Well, good morning. Welcome once again to TD Cowen’s 44th Annual Healthcare Conference. I'm Phil Nadeau, one of the biotech analysts here at Cowen, and it's my pleasure to moderate a fireside chat with Syndax. These are really exciting times for Syndax with two drugs, not just through pivotal trials, but on their way to approval. I'll hand it off to you guys to maybe give us a state of the company address. What are the biggest strengths, biggest challenges? What do you need to do to drive shareholder value over the next year or two?
Yeah, thanks, Phil. Thanks to TD Cowen for having us. Always a pleasure to see you, and thanks to all of you for joining. It is an exciting time for Syndax. I'm Michael Metzger. I'm the CEO of the company and been here for nine years and have had the pleasure of helping to build this wonderful organization where we have two molecules now through late-stage development and really on the precipice of being approved in 2024 and launching into, let's say, important market opportunities. We can talk about that. But I think that's the when we talk about KMT2A and NPM1, acute leukemia, and I know you know most of you are in the room for the prior discussion. These are two areas of high unmet medical need where no drugs, at least in relapse refractory, work at all.
We are really setting up our organization to launch both of these drugs in 2024 and be the first to market. In terms of strengths, I think we have a wonderful organization. We've developed both of these agents from first patient through submission of our packages to the FDA in less than four years. We've been able to really execute rather well in new areas of disease. Some of that is testament to the medicines themselves performing, but I would say our team has done a really good job charting the course and executing on our plan. We have challenges ahead of us, I'd say, on the commercial side as we start to launch new medicines. It's never easy for any company to launch into new markets.
We think we have a very unique opportunity because certainly our first indication will be KMT2A for revumenib, and that is an area of need where there are, as I said before, there's never been anything for these patients. I should not neglect to say that we have two agents, right? So we have axatilimab as well, which is a CSF-1R antibody, which is the first indication will be chronic graft-versus-host disease, third line. And it's a partner program with Incyte, and so we've set ourselves up for success with Incyte to launch that drug in 2024 as well. So the timeline for both of these launches could be weeks of each other, which is rather unique. And that too is a very robust market opportunity we can talk about in cGVHD as well.
With expansion opportunities to go beyond heme, to go beyond cGVHD, these are two franchises that should be around for a very long time and quite valuable as we build the company. Maybe we'll start there.
Before diving into each of the programs in a bit more detail, could you maybe give an overview of the data that both have produced, what's revumenib produced, particularly in this pivotal study, and same thing for axatilimab? What's the most important data for axatilimab?
Right. So with revumenib, we presented the pivotal data at ASH this year. We actually had monotherapy data, pivotal data. We had combination data as well, but I'll focus on the pivotal data in KMT2A. And that yielded an overall response rate of 63%. So that's 2/3 of patients actually responding and getting a clearance of all of their blasts. So that's quite a remarkable result in these patients. Again, we're treating third line plus, so third line plus patients, patients who have received other therapies and obviously have relapsed. So 63% overall response rate, the regulatory endpoint, 23% CR/CRH rate, which is a very good result as well. Many of these patients get to an MRD-negative response. So about 70% of patients reached an MRD-negative response. That's by the most sensitive measure, being able to detect whether they have tumor.
That is something physicians are very keen to see because that drives the decision to take them to transplant often. Remind you, in KMT2A, about 5% or less of the patients actually can go to transplant. In our trial, we showed 25% going to transplant, so about five times more, which is quite remarkable and important to physicians. The paradigm that we showed in the data is about 2/3 of patients get to a response. About 40% overall, 40% of the patients that responded went on to a transplant. And in phase I, we saw around the same as well. And then these patients go on, and about 70% of the patients who had gone through transplant went back on drug or were eligible to go back on or waiting to go back on therapy in a maintenance capacity.
So not only were they getting to a great response and getting to transplant in vastly higher numbers, but they're able to go back on and stay in the maintenance capacity, stay on treatment for quite a long time. Duration of response overall for every patient was between six and seven months. And as I mentioned, the MRD-negative response as well. And we showed in other data the ability to stay on drug. We've seen patients stay on for as much as three years in a maintenance capacity. And again, these are patients who are third line, fourth line, fifth line patients who generally have overall survival third line at less than three months, 2.4 months. So we're showing overall survival in that data set as well of it's eight months.
So quite a remarkable leap forward in terms of the ability to treat patients and for them to do very well. Switching to axatilimab, reprise that data. This was a 240-patient I should have mentioned the size of the patient population that we tested. The efficacy population for revumenib was 57 patients and a safety database of about 94 patients. Sorry, going back to axatilimab, this was a 240-patient trial, chronic GVHD failing two prior lines of therapy. The overall response rate, which is the primary endpoint of this trial based on 2014 NIH criteria, was 74%. We tested three different doses, two doses at every two weeks and one dose every four weeks. The best dose was the 0.3 mg per kg every two weeks, and that was overall response rate of 74%. More than half the patients were still on therapy as of 12 months.
They're doing very well, very low discontinuation rate. Patients have done really well. Side effect profile is extremely benign. And this is a drug that has a mechanism of action that's different than other therapies in this class or in this category, I should say. It attacks the macrophage, disease-causing macrophage. And so the ability to do that has both an anti-inflammatory and antifibrotic impact. And so we've been able if you look across all the organ systems affected by chronic cGVHD, they were all impacted quite robustly. So I think when you think about this drug and what we've been able to show in third line, heavily pretreated, these are patients who have been on other therapies for an average of about four years, and then they came on our trial, and they were seeing response within a month to two months. And this was self-reported outcome as well.
They're seeing very good symptom reduction burden within the first month, month and a half. So incredibly impactful drug at a very late line setting with a new mechanism should set us up very well to be a new entrant in chronic GVHD.
Maybe focusing on revumenib just for a few minutes. In terms of the pivotal data, one of the most impressive things to us was the 39% of patients who go to transplant. Discuss your opinion on the transplant data. Why are physicians so aggressive at getting patients to transplant, and how could that have impacted the primary endpoint, the CR/CRH?
Right. So maybe I'll start, and I'll let Neil take over. So look, I think KMT2A is a very aggressive disease. I already mentioned that physicians have nothing for these patients. Overall survival at third line is less than three months. So they're extremely aggressive to move them. Once a patient gets to an MRD-negative CR, they would like to move them to transplant. On average, these patients in our trial were in the mid-30s. So think about that. NPM1 patients are generally in the mid-60s. These patients are in the mid-30s, lots of children, lots of people who have a lot of living to do, hopefully, and they are fit for transplant. They just haven't had a drug that could actually impact them and keep them in a CR, especially an MRD-negative CR. We're able to get them there.
So they move extremely quickly.
Often, they have a donor lined up ready to go and get them into transplant. They're not waiting for count recovery. What I mean by that is when you have an overall response rate, you have a CR, a CRI, CRH, CRP. There's different gradations of how quickly your bone marrow has recovered at that point. Physicians, they don't care. They're so energized by the fact that you have an MRD-negative CR, they want to get them to transplant. So they don't wait for count recovery. They're going to actually give them a new bone marrow, which is an exciting thing. So they take them to transplant. In our phase one trial, we saw a little bit slower move to transplant only because it was the first time they were putting this drug in patients.
By the time they got to phase II and to a pivotal trial, they knew what this drug could do, and they quickly moved them just even a touch earlier to transplant. And so they left probably about, I think it was about eight patients with a CR but not yet a CR or CRH. So we didn't reach the regulatory endpoint with all of those patients, but the outcome is equally good, right? So you're getting them to transplant as quickly as possible. So there was a slight difference in what we saw in the and these are small numbers between the phase I and the phase II, but small difference between what we saw with the CR/CRH rates in the phase I. I think we reported updated data at ASH this year in the phase I in roughly 77 patients, I think it was, in the efficacy population.
And I think the CR/CRH rate was 31% or 32% relative to the phase II pivotal data, which was 23% on 57 patients. So again, I think that was the slight difference. These are small numbers, but overall response rate actually went up in the phase II, as you'd expect. Physicians are using the drug appropriately and moving their patients to transplant. And I think overall, we're going to see not only patients doing well but staying on drug for longer. I don't know if did I.
I'm not sure you asked much for me to say.
Maybe just one point, which is just to remind everyone that we had a highly statistically significant trial, right? So the p-value is 0.0036. So the observed CR/CRH rate is sufficient for approval, and the package is being reviewed under RTOR. But to the points that Michael made, there's that. There's the regulatory aspect of it, and we feel very comfortable given where we are from a regulatory perspective. But there's the real-world importance of the data, which is the 2/3 of patients that are responding because the clinical objective is to get patients to transplant. So I just want to clarify that people are thinking about that correctly.
On the regulatory, how would you quantify the benefit-risk here? You talked about the efficacy being very, very compelling. What were the safety side effects in the trial, particularly what was QTc and differentiation syndrome? How does that fit into the benefit-risk? And can you elaborate on how comfortable you are with the FDA?
Yeah. Look, patients are not coming off drug because of either of those adverse events. And I think that says everything, right? So they're manageable, particularly well, both of them are manageable, easily managed with respect to dose adjustment. Patients are staying on drug. When you weigh that against the benefit, which is really unprecedented in the KMT2A dataset then and the fact that what I just mentioned before is that the agency invited us to submit under the RTOR program. We feel very comfortable with where we are from a benefit-risk perspective. I mean, this is a I mean, Michael pointed out, the median overall survival in this population has been under three months. And a lot of these patients are getting to transplant. A lot of these patients are going on post-transplant maintenance. We've had I'm sorry I'm repeating, but these are important points.
We've had patients staying on therapy for three years in the post-transplant maintenance setting, and we've presented those data separately. So we feel confident. And I think that's one thing coming from the company, but how do the investigators feel about it? How do the KOLs feel about it? They feel very confident too. And I think the level of enthusiasm, particularly as we're moving now to frontline, right, the Beat AML data and the combinability there and the other datasets that we described at the end of December, sorry, beginning of December in terms of the combinability, I think that's an important factor to bear in mind too. So overall, we feel good.
You submitted in late December, I believe. When will we know what the PDUFA date is? How come we don't know already, actually? Has it been 60 days?
Well, it's not exactly a 60-day period. So I'll tell you. So this is RTOR. We submitted, and for those of you who aren't familiar with what RTOR is, Real-Time Oncology Review, this program came about, I think, in 2017 or 2018, originated with SNDX. So the agency was interested in moving programs ahead. And it gives you the advantage of earlier review. So what I mean by that is you have to be a you have to have BTD first. So breakthrough therapy is a prerequisite. They invite you into the program. They line up resources to work very collaboratively and closely with you. And we've had that relationship with the agency since the beginning of this program.
They invite you into this program, and then you agree on a module schedule at your pre-NDA meeting, right, when you're submitting modules to the agency, and they start reviewing right away. It's not like they're waiting to get your full package validated and then start your review. We actually started the review process in October. That's a huge advantage. There's no refuse-to-file period. We submitted all of our planned modules by the end of December, and there's no 60-day refuse-to-file period. They just have been reviewing all along. They expect to give us the PDUFA sometime in this first quarter. We expect it this month. It's imminent. The review process has been extremely robust. They will put an eight-month PDUFA clock on it.
So somewhere in the time frame of eight months, they'll set the clock, and then they usually do better, right? Based on a track record of RTOR, you've seen packages reviewed and approved within five months. You've seen it eight months, right? But generally speaking, it's something a little earlier than eight months where they'll come in and approve your drug. Again, the collaboration, the intensity of the review process has been rather remarkable. It's what we expected, but it's great to see. They're very engaged, and we expect to have a successful process.
Most investors think the KMT2A market's relatively small. I think you guys disagree. Where are investors wrong in their market assumptions?
Well, I think, look, when we're talking about KMT2A, relapse refractory, it's roughly 2,000 patients. If you think about it, about 27,000 AML/ALL patients, about 10% of which are KMT2A. Relapse refractory, so that's about 2,700 patients. Relapse refractory is about 2,000 patients. I think when you build this total addressable market, you have to obviously appreciate price, which is by the time we launch, is somewhere roughly $35,000-$40,000 a month is a decent estimate based on prior other therapies that are treated, targeted therapies in this space. You need to be able to look at the different segments of patients. So as I mentioned, 2/3 of patients are responding. A third probably stay on drug and don't really respond for about three months.
Then you have the other third that stay on drug and don't go to transplant, and we estimate that probably at about eight months. Again, we're going to be treating patients in the second line setting. And then when you think about the last third, these are patients who probably can stay on, as we've shown out, to three years so far, but we think we can have probably an average duration of roughly 18 months. If you put that all together, that's roughly nine-10 months across all the patient populations. At the price I quoted in 2,000 patients gets you to roughly a $750 million market opportunity without competition. Standard of care doesn't work. We know that. And right now, we are the only KMT2A agent that's available or will be available for some time.
So we think this is sort of white space within oncology, which is a rare place to be but an excellent place to start to build your franchise as we add on NPM1. That segment in relapse refractory should build this to a $2 billion segment. So we think it's rather significant. And right now, we'll be first to market by a nice margin. So we think we'll have a very unique offering very shortly.
In NPM1, on your recent earnings call, you reiterated that it'll complete enrollment late Q1, early Q2, which would put data into the fourth quarter. I think investors think there's some risk in that data because investors assume that the CR/CRH rate in NPM1 might be a little bit lower than what we saw in KMT2A. Why is that assumption invalid?
Well, I would say it's a little invalid because we have data now that, as we showed later in the fourth quarter last year, that updated our phase I dataset in NPM1, 14 patients at the RP2D. CR/CRH rate is now 36%. So I don't think anybody's posted better data than that. The most important thing is it's consistent with what we've shown for KMT2A, whether it's phase I, phase II. Overall response rate, CR/CRH rate may look a little higher. These are small numbers. But I think somewhere in the, I don't know, broadly speaking, 20%-30% range is a very viable estimate of what CR/CRH will look like. But I think you have to look at the totality of the data, the consistency of what we've shown, not just as monotherapy NPM1. We've now seen it in combination, right, with venetoclax.
We've shown it with Ven Inqovi in a relapse refractory setting. So we've seen these patients perform on our drug consistently, not only from an efficacy standpoint but from a safety standpoint as well. So I don't know why one would think that the point estimate would be lower in NPM1 now that we have more data.
Fair enough. Moving to the combo regimens, you mentioned data that was released in December. Could you briefly summarize the data that was released and the next steps for the program?
Sure.
Yeah. So thanks for the question. There were three datasets that we reported out on. One of them was actually presented at ASH. And the other two, we talked about it at the company event as well as the SAVE data, which was an ASH presentation as well. So in summary, the three trials were SAVE, which is an investigator-initiated trial, a combination of revumenib with venetoclax oral decitabine. The second trial was beat AML not in any particular order. Another one was beat AML, which is the frontline combination of revumenib with venetoclax or that component of the beat AML platform trial. And then the third one was a company-sponsored trial of MEMP102, which is a combination of fludarabine/cytarabine in a relapse refractory setting. And just quickly to summarize, the same two doses of revumenib were used in all three trials, 113 mg twice daily, 163 mg twice daily.
In all three trials, the dose-limiting toxicity windows for both doses were cleared, and all three trials are currently in the expansion phase. With respect to SAVE, we saw very high rates of response, 100% response rates, high levels of MRD negativity. We saw similarity with beat AML, very high levels of response of CR/CRH rates, sort of 85% compared to in the 60s for venetoclax alone, MRD negativity rates of 100% amongst the CR/CRH responders compared to that's 100% amongst the evaluable patients. Oh, it's at one more. One patient was unevaluable. And if you look at the historical precedent there, it was like 23%. And similarly, rates of response 3x higher on the AUGMENT-102 trial compared to historical precedent, where you'd really expect 10% or less of those patients to be achieving CR/CRH.
Then from a tolerability perspective, the common theme across all three trials was particularly from a myelosuppression perspective, which is important not only in the front line but even more important in the relapsed/refractory setting where you've got heavily pretreated friable patients. Revumenib does not appear to be adding myelotoxicity to the backbone therapies. So again, not getting into probably don't have time to get into even more detail, but the themes just to summarize the themes, both doses are combinable. Both doses are active. 163 is the presumptive monotherapy-proof dose in combination with a strong CYP3A4 inhibitor, by the way, and 113 is also highly active. So both doses were feasible across multiple different backbones, including chemotherapy and two other venetoclax-based HMA backbones both in the newly diagnosed but also in the relapsed/refractory setting in highly refractory patient populations.
So the totality of the evidence there gives us a lot of confidence in the combinability. And also, as we moved the venetoclax triplet to frontline, I mean, it was just very gratifying to see those data. And based on that, we've seen and felt a lot of enthusiasm with the investigators, so.
What are the next steps?
Next steps are so from a strategic perspective, I think objective number one currently is to get the revumenib/venetoclax phase III running by year-end. The beat AML group are doing a phenomenal job. I mean, hats off to them. They are super enthusiastic. Accrual is going extremely well. To expand both of those dose cohorts, regulatory interactions this year to refine, just lock down the study design, make sure that continuing the collaborative approach with the agency, with the FDA, making sure that we're fully aligned on that trial design and the dose selection and get that up and running by year-end. So that's objective number one. I have to say that it's interesting. I've been out and about talking to investigators as we often do. There's quite a lot of interest in the all-oral, right?
If you look at the SAVE data, it's an all-oral regimen, and people are kind of intrigued by that. But from a strategic perspective, it's important from an evidence generation perspective. That's something that could come later.
We've also started our 7+3 as well.
Yeah. 7+3 is active, and that would then set us up to initiate a so we've got the revumenib/venetoclax in the unfit population phase III by year-end and 7+3 active with an objective of initiating a pivotal phase III in the fit population during 2025.
You mentioned the $2 billion market potential in relapse refractory disease. How do the combination regimens increase the market potential?
Yeah. I think that's probably at least another $3 billion. I mean, obviously, it's not all additive, I would say. Frontline is more patients. You're addressing probably 9,000 patients in the frontline setting in both fit and unfit and to a lesser degree, somewhere in the 5,000-6,000 patients in relapse refractory. But obviously, if you have more impact in the frontline, potentially, you'll impact the relapse refractory TAMs as well.
Turning to axatilimab, you gave a good summary of the data early on in the talk. What gives you confidence that the benefit-risk there is positive, that the FDA will approve this?
Look, I think we've done hats off to the team doing great work on dose optimization here in the phase I. We've been able to explore doses starting at 0.15 mg per kg every two weeks, and the dose escalate up. Safety seems to be very good. I think we've characterized that. We designed this trial in close collaboration with the agency to look at a couple different doses to make sure we had the appropriate range. It turns out the best dose was the lowest dose we tested, and it's really well tolerated. I think just having a now priority review but having good agency interaction there in advance to design the trial and then robustly exploiting that really, I think, gives us what we need.
Where could axatilimab fit into the treatment paradigm?
So the first indication will be third-line. And we think this is a new mechanism of action that impacts both fibrotic and inflammatory mechanisms. I think this is a drug where we could introduce it either ahead of—I think patients could see it ahead of Rezurock, or they could see this drug after Rezurock. So this, again, will have an option depending on what the physician needs for their patient. So we've been able to show the mechanism has impact across all different organ systems. So we've seen some unusual things. For instance, in lung, we've been able to show complete responses, and nobody's shown that before in fifth-line patients, let alone earlier-line patients. It doesn't happen. So the ability to impact certain very difficult-to-treat organs may influence how physicians actually reach for this drug early on. And then ultimately, we'll look to combine it.
So Incyte's going to be initiating a few trials this year, one in combination with Jakafi and one in combination with steroids. And so we're looking to broaden out how do they utilize this drug in earlier-line settings, which, of course, has a larger market opportunity. We think relapse refractory third-line plus is probably approaching $2 billion as well. But if you move earlier line, you're going to get more and more of that 14,000 prevalence treatables about 11,000 patients in chronic GVHD. So that'll be accessible based on combinations.
Maybe just one add. I mean, as Michael mentioned earlier, in the monotherapy relapse refractory setting, 60% of patients stayed on therapy at a year. As we move the drug as the drug has moved up in the treatment paradigm, particularly in combination with ruxolitinib, I think there's a real opportunity because of non-overlapping mechanisms of action to extend the duration of therapy for patients earlier on because, of course, it's not great currently, right? They still tend to cycle through therapies quickly. So I see the combination as an opportunity to extend duration of treatment early on and given the antifibrotic mechanism potentially actually mitigate or aggravate the organ damage early on, which, of course, is potentially going to benefit patients greatly.
Last question, strategic. You recently opted in to co-promote with Incyte. What was the rationale behind that? What role does Syndax have in promoting axatilimab?
It was very simple. I think we said this from early on. I mean, one of the major reasons we were interested in doing this collaboration to begin with is that Incyte has a unique setup in this indication. They've helped build GVHD commercially, and I think with Jakafi and I think by working with them both from a development standpoint but certainly from a commercial standpoint, we'll be launching on the back of their success. I think that's the intent. When we opted in, it gives us the opportunity to have, again, a unique setup for us, two drugs launching at the exact same time in hematology. It doesn't happen. For a small company like ours, it's just very unusual.
So the ability for our reps to have potentially two products in the bag at the same time gives you a unique access opportunity into the physician's office. So it made perfect sense. It's a very focused footprint for both of these drug launches. So when we go and try to cover the universe of transplant physicians, it's very few reps that are required. And so it fits in very nicely with what we're doing with our commercial effort in revumenib. So again, there's great synergy across our organization to do both at the same time.
Great. With that, I think we're out of time.
Thank you.
Thank you for coming.