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

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 e-mail me at [email protected], 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; 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.

But Michael, maybe just to start out, if you could just give us a high level where you are? What are the lead assets? What are the key catalysts for 2024? I already alluded to 2 of them. And then we can take it from there and dig into the details.

Yes. 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 2 programs to molecules that were in late-stage development for versus revumenib, which we refer to as our first and best-in-class menin inhibitor. We're developing it in KMT2A and NPM1 acute leukemia. So that covers both AML and ALL for KMT2A and AML4 NPM1 adults and. Pediatrics. And so we filed -- as you mentioned, we filed an NDA for KMT2A at the end of last year, and we expect approval in 2024. NPM1, the other -- 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 are extensions beyond just GVHD. So 2, what we say, best first and best-in-class medicines very exciting time for the company and certainly lots of data and potential approvals this year to start there.

Okay. Awesome. So you're getting -- I think that you're getting close to the 60 days in terms of the acceptance of the NDA for revumenib. What's been the feedback so far to the extent you can comment with the FDA? Are you going to 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.

Yes, sure. So first of all, so we did -- as I mentioned earlier, we filed for approval. This is for revumenib. We filed for approval at the end of December. So we submitted our -- all of our modules, and we are sort of in a waiting game. This is done RTOR. So we 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 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 -- well, I think you had mentioned this, that 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 -- we've talked a lot at ASH and in other settings regarding the -- some of the key clinical metrics in AML, MRD negativity, transplant rates. Of course, the primary endpoint of your trial, which is CR/CRh. What do you think about just in terms of the overall clinical package? How much do you believe the FDA would be weighing in on some of these other endpoints like MRD negativity and transplant rates as they think about how to approve revumenib.

Yes. Look, I think we feel very confident about the data. It's been very well received, and we recently obviously put out a lot of data at ASH and presented at as a late breaker at this year's ASH or 2023 ASH and physicians have reviewed it extensively. I think the regulators have -- 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 initiated 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 think about it from an overall response perspective in the mid-60s, I mean 2/3 of patients have gotten a response. And then you think about duration of response, more than 6 months as of the date of 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 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. So 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 our -- what we've shown to date in terms of -- all of these measures has been not only robust, but serves well for what we think will be a really important product. And I think the agency recognizes that as they think about improving a product.

And as we think about how they frame the label and the addressable 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?

Yes, Neil, do you want to touch on that?

Yes, sure. Thanks for the question. So I just want to sort of remind you -- I mean, Michael mentioned it already, but we got BTD back in December 2022 for adult kids acute leukemia, so ALL and AML, based on the Phase I data, right? So we presented the Phase I data for KMT2A types. We presented the Phase I data at the agency, they gave us BTD broadly. The data in the package, the pivotal data are entirely consistent, highly consistent with what we presented -- the data that we've presented, which form the basis of BTD. So we're pretty confident that's the context to which we've been working with the agency all along, and we feel pretty confident that would be the label what they would approve. And just a reminder, it's not -- this isn't with a precedent, right, the Jakafi, KEYTRUDA for MSI-high tumors, there is precedent for this kind of broad indication based on the underlying molecular biology of proceeds.

Okay. We are getting some questions from the listeners. So someone just curious, just in terms of the regulatory, what are the expectations? I mean you mentioned RTOR, so maybe this is not as applicable. You obviously have breakthrough, so you have a very close dialogue -- ongoing dialogue. But priority review, is that something that's formally up for discussion? Or how do you think about that?

Yes. Generally, when you go through the -- so let me start in a different place. In order to get into the RTOR program, you need to be -- first, you have to have breakthrough therapy designation sign. So that's the first step. Second step would be RTOR programs. 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 the molecule through development and through the regulatory process as quickly as possible. So we would expect that to be -- we would expect that to be part of the overall scheme here.

Okay. And then another important question which was discussed with the KOLs at your event and ASH last December. 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, do you want to make a comment there?

Yes, 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 trials conducted, which included the fact that patients were allowed to go back on maintenance therapy for lung transplantation. So obviously, we're not going to 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, are there the things that we should be looking out for there in terms of warning language that you might anticipate or not. For example, like the QTC prolongation, is that something that we should expect to see in the label?

Neil?

Yes. 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 -- whether you asking something about highlighted in the label...

Yes. I mean if it's going to 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.

Warning of precaution, don't anticipate the box warning if that's where you were going, 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, what does the market look like in terms of the KMT2A-rearranged patient population? What would be the expectations on your duration of therapy, at market access, things of that nature, that would be great as we move forward and get closer to the launch?

Anjali, do you want to take that?

Yes, sure. Thanks, Yigal. Always happy to talk about the great opportunity we have in front of us for KMT2A. 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 is 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 to 3 months. And so they are very eager to have an agent that can help bring patients to transplant. It is able to get 2/3 of late-line patients. We had in the trial a median of fourth- or fifth-line patients, 63% of whom responded with complete tumor clearance and physicians who are able to action on that. We had 60% of those responders that went to transplant -- were going to transplant before they achieved a CR/CRh even. So any level of tumor clearance and especially because such a high proportion of those clearances were MRD negative, they 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 and when we did that, they responded very uniformly trying to get all of their patients back on drug after transplant. And we anticipate that's what will happen in the post-approval setting. And so if you look at the way, again, in the trial of things pour out, we had 2/3 of patients respond, 1/3 of patients who did not respond. And if you break out of the patients that responded, about half went to transplant, 45% and 71% were put on therapy post-transplant. We anticipate -- we've seen in the data set that we're collecting in shared at ASH patients staying on in the post-transplant setting for over 3 years, and we've had multiple patients ongoing over 1 year. And 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. And so in that population that goes to transplant, we're estimating a median duration of 18 months. That's 1/3 of the patients. The other 1/3 of patients that respond, but don't go to transplant, we estimate they could stay on this median of 8 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 our second line, on average, after they've shown resistance or are refractory to intensive chemo, they could go straight to revumenib. And then we saw 1/3 of patients in the trial that didn't not respond, and we would anticipate they would stay on 3 months to know that they were not responders on average. And that gives you across those patients that are -- that we would be targeting about a 9-month median duration. The population of patients that would be eligible for this drug in the relapsed/refractory setting with KMT2A are rearrangements, is about 2,000 patients. So that incorporates both the AML and the ALL population that relapse and the price point here has already been set with the approvals of VANFLYTA, IDHIFA, TIBSOVO in the mid -- mid-30,000. I think they're all about 34,000 today. They take price increases. And with the data set 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 to $750 million for KMT2Ar alone in the U.S., relapsed/refractory setting.

And for the ones that went to transplant, they didn't receive revumenib what was the reason? I mean do you think that everyone should kind of 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 engraftment? What was the reason they didn't get it?

Yes, that's right, Yigal. And there's only about 3 patients that fit that category. And unfortunately, a couple of them did not have a successful transplant. We also had to 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 pretty much everybody elect to go back on therapy.

Okay. That makes a lot of sense.

And 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 and 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. In the 18 months, that's -- is that post-transplant or that's the total duration, just so I'm clear. I'm just could not understand.

Yes. It was to assume the total duration of therapy that patients could be on. Obviously, 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 benefit from therapy and be able to stay on treatment longer. So -- and in some ways, we believe this is a conservative estimate.

Because I remember when I asked the question at your event at ASH, I think they said, one of the KOL 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.

Yes. And we've heard as much as out beyond 2, 3 years because they don't want to 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 in the risk benefit of receiving this drug is so manageable that they don't see a reason to take them off unless they're progressing or have some issues.

Right. Okay. All right. Let's move on and shift a little bit to NPM1. So I think you said the enrollment of the pivotal cohort is you're guiding to sometime sort of towards the end of this quarter, 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?

Yes. Look, it's gone well. We're happy with it. And I think the guidance is, as you stated, we should be complete by the end of the first quarter, 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 robust and good. So we're happy where we're at with that.

And are you going to sort of follow a similar playbook in terms of how you release the KMT2A pivotal last year, a similar setup for NPM1, is that should that be the expectation?

Well, it's a little early to say how we're going to release the data. I think we expect to do it in the fourth quarter and how that lines up exactly is a little bit up in the air at this point, both magnifies and exactly what information will be available. But 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 2 cohorts that were put together with agency buy in there. But on NPM1, we'll have 64 patients -- adult patients, and there may be some pediatric patients as well. That'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 -- 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?

Yes. I think I was just alluding to that the differences between KMT2A and NPM1. So KMT2A was a bit of a special circumstance and that we had 2 different cohorts, both size the same 64 patients in AML, 64 patients in ALL. Under BTD, agency, as we talked about earlier, gave us a broad designation for covering adult and pediatric for KMT2A, whether they're AML or ALL patients. That allowed us to come up with an opportunity to pull the 2 cohorts together and do an interim analysis, which we hit on last year and then form the basis of our NDA. Little different for NPM1 in the sense that it's just AML. So we're enrolling the full 64%, and we expect to present that as our data package to the agency, but it will 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 said in the past that you wouldn't expect a difference in response necessarily, but 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 the 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, do you want to handle that one?

Yes, sure. Thanks, Yigal. Yes, Yigal, what we've been saying 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 gather more data in that population. Obviously, what you said is true, the NPM1 population being significantly older than the KMT2A and maybe considered unfit for transplant 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 CRp or CRi into a CR or CRh. So nominally, it's possible your CR/CRh rate could look slightly different. But I think generally, we believe the overall response rate is what's most important because it allows physicians to action on that response in the tumor -- full tumor clearance. And what we've seen so far has been very consistent across the 2 populations. So we anticipate it to be very similar whether there's a nominal difference, it's hard to know.

And while you have the floor, do you want to maybe just go through a little bit on the commercial side and talk about the opportunity. I mean, obviously, NPM1 is a 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?

Yes. 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 KMT2A is a vast majority are fit as they're on average, much younger population. In 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 if 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. The 2 standards of care therapy, I mentioned ven/aza and 7+3 are what they reach for initially. And many of these KMT -- NPM1 patients do have co-mutations, some of which are actionable like FLT3 and IDH. So they can combine with 7+3 and 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 we may be looking initially at more of a third-line population for NPM1 with some for the unfit population, maybe in the second line setting. But once they get to that second or third relapse, they really don't have anything. And so it does become much more similar. In terms of actual patient numbers, I think the NPM1 population starts off in the U.S., close to 6,000 patients with AML, let's say 1/3 of the AML population. And we anticipate by the third relapse you have about 3,000 patients that are in need of something to use to benefit them. And what we hear from our market researchers 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 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 2 forces that are posing you have the, as you mentioned, less fit and so they may be less likely to go to transplant. But then you also have a more challenging population. So they may work to balance out. I'm not sure. Do you think there'll be meaningfully different durability on an NPM1 or...

Well, we've seen the patients that have come into our trial actually have been very similar. The overall response rate has been about 50% so far similar to 63% within the [error bars]. The CR/CRh rate is upwards of around 37%, which, again, we feel like if the KMT2A population wasn't going to transplant as readily may have gotten there as well. And 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 in Phase II is 6.5 months. And again, with the numbers that we're dealing with, we don't think that's significantly different, and we anticipate 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 got quite a lot of time at ASH 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, the SAVE AML and the AUGMENT-102 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 menin to earlier line setting? And what will be the next steps to develop combo work?

Yes, I'm going to let Neil address it and just say a couple before he kicks it off. I think it's -- 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 and cobi], 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.

Sure. Thank you. So just general statement about all 3 trials before I get into some of the data. There are 2 doses of revumenib, the same 2 doses tested in each of the trials, 113 milligrams b.i.d., 163 milligrams b.i.d. this is for all 3. So starting with SAVE, which, as Michael mentioned, is a combination of revumenib with venetoclax, oral decitabine in a relapsed/refractory population, [indiscernible] conducted by the CISA that was reported out at ASH. And also we talked a bit about it earlier in the -- late last year, too. This is a very heavily pretreated population, right? So they had a median number of cryotherapies of 3, 1/3 of them had -- or more than half of them have failed part of venetoclax, 2/3 of them have been transplanted. And despite that, the overall response rate was 100%. The CRC rate was 78%, CRh rate was 44%. And all of the patients were assessable, only one patient was not assessable for MRD, all of them were MRD negative. So really quite impressive, just given the extent of cryotherapies and including transplant that these patients have failed. In terms of safety, there was really no new safety findings; myelosuppression -- specifically myelosuppression was similar to what you'd expect with ven and 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, 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 typical for what you would expect in that population. And we saw very robust data coming out of that trial, complete response -- sorry, CRC was 100%, CR/CRh was 85% and again, 100% MRD -- 100% MRD negativity. I should correct myself. It was actually -- the 100% MRD negativity refers to the BEAT AML trials. So one patient in the BEAT AML trial was not assessed for MRD, apologies for that. And again, in terms of the overall safety profile, the patients -- the safety profile was really consistent with what would be expecting only 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 102, which is a combination of revumenib with company-sponsored trial, a combination of revumenib with fludarabine/cytarabine in relapsed/refractory AML population. And again, very heavily pretreated median number of cryotherapies I think was 4. 50% of those patients have failed cryotherapy with [indiscernible]. And again, response rates were good, 33%, far exceeding what you would expect from just chemotherapy alone in this population, given the extent of the cryotherapies, which would be 10% or less. And notably, patients went to transplant. So there was, I think, a 33% transplant rate on that trial. And by the way, in the SAVE trial, it was a 56% transplant rate. So taken in totality, when you synthesize, Michael sort of referred to this a little bit earlier on, but when you take all of those data together, and this is -- it really confirms or begins to confirm that revumenib is combinable, right? I say it confirms the dose-limiting toxicity windows have been cleared. We're expanding the all 3 trials. So we're just now trying to get some more precision around what the RP2D would be with each of those combinations. But going back to something that was said earlier on, revumenib is extremely well tolerated as a monotherapy. We've had patients on treatment for up to 3 years in the post-transplant maintenance side. And now what we're seeing with these 3 combination data sets is that it's combinable, right? And it's combinable in a number of different populations newly diagnosed refractory with different backbones. And so based on that, I think you're asking where this brings us, right? Based on that, we're moving -- we're highly encouraged to move quickly to initiate a pivotal trial of revumenib in combination with ven/aza versus ven/aza in infant, adult and 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've -- we're about to initiate a combination of revumenib with 7+3 standard chemotherapy for fit AML population. Now so -- that will -- obviously, it's designed as a dose-ranging trial, but we're -- just based on everything that I was saying for the last few minutes in terms of the combinability with other standards of care, including chemotherapy, 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 where we are. I'm not sure if I left anything out I'll ask Michael or Anjali.

No, I think that covers it.

And I think -- no, that was great. I think just for those who may be less familiar with the story, these -- the studies that you're mentioning in combination in the frontline trial are those genotype agnostic? Or are you looking at specific populations? Can you just clarify so people clear...

Yes, thanks for the clarifying question. So I think for the fit -- the unfit -- the ven/aza will be primarily an NPM1 trial. We're talking -- we will probably allow KMT2A patients. But NPM1 is the more prevalent population amongst 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, we won't compromise the trial design. It will be powered around NPM1. I haven't really gone into detail. I don't 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. 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 the 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 our strategic -- our strategic focus is more in the direction that I described earlier.

Okay. Let's just spend literally a minute or 2 on menin outside of AML and ALL. You have a study in CRC. It's -- I think you've kind of built it as a signal-seeking study. 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?

Okay. Let's get one thing off the table. We're not doing in diabetes, right? We've assessed it, and we don't believe that we should be doing anything there. With respect to outside of solid tumor oncology in particular, you referenced the CRC trial that's ongoing. So just some background there. You have like pretty sophisticated audience. So I'm sure I probably don't have to give you guys this lesson, but 90% of colorectal -- the Wnt/b-catenin signaling is implicated in the oncogenesis in over 90% of colorectal cancers. And there were data published some years ago, indicating that disruption of -- or dislodgement of MLL1 from the Wnt/b-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 disruption of the signaling pathway that results in suppression of cancer cell of -- in vitro cancer cell growth -- colorectal cancer cell growth. And that really encouraged us to start the trial that you 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. And I think what we've said is that we provide an update by -- during the first half and probably later in the first half. I think that's what we said before. So what's the...

Okay. Sounds good. All right. So axatilimab, let's switch over to the CSF-1 access of the company. So again, big development with the filing of the BLA by your partner insight. I assume that's insights moves 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.

Yes, this will be a short answer, Yigal. So we did -- our 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 potentially get announced. But we don't have confirmation and how that will work, yes. So we have to work with our partner on it. And the acceptance window, 60-day window is pretty traditional on a traditional -- traditionally filed not under RTOR, but traditionally filed BLA. So that's a reasonable time frame. And right, so again, we'll be in close contact to 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 co-commercialization. Tell us about what kind of investment you're going to make in the commercial effort in terms of deployment of capital as well as personnel? And would there be any overlap with revumenib or no?

Yes. 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 roughly the same set of doctors. And so there's a great overlap between what we're doing with revumenib and what we're doing with axatilimab. That's -- that's precisely why it made sense for us to opt into the co-promote having 2 products in the bag versus one product in the bag. But these reps gives the opportunity for physicians to dialogue about the data more robustly. So I think that's -- 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 how we deploy relative to revumenib and the specifics there are will be -- are being worked out. But it's highly -- I would call it, highly synergistic targeting of physicians with 2 products.

Okay. Obviously, you're entering the space where there is a decent amount of competition as we all know, with some of the other products for GVHD -- chronic GVHD. So it would be great if you could just kind of give us the sales pitch as it were as to where you see the differentiation for axatilamab? And 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.

Yes, sure. Thanks, Yigal. So 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 meaningfully impact the disease, and that's what we're seeing in the trial. And unlike the other therapies, AGAVE enrolled patients who have had a median of 4 years since diagnosis, which is significantly longer than the 2 years and less was seen with the other agents. And had -- because of that much more severe patients with much more involvement across the most devastating manifestations like lung and skin. And yet numerically, we saw a very similar response rates across all organ systems. And impact, especially on some of these fibrotic systems. For instance, I think we showed a 1/3 of our long responses were complete responses, which had never been seen before. And I think that speaks very strongly to the benefit that axatilamab 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 we are seeing a strong reception from physicians that we talk to. And 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 ahead of REZUROCK or after any of these therapies because they're really -- this is a chronic disease as patients do cycle 2 therapies. They're not acutely dying like we see with the population we're targeting for revumenib and so there is an opportunity to access these patients at any point in their cycle. And 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.

Yes. I remember when we did our KOL checks last year, the comment was that it was a 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 or whatever all the other ones we're doing. I also got a lot of questions with regard to what Incyte is going to do with the combo with Jakafi, I guess it's not clear or they haven't spelled out in super detail. Are they going to try to go frontline, meaning real front line like before steroids? Or is this going to be Jakafi plus axatilimab after some initial attempt with steroids. Just curious or has that not worked out yet?

Yes. Anjali, you're unmuted, so you might as well take that as well.

I think 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 eliminate the utilization of steroids, but they will see steroids in the acute setting and 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're talking about the MOA, and think of fibrotic aspects, you are also developing with Incyte, the study in IPF, idiopathic pulmonary fibrosis what's the latest there as far as day timing and data?

Yes. It's a very exciting development for the molecule for the franchise. So maybe I'll let Neil touch on that as well.

Yes, sure. Thanks for the question. So yes, we're very excited. Anjali actually referenced some of the data that has us excited to go into IPF [indiscernible] which is the effect in chronic GVHD and lung. And in fact, not only from the AGAVE trial, but also from the earlier study as well. We've seen a 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 observed earlier. And the mechanism is a credible one, right, in IPS. And so the trial that we've -- is now active is a randomized Phase II trial. Target across 135 patients randomized 1:1. It's on the background of standard of care. So patients can be on [indiscernible]. It's a 26-week readout. And so -- and obviously, the endpoint is the effects on Fc, so slight rate decline or even improvement in Fc compared to placebo. It's a little too early to talk about timing. We just announced 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. There is a high level of enthusiasm actually in the investigator community, and we are making extremely good progress in terms of activating Incyte and so forth. But I just can't be too precise 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 2 assets we've talked about by licensing pathway. Are you thinking about bolting on new assets at this stage? Are you going to focus on the lease 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 a good financial condition. We said we have cash through at least end of '26. And so in terms of what we can do, and obviously, what we're working on, we have a [VAS program, 2 VAS] 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 being in the fortunate position to have these 2 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 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 2 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.

Thanks, Yigal.

Yes, thank you, Yigal. Have a great day.

You, too.

Bye-bye.