to the podium. Welcome.
Thank you. Perfect. Good morning. It's 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.
I hope kind of some of the slides that I'll show you will really highlight how rapidly the field is changing. Again, this is even early post-approval, even when it was only for KMT2A. To essentially set the landscape, 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 relapse 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 survival is around six months. There are other groups. 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 inevitably lead to relapse. And thus, eradicating it, both in the setting of intensive and non-intensive 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 if we had the sort of menin education session , I think there was maybe actually two 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, blasts do clear 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 multilineage 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 surgeries, 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. We know that we're used CR/CRh for label approvals. But when you have your patient in front of you, actually, I'd like to because this is really not in the full data set as far as MLFS. I have a young patient, actually, post-heart transplant, post-allo transplant. We only had fusion panels this past year, relapsed after multiple therapies, and ended up having a WT1 RAS phenotype, which we now recognize as quite classic for NUP98 rearrangement. We identified the fusion in that patient. He's only had blast clearance, but he had an extreme amount of extramedullary disease. He was really not even able to get out of the hospital. Actually, he had a hospice discussion. He's only 20-something years old.
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 nine months now alive where he would have been dead, essentially, probably within the month from that back. I think sometimes people will say, "Hey, does ORR matter or not?" There are clear major instances where MLFS is just dramatically impactful. Again, this is the first real-world evidence. And I think 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. How are we managing these patients now? We are all going to be significantly older by the readouts of those trials. The 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. Four lines of therapy. You can see we have treated some patients in the frontline setting, but up to six lines of therapy. The vast majority of patients having venetoclax, which we know has an OS, typically of sub-four months in the relapse state and around a third 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 three 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's plot. But the overall response rate is the majority of patients, and the composite complete response rate now, particularly in combination therapy, is almost two-thirds 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.
I would say at our institution for NPM1, we always do flow and deep molecular, about 10 to the negative 4 to 10 to 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. Three-quarters of those patients achieving response. Four patients were bridged to transplant. I wouldn't focus on the percentage of patients. You've 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. Just like to highlight, this is an extremely rare thing. 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 three-quarters 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, etc., 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 one month, time to best response of two months. I would like to highlight, and
Dr. Jabbour and I have talked a lot about this, as well as Dr. Searle 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 alive in 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. One year out, was still an MRD negative complete remission and had a pretty florid extramedullary relapse. We treated him with definitive craniospinal radiation. He remains on revumenib and is 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 four.
But I think 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 three patients, but no patients have come off. Now, DS was in two. 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 is tropical like Houston. So transplant and KMT2Ar disease, I think there's a limit how much we can do with transplant. 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 KMT2Ar disease are really bad patients, and even if 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 are experiences 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, eight KMT2Ar disease and two NUP98 rearrangement. They failed transplant. Half of them had two transplants already. So that patient population is really bad and here, I urge you not to compare numbers to numbers. I get calls from investors or others telling me, "What do you think about this one and this one?" You have to put things in context.
You have a patient who failed already two prior transplantations. These are not patients coming frontline to get one drug. They were treated with mainly revumenib-based therapy, be it on clinical trials or compassionate, or even some of them in combination in a SAVE trial that I will share with you in the next few slides. Good thing about it, these patients responded, and then before transplant, all were MRD negative, so yes, we want CR. Yes, we want CRp. You want whatever, but the key factor is if you get transplanted somebody in an 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.
Here, we have patients who did respond well thanks to the menin inhibitors and in particular revumenib here. 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. Therefore, this is trickier because these patients have a very frail graft. The earliest you can start therapy is when the blood cells are above a certain level and the engraft. Therefore, median to start was around three months. The good thing is these patients did get most of them get the whole duration of treatment. Median was 11 months. 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's 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 two transplants, and they're frail numbers. And yet, the blood cells 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 to hold therapy, decrease the dose, and resume therapy. And in certain patients, we were able to re-escalate back to the normal dose. And 90% of the patients remain free of relapse. To put things in context, the median survival is only four 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 one 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 use off-label. I go for transplant. I do it post-transplant. I try to eradicate minimal disease. And this is the proof here in 10 patients where you can give them good maintenance therapy. They are MRD negative, and you lead to 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 a 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 already two prior transplantations. Therefore, seeing thrombocytopenias, this is not unusual, but very manageable.
Here, we have only three patients who had Grade 3 thrombocytopenias. Grade 2 and Grade 1 are irrelevant in the practice of transplant in patients who failed multiple therapies. Yet, among these patients, that did not lead to treatment discontinuation. In contrast, we had to hold, resume at a lower dose, and re-escalate whenever possible. Therefore, I think the adverse event profile is highly manageable. No patient had to stop the drug because of adverse events. Therefore, I think this data supports 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 a prospective trial to be proven. I know there are ongoing trials to address this point as well. Very encouraging evidence of the activity of revumenib post-transplant as a maintenance strategy.
Now, here will come where the money is, correct? The SAVE, Save Life of People. And I think this acronym is really interesting. And I want to give credit to my colleague, Dr. Issa, who I'm working closely with at MD Anderson, and we brainstorm every single day. Yes, we have a drug approved. I think the research and the benefit start after approval. I don't care how narrow the label is, but I want the drug 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, when I 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 BCL-2 inhibition and menin inhibition, a triplet of HMA oral formulation, venetoclax BCL-2 inhibitors, and revumenib. And we explore different dose levels. And of course, we explore the combination with or without azoles to make those adjustments. The study was first opened 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 a single agent drug. So very encouraging. Furthermore, with the combination, we did not see evidence of resistance on MEN1, which is quite reassuring as well that you can give the drug in 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 an induction and 22 days 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 14, and we will hold ven 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.
Finally, we offer maintenance therapy post-transplantation for a duration of at least one year. My colleagues showed the data yesterday from the SAVE update on 21 patients. We enrolled 14 patients with NPM1 and seven patients with KMT2Ar 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 KMT2Ar disease up to 77, so younger populations. Second feature, very important. Look at the comorbidities. 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 and NRAS/KRAS, and we know from the VIALE-A, 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 is really hard to treat. And therefore, we have to put the results in a context as I showed you here. And I will come back to this when I go on more granular data. Side effect. I hate to show this slide first, but here's how it is. Because when I treat 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 QT prolongation. I never cared about it, and I was surprised when Syndax told me about QT prolongation, which is 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 has a pulse, and therefore, having QT prolongation, this is less of the least of my concern, particularly that we're 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 a relevance, but I keep a low threshold for it to implement [higher] steroid whenever I see it, mainly in somebody with hyperleukocytosis and monoblastic leukemias, as was seen in this patient here.
But none of them was Grade 4 and above. We had zero fatality from this. And this is highly manageable. But when you give the chemotherapy, you want to get the tumor burden lowered. And then you want 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. No, I'll tell you more information in a subsequent slide. Look at the efficacy. Objective response rate, overall, 86%. In NPM1, it was 86%, came to the same. Very high response rate. And CR/CRh is 79%. This is way higher than what you expect with the Aza/Ven alone.
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 combine Aza/Ven plus or minus menin inhibitors revumenib are being designed or other menin inhibitors. In the CR/CRh, we're meeting our primary endpoint. Early deaths, yes, we had two patients, unfortunately, who 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 comorbidities. They are really bad patients and tough to treat. And we're learning how to optimize our supportive care and how to optimize adjustment of the dose of the drug in order to avoid these kinds 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 assay I will show you next with NGS that can allow us to go 10 ^ - 5 and eradicate the disease before we go for transplant or other strategies. So we're using Invivoscribe assay at MD Anderson. And we're able to assess the NGS MRD negativity in this patient population. The numbers are small, but 80% within two cycles became MRD negative by NGS. Why is it important? It's important because if you look at the right side, there are two patients who did not get into MRD negativity by NGS. And these two 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 as well, we're comparing historical data with aza/v en 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 a safer drug, less of a complication, and a better outcome. Okay. Here is the survival overall. Follow-up is still nine months. It's a short follow-up. The median survival has not been reached. And so the median event-free survival at one year. It was 57% 12-month survival and 50% for EFS. Then I'm showing you the data by genotype, NPM1 and KMT2Ar disease. In neither one, the median has been reached.
And the 12-month survival is 53% for the NPM1 and 69% survival for KMT2Ar 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 we 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 patient who really did not do well, unfortunately. First of all, a third of these patients, despite their age, remember, it's a 70-year-old people, went on to receive transplantation. So we've heard Dr. Fathi yesterday in the session doing HMA/ ven. But I'm not saying HMA should 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 three relapses. I want to focus mainly on two patients with the NPM1 mutation because these patients have a really bad disease. One of them, for example, patient number 67, wasn't compliant, did not take the medication, missed half of the dose of revumenib. And yet, they had KRAS, SRSF2, TET2, trisomy 8, 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, [unclear] 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 a vast majority of these patients by flow and by NGS. And finally, for the KMT2Ar 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're meeting our endpoint. High response rate in both NPM1 and KMT2Ar disease with the larger samples and longer follow-up to confirm these findings. However, one last word of caution. 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 ven. 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 ven that will be shown 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 at a time of history where we're making difference and making cancer history. It's MD Anderson logo. Thank you very much.
Thank you. Going to ask Dr. Swoboda to come up, share the experience of another important combination with intensive chemotherapy. Dr. Swoboda.
Okay. You guys hear me okay? No. That makes no note. Can you guys hear me okay? There we go. Hi. 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 one clinical trial. It focuses on three different populations: KMT2A, which obviously AUGMENT-101 clearly focused on, NUP98, which I think is an extremely important subset of patients. We've seen from early data with revumenib that that population, 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, they focused at the mandated, ultimately an inclusion of only high-risk NPM1 patients.
And so that was NPM1 plus a chromosome 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 the dose level one is below our dose of what we see in the AUGMENT-101 at the 220 and 110 dose. And then the dose level two is sort of our standard dosing with revumenib at 270 and 160. And 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 one, the majority of patients were KMT2A.
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 two, as I said, we broadened the expansion of that NPM1 cohort. The age ultimately increased where the median age was around 57 in the dose level two cohort. It started to shift where now the majority of patients are NPM1 mutant. This is just looking at some of the safety data. I think it's important to walk through. I think the most important part is zero 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 three QTc event. And the rest were relatively low grade. Of the one grade three, 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 then there was another infection patient. So things that you would honestly expect when you're treating these KMT2A. We're to remember they tend to be a very prolific disease, oftentimes come in very sick. And so it's not unexpected with intensive chemotherapy that you might see some complications 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 two did not change that parameters as far as count 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, and in this study, we have two 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 one, 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 on, 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 five out of seven out of thirteen patients proceeded to transplant, and of those four out of seven 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 Rev 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 had less than 21 days of Rev, were less than 28 days on therapy during this data cut. And so overall, I think, like I said earlier, as that data continues to mature, I think the response rates will sort of equal out a little bit better.
As you can see, dose level one was 100% with 100% CR. Importantly, measuring MRD status in this population is key. There was 100% MRD in the dose level one patient population. This was by multi-parameter 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. In the dose level two, 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. When you look at the data combined, I think it's very encouraging.
And so overall, the safety of intensive chemotherapy and 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 suggest 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, one that I think Syndax designed actually very well and in just the NPM1 population. Thank you.
Yeah. 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.
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 led to our approvals originally in KMT2A disease and then more recently NPM1, including pediatrics, children above one year old, and ALL. 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. 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. 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 are going to bring the greatest benefit to patients. So we have generated compelling data with Ven/Aza combinations, 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, Josh 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 a 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 US. This is revumenib added to a backbone of Ven/Aza.
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. It is enrolling well. We're actively initiating sites. We envisage that it will execute extremely well through next year. 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. 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 a viable alternative option for them.
And then, of course, we have our pivotal REVEAL newly diagnosed patients. This is a randomized control study for patients with NPM1 disease on a backbone of 7+3 intensive chemotherapy. It is designed with registrational intent. It has two dual primary endpoints, event-free survival and MRD negative CR BM. And I am pleased to say that we have had our first site opened. And we are envisioning 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 CSF1 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 two 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 a 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 onto 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 to 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 and what settings and what your experience has been.
Yeah, 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 were coming out post-transplant. And we really wanted to initiate them on a targeted therapy that would ultimately hopefully reduce their risk of relapse in that setting. And so we put several patients right off the bat on post-transplant maintenance.
As we've got practice 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 we had maybe one patient that we've used it as a single agent. The reality is the majority outside of the context of post-transplant maintenance. The reality is the rest of the patients in the setting of relapse or even in the frontline setting, we're using it in combinations in all of 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 anyway. 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 Revuforj. I don't know if you'd like to just share a little bit about your clinical experience with Revuforj.
Yeah. No, definitely. So as a transplanter, having better AML therapeutics to get patients to transplant is extremely important. As 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, we really look at maintenance as being a key tool for us, right? The traditional way of thinking about it is like you threw everything you had at these patients until they got to transplant, and then 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, took the patient to transplant, and I actually restarted the maintenance at probably day 14, which was probably a little bit bold, but I will say that I was quite worried that I felt like the only thing that had worked for this patient, and we had been anticipating trying to get to transplant so directly. Now, yeah, we dealt with some cytopenias earlier on, but the patient's been able to stay on, continues on, is almost a year out, and remains in likely 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 for MRD eradication.
Go ahead.
Y eah, 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 non-intensive. Essentially, if you're positive, the vast majority will relapse. And if you're negative, these are patients that maybe even with non-intensive-based therapies, are we curing more? I think how we best eradicate it. Again, we had even several in our Andrew Wei last year presented eight patients, three of eight cleared, five of eight had significant reductions.
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. Once we're checking MRD all the time, and if we're making a change, we're often reassessing all the time. Is single, double, or triplet the right for MRD erasing, I think. No, anytime 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. Is adaptive approaches best? Obviously, we'll get to Eli's opinion in a moment.
But if I have a patient, for example, on HMA venetoclax, we know after about four cycles, we often get our best molecular remission. If the patient's positive, adding on is also. 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 patient's management.
Oh, 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 pathophysiology. 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 immunoblastic. 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 a surrogate for approval. And I hope one day in AML, that will be the same too.
Dr. Jabbour, this way you have the mic. May I ask you, obviously, yesterday Amir Fathi presented the 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, and that's only one day old, and there's a lot to reflect on, but how you think that may change the paradigm and how we should maybe be thinking about that as it relates to our program.
Okay. I want to be bold as much as I can. I came to ASH, and people asked me, "Wow, we have a new standard of care for AML." This is not what the aim of the study is. Remember, three-quarters 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 the doctor in a community in Montana or in Spokane or somewhere, no funds for these regions, but you see one AML every other year, they give them HMA/ ven as 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, deletional 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.
No, that's great. That's great. Maybe Dr. Sallman, do you want to go to the floor? Please. Yeah, let's do that. Let's open the floor to questions.
Dave at UBS, just a couple of questions. One is for the physicians, maybe just think about there are right now two menin inhibitors for NPM1, relapsed refractory NPM1 and AML. So I'm just curious, how are you deciding between these two drugs? What are some considerations when you're deciding to choose between these two?
Maybe I can start with the comment there. Ultimately, we have a lot of experience with revumenib as first to market. 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. QTc is not an issue. Drug-drug interactions, we deal with venetoclax. We do this all day, every day with our pharmacists. 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 ziftomenib, there is the interaction with antacids. 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 of the context of the clinical trial, I'm really finding a hard time to pick a patient that would maximally benefit from ziftomenib, over revumenib. The only patient that I could think of would be someone with significant cardiac toxicity. But I'm seriously, what do others think there?
I think the two approval are good, but they're 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. We have the safest is to go for a triplet and build on it and make the best of it. Toxicities are not an issue. QT prolongation or DS, you have to hit a little threshold to intervene. But that is not an issue for me. One thing I was asked by your colleagues one day, I said, "You're 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 buy the hybrid. I want to have the NPM1 and KMT2A disease both inhibited." And so I choose. For the same price, why not buying a hybrid? Yes.
Clara Dong from Jefferies, thanks for hosting us, so one question on GVHD and one on Revu. So for GVHD, among the 19 patients who transitioned to a different dosing, would baseline factors help investigators feel more confident that the patient was stable enough for Q4W dosing? And if there are any 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 they were achieving early cycles. And that being said, is there a rationale to abbreviate venetoclax for the sake of minimizing exposure earlier?
Should we start with the Q4?
Yeah. So the chronic GVHD question. So I think 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 four-week dosing. You wouldn't want to take something if you really felt like you had more on the table to achieve, you probably are going to keep them on the every two-week and then go down the four. But ultimately, when you think about this go to every four-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 two-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 safe, time to MRD remission is around two cycles. You get MRD negativity. I think the key for the future is how to optimize use of ven, oral decitabine, and menin inhibitors. And that is true for all menin inhibitors. Whether it's ziftomenib, revumenib, bleximenib, enzomenib, 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, build SAVE again, I may use four days of oral decitabine. The Ven, in my practice, I never go beyond 14 days in subsequent courses, even reduce to seven days, and I give 28 days of menin inhibition and recycle.
Hi, Phil Nadeau from TD Cowen. Two questions on Revu. First, on post-transplant maintenance. Seems to be a theme both from the presentation and what Dr. Swoboda just said about 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 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 K M T2A? Thanks.
Should we talk about dosing in maintenance?
Yeah. I think right now there is additional work to be done. Because I think the reality is most of these K M T2A 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? 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 it earlier than that in real-life practice. Yeah, I would just comment. I think one nice thing, we also have 25 mg tablets. There is actually some additional titration that you can. I think there's differential practices based on azoles.
I saw it 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 annoying to monitor. We're monitoring the counts all the times and tweaking. But again, the vast majority of patients are able to stay on. I'm a little bit hesitant to pull 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 standpoint, 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.
I'm sure 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. We also have experience of different dosing because of the flexibility that's built in with Revuforj that clinicians can use for all the reasons that we just discussed. In terms of the frontline studies, I would just say the following. Firstly, we have generated now really compelling data for KMT2A subset, both in relapsed refractory, now in the frontline with both intensive chemotherapy, you saw that, and also with ven/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.
By doing that, we have a focus by including KMT2A both in the EVOLVE-2 study with HOVON. They are included in that study. Then we have two approaches. One working with the NCI MyeloMATCH, where we have a cohort for KMT2A on a backbone of 7+3. We are also planning based on all of the data that's being generated, a combination with ven/a za 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. We have time for another question, Greg.
Thank you. This is Jeff from B. Riley. I want to have one question. For post-transplantation maintenance, is the developing standard to treat for a 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 want to give treatment for lifetime post-transplant, of course. Yes, it will be bettered by your MRD negativity. Somebody being for transplant in an MRD negative situation, you want to design a program for one year or two, but not beyond that. If post-transplant, you remain MRD positive, then you have to think differently. Maybe not the menin inhibitor alone is a good enough option. Usually, you go for maintenance in somebody who's either MRD negative or MRD positive peritransplant, and you try to get them into MRD negativity. I'll do in my practice, I'll do two years of maintenance and then stop thereafter.
And I think the re-disease eval at that two-year time point is important because we learned in MORPHO, for example, with some patients that were on placebo, they came off, they relapsed. 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, 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. That's great. 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 and prior medical meetings that combinations are clearly more effective in relapse 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 one of the two?
I think going for transplant in an MRD negative situation is the best way to go. And usually, you can get into this type of response with two or three cycles.
So usually, I see somebody in my clinic. I want to time them for transplant. That will give me two, three months to get them to MRD negativity and go for transplant. In every frontline trial, we have a maintenance component to it, be it one year or longer. Again, as Dr. Sallman mentioned, reassess MRD status or [unclear] therapy and go from there. So in every frontline regimen, Rev maintenance is designed to, and two to three cycles to get you into MRD negativity and go for transplantation.
That's great.
I just tell you, I'd say 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 doublet therapy, even in NPM1, probably four is where we get most patients there. But like you said, if you get there at two, go at two. If you get there at three, go there at three. But you have time to even treat even four to six cycles. Probably it wouldn't go that long. But up to four, I think, is very reasonable to achieve that, particularly frontline where relapse is not that big.
And NPM1 in particular. KMT2A is different in this one.
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 depth 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. Thank you.