Great, everyone, thanks for continuing to join us on this week of Virtual Oncology Days. My name is Brad Canino. Really happy to be joined for the next Fireside with the crew from Syndax. We've got Michael Metzger, CEO; Neil Gallagher, President, R&D; Anjali Ganguli, CBO; and Keith Goldman, CFO. Full house today. Thanks so much for joining us. Michael, let me first offer congratulations for all the progress made to date this year, with the two PDUFA date announcements. So could you just start off with an overview of the milestones and priorities for Syndax for the rest of the year?
Well, thank you, Brad. Thanks for having us today. Always, a pleasure to be with you at your conference and otherwise, and for all the great coverage of Syndax over the last period. So, look, you're right. It is an exciting time for the company as we push forward here with our two programs. Our two molecules are under review with the FDA for potential approval. We have PDUFA dates, which were announced this past quarter, and Revumenib is September 28th or September 26th, rather, is the PDUFA date. The program is being reviewed under RTOR, which is Real-Time Oncology Review, so that's quite an advantage in terms of timing for us, and we'll talk a little bit about that.
Important milestone for the company, Axetilimab, as BLA was filed, and we have an action date of August 28th, so roughly one month apart. So that's those are two very important milestones, approval milestones, potentially for the company. And of course, launches thereafter. We do expect to launch these products in close proximity to approval, which means we'll have two products on the market and be a full commercial company as of this year. So it's a really important, you know, transition for the company as we build out our commercial organization as well. So beyond those, really important milestones, regulatory milestones, we will have data on for specifically for Revumenib, combination data that continues to evolve.
We haven't announced exactly where we'll have that data this year, but we'll have additional data for both frontline patients and relapsed/refractory patients in combination with venetoclax. So those are, you know, important studies that continue, and data will be presented in the second half of the year. We're also starting pivotal trials for Revumenib in frontline patients, which will lead hopefully to approvals down the line. But a lot of data coming. In addition to that, we have a pivotal trial that's reading out our second pivotal trial for Revumenib. For NPM1 patients, we did enroll a big milestone for the company, enrolling our pivotal trial, 64 patients, 64 adult patients in AML, NPM1.
That was enrolled in the first quarter, which puts us into the fourth quarter for data that will be presented in that time, the top line at least. So it's, you know, as I mentioned, a really important time for the company, for Revumenib to have, you know, not only an approval, but second indication with data. This year will be, you know, sort of game-changing as a first mover in the... with becoming a more competitive menin space, with companies behind us.
Yeah. And now as Syndax moves towards a commercial company, as mentioned, 2 approvals potential this year. Comment on the work being conducted for sales force preparedness and how Incyte, your partner, might be involved with that.
Right. So axetilimab, you should know that axetilimab was partnered with Incyte back a few years ago. That's a global partnership. In the US, we have a 50/50 profit and loss split, so we essentially split the P and L, which means that we do contribute to development as well as sales and marketing. And, you know, as you know, Incyte is the category leader in chronic graft-versus-host disease. That's where our first indication will come. And so they have the obligation to lead commercialization, so we are very involved with the commercialization effort as well. We did opt into our co-promotion of up to 30% of the effort for that sales and marketing. So what that means is Incyte will lead the effort.
They are deploying reps and customer-facing representatives who call on physicians for chronic graft-versus-host disease, which is ultimately a subset of the physicians who treat leukemia. Those are the same physicians in large part who will be prescribing Revumenib as well. So we are building a field force of customer-facing representatives that can go out in the United States, promote both Revumenib and axetilimab, which is a huge advantage to have two products launching roughly at the same time, first and best-in-class products. Revumenib, as I said, Revumenib will be the main focus in terms of, yeah, Syndax. Axetilimab will be led by Incyte, which with our participation as well. So we are intimately involved, and there's great synergy between what we're doing for both products.
Now, you mentioned Revumenib has was conducted under the RTOR filing. In your analysis of previous RTOR filings, do they tend to come with an approval before the PDUFA date?
Well, it's interesting, and they do often come before the PDUFA date. I think that's one of the advantages of RTOR, is that you start the process of review earlier than when you have your full submission. So, when you have your pre-NDA meeting, and they invite you into the process, if you're lucky enough to be included, you have this ability to start submitting modules early, so before they take the whole application and deem it complete. So we started submitting modules back in October of last year. We completed our plan modules by the end of 2023, and we've had lots of interaction with the agency over the months since.
What ends up happening if as long as your review process doesn't uncover something you know unforeseen, you generally have an accelerated timeframe by which to get approved. So they put a PDUFA date, standard PDUFA date with priority review on the calendar, and generally based on 25 or so applications that have gone through the RTOR process, the vast majority of them come in slightly ahead of that. So without speculating too much, we are excited about how the review is going, and so we expect sometime in the third quarter to have it approved.
Okay. You mentioned the increase in competition in the MEK inhibitor space. What do you believe is the advantage of your likely first mover commercial status, both in the KMT2A subgroup and beyond?
Being first to market is incredibly important. I think we know that, and I think there's been some really nice work done and published on first mover advantage and the meaningfulness of that, whereby, you know, oncology companies specifically have done that brought first and best-in-class products to market have really owned the lion's share of the competitive space. And so with the profile we have today, the fact that we will be, we believe, come to market for KMT2A and NPM1, both of them well in advance of competition, we think that we can build really, you know, very significant competitive immunity in this space. And it really comes down to physicians having the opportunity to work broadly with our agent and prescribe it and get comfortable.
It just makes it that much more, let's say, comfortable for them to continue with a product that they believe does the right thing for their patients, is easy to administer, and ultimately, there's really very little reason to switch off of something that's working well for patients and that you understand quite well. So another competitor would have to come with significantly better profile, both efficacy and safety, in order to make a significant inroad, you know, against what we'll have in the market for a couple of years. So I think it sets us up very well to have access to all the patients, and physicians will get comfortable and start to use the drug in a variety of capacities as data starts to emerge on our molecule.
So I think it's not just, you know, my word, but I think certainly the history of, certainly since 2010, as the landscape has changed, you're seeing first mover advantage be even more meaningful for oncology companies.
Okay. What's a good proxy for the potential Revumenib launch dynamics in its first relapsed/refractory setting? Should we be looking at the initial quarters of IDH and FLT3 inhibitors, or what else should we consider?
Maybe Anjali, do you want to take that question?
Yeah, sure. Thanks, Brad. I think it's a great question. You know what? In general, with launches, there's always nuances that you know make analogues somewhat usable, but maybe not completely. I think the setup we have with a follow-on indication on the heels of our initial indication are gonna make it very difficult to look at one particular analogue. But I do think, you know, midostaurin, for instance, being such, you know, the first targeted therapy coming into AML and in such a high unmet need and they had a very strong ramp. I think you can look at, you know, the first 4-6 quarters of a molecule like that as a proxy for what we could do ahead of the next indication.
But there, you know, you do have to take into consideration, the data will come out hopefully very soon after the the initial launch of indication one, which could lead to utilization and availability of Revumenib beyond its initial, indication. So, you know, I think, I think there are a lot of nuances you'll have to paint onto your analogue, but, we do think that there could be a very strong uptake and launch curve because of the high unmet need, because standard of care is not addressing patients appropriately. And the knowledge base, right? The last two ASH meetings, menin inhibition has been the talk of the meeting. And so I think the understanding of this new mechanism in this space is also very strong.
How should we think about the Revumenib duration of treatment in the commercial setting, in the relapsed/refractory AML setting, and given there will be this component of transplant and maintenance dynamic that you've talked a lot about?
Yeah.
Is it-
No, it's a great follow-on. I think, you know, we're seeing in the study a significant portion of patients who have had a transplant go on to receive maintenance, and we anticipate that in the clinical trial section of the label that will be described, so physicians can understand that this is part of how to treat the patient and part of the dataset that we've produced. We also anticipate having a publication that goes into more detail on the trial and be supportive of that dynamic.
But, you know, the way, the way the patient population we treated broke out, and again, we think that that population may represent a later line patient than what we would, and what Revumenib would be addressing in the real-world setting, because a median prior therapies were three in the, in the, clinical pivotal trial. But we anticipate once we're on the market, because of the unmet need, because there's nothing else, this could be a second-line treatment of choice for physicians very readily. So that may change exactly how, patients respond to therapy. As you know, the earlier you can treat them, the better they do, and the longer they can stay on therapy.
That being said, what we saw in the clinical trial was that a third of patients did not respond to treatment, and on average, it took them about 3 months to progress or come off therapy. The remaining two-thirds of patients were almost split 50/50 on those who went to transplant and those who didn't. Again, if you're talking about moving from fourth line to second line, we anticipate that the length of time those patients can stay on therapy, the ability to respond to treatment, will be higher, and so you've got you know a lot of upside in these numbers.
But what we're anticipating is, if you're a patient who stays on treatment, is not able to go to transplant, either because of your, you know, your fitness level or because you don't have a donor, the average duration of treatment could be around eight months. If you do go on to transplant, we anticipate that could be a much longer duration, 'cause we do expect many of those patients to come back on and stay on for a longer period of time.
What we've seen in our current data set, which includes, you know, patients who were in the trial, but also patients who were treated in a compassionate use setting because physicians were asking us to be able to put some of these, you know, phase I patients on restart Revumenib therapy after transplant, even though it wasn't part of the initial phase I program. We've seen patients stay on for 3 years on Revumenib, and these are, again, late-line patients, fifth-line, fourth-line patients who have had multiple prior transplants, are able to tolerate Revumenib for a very long time. So we anticipate, you know, as we move to earlier lines, second line, patients could stay on, Revumenib post-transplant around 18 months. So, you know, that is sort of our current estimate.
We will look to collect real-world data to help us hone what this is truly gonna look like, and, you know, how long patients could stay on, I think, is up in the air. As I said, we've had late-line patients stay on a long time, and we've heard from thought leaders that because of the aggressiveness of this disease, they don't see a reason to stop therapy, because there's nothing else to give them. There's actually nothing else in development for KMT2A patients right now, and so it would be a long time before they would have another option if one comes along. These patients are much younger than the typical AML patient. We're talking a median age of 34 in our trial.
There is a lot of reason to treat as aggressively and try to maintain that response as long as possible, and so we do think that a majority of patients would see revumenib post-transplant.
Right. Very helpful dynamics. You also mentioned the NPM1 cohort read out at the end of this year. What would be a good outcome for that single-arm cohort?
Neil, would you like to take that question?
Yeah, sure.
Thanks, thanks for the question. So, you know, maybe just to frame the answer, I... You know, we've been sort of fairly pleased with how predictably revumenib has performed right across phase I, phase II. We've seen a consistency of effect from phase I to phase II. We've seen consistency of effect between KMT2A and NPM1 across the board. And we're, you know, we're not gonna lock ourselves down to a specific point estimate. We don't have the data. I know the data, but, you know, we've previously said that, you know, within the range of 20%-30% for the point estimate is, you know, where we would anticipate it to fall with, you know, with robust duration of response and a safety profile that is also predictable, right?
So the safety profile has really held up over time. And again, I stress we don't know the data, but that's what we anticipate would happen just based on, you know, based on the predicate to date. And I should emphasize, that range falls within, you know, what would be approvable, right? So, you know, the study is designed with that in mind. That's our anticipation with respect to what would be required from a regulatory perspective. So that's where we feel it will.
Okay. Okay. And I think a big question for everyone, too, beyond NPM1, is how the combination data evolved over 2024. You know, thinking about EHA and ASH as possible venues where investors could expect an update. And then even just beyond the timing, it's a question of what is important to showcase at the next update, and based on conversations you've had with investors, physicians, patients, et cetera, about the profile of the drug at the further combination updates?
... Yeah, well, first of all, let me handle the timing of this. I think the combinations are, we're working in collaboration with Beat AML, and Dr. Issa’s conducting a trial called SAVE, which was presented last year at ASH. So those are the two combinations, one in frontline Beat AML, and the SAVE trial being conducted in relapsed refractory patients. We do expect there to be an update for both this year at some point. We don't speculate until we have abstracts out that when that'll be, but it'll encompass, you know, additional patients, right? We expect additional patients. We expect longer follow-up, but similar type measures as we've looked at all along, right?
So CRh, overall response rate, MRD negativity, time on therapy, and obviously, duration of response. But, the combinability of our drug with, with venetoclax, all of that will be on display, and you obviously want to be able to, get to an RP2D. So that's sort of, you know, we're testing our active doses, and so we need to have, you know, more patients, and that's what we're accumulating with, in combination with, with these agents. So I think we'll have more data, and, and it's hopefully what we would expect is high rates of, response and good safety across the board. So that's, that's what we've seen so far, and we expect that to continue.
Neil, I don't know if you want to add anything to that in terms of what's expected.
Yeah. No, I think you hit it. I think that what we're working hard, you know, obviously, a lot of this work has been done in collaboration, but it's really setting us up for identifying the dose, particularly with the venetoclax combination in the newly diagnosed patients, the dose that we would take forward into phase III. So, dose or doses, right? And so, I think that's right. And just, you know, not only do we anticipate or both anticipate and would, of course, like to see, is we've been seeing very high rates of MRD negative CR. So not only are the responses, the response rates high, but, you know, the MRD negative rates are extremely high, and we've seen that across, you know, different data sets.
So we anticipate hopefully seeing more of the same. But really, you know, anticipating the set-up for earlier phase, early phase, pivotal trials is also important.
Yeah. Now, how quickly can you feasibly be in a phase III trial in frontline AML? And can you say anything about, at this stage, about the design and scope of that potential trial?
Sure. Shall I take that?
Sure.
Yeah.
Yeah, go ahead.
Look, we're likely—it's probable that we will be running more than one phase III trial. I think we've been, you know, fairly open with at least two of the options, right? So the one that's most advanced is the phase III that would be based on the Beat AML data, right? So that the combination of venetoclax in the unfit population. And that is the most advanced, right? So that's the one that we have also said, you know, several times publicly, it is our intention to initiate that phase III by year-end. In addition to that, we are currently dose ranging in combination with induction consolidation chemotherapy in the fit population.
You know, that's gonna set us up to initiate a phase III a little bit later, you know, probably during the course of 2025. We haven't been very specific about that timing. The specifics of the designs, we haven't really sort of gone beyond what I've just said, because, of course, we need to align with health authorities, actually globally, not just the agency, but also in other jurisdictions where we would be conducting those phase III's, and that's in hand, right? So we're currently planning those interactions. And in addition to that, you can anticipate that we you know, there will be other studies. We haven't said specifically what they are.
We're in a competitive space, but there are other patient subgroups that we will want to generate, you know, within whom we would wanna generate evidence. They could be pivotal, they may be evidence generating, and we'll communicate more of those details in due course, but we haven't, we haven't as yet.
Okay. We might not have time to get to axetilimab future development plans, but with the commercial launch coming up, I think the key question is, you know, how do you compete in third-line versus belumosudil? And the question for me specifically is: What type of patient in that third-line setting do you expect to reach for axetilimab over the available product to date?
Anjali, you wanna take that final word?
Yeah, and I'll try to be really quick. I think it's a really good question. I think the biggest distinction for axetilimab is its ability to target both the fibrotic and the inflammation process, and we're not seeing that with the agents that are out there today. Physicians are not getting what they need in controlling the disease. And so... and I think I would highlight that Rezurock isn't so distinct from the mechanism of how Jakafi and ibrutinib work. So it may depend on what kind of response patients have to those prior therapies that may push them to wanna change completely how they're addressing the disease. It may also be, you know, are there more fibrotic manifestations that they're seeing?
This patient really needs early control of the fibrosis in order to improve their diagnosis, their standard of life, and so that could also be a driver for earlier use of axetilimab. You know, axetilimab is addressing the key components of GVHD progression, like no other therapy, and I think that will drive utilization for a choice for physicians and for patients. And you're not trading off safety and tolerability for improved efficacy, which I think just enhances the value proposition of our drug.
Okay. Maybe we can squeeze in one more just on the next steps for combination development and when that story might start to emerge time-wise, because I know you're just starting to get into these combination trials. But do you have a sense for timing yet in terms of first data updates, et cetera, when that could be reasonably expected?
Yeah, no, it's an important question, Brad. I think the... So Incyte will be leading those combination trials, and they had at least publicly said that sometime mid-year, those trials will begin. I think we haven't ironed out yet what that means in terms of data disclosure and when they'll first complete, and then we'll have data. So we'll take a little bit of time. These are phase II trials, and so they'll be, you know, well powered, and we'll get a good, good signal out of those trials. But I think it's important to note that we're just getting started in the middle of this year.
So as data emerges, I think there will also obviously be some real-world experience with the drug, which will be super helpful to physicians in understanding how they use our drug, potentially even in combination with other drugs. You know, that's how they tend to deploy them over time. So as we accumulate data, we'll be more specific in communicating that based on what our partner is saying as well.
Okay. Very good. Well, thank you so much for joining me for the Fireside at Stifel Conference, and thanks, everyone, for listening in.
Thanks, Brad.
Thank you, Brad. It's great to be with you.
Thank you, everyone.
Bye-bye.