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

Okay. This is Yigal Nochomovitz. I'm one of the biotech analysts at Citi. This is the continuation of our Virtual Oncology Summit in February. It's my pleasure to have with me from Syndax Pharmaceuticals, members of senior management including none other than Michael Metzger, the CEO; the CFO, Keith Goldan; and Briggs Morrison, President, Head of R&D. So gentlemen, thank you so much for taking a few minutes out of your schedules to chat. We really appreciate it.

Maybe, Michael, if you wouldn't mind, just for those less familiar with Syndax, just to give us a quick elevator pitch, 2 or 3 minutes just highlighting the focus of the company, your key objectives, the key programs and some of the key catalysts that you're anticipating for the balance of 2023.

Sure. Thanks, Yigal. Thanks to you and the Citi team for inviting us today. It's always a great opportunity to speak with you and share our thoughts on the company. I'd like to just start off by saying we're in a really unique position today. Syndax is advancing 2 pipeline agents. We're in ongoing pivotal trials with data and potential regulatory filings in 2023, potential approvals down the line in '24. So a very exciting time for the company as we look to transition to a fully integrated commercial stage company. But before we get to that, we'd like to talk a little bit about both of our assets, which are poised to be both first-to-market and potentially best-in-class targeted medicines within the [ heme ] space and address -- addressing multibillion-dollar market opportunities. What we're, first and foremost, probably going to spend most of the time talking about today is our Menin inhibitor, which will be the first -- we believe the first Menin inhibitor approved. It would be the only 1 to have 2 indications, specifically KMT2A and NPM1. We're talking about relapsed/refractory acute leukemia. And these are 2 specific areas of acute leukemia that we're focused on in this agent. And so our best assessment will also be first-to-market for NPM1. So really exciting agent for that -- for these patients who have a high unmet medical needs. The second agent, we'll talk about today is axatilimab, which is the first-in-class monoclonal antibody targeting CSF1 receptor, essentially no competition on the effectiveness for chronic graft-versus-host disease, again relapsed/refractory disease there as well. Longer term, we're excited that both of these programs offer potential for very broad franchise opportunities beyond these initial registration indications that we just described. We're also well capitalized. The company raised $172.5 million at the end of last year, which brings us to roughly $500 million of performing cash as of today. We'll be able to deliver with the balance of -- cash on the balance sheet, be able to deliver significant clinical and regulatory milestones, launched both of these products as described and also execute on selected business development transactions, which, as many of you know, is the basis of our business model to bring in additional molecules through licensing or acquisitions and that would be the early pipeline... Overall, very exciting time to be at Syndax is the part of the story [indiscernible].

Michael, we lost your audio.

Sorry, can you hear me?

Yes. Maybe go a little closer to the mic.

Sorry about that. We expect to have a really exciting year as we get these advances molecules towards approval. Okay. Maybe I'll pause there and hand it back to you, Yigal.

Sure. Okay. Well, let's obviously start with Revumenib. What are the specific objectives for this year? What are the specific milestones in terms of data and development there?

Well, you have to interrupt me if I lose my audio again, but let me start with AUGMENT-101, which is...

I'm just wondering -- Mike, I'm just wondering, maybe if you turn off your video, it might help with the bandwidth, that's -- sometimes that's an issue, if you don't mind, sorry.

Not at all. Hopefully, that helps.

Yes.

Okay. So where I was -- starting as AUGMENT-101 which is our pivotal trial, and I'll start with that. So this is our pivotal trial enrolling our relapsed/refractory adult and pediatric patients. As many of you know, this is 3 -- it comprises 3 separate trials, KMT2A AML, KMT2A ALL and NPM1 AML. 64 patients, adult patients and up to 20 -- sorry, 20 pediatric patients in each of these separate trials. And each of these trials could serve as a separate regulatory filing supporting approval. In terms of timelines and milestones. The first of the 3 trials will be enrolled by the end of the first quarter of this year, with top line data coming in the third quarter and the first filing in the fourth quarter of 2023 this year, and then approval in 2024. And just a reminder, we've not yet guided as to which of 3 of these trials will enroll first. Then, we think more broadly about the development program, so that was relapsed/refractory disease and our potential of first approvals. We move on to what we're doing in the frontline setting with Beat-AML and INTERCEPT trials, I'll describe those. And then I'll come back to what we're doing with AUGMENT-102, which is a relapsed/refractory trial. First, BAML is an umbrella trial in collaboration with Leukemia Lymphoma Society. It's part of a collaboration that Revumenib, really the first Menin inhibitor be included in the trial to be combined with venetoclax and azacytidine in newly diagnosed, in outpatients who are unfit for induction chemotherapy. The trial was a safety as well as initial efficacy. Initial data from this trial will be available, we expect by the end of the year. In terms of the INTERCEPT trial, the trial designed to explore the activity of Revumenib patients with AML who had MRD-positive disease, and it's being run by the Australian leukemia and lymphoma group, and it's now enrolling patients as well. In the trial, we will enroll patients with measurable residual disease progression following initial treatment. And as many of you know, that's a group of patients with very high risk of relapse, and it represents a very important unmet medical need. And then lastly, the AUGMENT-102 trial is designed to assess the Revumenib combination with standard salvage chemotherapy and it's a regimen typically used for pediatric patients, although adult patients may receive it as well. And this is geared towards relapsed/refractory ALL and AML, and that trial will have initial data in the later part of 2023. So those are 3 really important trials. We are looking at some additional trials as well, which we cannot get [indiscernible]

Okay. So just to clarify, so for AUGMENT-101 with the 3 cohorts, that's 64 in total, correct?

64 per arm. So there are 3 separate arms, right? So there's 2 KMT2A arms, 1 for AML, 1 for ALL and 1 for NPM1 AML. Each of them have the same amount of patients, right, 64 adult patients, up to 20 pediatric patients. They enroll separately. In fact, all 3 of those trials are enrolling in each of our centers worldwide. So they -- each of them can be sufficient for potential approval in those indications. And as I said, they're all enrolling now, and we'll have the first of the 3 fully enrolled by the end of the first quarter, data in the third quarter and then a filing -- first filing by the...

I actually just got an e-mail question from an investor. I think -- just to clarify, so I think you mentioned that you're attempting to be first-to-market in NPM1. So the question I got was just in terms of prioritizing enrollment for those 3 cohorts, which is why I was asking about that earlier. Are you prioritizing the NPM1 AML cohort in terms of enrollment for AUGMENT-101? Just -- I think the question basically is where would we get data first with MLLr or with NPM1?

Yes. It's a good question. I don't think we haven't done as I was mentioning earlier, we haven't guided yet to which of the -- whether it's KMT2A or NPM1 will enroll first. All of them enroll separately. And so they are -- you can think of them as separate patient populations enrolling at each of our sites. So there's no particular priority between the 3. I would say that [ we're in the all ] equally opportunistic and we can have patients flowing into each of the 3 arms.

Okay. So just to clarify as well. So the top line data in the third quarter for all 3 or just not necessarily all 3, just -- could you just clarify?

Right. We said the first of the 3.

First of the 3. Okay. And then filing in the fourth quarter, so that's interesting because that's quite a very efficient turnaround time to have the top line in the third quarter and file in the fourth quarter. So could you just expand on that because that's fast.

Yes. I know, I think -- look, I think -- the way we think about it, timeline is -- we follow these patients for 6 months following last patient, last visit. And so that gets us into some time in the third quarter. And turning around quick filing and putting the filing together by the end of the year, I agree is efficient, but we think we will.

Okay. And then you talked about some of the other trials, the beat-AML, the 102 and INTERCEPT. What about -- do you think you're going to go into first line for Revumenib at this point?

Right. So the beat-AML trial is a frontline trial. That's an initial safety portion of that trial, but it's looking at patients that are unfit for chemotherapy consolidation and instead are getting Ven/Aza as generally standard of care. This would be a combination with Ven/Aza, to see if we can improve on average. So that is, in fact, of 1 frontline trial that is starting or has started and we're enrolling patients. And then there -- from the fit population, generally, those are patients who get 7+3 consolidation treatment, and that is a large -- slightly larger population than the unfit population, and we'll be looking to put a trial in place sometime in the near future.

Yes. Sorry, I should have been clear. I was referring to the fit patients. But nonetheless, with beat-AML, so if that was positive or productive, I mean, would you then need to run your own study or -- would that be enough to move forward with the drug application?

Yes, it's -- the way it is designed, it's Phase I [indiscernible] Phase II/III. So that Phase II/III could serve as a potential regulatory filing. And that's something that is an open option to us. We could additionally do company-sponsored trial as well. So there's some options open to us, but that -- the design is such that we have the opportunity to go into a registration trial following the Phase I.

Okay. Well, I'm getting a lot of very specific questions from investors, which I guess is great. There is a lot of interest on axatilimab. Let me see here. That's -- we'll come to those later. Okay. We'll get to that later. So I think you answered the question about the prioritization. In terms of efficacy metrics. So what should people be expecting in terms of how to think about the bar for 101 relative to what's already been disclosed based on the Phase I data at ASH last year.

Right. So look, I think, the ASH data set was rather robust. As you recall, has a 68 patients, 60 of whom have the -- either KMT2A or NPM1 mutations. I think the idea here is that, that data set kind of 30% CR/CRh rate was very competitive with other targeted therapies. I think the bar -- we will be talking about the bar on -- there's bar of approval, which obviously is the regulatory bar where you've seen drugs, other drugs be approved that were within the AML space with a CR/CRh rate of about 20% and a median duration of response of 4.6 months at the low end, all the way up to roughly 30% CR/CRh rate as well as 7, 8 months of median duration of response. And I think what we've shown at ASH, 30% response rate and median duration of 9.1 months was very competitive with that. And certainly, to be first or best-in-class, we think this is representative of such a profile. So I think the idea, the hope with Phase I being with rather the Phase II pivotal trials being similar in inclusion criteria and protocol to what we had in the Phase I in terms of having a certain number of patients as well as the demographics and so forth that were going to be including Phase II, we expect we should have similar results as what we've seen in the Phase 1. One key difference being that patients who have received a stem cell transplant and -- following treatment with Revumenib have the opportunity in Phase II where they didn't have necessarily opportunity on protocol to go back on Revumenib, which could extend the median duration that we see in these patients in a pivotal trial. So that's one. I think, an important difference that we may see in the trial that could lead to slightly better results. But ultimately, we think that the -- not only is the bar achievable, regulatory bar, but we think the bar that we've set with our efficacy, safety as well as median duration response is quite competitive. It should be really strong for us in...

Actually, that's interesting. That was my next question. So if they go back on after transplant, I mean, obviously, that would be great for the commercial. But in terms of how does that work in terms of counting duration? Is it just basically gets tacked on at the back end? Or how does that work from a data capture perspective?

All right. So patients are not censored for transplant. So the way it works is that we follow patients to relapse. So in terms of -- they have treatment, they go on treatment, they stay on Revumenib. At the time of relapse, that's their -- that's the point where they come off trial, that's time of duration. If they have a transplant during that period of time, they are counted as not relapsed yet. So they're still in remission. And until they -- whether they go back on therapy after they've been grafted and transplant or they just stay in remission, that's all considered part of the timeline for duration response.

Not to be too specific, but I guess I'll ask. I mean when you do count it, do you count the intervening time when they're going through the transplant as part of the duration or that just you don't count that time?

You do count that -- That's included in the time of the duration.

Interesting. Okay. Very interesting. All right.

By the way, that's included as part of the guidelines, the FDA guidelines that talk about how to score -- remission score duration response.

Okay. And then I guess, more just of a biology question. I mean obviously, as you already highlighted it, in KMT2A and NPM1, I mean the CR/CRh responses were very, very similar at the recommended Phase II dose. Is that consistent with your view and understanding of the biology in these 2 different mutational subsets that they would be similar?

Sure. Maybe I'll ask Briggs to jump in. Take that.

Yes. Short answer to that is yes, Yigal. You may remember when we started the clinical program, our hypothesis all along was that the activity would be roughly the same in KMT2Ar, used to be known as MLLr and NPM1. And you may remember when we first started the program, people used to ask us a lot about NPM1 because we didn't really understand at the molecular level exactly how Revumenib worked in NPM1 disease, and I used to joke that there's post-docs and graduate students all over America trying to figure it out. Well, they've made a lot of progress. And there's actually been a couple of very nice papers come out -- came out last year, which now shows us in more detail the molecular mechanisms of why Revumenib works in NPM1 disease. So at the beginning, we thought they were going to be roughly the same. The clinical data is showing us that they're roughly the same. And the science has now progressed where we really understand why they're roughly the same.

Okay. And another question we get a lot covering the stock. Just with respect to the -- how to think about the MRD negativity endpoint in conjunction with sort of a CR/CRh type endpoint. So what is the -- from the clinical perspective, how much do docs care about the MRD negativity and then going beyond that and getting the CR/CRh?

Briggs, do you want to take that?

Yes. Sure. So remember, just to clarify that we talk about overall response. So overall response is basically when you repeat their bone marrow, do you see any leukemia in the bone marrow. And so that's the overall CR rate. The CR -- whether you call it a CR or a CRh or a CRp or an MLFS that all has to do with what else is going on in the blood count. So a full CR is, there's no leukemia in the bone marrow and their blood counts are normal. A CRh is, there's no leukemia in the bone marrow and their blood counts are at least half normal. A CRp means that your white count has come back, but your platelets are not yet normal, and a CRi is the opposite of that. So those are all sort of clinical ways of scoring how the patient is doing. The FDA has landed on CR plus CRh, essentially because they're saying if you have no leukemia in the bone marrow and your blood counts are normal or if you have no leukemia in the bone marrow and your blood counts are half normal, you're basically in good shape. You're not going to have bleeding, you're not going to have infections, you're not going to need transfusions. Clinically, you're doing well. MRD negativity is a different way of looking at this, and that's when we take the bone marrow, we look and say, is there any leukemia left, you can look under the microscope and that's the standard. So standard CR means by microscopic analysis, there's no leukemia, but there are more sensitive tests. And these more sensitive tests can look for -- at a much more -- specificity is much greater for -- are there any leukemic cells. The reason that physicians use that is primarily to see how deep is the response. So if I look and I see no leukemia under the microscope and I do a really, really sensitive test, and I still don't see any leukemia, that means I've gotten a very, very deep response, and that's what I think when you hear Dr. Stein talk about our -- the clinical implications of our data at various sessions we've had with him. He points out, it's uncommon for these target -- the previous targeted agents to give you such deep responses. That's why we emphasize the MRD negativity. The other point around MRD negativity is it's been well demonstrated in multiple studies that if patients go to transplant, the ones who are MRD-negative do much better than the ones who are not. So if you have a CR under the microscope, and you're MRD negative, those patients tend to do much better when they go to transplant. MRD negativity is not a regulatory end point in the construct that we're applying, but it is quite important to the physicians to say how deep is the response they're getting from our drug.

Okay. So it's sort of a different metric. It's not necessarily -- is it an even higher standard or that's not the correct way to think about it?

I think it is the correct way to think about it because it's -- so as you saw of our CR/CRh patients, about 80% of them have MRD negative. Some of them don't. And so it is a higher standard of I've gotten -- I've really, really gotten rid of the leukemia and the blood counts have all come back to normal, that portends a good outcome for the patient.

We're getting more questions from the clients. Another 1 on transplant, I just -- someone's asking about can you just kind of comment briefly how long does the actual transplant take and the sort of the percent of time on drug relative to the starting of therapy to the time you eventually come off. I mean there's that period where you're not taking the drug when you're doing the transplant where you are -- where it's still counted as you mentioned, Michael, but I'm just curious, how long does the transplant part actually takes? People can understand the true time on drug.

Yes, Briggs?

Yes. So again, a bone marrow transplant is essentially intensive chemotherapy and then a reinfusion of bone marrow from a donor. So there's a relatively short period of time, maybe 4 to 6 weeks where the patient is waiting for those blood counts to come back to normal from the transplant and then they go back on drug. So it's -- vast majority of the time, they're on drug.

And then another question just related to duration of response and the potential for that duration to be even better in the phase -- in the pivotal versus the Phase 1. So if you -- I don't know if you talked about the specific slice of the analysis, but for the patients who were able to go to transplant under the adjusted protocol in the Phase I, if you just look at those patients, what was the duration of response for them?

Right. Well, just to clarify. So the patients were went to transplant in the Phase I were not able to go back on drug during the Phase 1 period. We did do some -- we were able to get new capacity to use some patients -- the ability to get back on drug post transplant, but the vast majority we're not able to accommodate that way. So the Phase II portion of the trial was set up in order to accommodate that. So these patients were able -- if the physician thought they were -- and they had a donor ready to provide, they were able to go, get their transplant and then go back on drug thereafter. That will be something that the experience will see in the Phase II. Obviously, we haven't seen [ that data. ] Sorry, and the rest of your question?

No, no. I think you answered it. Okay. That make sense. And then sorry, there's so much interest from the investors. So these are some more questions. Someone is curious about breakthrough designation. So for NPM1, once you have more than [ 20 ] valuable, would you potentially be seeking that BTD designation?

Yes. Look, it's possible. I think we generally don't comment on our regulatory status on where we are with things. I think the idea being -- I think the person asked the question how to write, you need at least 20 patients and you need sufficient follow-up on those 20 patients. Obviously, we didn't have that in the Phase I experience. We only had 11 patients, NPM1 within the Phase I. Obviously, we'll have more than that, we will have sufficient number in Phase II. But that's an ongoing trial, and so we'll have to see where we are, when we can apply for that.

Okay. Okay. So that would be at least [ 20 ] at the RPTD.

Correct.

Yes. Okay. Makes sense. And then this is a complicated question here. I guess you've kind of talked about this already in terms of the ordering. We don't know exactly which -- you're not prepared at this point to sort of say what the order of events would be in terms of approval in KMT2A versus NPM1 at this point in time. Is that -- that's correct?

Yes. That's correct.

I guess someone is trying to ask about -- okay. But what about guidelines and -- NCCN guidelines, just talk about more generally how that part is going to work? And when would you be seeking that type of validation for both for KMT2A and NPM1?

Briggs, do you want to dive into that?

Yes. So look, I think, Yigal, we have, as Michael walked you through 3 pivotal -- essentially 3 parallel pivotal trials, MLLr AML, MLLr ALL and NPM1c. As each one of those reads out and we have a database that informs the benefit risk of the drug in those particular populations. That's when we would think about engaging in the NCCN guideline process. As Michael pointed out, the Breakthrough Therapy designation was for KMT2Ar, all encompassing, independent of whether it's AML or ALL, adult or peds. So obviously, if we were to get that type of an indication, we could approach the NCCN guidelines process with that data set.

And I know, I know, I know I keep coming back to this, but I know you can't commit to the order of events at this point, but do you think that there might be a point later in the year, maybe in the summer, where you'd be in a position to provide a little bit more clarity on which cohort or cohorts would be appearing first in terms of data for the third quarter?

For sure. I think as we move into a little bit further into the year, I think we'll have -- we had said that we'll have the first of the 3 enrolled in the first quarter, right? So I think you'll start to understand what the order of events will be based on reveal of which is the first.

Okay. And then maybe just comment a little bit on the -- we talked about efficacy quite a bit. But on the safety tolerability side of the equation, just talk about how you see your drug competing in the Menin space on some of the key questions on safety, obviously, QTc and differentiation syndrome. How are you feeling about that?

So it's really a long. I think, a very safe and tolerable drug to date. There is, as you pointed out, differentiation syndrome, which others have seen in their programs. We've seen it, too, Grade 2, but not anything higher than that. And it's something that we manage with steroids and hydroxyurea and it's essentially very manageable and identifiable by a physician. It hasn't manifested to anything more serious. With regard to QT. I'll just go back and say that it's -- we've -- none of these patients have discontinued because of QTc prolongation. We haven't seen any arrhythmias or anything more serious, just odds that physicians would necessarily get concerned about. So this is asymptomatic QTc prolongation, which I'll also point out that many physicians who treat these patients have seen with other drugs, so this is not an unknown side effect of therapy, but it's one that is very manageable. Identifiable, manageable and reversible to a point where it doesn't matter, and patients actually don't know that it's happening. So overall. I think the safety and tolerability of the drug is quite good. And it's allowing patients to stay on for multiple cycles and do really, really well.

Okay. Got it. And you had another question from an investor on your filing strategy. Someone was kind of curious in terms of just the -- again, going back to the order of operations, since these data sets might come in sequentially, is the plan to file whatever -- whichever one comes first, whether it's KMT2A, AML, ALL or NPM1, AML file on that one first, and then the others follow suit as sNDAs? Or would this be different and be more of like rolling submission where they're all going to -- where when you get the first label from the FDA, it will encompass all 3 populations?

Yes. Briggs, do you want to jump in on that question?

Right. So because we haven't given you the -- which ones first, as Michael said, I'll answer it more in theoretic terms. So if all 3 were to enroll -- be done enrolling and all 3 were filed at the same time, then we could get a label for -- that the broad came to a population and NPM1 all at the same time. If one of the populations completed materially earlier than the others, and we decided to file that one then the subsequent ones would be sNDAs as you point out.

Okay. That is very clear. Okay. Let's see. Just a little bit on that -- we'll move to GVHD in a second. But in terms of Revumenib, I know you've done some initial work in solid tumors. So can we talk about that, Michael, a little bit in the strategy there?

Yes. So I think we had announced that we are initiating a trial in colorectal cancer or metastatic colorectal cancer and this is something that we felt that there was some recent really good science published that shows that the mechanism of action of Revumenib could have an impact on beta-catenin -- patient heightened, augmented beta-catenin, patients who -- that could be colorectal cancer, it could be other forms of cancer where beta-catenin pathway is upregulated, and so I'll ask Grace to go a little bit more into the depth of the science here. But essentially, this would be a signal-seeking trial, 20 to 30 patients, and we hope to get some initial data this year. This is a patient population that is unfortunately rather large in a metastatic colorectal area of 50,000-plus patients, high unmet medical need. A couple of approved agents that don't have, I'd say, a good track record of success. They're approved, but they don't have, really, a disease -- good disease control rate. It's somewhere in the 10% to 15% as well as, I think, the -- poorly, they are not very well-tolerated. So I think the opportunity for revumenib is to have an impact and we're looking to see if we can, not only see some early responses in this population, but also perhaps even stable disease, which, as I mentioned, the disease control rate is low. So bar of response somewhere in the 10% range or higher would be -- actually be meaningful in this population. So we'll be looking at that small number of patients to see if we see a signal. Again, it's not the main thrust of our program, but it's something that if it were to be successful, then we would follow along with additional Phase II and phase -- potentially pivotal trials, but that's a ways off. Right now we're focused on seeing if there's an early signal, and then we'll follow up with additional work there. But it's potentially an exciting area of science that could lead to other solid tumors. And naturally, that's a big expansion of this drug beyond what we're doing in leukemia. Maybe I'll ask Briggs, do you want to touch on the science, Briggs?

Yes. So again, just briefly, Yigal, I mean, I mentioned earlier that we've now learned a lot more about how menin inhibitors work in NPM1 disease. So it turns out that this mutant form of NPM1 acts in the nucleus. It sits on the chromosome and turns on a cancer gene transcript profile that's very similar to what you see with the fusion protein. It's quite interesting that in colorectal cancer, it seems to be a very, very similar story, except it's not NPM1 that is sitting on chromatin and turning on a gene transcription profile, it's beta-catenin. But still seems to be dependent upon the menin-MLLr interaction just as NPM1 is. So as Michael said, we're testing to see if that translates in the clinic. If it does, if we see the same kind of clinical activity in colorectal cancer that we're seeing with a menin inhibitor in NPM1 AML, where roughly 1/3 of the patients are getting these nice responses, I think that will be really quite significant for the patients with colorectal cancer. So we're in the early stages. We don't know if it's going to translate, but the science is actually very similar to the story around NPM1, and that's why we thought it was important to explore in the clinic.

Okay. Let's -- great. I want to make sure we get to axatilimab since that's a very interesting program, which I don't think gets enough attention. So let's talk about the mechanism, the CSF-1 mechanism. How is this differentiated? And how could axatilimab change the treatment paradigm for the chronic GVHD?

Right. So thanks for spending some time on axatilimab. We do think this is underappreciated as a program. And I think that's an exciting place for us to focus on time. And certainly, this is a module, which we've had really some very nice data come out of NASH, not this past year with the year before, Phase I/II data that really set up the profile as potentially differentiated from the other approved agents. And I'll say that the -- just starting with the mechanism. It's focus, the CSF-1R antibody, focused on the macrophage monocyte niche. And so if you think about Rezurock, the newly approved agent and launch agent from Sanofi or Jakafi, which is Incyte's drug, our partner. These are agents focused on the B cells and ours focused on the monocyte and macrophage and the influence at this state. What that means for us is that this is really a mechanism that is fundamental to the fibrotic process and our ability to interrupt that process really has -- could have a profound effect on the chronic graft versus sort disease that we see in these patients. It's a multi-organ disease. So you see manifestations in things like the lung and the skin and the eye and esophagus and GI tract and so on. And so the ability to treat multiple fibrotic organs is something that we believe this mechanism could potentially do. And we've shown those effects in our Phase I/II trial, which I mentioned just a minute ago. So I think the idea that this is a distinct mechanism, potentially combinable with these other standard of care agents could be very meaningful. And again, this is a drug that we're looking at third-line plus chronic graft versus host disease for our first approval, potential approval. The ability here is to maybe move up line into combinations with Jakafi, for instance, which there'll be a trials starting this year to look at how do you certainly bring down the utilization of steroids, which is first-line treatment but has its side effects and drawbacks for a longer term. So I think the idea here is can we fundamentally change the treatment paradigm, not only with the new mechanism in relapsed/refractory disease, but also in combination moving up line and offering patients earlier intervention that could really help their disease.

Okay. So AGAVE-201 is the Phase II pivotal that you're undertaking currently. So just -- can you just review the design and so everyone is clear, what is -- what should be the expectations for what would be defined as success in that trial?

Sure. Briggs, do you want to jump in on that one?

Yes, sure. So again, just to remind folks, AGAVE-201 is a randomized trial where patients are randomized to 2 different doses of axatilimab that are administered every 2 weeks and 1 dose that is administered every 4 weeks. So it's, either 0.3 or 1 every 2 weeks or 3 mg per kg every 4 weeks. These are relapsed refractory chronic GVHD patients, similar to what we enrolled in the Phase I/II trial. And again, the top line data, the middle of this year. I think, again, from your question, Yigal, about what is the sort of the efficacy bar here. We presented, I think, some -- and published very nice data from the Phase I/II program, which showed a very nice response rate in this patient population. Competitive with other agents that are in this space, and Michael can comment more about that. But I think if we were to see efficacy and safety in AGAVE-201 that parallels what we saw in the Phase I/II experience, I think we'd be quite excited about that, and we think it would provide a quite nice alternative mechanism, as Michael pointed out, for the treatment of these patients.

Okay. And then it's interesting, I think -- did I hear you correctly, so 0.3 mg every 2 weeks, but 3 mg every 4 weeks? So just talk about the -- that's interesting. It's an order of magnitude higher, but…

Yes. So there are 2 doses every 2 weeks, 0.3 and 1, okay? And remember, the 1 mg per kg was what we did the Phase II expansion, the data that we presented was sort of this Phase I dose escalation and then a Phase II expansion. That was at 1 mg per kg every 2 weeks. If you think about -- if you're going to go every 4 weeks, a direct link from 1 mg per kg would be instead of 1 mg every 2 weeks, you'd do 2 mgs every 4 weeks. Based upon the Phase I data, we thought we might need to go a little bit higher. So that's the 3 mg every 4 weeks. So it's a -- we're looking at that just as a potential -- a little easier regimen for patients instead of coming in every 2 weeks.

Okay. And then one question we're getting online is, how do you -- how are you doing the statistical analysis when you analyze here the 3 different doses? How does that part work in terms of, like, is there an alpha split on the different doses? Or is it not? What have you got?

No. Essentially, each one -- statistically, they're sort of -- each is -- they're like parallel arms. As long as an arm beats what is the presumed null hypothesis, then that is a -- and has adequate safety, then that is a potentially registerable dose. And so there's no not a -- it's not powered between dose comparisons. It's really each dose compared to its null hypothesis.

Okay. And then just going back to my question around the dose scaling relative to the time frame as you were talking about. So the Phase I data is, correct me if I'm wrong, but apparently the Phase I data suggests that actually the 3 mg per kg every 4 weeks may actually be less effective than the 1 mg per kg every 2 weeks. Is that true? And if so, how does that translate into thinking about the Phase II?

Yes. I wouldn't -- I think the numbers are kind of too small to make any strong conclusions between the doses. That's why we're doing an official dose-ranging trial where we studied enough patients at each one. So I do think there was also a little bit of a trend that we might see a little more toxicity with the 3 mgs. Although you're giving it every 4 weeks, you are giving 3 mg per kg on that day of dosing. So that's why we're looking at this range of doses as you pointed out. It is a nice range and I think we feel very comfortable that within that range, we're going to find a dose that gives a very favorable benefit risk for patients.

And should the Rezurock response rate in GVHD, I think it was 75% at 200 mg QD through the cycle 7 in their trial, is that a benchmark that is relevant here? Or should we not be thinking about that as a benchmark?

Yes. I mean, it's 1 benchmark. I think there's -- Jakafi was, I think, in the 50% range or a little higher than that. So I think in our data, it was around 70% -- 68%, 70%. So it's -- we're right in that zone. And I think that's -- those are all really good results. The key to this population is obviously efficacy and tolerability. Patients tend to -- none of them are curative treatments. And so you tend -- patients tend to see 1 after the other. They get sequenced. So -- and there's really no set paradigm for how these patients are treated after the front line. So in other words, we've seen, in our trial, in our Phase I, we had a handful of patients who actually had seen Jakafi and also Rezurock before coming in our trials. We expect that in the real world that -- in which our drug gets approved, that it will have utilization in the third line plus, but it could work out where the patients -- if they have certain manifestations or the experience and such that physicians become comfortable, it could be used earlier as well. So there's -- the fact that these patients go from one to the next over their sort of 5-year average survival time during their chronic graft versus host disease journey, I think that's a reasonably good setup for multiple drugs doing quite well in this space. And as you've seen the Sanofi drug, the Rezurock drug has done very well in its first year of sales. I think roughly $200 million to $250 million of first year of sales. So I think this is -- when you're talking about benchmark of where they are efficacy-wise, I think that's important. That whole -- that range that I just mentioned, but also the safety, tolerability and ability to stay on therapy. Again, we are treating really, really happily pretreated patients and they are doing quite well. So I think all of that needs to be kind of factored in.

Okay. And lots of questions on axatilimab, which is great. What about secondary endpoints? How important are those to the value proposition? And I believe you also are working on a subcu version, where does that stand?

Yes. Briggs, maybe you want to comment on the secondaries and then we could mention about the subcu.

Yes. Look, I think it is a complicated disease. So some of the other things we're looking at are can we taper off the steroids in patients as they respond so well to axatilimab. I think that is -- as we've talked with physicians, that's a critical factor. Steroids are the mainstay of the treatment of this disease and yet they have their toxicity, so to be able to lower the dose there. I think the quality of life instruments that are used in this disease are also quite informative to practicing physicians. So we have a suite of secondary endpoints that will help round out the characterization of both the benefit and the and the tolerability of the drug. And Michael, I'll let you take the other question.

Right. So on subcu, I think we haven't said much about subcu, and I'm not going to say much more here. I'll just say that it is something that is something that we're considering with our partner. I think the idea is that this is an IV infusion. As Briggs pointed out, the regimen is, either once every 2 weeks, or once every 4 weeks depending on dose. But I think this is, again, a very well-tolerated agent and physicians, specifically in chronic phase of their disease, seem to keep a very close eye, high-touch patient interaction. And so the patients tend to be in the office relatively frequently. And so this regimen doesn't seem to be anything other than, let's say, manageable and immediate for patients. And so I think that's something that doesn't really factor in much. I do think the subcu, as we've looked at -- we're looking at a 4-week dosing regimen and subcu could potentially add to the -- continues down the line. But we feel quite strongly that this is a very manageable, easy-to-administer regimen.

What about some of the -- there are some oral CSF-1Rs, I believe. There's a company called Abbisko. Any thoughts on that in terms of competitive positioning? I believe they're working in GVHD, and they also had a breakthrough in a tenosynovial giant cell tumors.

Right. So as you know, the CSF-1 is not an undiscovered mechanism. Obviously, we're not the first to pioneer and we are the first to pioneer it in chronic graft versus host disease. I think the effect that we have an antibody versus a small molecule, so our molecule is very clean, has a profile that we think is uniquely suited to hitting the target and also maintaining patients. So that's, we think, unique to antibodies, such as ours. I think small molecules may have a little bit more difficult time dosing patients and deriving the type of efficacy and safety that we get with our molecule. So we're obviously well ahead of the field. There -- its success -- sometimes you have competitors, and that's okay. But we feel like our molecule has unique benefits and unique attributes that position it well versus the competition.

And then also, just in terms of approvability and the strategy there, would you go for accelerated approval here? Or, like, full approval? I believe Rezurock got a full approval. What's the…

Yes. No, it's a full approval file. So this is, as you pointed out, Rezurock was approved with a full approval as well as the other agents. I think the idea here is that this is a trial that's, in a lot of ways, very, very similar to what Rezurock completed a few years ago. So I think based on guidance, based on our interactions with the FDA, this should be a bullet-proof.

Okay. And then just to bring Keith into the conversation, maybe just a quick recap of the financial strength of the company and the runway and how you're thinking about capital needs going forward.

Yes. I'll just -- Michael touched upon it in his opening remarks, but I'll just recap that. On a pro forma basis, we had $500 million on the balance sheet at $930 million. Our -- we'll update that number, obviously, in our 4Q earnings, which is upcoming. We gave guidance that, that $500 million pro forma was good to get us into the -- or sufficient to get us into the second half of 2025. So combining that runway with the milestones, clinical, regulatory and commercial that Michael has been reviewing for the past hour or so gives us confidence that we have enough cash to execute against our business plan, achieve all of the upcoming catalysts milestones that we have in front of us and get us a year-plus past and expected launch date.

Okay. And we have a little more time. So Michael, just to close out, talk a little bit about what are you doing on the commercial side at this point. How far have you gotten in terms of thinking about how you would develop a launch strategy for revumenib. Are you -- and then second, what -- is there anything going on in terms of bringing in additional assets? Or you got your plate full? And I guess the last question is, what is the 1 thing you think the Street is missing here in terms of understanding Syndax?

Yes. And it's probably 3 or 4 questions in one. So I think, look, we're very busy this year. I think we're hiring incredible talent at Syndax. We've really put together a great team to execute on both of these first and best-in-class agents. In terms of commercial organization, where we hired our Chief Commercial Officer, Steve Sabus, he'll be helping to expand our commercial team. It's a very focused effort in leukemia. We do have 2 agents on the axatilimab program. It will be led commercially by Incyte, our partner. We have the opportunity to collaborate there, "out," and we'll make that election closer to the approval time line. But essentially, it's roughly 40 reps in the U.S. in terms of sales force. We are planning to commercialize ourselves in the U.S. Ex-U.S., we'll look for a partner when time is right. And we do think, just in terms of how we're positioning ourselves for the launch, I think there are some -- there are definitely some synergies we see between axatilimab and revumenib in terms of the sales force. But we'll be working, as I mentioned, with Incyte in terms of our election and how that would work out. But essentially, we have a program where we can bring both drugs to market, we believe, and then launch them successfully in a year's time with a very focused effort around revumenib and potentially axatilimab as well. So a very exciting time for the company. What is the Street missing or what are people missing about our story, I kind of hesitated there for a second because you start to get all these questions about axatilimab. And I would say that I think there's a tremendous amount of value to be created for both of these molecules. I think people don't fully appreciate how rare it is for a company, less than $2 billion in market cap to have 2 filings and 1 year, potentially, 2 approvals in the next 18 months with 2 first investment class agents. I mean, that's a very rare setup, so I think some people are missing that fact that -- I don't know, that you can potentially name another company in this situation, so that's exciting. But I was hesitating because of axatilimab, which you're getting a lot of questions on, but that seems to be a rather new phenomenon. Maybe people are catching on to axatilimab, and that there's significant need in chronic graft versus pose disease. I think until the launch of maybe Sanofi's drug and the success that Incyte has seen with Jakafi in the space, I don't think the commercial opportunity was really appreciated for this agent. And so maybe it was a little left behind what we were doing with revumenib. But I think we have 2 agents that are worthy of attention and investment. And we're well-resourced, as Keith pointed out, to really take advantage of the opportunity. So I do think that perhaps axatilimab is something to pay attention to. As we said in the middle of this year, we'll have -- I don't know if we talked much about the timing, but the -- in the middle of this year, we'll have top line data for that agent, for axatilimab with the filing of BLA by the end of the year. So again, not to be left behind or ignored. It's a big opportunity for us.

And any comments on the pipeline expansion, BD efforts?

Sure. Thank you. Yes. So look, we think this is an important part of what we do. The reason we have 2 agents in the position that we do is because not only do we have a great team, but I think you have to get the first. And so business development has been a focus from the beginning when Briggs and I came together several years ago, and it continues to be such. So we're looking for earlier stage assets. Targeted therapy remains a focus in oncology, call it, late preclinical, early clinical stage assets. The advantage there is, of course, that we use our expertise to do translational medicine to bring these into the clinic and differentiate them through good R&D. And I would say that they're relatively resourced. Not intensive, but I'd say they're able to be fit into our pipeline. And so I think this is a -- that's an area of -- something -- an area of focus for us going forward. We have a very high bar for bringing new assets in, so this is not something we take lightly because our investment is certainly focused on our later-stage assets at this point. But we would welcome, potentially, bringing another asset or 2 in the not-too-distant future to complement what we have within the namespace or otherwise within oncology.

All right. Perfect. Well, I think we used the hour very efficiently. We got a lot accomplished, very comprehensive. So Michael, Keith, Briggs, thank you very, very much. This is great, and I'm sure we'll chat soon with your earnings. Thanks, again.

Thank you.

Thank you so much.

Thanks, Yigal. Appreciate it.

Have a good day. Bye-bye.