Welcome to the next Fireside Chat with Syndax Pharmaceuticals. Michael Schmidt, biotech analyst with Guggenheim. I'm very pleased to welcome Mike Metzger from Syndax, CEO. Welcome, Mike-
Thank you.
and team. Thanks for joining us today. So yeah, maybe jumping right into Q&A, starting with revumenib, obviously, where we've had, you know, generally very positive, physician feedback, from, you know, coming out of ASH, where you had, combination data presented. Yeah, but you also have the, the NDA filing coming up, for, KMT2A-r relapsed refractory AML as single agent. So, maybe, help us understand how folks should think about the initial commercial opportunity in that particular indication.
Sure. Thanks for, Michael, for having us and for your coverage. Great to be with you all. It's an exciting time for the company, and I think, we have two molecules, which we'll talk about today. Revumenib, which is this—the first question relates to revumenib, small molecule, blocking the interaction between menin and MLL1. Most of you know the story. We did present pivotal data, this year at ASH, as well as combination data, and so the program is now, you know, fully moving ahead towards, potential commercialization. And we should have that, the first indication approved, we believe, in the middle of this year, and that's for KMT2A acute leukemia, adults and pediatrics, ALL and AML.
So it'll be a disease, what you call a disease-agnostic indication, which will be the first of its kind in leukemia. So it is a very exciting, groundbreaking set of circumstances for the molecule, and for the company. The commercial opportunity, the first commercial opportunity will be in KMT2A patients, and so again, adults and pediatric patients. As you know, AML, ALL, about a 27,000 patient population in the U.S. About 10% are KMT2A for both AML and ALL. That amounts to about 2,700 patients in the U.S., and we are treating patients in the relapsed refractory setting. So these are patients who have failed prior therapy, come on our treatment as a monotherapy. That amounts to roughly 2,000 patients who have failed frontline therapy and come on, could potentially come on our drug.
The opportunity there is, of course, there's nothing for these patients. These are. This is probably the worst prognosis for a patient to get in AML and ALL. And so they have a very poor prognosis. Most of these patients, again, go on to need other therapy beyond frontline, either 7 + 3, or, in some cases, get venetoclax, as well. And so this is an opportunity where physicians have nothing for these patients, and, with a very poor prognosis, they're looking to put them on therapy.
So if you, if you look at our data and extrapolate, duration of response, median duration of response over a number of different situations, whether these patients have received therapy and go on to transplant or don't go on to transplant, I think median time, our estimate is somewhere in the 9-12-month range, overall. At the average price of probably $35,000-$40,000 a month, 2,000 patients, it's a roughly $750 million market segment with really no competition. Standard of care, nothing seems to work for these patients. In terms of competition, there's really nobody developing KMT2A for KMT2A today. We should come to market in mid-2024 and have a very unique setup for our drug as a new entrant.
Right. And then, you know, as we think ahead of, you know, sort of, about that launch of coming up later this year, can you just talk about your commercial sort of preparations there and, you know, how you think about building out or have built out the field force for example?
Sure. First-time launch for our company, which is a very exciting build-out, new commercial organization. We've hired our leadership in advance of putting a field force together, and so this year and last year, we were planning and executing on putting the leadership and then, of course, doing disease awareness and really building the market for KMT2A launch. We will bring a field force of roughly 40-50 reps to bear. And these are specialty reps, of course, and we'll also have a full MSL field force to complement that. And we have not hired the field force reps yet, but we expect to in the coming months, and we're certainly getting ready to bring the drug to market.
So all the planning is in place, the leadership's in place, field force comes sort of last, but it is a very targeted opportunity, right? So we have, you know, the amount of field, the amount of representatives that we'll put in, put on the field, that's, you know, enough, we think, to cover almost 100% of the call point for revumenib. So very doable for a small company to hit the ground running.
Right. Then there's obviously also opportunity as a monotherapy in the NPM1 subset, where you're running a study-
Yes.
And I think you got the data around the end of this year. I think you talked about this subset of AML patients potentially being somewhat older, perhaps less fit than the KMT2A-r patients. You know, what are—relative to KMT2A, what are your expectations for, you know, activity, response rates, and also duration of therapy in the NPM1 group?
Right. So the majority of the NPM1 population are, I'd say, on the unfit side of the equation, where you have these patients receive venetoclax and azacitidine in the frontline setting and do reasonably well. At first, many of them do relapse, and so they're in need of additional therapy. The opportunity here is, in relapse/refractory, is about 3,000-3,500 patients. And you could do similar math in terms of how long patients are likely to stay on, the number of patients that go to transplant, the pricing, and so forth. So it extends the market opportunity to probably $1.5 billion-$2 billion in relapse/refractory, so that's the TAM there. And we will be the first to come to market with not only KMT2A, but also NPM1.
That data set will come to light at the end of this year, so we'll have our pivotal trial enrolled by the end of the first quarter, beginning of the second quarter. We will have the data from that trial in the fourth quarter. Towards the end of the year, we expect to file that package through an sNDA process, so it is a shorter time period than what we've gone through with our NDA, and we expect to have the drug on the market in 2025. So first indication, second indication, an extension in terms of the size of the opportunity, same physician audience, very similar in terms of efficacy, safety, and durability, patients going to transplant and doing quite well on the therapy. So it's, it's, it's an extension, if you will, of what KMT2A looks like. It's just more patients.
Right. And so it sounds like, you know, the long treatment duration that we've seen in KMT2A subset, where you saw this transplant dynamic, would you expect that to play out in the NPM1 patients as well?
We do. In fact, that's what we saw in our phase I trial. In the phase I experience, the response rate in NPM1 overall response rate was north of 50%. The CR/CRh rate was 36%, so best-in-class efficacy there. Very similar to what we saw in KMT2A. Patients got to MRD negative responses and very high percentage, upwards of 70+% . These patients are doing very well in getting to ultimately the state where they could be transplanted. Again, many of them in our trial have failed prior ven, have had prior stem cell transplants, and yet we're able to get them to a transplant. That's a great setup for these patients, and then ultimately, putting them back on therapy is something that physicians are keen to do.
They're doing it with KMT2A because they're at high risk of relapse. They keep them on in a maintenance capacity, and they would do the same for NPM1 patients as well. So a very, again, very similar set of circumstances, but we would hope and we would expect, based on the data that we've seen, that that would carry through.
Great. Then maybe switching over to your, you know, the first-line opportunity, namely for revumenib. And, you know, we've seen some data from you guys at ASH in combination with various agents. We've also seen some data from your competitor recently, Curis, through phase 1 data. Maybe first of all, to step back, just to talk about your overall strategy for moving into the frontline AML setting. What are some of the activities you're-
Sure.
Planning? Well, maybe I'll let Anjali speak.
Oh, sure. I mean, I think as Michael alluded to earlier, the frontline setting has basically two categories of patients. Those are who are fit to tolerate and can tolerate intensive chemotherapy, and I think that is what physicians would primarily want—how they'd want to treat their patients. But there are, especially as we talked about in the NPM1 population, there are incidences at an older age and may not be able to tolerate. And so there is a population that are deemed unfit for intensive chemo, and they would get traditionally Ven/Aza or Aza alone if they can't tolerate ven. So that basically covers all instances of treating AML.
What we're aiming to do, and we've already started this, is to add on to those two standards of care treatment to show that revumenib can be used in combination and can bring additional efficacy, without, you know, impacting the tolerability or safety profile of those, of those regimens, and can, you know, improve the overall survival and potential, you know, quality of life for these patients. As I said, we've started combinations with Ven/Aza in the front line. We presented some of that data at the end of last year at ASH, showing strong enhancement on top of Ven/Aza. You know, we had a 100% CR/CRc rate in that population, and all of the patients that we looked at achieved an MRD negative response.
So I think that highlights the enhancement over what you would expect from Ven/Aza alone. If you look at the pivotal trial for VIALE-A, they had a 24% MRD negative rate, so that is a significant improvement. And again, no impact on the tolerability of the combination regimen. We are initiating a combination with 7 + 3 this quarter, and we look to see something similar in that we're enhancing standard of care in that population, and then we would enter the pivotal stage for both of those. We have guided to starting that pivotal trial with Ven/Aza by the end of this year.
What else do you need to learn before being able to ramp up the Ven/Aza registration study?
Really, I mean, we're getting to an RP2D. I mean, I think we're basically there, but I think you, by definition, you need to expand the number of patients. We're looking at two doses, the same doses we took forward. We know they're active doses, the RP2D from the monotherapy, 163 on a strong CYP inhibitor twice a day and also 113. Both have been deemed RP2Ds, if you will, coming out of the phase I. And so we know these are active doses. It does give physicians the opportunity, if they would like to dose down for any number of reasons, that they have some flexibility in dosing. So we're expanding both, and we expect to have them that done relatively soon. But there's nothing. I mean, again, it's 13 patients we've shown to date.
We'd obviously like to see more patients.
Right.
But we feel extremely, and more importantly, I think the physicians feel extremely encouraged by what they're seeing, and so just additional patient experience.
Right. And so it seems like some of the class side effects, like differentiation syndrome, might actually be lower in combination for this class of drugs. Is that something that you're seeing as well, and could that perhaps even you know, increase the clinical profile in frontline?
Yeah, look, I think you move to the frontline, you have the opportunity to reduce side effects that you don't maybe or eliminate side effects that you don't necessarily see as much, or you see more, I should say, in the relapsed refractory setting. We're treating on average fourth line patients. These patients have most—most of them have failed stem cell transplants and ven-aza. They're incredibly, you know, beat up at this point, and so the opportunity to treat them earlier should lessen the side effect. Now, I will say on things like differentiation syndrome, if you dose them with chemotherapy, you're going to see less differentiation syndrome. That's just a fact, right? It's how it works. And so we would expect that, you know, when you treat with ven and aza, in particular, that's chemo, right?
7 + 3, you're going to be able to control DS, you're going to be able to control other potential side effects, but you may introduce other side effects in combination. So you have to look at that, and I think that's obviously what we're doing.
Right. And then you said you're just starting the 7 + 3 combo in a fit patient group. Yeah, anything... Again, is it, you know, what do you need to see here before you can actually start the phase 3?
It's a safety, it's a safety and tolerability look, right? I mean, obviously, we expect to add to 7 + 3 in terms of efficacy. We've established a monotherapy dose in KMT2A and NPM1, and so we know there's very good activity there, so we expect to add to 7 + 3. There's you know a high rate of response in the front line, whether it's Ven/Aza or 7 + 3. So you're going to be looking for things like MRD negativity, patients going to transplant, duration. As Anjali pointed out, a lot of these patients fail. They initially respond, but fail quickly, especially with 7 + 3. So you're looking for time on therapy and for them to achieve a better level of response.
Great. And then, you know, you're obviously also doing the AUGMENT 1 and 2 study in combination with chemo in later stage patients. You know, again, you know, how does that trial potentially enhance the opportunity for the drug?
Yeah. Do you want to touch on that?
Yeah, I mean, I think that so that trial was developed as a response to what physicians were looking to do, especially in the pediatric setting. They wanted to understand. They used that FLA or fludarabine, cytarabine regimen pretty consistently as a salvage option for these patients, and they see the value of bringing revumenib into that combination, and so it'll, you know, things like that trial or even the SAVE trial with ven HMA allows physicians to incorporate ven into their, you know, how they want to treat, and it showcases how combinable revumenib is across all of these standards of care. And so those are the kinds of trials we want to do to create more opportunity for revumenib to become the backbone of treatment for these NPM1 and KMT2A patients.
Right. And so, you know, menins are a very exciting new class, obviously, for the treatment of AML and aggressive lymphomas, leukemias, I'm sorry. There's a few other molecules coming behind. I think you guys are first in class or on track to be first in class, but it's a competitive space. So how do you envision the space to play out longer term with multiple, you know, therapies potentially reaching the market?
Yeah. No, it's a, it's an important question. I think, as you pointed out, we're first-in-class, we believe best-in-class. I think the efficacy data, safety data that we put up, the profile that we have, not only as a monotherapy in KMT2A and NPM1, but now in combination, showing in newly diagnosed patients and also in relapsed refractory patients, I think that sets our profile apart. You have to accumulate data in this business, and so, you know, I think we've put up a fair amount of data that shows that we will be there first, and we will be there with the best-in-class profile. Now, others have to come behind us.
We believe our lead is somewhere 2+ years in terms of coming to market, and as I pointed out, we'll be the only drug to have an indication for KMT2A, and ALL, AML, adults and pediatrics, and that's an important... Being first is actually very important to come to market. You build an experience, set of experiences with physicians when they use your drug, and I think we'll be, we'll have that opportunity, and we'll leverage that. And then, certainly, we'll have NPM1, we'll also be the first to introduce an NPM1 indication. So I think that experience in relapsed refractory will build a very important competitive differentiation for us. And then, obviously, we'll look to move to the front line, which is a longer-term play, but physicians tend to use these medicines how they deem fit, right?
Once it's approved, you get, you accumulate additional data, whether it's in combination in the maintenance setting and so forth. So that's our plan. Our plan is to move into earlier lines, and that experience will, I think, accrue to our benefit.
Great. Thanks. And then maybe switching gears over to axatilimab, which is your you know GVHD drug, where you recently exercised your option with your partner Incyte to co-promote in the U.S. as a post-approval. Sort of, yeah, remind us of sort of the you know what what what drove that decision-
Sure.
-and sort of talk about your responsibility in terms of, you know, building out commercial infrastructure for that.
Yeah. So thank you. I, it axatilimab is our, is our other important program that we like to talk about. Obviously, it's a big opportunity, and in third-line GVHD, this is a monotherapy, which we had the plenary at ASH this year. Hopefully, you, many of you saw that. The. It's a new mechanism, so it's a CSF-1R antibody, and really affects fibrosis and inflammation. First, we think mechanism of that kind to really impact the disease in a unique way. And so this is something where we signed an agreement with Incyte a couple of years ago. It's a global agreement, co-development and co-promotion option, specifically in the U.S., where we have up to 30% of the FTE effort.
As you pointed out, we exercised our option to do that, which we think is really unique for our company in the sense that this is a very much of a overlapping call point with what we're doing with revumenib, right? So these are leukemia and transplant physicians who we can call on for third-line GVHD as well as revumenib. So exercising the co-promote was sort of a no-brainer, right? It gives us the opportunity to put two products in the bag at the same time. Physicians wanna understand the latest science, the latest data, and to be able to be in front of them with two unique agents, first of their kind, in diseases of high unmet medical need, we think really will accrue benefit to both programs.
So, we're excited about not only the fact that we're able to co-promote, but we have an excellent partner at Incyte who has built this market. They are, as you know, approved with ruxolitinib in chronic graft-versus-host disease in the second line, in the chronic space. So not only are they knowledgeable about this market and how to address physician audience, but they can take a new entrant, and ultimately, we're looking to combine our drug with ruxolitinib in earlier line patients. So that's the future of exploiting the whole continuum of disease in GVHD. And obviously, we also have some extensions to that as well. We just started an IPF trial, which is another really exciting area of exploration for us.
Right. And so, yeah, I think the mechanism of the drug is quite interesting, especially in thinking about the future opportunities in fibrosis, for example. Can you talk about some of the findings from the prior trials and, you know, how that may increase perhaps your confidence-
Yeah.
in the fibrosis space?
Sure. Do you wanna-
Oh, sure. Yeah. You know, I think, Michael, I'll just remind you that even in AGAVE, we had some really significant benefits in lung. It's the first time we showed or anyone has shown complete responses in lung GVHD, which means you're bringing patients back to a normal FEV1 level. And so I think that highlights the impact axatilimab can have on fibrosis and lung function overall.
And we're looking to do that same analysis in the AGAVE trial, but last year at the ATS meeting, we presented an assessment of patients that were treated in our phase two trial who had bronchiolitis obliterans syndrome, which is also a very severe lung fibrotic disease, and showed that, you know, nine patients where we had background FEV levels, we either maintained their FEV and did not, you know, stop decline or actually improved FEV levels. So that, that I think, is extremely encouraging.
The respiratory community is very excited about the opportunity to bring revumenib into that space, and, you know, couple that with some preclinical data that suggests that both the CSF-1 pathway as well as macrophages are playing a significant role in the disease, I think provides a pretty robust data set that we should see efficacy-
Right.
in our IPF population.
Right. And maybe I'll just point out also just a... The fact that we're seeing the type of efficacy, almost, you know, three-quarters of the patients getting to a response, and these are tough endpoints. They've been on therapy, other therapies for average four years. So these are not newly diagnosed patients. They've been really, really heavily pretreated and failed everything else, including the marketed agents that are newest to the market. So I think we're seeing it in lung, we're seeing it in skin, we're seeing it across all organ systems. It gives the physician really the opportunity to treat all their patients. And so I think the IPF story is an excellent corollary. It's. We learned a lot from GVHD.
Right.
So we're taking that to the next level.
I mean, can you just remind us of that? I think you're running a phase 2 study now. What is, you know, what is the design of the study? How has it been enrolling, and when will we see some data from that?
Right. So we just started enrolling. So we—I think we announced our first patients are into that trial. It's a 135-patient, phase 2 signal-seeking trial, 26-week endpoint. So it'll enroll throughout this year, for sure. We haven't given specific guidance in terms of when we should expect enrollment to complete, but it is a randomized trial on top of standard of care versus standard of care. So when we think about IPF, this is an area of high unmet need. It is also an area where drugs have not necessarily proven their point beyond phase 2 very often, right? So it's a, it's a difficult, it's a difficult disease to prove your point.
I think our view on this is put a trial design together where you can really evaluate patients over a meaningful interval and look at. It's an FEV1.
FVC.
FVC, FVC, yeah, FVC endpoint. So it's a hard endpoint, and we're looking at, you know, a specific population over that period. So we feel like it's a good test of the drug. It's, again, we'll have to take it into a phase 3, assuming it's positive, but it's a robust trial.
Great. Well, with that, I think it's time to wrap up. So we'll, we'll expect likely FDA approval of two drugs in the second half.
Yeah.
And then data around year-end, it sounds like.
That's right. Yes.
Great. Thanks, Michael and Anjali.