Hi, welcome back everyone, to the next session of Citi's 2024 Virtual Oncology Leadership Summit. As a reminder, if you have questions for the company, just email me, yigal.nochomovitz@citi.com, and I will do my best to relay to the management team. So with that, it's my very great pleasure to welcome the senior leadership of Syndax Pharmaceuticals. I have with me the CEO, Michael Metzger, the President, Head of Research and Development, Neil Gallagher, and Anjali Ganguli, the Chief Business Officer. So welcome, all of you. Thank you so much for taking the time out of a very busy time in the company with the recent filing of both of the applications with the FDA, which we'll get into.
Michael, maybe just to start out, if you could just give us a high level, you know, where you are, what are the lead assets, what are the key catalysts for 2024? I already alluded to two of them. Then we can take it from there and dig into the details.
Yeah. Well, first of all, thank you, Yigal. Thanks for having us to your conference, and good to see you again, and for your coverage, which is always very good. So, pleasure to be with everybody today and to talk a little bit about the company. Many of you hopefully know about Syndax and what we've been up to of late. We do have two programs, two molecules that we're in late-stage development for. First is revumenib, which we refer to as our first-in-class menin inhibitor. We're developing it in KMT2A and NPM1 acute leukemias, so that covers both AML and ALL for KMT2A, and AML for NPM1, adults and pediatrics. And so, as you mentioned, we filed an NDA for KMT2A at the end of last year, and we expect approval in 2024.
NPM1, the other, the second indication, is in a pivotal trial as well, and we expect to have data in the fourth quarter, with approval in 2025. We are doing lots of other work with the molecule beyond these first indications. Very exciting and broad program, both in relapsed, refractory, and frontline, AML and ALL. We are doing combinations and do expect to have ongoing data probably later this year, and we'll talk more about that. And then for our second molecule, axatilimab, it's a CSF-1R monoclonal antibody. First indication is chronic graft-versus-host disease. We have a BLA that's been filed with the agency. This is for relapsed/refractory third line, that's the first indication, and we expect approval in the third quarter of this year.
Other indications are in development, earlier lines of GVHD, as well as in combination. And then, in IPF, we recently started a trial there, so there's extensions beyond just GVHD. So too, what we say, best-first-in-best-in-class medicines. Very exciting time for the company, and certainly lots of data and potential approvals this year. So start there.
Okay, awesome. So I think you're getting close to the 60 days in terms of acceptance of the NDA for revumenib. What's been the feedback so far, to the extent you can comment, with the FDA? Are you gonna be announcing the acceptance of the filing and the PDUFA date? What can you share at a high level, just in terms of the regulatory, and then we can move into some of the clinical data.
Yeah, sure. So, first of all, we filed for approval, this is for revumenib. We filed for approval at the end of December. So we submitted all of our modules, and we are sort of in a waiting game. This is done under RTOR. So we were admitted into the RTOR program, and there's really no formal acceptance period under RTOR. It's an iterative process where, actually, we were accepted into the program last fall, and we started submitting information, and it was being reviewed by the agency on an ongoing basis. So there's no refuse-to-file period. It's just an open dialogue and ongoing work stream with the agency.
We do expect to receive our PDUFA date sometime in the first quarter, which will put us sometime in the third quarter for potential approval. And so that's kind of, you know, how we, how the process has gone. It's gone very well. We've been in active dialogue and working quite hard as a team. And in terms of whether we'll- I think you had mentioned, asked if we would announce our PDUFA date when we have it, and we would expect that we would do that, yes.
Okay, so investors, we should not expect this typical 60-day clock, given the RTOR process. That's important for people to understand.
Correct.
Okay. And then as far as... You know, we've talked a lot at, at ASH and, and, and in other settings regarding the, you know, some of the key clinical metrics in, in AML, MRD negativity, transplant rates. Of course, the, the primary endpoint of your trial, which is CR/CRh. You know, what do you think about, just in terms of the overall clinical package, you know, how much do you believe the FDA would be weighing in on some of these, these other endpoints, like MRD negativity and transplant rates, as they think about how to approve, how to approve revumenib?
Yeah, look, I think we feel very confident about the data. It's been very well-received. You know, and we recently obviously put out a lot of data at ASH and presented it as a late breaker at this year's ASH, or 2023 ASH. And physicians have you know, reviewed it extensively. I think the regulators have, you know, we've been working closely with the agency since receiving, well, from the beginning of the program, but we certainly received breakthrough therapy designation in 2022. We had admission into the RTOR program, as I mentioned to you. So we've been in constant dialogue. I think the data that we've put out to date is quite strong, and it's, you know, you think about it from an overall response perspective in the mid-60s.
That means two-thirds of patients have gotten a response. And then you think about duration of response, more than 6 months as of the data cutoff. Certainly CR/CRh being the regulatory endpoint in the mid-20s, 23%. AML was a little bit higher, about 24.5%. We've shown data, you know, in MRD negativity at roughly 70%. Many patients going on to transplant, many times the amount of patients who have KMT2A going on to transplant. I think the robustness of the data, the not only the regulatory endpoint, but all of the different parameters, the agency thinks about risk-benefit in a high risk, high unmet medical need area.
And so I think what we've shown to date in terms of all of these measures has been not only robust, but you know, serves well for what we think will be a you know, a really important product. And I think the agency recognizes that as they think about approving a product.
And as we think about how they'll frame the label and the adjustable population, obviously, you have data for AML, but you also have some ALL patients, although a smaller cohort. My understanding is you're going for the AML, ALL sort of broad label. What can you say about the expectations around having ALL included as well?
Yeah. Neil, do you wanna, do you wanna touch on that?
Yeah, sure. Thanks for the question. So, I just wanna sort of remind you, I mean, Michael mentioned it already, but we got BTD back in December 2022 for adults, kids, acute leukemia, so ALL and AML, based on the phase I data, right? So we presented the, the phase I data for KMT2A. We presented the, the phase I data to the agency. They gave us BTD, broadly. The data in the package, the pivotal data, are entirely consistent, highly, highly consistent with what we presented, the data that we presented, which formed the basis of, of BTD. So, you know, we're, we're pretty confident. You know, that's, that's the context to which we've been working with the agency all along, and we feel pretty confident that that, you know, that would be the label that they would approve.
You know, just a reminder, it's not—this isn't without precedent, right? You know, Vitrakvi, Keytruda for MSI-high tumors. You know, there is precedent for this kind of broad indication based on the underlying molecular biology of the disease.
Okay. We are getting some questions from the listeners. So one, someone just curious, just in terms of the regulatory, what are their expectations? I mean, you mentioned RTOR, so maybe this is not as applicable. You know, obviously a breakthrough, so you have very close dialogue, ongoing dialogue, but priority review, is that something that's formally up for discussion, or how do you think about that?
Yeah, generally, as when you go through the... So let me start a different place. When in order to get into the RTOR program, you need to be. First, you have to have breakthrough therapy designation signed. So that's the first step. Second step would be RTOR program, and usually, as part of that assignment, you are given priority review. So that's something that we would think is potentially in the cards. And that obviously is. It's all part of a program to move a molecule through development and through the regulatory processes as quickly as possible. So we would expect that to be part of the overall scheme here.
Okay. And then, you know, another important question, this was discussed with the KOLs at your event in ASH last December. You know, the significance of the post-transplant maintenance setting, is that type of language, the resumption of revumenib post-transplant, something that could potentially end up in the label? Or how do you see that evolving?
Neil, you wanna make a comment there?
Yeah, sure. So we anticipate having language in Section 14. So we said previously, we don't anticipate having an indication, but we anticipate having language in Section 14 that describes how the clinical trial was conducted, which included the fact that patients were allowed to go back on maintenance therapy following transplantation. So obviously, we're not gonna get into the exact wording of what we expect. That's for a discussion with the agency.
Okay, and then with regard to the safety side, you know, are there the things that we should be looking out for there in terms of warning language that you might anticipate, or not? I mean, for example, like the QTc prolongation, is that something that we should expect to see in the label?
Neil?
Yeah, well, we will anticipate to see all of the safety information in the label, for sure. So the data will be in there. But if you-- I don't know if you were asking something-- were you asking something about, you know, highlighted in the label or in some way?
Yeah, I mean, if it's gonna be called out more specifically or not, or just as you say, it would just be in the list of AEs, as you would typically see.
A warning and precaution. Don't anticipate a boxed warning, if that's where you were going.
Yeah.
We're not anticipating that.
Okay, okay. And then I think it would be helpful if you could spend some time, and maybe Anjali could comment as well, on the commercial opportunity. You know, what does the market look like in terms of the KMT2A rearranged patient population? What would be the expectations on durability, duration of therapy, at market access, things of that nature? That would be great as we, as we move forward and get closer to the launch. Anjali, you wanna take that?
Yeah, sure. Thanks, Yigal. Always happy to talk about the great opportunity we have in front of us for KMT2A. You know, as we've presented that data, and Michael alluded to the great reception we had at ASH. Physicians universally that we've talked to have indicated that this is a huge breakthrough for this population. There really is nothing that works well for them available today. They push very hard to treat with intensive chemotherapy and see if they can get patients to transplant, as the only option available for a potential cure. But the median 5-year survival is very, very low, and if they're a relapsed refractory population, their median survival is 2-3 months. And so they are very eager to have an agent that can help bring patients to transplant.
You know, it was able to get two-thirds of late line patients. You know, we had, in the trial, a median of fourth or fifth line patients, 63% of whom responded with complete tumor clearance, and physicians were able to action on that. We had, 60% of those responders that went to transplant, were going to transplant before they achieved a CR or CRh even. So, any level of tumor clearance, and especially because such a high proportion of those clearances were MRD negative, we really were able to get those patients to transplant, and they were very eager to put them back on therapy after transplant. That was something that they guided us to incorporate into our trial, in the phase II.
When we did that, they responded very uniformly, trying to get all of their patients back on drug after transplant. We anticipate that's what will happen in the post-approval setting. So if you look at the way, again, in the trial, things bore out, we had two-thirds of patients respond, one-third of patients who did not respond. If you break out, you know, of the patients that responded, about half went to transplant, 45%, and 71% were put on therapy post-transplant. We anticipate. You know, we've seen in the dataset that we're collecting and shared at ASH, patients staying on in the post-transplant setting for over three years, and we've had multiple patients ongoing over one year.
We anticipate that the goal for these patients would be to keep them on as long as possible, because there really is nothing else once they fail revumenib. So, in that population that goes to transplant, we're estimating a median duration of 18 months. That's one-third of the patients. The other third of patients that respond but don't go to transplant, we estimate they could stay on as a median of eight months. Again, we're anticipating that it's not these patients that are fifth line that are receiving revumenib, it's going to be patients who are second line on average, you know, after they've shown resistance or are refractory to intensive chemo, they could go straight to revumenib.
And then we saw a third of patients in the trial that did not respond, and we would anticipate they would stay on, you know, three months to know that they were not responders on average. And that gives you across those patients that we would be targeting about a nine-month median duration. The population of patients that would be eligible for this drug in the relapsed refractory setting with KMT2A rearrangements is about 2,000 patients, so that it incorporates both the AML and the ALL population. That relapse and, you know, the price point here is already been set with the approvals of Vanflyta, Idhifa, Tibsovo in the mid-$35,000, you know, mid-$30,000. I think they're all about $34,000 today.
They take price increases and, you know, with the dataset we're generating, we're hearing that there is an opportunity to at least price at parity to those agents. And so that gives you an opportunity around $700 million-$750 million for KMT2AR alone in the U.S. relapsed refractory setting.
For the ones that went to transplant that didn't receive revumenib, what was the reason? I mean, you would think that everyone should kinda go back on... Assuming the transplant was successful, that everyone should go back on the drug. Maybe those ones just didn't have a successful graft, then what was the reason they didn't get it?
Yeah, that's right, Yigal. In a, you know, there was only about three patients that fit that category, and unfortunately a couple of them did not have a successful transplant. We also had to, you know, make sure the protocol was set up appropriately. We extended the period of time that physicians had to elect to put a patient back on treatment, and when we first started, it was a little bit shorter than it needed to be. So when we extended it, to give them a little more time to get ready, post-transplant, for retreatment. Then we saw, you know, pretty much everybody elect to go back on therapy.
Okay. That makes a lot of sense.
That's exactly what we heard at our investor presentation at ASH, that if a patient responded well to revumenib and was able to go to transplant, there is no reason that they wouldn't put them back on after transplant. And as Neil alluded to, we anticipate the data in the label suggesting how patients were treated during the trial, as well as the publication at ASH. You know, we anticipate publishing the totality of the phase II data. All of that should support the ability of physicians to be able to do just that.
Okay, and the 18 months, that's—is that post-transplant or that's the total duration? Just so I'm clear, just so everyone understands.
Yeah, it was, it was to assume the total duration of therapy that patients could be on. Obviously, you know, as we're talking about moving from the fifth line to the second line, there could be an enhancement of that duration because patients are more fit, more likely to have a benefit from therapy, and be able to stay on treatment longer. So and in some ways, we believe this is a conservative estimate.
Well, 'cause I remember when I asked the question at your event at ASH, I think they said, one of the KOLs said a year post-transplant, just for post-transplant. So then the 12 months plus whatever you had pre-transplant, gets you more than 18 months. So anyway, that was my math.
Yeah. And we've heard as much as, you know, out beyond two, three years, because they don't wanna take them off, because there's nothing else to give them, and the risk of relapse in that population is so high today that they're... You know, and the risk-benefit of receiving this drug is, so manageable that they, they don't see a reason to take them off unless, you know, they're progressing or have some issues.
Right. Okay. All right, let's move on and shift a little bit to NPM1. So, Mike, I think you said the enrollment in the pivotal cohort is, you're guiding to sometime sort of towards the end of this quarter or beginning of next quarter, and then the top line data at the end of the year, filing in early 2025. What can you tell us in terms of just the latest status on enrollment for the NPM1 pivotal?
Yeah, look, it's gone, it's gone well. We're, we're happy with it, and I think, I think the guidance is, as you stated, we should be complete by the end of the first quarter or beginning of the second quarter. And, as you know, we have a robust program, global program, and enrolling patients nicely in different geographies. So it's been, it's been, it's been robust and good. So we're, we're happy where we're at with that.
Are you gonna sort of follow a similar playbook in terms of how you released the KMT2A pivotal last year? A similar setup for NPM1, is that? Should that be the expectation?
Well, you know, it's a little early to say how we're gonna release the data. I think, you know, we expect to do it in the first quarter, and how that lines up exactly is a little bit up in the air at this point both venue-wise, and exactly, what information will be available. But, you know, there's very similar trial designs, notwithstanding the fact that, we did a pooled analysis for KMT2A, and, that was a special circumstance because of the two cohorts that were put together with agency, you know, buy-in there. But on NPM1, we'll have 64 patients, adult patients, and, there may be some pediatric patients as well.
There's up to 20 are allowed in by protocol, though it's not really a pediatric disease as much. But in terms of the type of data that we... You know, the measurement, the measures and the endpoints all same, similar, to what, we yield for KMT2A. So the information should be roughly similar.
And just, is there anything you can discuss that's built into the protocol, which could afford an early look, for example, an interim? And if so, what might trigger that?
Yeah, I think I was just alluding to that, the differences between KMT2A and NPM1. So KMT2A was a bit of a special circumstance in that we had, two different cohorts, both sized the same, 64 patients, AML, 64 patients in ALL. Under BTD, the agency, as we talked about earlier, gave us a broad designation for covering adults and pediatric for KMT2A, whether they're AML or ALL patients. That allowed us to come up with an opportunity to pool the two cohorts together, and do an interim analysis, which we, we hit on, last year, and then formed the basis of our NDA. Little different for NPM1, in the sense that it's just, it's just AML, so we're enrolling the full 64.
We expect to present that as our data package to the agency, but it'll be done under sNDA rather than NDA, as a second indication.
Okay. And then in terms of the efficacy on the primary endpoint on CR/CRh, I think you've said in the past that you wouldn't expect a difference in response necessarily, but that you potentially could see a higher CR/CRh. And NPM1, as you pointed out, it's an older population, less likely to get transplant. So you could have a higher probability of a CR/CRh. Would you agree with that statement? And what are your thoughts on what you'd like to see for the CR/CRh?
Sure. Anjali, you wanna handle that one?
Yeah, sure. Thanks, Yigal. Yeah, you know, Yigal, what we've been saying and, and what we've observed, and I think others in this space have observed, is that the KMT2A and NPM1 response rates, efficacy, safety, all of that seem very, very consistent with menin inhibition. And so we would anticipate the overall response rates to be very similar across KMT2A versus NPM1, as we, you know, gather more data in that population.
Obviously, you know, what you said is true, the NPM1 population being significantly older than the KMT2A, and maybe, you know, considered unfit for transplant from the, from initial diagnosis, may be less likely to go to transplant, and physicians may be less aggressive on taking them to transplant, giving them more time to, mature their response from a, you know, CRp or CRi into a CR or CRh. So nominally, it's possible your CR or CRh rate could look slightly different. But, you know, I think generally we believe the overall response rate is what's most important, because it allows physicians to, action on that response and that tumor, you know, full tumor clearance. And what we've seen so far has been very consistent across the two populations. So we anticipate it to be very similar.
Whether there's, you know, a nominal difference, it's hard to know.
While you have the floor, you wanna maybe just go through a little bit on the, on the commercial side and talk about the, the opportunity? I mean, obviously, the NPM1 is a bigger, bigger market. What are the dynamics there? Are they similar in terms of KMT2A? As you discussed before, are there some notable differences that we should be aware of?
Yeah, no, that's right. There are, I think, initially, definitely some differences with KMT2A and NPM1. The NPM1 population, as I just said, is older, and so unlike KMT2A, they do split between what is considered fit for intensive chemotherapy and unfit for intensive chemotherapy, whereas NPM, KMT2A is, you know, a vast majority are fit, as they're, you know, on average, a much younger population. And NPM1 patients tend to be more chemo responsive. They do have really high response rates to 7+3 in the fit setting, as well as Ven/Aza in the unfit setting. So I think initially... And their prognosis initially is thought to be much better, but once they relapse, they become more similar to the KMT2A prognosis.
So physicians are looking to get them to transplant in first relapse or second, and especially in second relapse and beyond. And they run out of options. You know, the two standards of care therapy, I mentioned Ven/Aza and 7+3, are what they reach for initially. And, you know, many of these KMT2A or NPM1 patients do have co-mutations, some of which are actionable, like FLT3 and IDH. So they can combine with seven plus three and, you know, midostaurin or now Vanflyta, upfront, and try to treat those other actionable mutations. But once they've gotten past that first relapse, or in some cases second relapse, they really don't have options for treatment, and they have a much more dire prognosis.
So, you know, we may be looking initially at more of a third-line population for NPM1, with, you know, some, you know, for the unfit population, maybe in the, in the second line, setting. But, once they get to that, you know, second or third relapse, they really don't have anything, and so, so it does become much more similar. In terms of actual patient numbers, I think the NPM1 population starts off at, in the U.S., close to 6,000 patients with AML, so it's like a third of, of the AML population. And, we anticipate by the third relapse, you have about 3,000 patients that are in need of something to, to use to benefit them.
What we hear from our market research here is also very strong anticipation for menin inhibitors in that second or third line setting for patients, because they don't have a lot of options, and something that is, you know, tolerable and effective and could give them optionality is really a high would really address the unmet need in that setting.
And then, how are you thinking about the durability in NPM1? Because you sort of have, you know, two forces that are opposing. You have the, as you mentioned, the less fit, and so they may be less likely to go to transplant. But then you also have, you know, a more challenging population, so, they may work to balance out. I'm not sure. Do you think there'd be meaningfully different durability on an NPM1, or do you have any-
Well, you know, we've seen the patients that have come into our trial actually have been very similar. You know, the overall response rate has been about 50% so far, similar to 63%, you know, within the error bars. The CR/CRh rate is, you know, upwards of around 37%, which again, you know, we feel like if the KMT2A population wasn't going to transplant as readily, may have gotten there as well.
Yeah.
The percent of patients that are going to transplant, at least in the population we've tested, is very similar, about 43%, so very similar to the 45 I quoted for KMT2A. And what we saw in the phase I for duration of response was 9 months, and then in the KMT2A population, phase II was 6.5 months. And again, you know, with the numbers that we're dealing with, we don't think that's significantly different, and we anticipate, you know, based on the totality of the evidence, that the overall efficacy could be very similar across all of these parameters. So today, we don't think there's a significant difference as we go.
Okay, and, you know, you devoted quite a lot of time at ASH to talking about some of the very interesting new combo work that you're doing in the earlier line settings, across multiple different mechanisms, Beat AML, SAVE AML, and the Augment 1 or 2 trial. I think it would be helpful, Mike, if you could just kind of recap some of those conclusions. What have you learned about how to advance revumenib into earlier line setting, and what will be the next steps to develop the combo work?
Yeah, I'm gonna let Neil address it, just say a couple before he kicks it off. I think we were obviously very excited about the data at ASH, in combination, looking not only at newly diagnosed patients, in combination with Ven/Aza, that's the Beat AML trial, but also looking at relapsed refractory patients, right? With another combination with ven, ven and Inqovi, which is an all-oral regimen, and then, of course, combination with chemotherapy in relapsed refractory patients. So I think we're trying, as a theme here, we're trying to cover the key pillars of combination, what we can combine our drug with, and Neil can recap some of that data for us.
Yeah, sure. Thank you. So just to, just general statement about all three trials before I get into some of the data. There were two doses of revumenib, the same two doses tested in each of the trials. 130 milligrams BID, 163 milligrams BID. This is for all three. So, yeah, starting with SAVE, which, as Michael mentioned, is a combination of revumenib with venetoclax and oral decitabine in a relapsed refractory population. It's an IST being conducted by Ghayas Issa that was reported out at ASH. And also, we talked a bit about it earlier in the late last year, too. This was a very heavily pretreated population, right? So they had a median number of prior therapies of three.
A third of them had, or more than half of them had failed part of venetoclax, two-thirds of them had been transplanted. You know, despite that, the overall response rate was 100%, the CR rate was 78%, the CR, CRh rate was 44%, and all of the patients who were assessable, only one patient was not assessable for MRD, all of them were MRD negative. So, you know, really quite impressive, just given the extent of prior therapies and including transplant, that these patients had failed. In terms of safety, there was really no new safety findings, myelosuppression, specifically, myelosuppression was, you know, similar to what you'd expect with ven and a and a hypomethylating agent in this particular population.
Moving on to Beat AML, obviously, Beat AML is a platform trial. Revumenib has been combined with Ven/Aza, which, of course, is the standard of care in treatment-naive older patients, unfit patients, AML patients. So as I mentioned, same 2 doses. And I should have mentioned, by the way, in all 3 trials, that for both dose cohorts, the DLT windows were cleared. So in all 3 trials now, they're in the sort of expansion phase for the dose cohorts. So Beat AML, same 2 doses, clear the dose-limited toxicity window. As I mentioned, an unfit population, median age 73, very, you know, typical of what you would expect in that population. And, you know, we saw very robust data coming out of that trial.
Complete response, sorry, CRc was 100%, CRh was 85%, and again, 100%, MRD, 100% MRD negativity. I should correct myself, it was actually the 100% MRD negativity refers to the, the Beat AML trial. It was the 1 patient in the Beat AML trial was not assessed for MRD, so, apologies for that. And again, in terms of the overall safety profile, the patients, you know, the safety profile was really consistent with what would be expected, no new safety findings. And again, specific to the myelosuppression, very much what you'd expect from Ven/Aza in the unfit adult AML population. And then the third trial is Augment 1 or 2, which is a combination of revumenib.
It's a company-sponsored trial, a combination of revumenib with fludarabine cytarabine in a relapsed refractory AML population. And again, very heavily pretreated, median number of prior therapies, I think, was 4. Fifty percent of those patients had failed prior therapy with FLAG. And again, you know, response rates were good, 33%, far exceeding what you would expect from just chemotherapy alone in this population, given the extent of the prior therapies, which would be 10% or less. And notably, you know, patients went to transplant. So there was, I think, a 33% transplant rate on that trial. And by the way, in the SAVE trial, there was a 56% transplant rate. So, you know, taken in totality-...
You know, when you synthesize, and Michael sort of referred to this a little bit early on, but when you take all of those, those data together, and this is, it, it, it really confirms or begins to confirm that revumenib is combinable, right? I, I say confirms the dose-limiting toxicity windows have been cleared. We're expanding the, the, all, all three trials. So we're just now trying to get some more precision around what the RP2D would be in, with each of those combinations. But, you know, going back to something that was said earlier on, you know, revumenib is extremely well-tolerated as a, as, as a monotherapy. We've had patients on treatment for, you know, up to three years in the post-transplant maintenance setting. And now what we're seeing with the, these three combination datasets is that it's combinable, right?
It's combinable in a number of different populations: newly diagnosed, refractory, with different backbones. And so based on that, I think you were asking where this brings us, right? Based on that, we're moving, you know, we're highly encouraged to move quickly to initiate a pivotal trial of revumenib in combination with venetoclax versus venetoclax in the unfit adult AML population, this year. It will be later in the year, but we're moving to initiate that trial this year. And in addition, we're about to initiate a combination of revumenib with 7+3 standard chemotherapy for the fit AML population.
Now, so, that will obviously, it's designed as a dose-ranging trial, but it, you know, we're just based on everything that I've been saying for the last few minutes in terms of the combinability with other standards of care, including chemotherapy, you know, there's no technical reason to think that revumenib can't be combined with 7+3, right? And therefore, as we move through that trial, we'll generate safety data, we'll generate, obviously, evidence of activity, and that will then set us up for various strategic options for pivotal trials in the fit population, in 2025. So that's, that's where we are. I'm not sure if I left anything out, I'll ask Michael or Angie.
No, I think that covers it. Thank you.
Okay.
I think, no, that was great. I think just for those maybe less familiar with the story, these frontline studies that you're mentioning in combination in the frontline trial, are those, you know, genotype agnostic, or are you looking at specific populations? Can you just clarify so people are clear there?
Yeah, it's a good, it's thanks, thanks for the clarifying question. So I think, you know, it, for the fit, the unfit, the rev/ven will be primarily an NPM1 trial. We're talking, you know, we will probably allow in KMT2A patients, but, you know, NPM1 is the more prevalent population among unfit AML patients. KMT2A tends to occur in the younger, so there'll be quite, there won't be that many of them. But investigators are actually quite keen to include KMT2A patients. We would analyze them separately, so from a statistical perspective, you know, we won't compromise the trial design. It'll be powered around NPM1. I haven't really gone into detail, I don't, you know, about what we would do in the fit population. I don't really want to do that just from a competitive perspective right now.
Okay.
But certainly for the unfit, you can think of it as primarily an NPM1 trial from a statistical design with sort of a subgroup of KMT2A patients in there. We would look for consistency of effect in the KMT2A population.
Okay. And then if we, if you were to venture further into some of the other MOAs in AML, like a FLT3, is that in the cards? Are there reasons why that may not work or not, or that could work?
I don't think there are reasons why it wouldn't work. It's not—it hasn't been our focus, right? The company-sponsored, from a company-sponsored trial focus. We do have a number of investigators that are interested in that particular combination. In fact, there's an IST that's been posted, but with gilteritinib. And there's another IST that's under consideration, which will be a combination with midostaurin. I think the gilteritinib combination is active. It's certainly posted on ClinicalTrials.gov. So, you know, our strategic focus is more in the direction that I've described earlier.
Okay, let's just spend literally a minute or two on menin outside of AML and ALL. You have a study in CRC, it's I think you've kind of billed it as a signal-seeking study. What, what's the quick update there? And then, obviously, there are people working on things outside of cancer for the menin space, i.e., diabetes. Anything to say there? And then let's talk about axatilimab.
Sure.
Thanks.
Michael, is that it?
Yeah, go ahead.
Okay, let's get one thing off the table: we're not doing diabetes, right? We've assessed it, and we don't believe that we should be doing anything there. With respect to outside of yeah, solid tumor oncology in particular, you referenced the CRC trial that's ongoing. So just some background there. You know, like, a pretty sophisticated audience, so I'm sure I probably don't have to give you guys this lesson, but 90% of colorectal cancer, the Wnt beta-catenin signaling is implicated in the oncogenesis in over 90% of colorectal cancers.
There were data published some years ago indicating that disruption of, or dislodgement of MLL1 from the Wnt beta-catenin complex actually mitigated CRC cancer cell growth, right? And the effects that were described were kind of similar to what we see in acute leukemias. So you've got this, like, disruption of this signaling pathway that results in suppression of in vitro cancer cell growth, colorectal cancer cell growth, and that really encouraged us to start the trial that you've referenced already, which is ongoing. Obviously, it's safety, but we are collecting efficacy information, efficacy data rather, as well as biomarker data, for instance.
I think what we've said is that we'll provide an update by, during the first half, probably later in the first half. I think that's what we said before.
Right.
Watch this space.
Okay. Sounds good. All right, so axatilimab, let's switch over to the, CSF-1R axis of the company. So again, big, big, big development with the, filing of the, of the BLA by, by your partner Incyte. I assume that's Incyte's news to, to share when the acceptance of the BLA, but can you just confirm that, and anything you can say at this point in terms of feedback from the FDA, but I know you may be limited in how much you can talk about that.
Yeah, this will be a short answer, Yigal. Right. So Incyte did file the BLA at the end of last year. We announced that. We'll obviously, when the PDUFA is in hand, it will, you know, potentially get announced, but we don't have confirmation that, and you know, how that'll work yet. So we have to work with our partner on it. And the acceptance window, you know, 60-day window is pretty traditional, on a traditional, traditionally filed, not under RTOR, but traditionally filed BLA, so that's a reasonable timeframe.
Right, so, you know, again, we'll be in close contact and be following the guidance that we strike together as partners and how we announce that.
Okay, and so obviously you also opted in, last year, I don't recall exactly when, but quite recently, towards the end of last year, on the, on the co-promote, co-commercialization. What... Tell us about what kind of investment you're gonna make in the, in the commercial effort, in terms of deployment of capital as well as personnel, and would there be any overlap with revumenib or no?
Yeah, look, it's an important part of what we're going to be doing. Naturally, this is a focused footprint, if you will, or a call point, whereby these are physicians, these are transplanters primarily, they're not that many in the U.S., it's a subset of leukemia specialists. So we're calling on this, roughly the same set of doctors, and so there's great overlap between what we're doing with revumenib and what we're doing with axatilimab. That's precisely why it made sense for us to opt into the co-promote. Having two products in the bag versus one product in the bag for these reps gives the opportunity for physicians to dialogue about the data more, you know, more robustly.
So, I think that's, you know, in terms of what we've opted in for, we have the right to opt into up to 30% of the FTE effort, and so that's what we will do. And, you know, how we deploy relative to revumenib and the specifics there will be, you know, are being worked out, but it's highly, I would call it, highly synergistic, you know, targeting of physicians with two products.
Okay. And obviously, obviously, you're entering a space where there is, you know, a decent amount of competition, as we all know, with some of the other products for GVHD, chronic GVHD. So, you know, it'd be great if you could just kind of give us the sales pitch, as it were, as to where you see the differentiation for axatilimab, how it could add to the optionality in the therapeutic landscape, in addition to what we already have with Jakafi, Rezurock, and Imbruvica, and how you could potentially see taking axatilimab into the earlier settings, earlier lines, which, as we know, is important.
It is. It is important. Maybe I'll let Anjali address the commercial question first.
Yeah, sure. Thanks. Thanks, Yigal. So you know, I think fundamentally, the mechanism of action for axatilimab differentiates it from all the other therapies that have been approved for chronic graft-versus-host disease. So unlike Jakafi, Rezurock, and even ibrutinib, axatilimab is not targeting the T or B-cell signaling pathways. It's going after a whole cell type called the macrophage, monocyte-derived macrophage, and by doing so, it is active not only on the inflammatory pathways, but also the fibrotic pathways that drive and characterize this disease, and ultimately lead to end organ damage and patient death. And so it has an ability to very meaningfully impact the disease, and that's what we're seeing in the trial.
You know, and unlike the other therapies, AGAVE enrolled patients who have had a median of four years since diagnosis, which is significantly longer than the two years and less was seen with the other agents. And had, because of that, much more severe patients with much more involvement across some of, you know, the most devastating manifestations, like lung and skin, and yet numerically, we saw very similar response rates across all organ systems, and an impact, especially on some of these fibrotic systems. For instance, I think we showed a third of our lung responses were complete responses, which had never been seen before.
And I think that speaks very strongly to the benefit that axatilimab can bring to these patients, and it is a strong rationale for moving it earlier in the treatment paradigm, so that you can hopefully change the progression of the disease in these patients, and that's what Incyte is looking to start a study in combination with Jakafi to see if you could suppress both of those axes at once and maybe eliminate the need for steroids in treatment, which I think physicians are really focused on: How do I decrease the amount of steroid usage? Because it does help manage the disease acutely, but in the long term, actually causes a lot of the devastating side effects you see in these patients.
So I think fundamentally, the mechanism will drive a lot of interest and uptake, and, you know, we are seeing a strong reception from physicians that we talk to. And, you know, at ASH, at the plenary, we got a really strong reception at the presentation. It was really exciting to see that. But I think there are a number of things that could drive uptake for axatilimab, you know, ahead of Rezurock or, after any of these therapies, because they're really... This is a chronic disease. These patients do cycle through therapies. They're not, you know, acutely dying like we see with the population we're targeting with revumenib. And so there is an opportunity to access these patients at any point in their cycle.
We've also seen in these late-stage patients, the ability to stay on therapy for really extended periods of time. So I think the commercial opportunity is actually very large and underappreciated for axatilimab, even in this third-line plus setting.
Yeah, I remember when we did our KOL checks last year, the comment was there was very, very good optionality in terms of the mechanism of action of axatilimab playing well with the other mechanisms, given it was kind of orthogonal to whatever all the other ones were doing. You know, I also got a lot of questions with regard to what Incyte's gonna do with the combo with Jakafi. I guess it's not clear, or they haven't spelled it out in super detail. Are they gonna try to go frontline, meaning real frontline, like before steroids, or is this gonna be Jakafi plus axatilimab after some initial attempt with steroids? Just curious, or has that not worked out yet?
Yeah, Anjali, you're unmuted, so you might as well take that as well, if you wanna -
I think that that is something that, we're working through with Incyte and with the FDA, exactly how best to address that population. The goal would be to, decrease or, or eliminate the utilization of steroids, but, you know, they will see steroids in the acute setting and, and, you know, may need to manage early on, with some steroids. So we're just trying to take it into consideration and make sure that the trial we run is the most useful for physicians to be able to translate to how they would like to practice.
Okay, and you touched on, when you were talking about the MOA, the, you know, antifibrotic aspects. You are also developing with Incyte, the study in IPF, idiopathic pulmonary fibrosis. What's the latest there as far as date, timing, and data concerns?
Yeah, it's a very exciting development for the molecule, the franchise, so maybe I'll let Neil touch on that as well.
Yeah, sure. Thank you. Thanks for the question. So yes, we're very excited. And Anjali, Anjali actually referenced some of the data that has us excited to go into IPF very strong, which is the effects in chronic GVHD in the lung. And in fact, not only, you know, from AGAVE, from the AGAVE trial, but also from the earlier study as well. You know, we've seen reversal of or improvement, should I say, in FEV1 in patients with bronchiolitis obliterans, for instance, and we reported that, in the middle of last year, at ATS. And of course, then the responses in lung that were observed in AGAVE were entirely consistent with what we'd observed earlier. And you know, the mechanism is a credible one, right, in IPF.
And so the trial is now active and is a randomized phase II trial. Target accrual is 135 patients, randomized 1:1. It's on the background of standard of care, so patients can be on nintedanib with pirfenidone. It's a 26-week readout, and so... And obviously, the endpoint is, you know, the effects on FVC, so it's lung rate of decline or even improvement in FVC compared to placebo. It's a little too early to talk about timing. You know, we just announced, you know, that we've initiated the trial, so I don't think that I feel very confident or comfortable, rather, talking about accrual, rates of accrual yet.
You know, there is a high level of enthusiasm, actually, in the investigator community, and we are, you know, we are making extremely good progress in terms of, you know, site and, you know, activating the sites and so forth. But I just can't be too precise about about some of the details now. And we'd be happy, once we get some more of that precision around it, we'll be happy to share some more information.
Okay, understood. Understood. And then, Michael, just to round out, tell us just quickly, in terms of the financial strength of the company where do you stand with the cash and the runway? Obviously, you brought in the two assets we've talked about by a licensing pathway. Are you, are you thinking about bolting on new, new assets, at this stage, or are you gonna focus on, on the these late-stage opportunities?
Right. So maybe the cash question first. So we did raise $258 million through offerings in the fourth quarter. So pro forma cash $635 million. We'll update that number at the end of this month, when we bring the cash forward current to the end of the year. But certainly the company is in good financial condition. We said we have cash through at least to end of 2026. And so in terms of what we can do, and obviously what we're working on, we have a vast program, two vast programs that we're invested in. And this allows us to launch both products and complete our trials on a timely basis, and expand into new indications.
In addition to that, you mentioned business development, which is, of course... The business model of the company is to in-license or acquire assets. That's how we've come to be in the fortunate position to have these two assets in late-stage development. They were in-licensed preclinical assets. We do continue to work very hard to bring in additional assets. We have a high bar. Targeted oncology is the focus, and generally speaking, we're looking to backfill the pipeline, so it would be earlier-stage assets, as well. So somewhere in the lead-stage preclinical to early clinical stage assets, and we're working hard to potentially bring in additional assets.
We generally don't comment on business development until it's complete, but we're encouraged by, encouraged certainly by what some of the things that we've seen of late. So it is an exciting, a very exciting time for the company to be in the fortunate position we are, to be nearing commercialization of these two assets and have such, I'd say, broad expansion opportunities for both, as well as the capability to bring in additional assets and build this into a fully integrated company.
All right. Very good. Thank you so much. Congrats on all the progress, and we look forward to hopefully very good pieces of news soon in terms of the near-term approvals for both assets. So thanks again, and I'm sure we'll be chatting soon. Thank you.
Thank you, Yigal
Thanks, you all.
Have a great day. Thanks.
All right, you too.