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

All right. Thanks, everyone, for joining us at the Goldman Sachs Global Healthcare Conference. I'm glad you're all here even though the sun finally started shining, which is good news. Yes, we'll start out with we are required to make certain disclosures in public appearances about Goldman Sachs' relationship with the company that we discussed, the disclosures related to investment banking relationship, compensation received, or 1% or more ownership. We are prepared to read aloud disclosures for any issuer during the sessions upon your request. However, these disclosures are available in our most recent reports available to you as clients as clients on our firm's portal. In addition, a bit to those disclosures are available by ticker on the firm's public website. Goldman Sachs agreed to host this conference on the basis that no third-party seeker will provide confidential or material nonpublic information. In addition, by attending this conference, you provide Goldman Sachs right to record or redistribute the conference information. If you use a third-party speakers do not necessarily reflect those of Goldman Sachs. So really excited to be joined by the team from Syndax Pharmaceuticals today ahead of several events coming not like in months or years, but in weeks. So it's a pretty exciting time to be in front of the Syndax team.

So maybe let's start at a high level. Why don't you give us an overview of where things are and where things are headed?

Yes. Thanks, Madhu. Thanks for having us. It's a pleasure to be here at Goldman. I hadn't heard that full disclosure statement. So that's always a good thing to start off with. But -- but thanks for joining us. As Madhu said, it's a really exciting time for Syndax. We've been in business for a number of years. But now we find ourselves with 2 pivotal programs, which we will probably discuss today in great depth, revumenib and axatilimab. We'll plan to have pivotal data for axatilimab in middle of this year. So in a very short period of time, we'll have 240-patient trial reading out and then we'll have with our partner filing a BLA by the end of the year. So that will be exciting. And then, obviously, a lot of work ongoing beyond our first initial registration program for chronic graft versus host disease with axatilimab in the frontline setting, and we're also starting an IPF trial before the end of the year. So a lot of work ongoing beyond what was our first indication for axatilimab and it's exciting. And then we have revumenib, which is our Menin inhibitor, first and best-in-class as well, new mechanism and now an exciting area for leukemic patients, having either KMT2A, rearranged leukemia or NPM1 leukemia as well. So this is the first agent that will be indicated we hope for KMT2A and NPM1 broadest potential opportunity up to 40% of patients in acute leukemia. So again, very excited. We'll have our first pivotal study reading out in the third quarter of this year and then an NDA filing before the end of the year. So again, lots going on and the opportunity to be sort of first and best-in-class doesn't come too often for a company our size. So...

Okay. So maybe before we get into kind of those 2 readouts in those 2 programs, let me tell a little bit of a hot take from the weekend. Obviously, you all had data at the European Hematology meeting. Can you kind of walk through that data and also where you kind of -- how we should think about those results?

Sure. Maybe Neil, do you want to...

Yes, sure. So we presented the data from [indiscernible] program. So one of the things that it's important to bear in mind is that these were extremely sick patients who couldn't be included -- for instance, couldn't be included in the pivotal program because they have CNS involvement or graft versus host disease or comorbidities, including other malignancies. And also included -- I don't go through all of the data because it's quite a complex presentation, but maybe just to draw your attention to, in particular, 6 patients who had undergone response to revumenib, got transplanted, also incredibly heavily pretreated, including several of them had failed more than one prior transplant. And in those 6 patients, then went on to revumenib maintenance within the [indiscernible] program. At the time -- so 4 of them, I think, stayed on treatment for over 5 months. And at the time of the cutoff for the post -- for the data that we presented in the poster, 3 of them are still ongoing. One patient is still ongoing at almost a year, like 330-something days and 2 other patients also for extended periods of time. So we thought it was important to get those data out there because we believe in the pivotal study, of course, patients can respond, become MRD negative, be transplanted and then on protocol, go back onto ready amount of maintenance therapy. So we thought it was important to share the information that we shared over the weekend in that context because we believe that that's going to be the standard of -- that will be the practice of medicine once revumenib is approved for those patients.

Okay. So with that connect, I will come back to any minute. But let's start with the more products we readout with your CSF-1 receptor drug axatilimab. So I guess kind of as you think about the catalyst path of this program, how should we start thinking about like the data through mid-'23, on forward to 2024?

Yes. I think I mentioned briefly when we'll have -- again, this is third line. The indication will be for third line chronic graft versus host disease, patients who had failed at least one prior therapy. And again, the data will be in 240 patients. It's a randomized trial. So you'll see patients at different doses, 3 different doses. One is a convenient dose, 3 milligrams every 4 weeks and then 2 other doses at 2 weeks. The data should be available in the middle of this year. We can't necessarily be more specific than that as of now. But data will come, and we'll present that with our -- at hopefully at a medical meeting before the end of the year as well. And then we'll have a BLA filing before the end of the year as well.

Okay. So maybe starting with that program the mid-'23 [indiscernible] readout. At a high level, can you walk us through the rationale for CSF-1 pathway inhibition in chronic graft versus host disease?

Sure. Maybe Neil, do you want to take that?

Yes, sure. So CSF-1R signaling is important for the -- for monocytes basically becoming macrophages. And once the macrophages are localized in the tissue, in this case, it could be any -- multiple different anti-CSF at the body -- ghost versus host disease affects, many different organ systems. Then the macrophages can adopt a couple of different phenotypes, actually 2 different pheno as they can be pro-fibrotic or pro-inflammatory. And so, there are -- and all of that goes back to CSF-1R signaling. So the hypothesis switch is now proven from our initial clinical data that if you block CSF-1 signaling that you will block these pathogenic mechanisms mediated through macrophages in the tissues. And because it's the same or similar in all of the affected tissues, we've seen activity throughout different system organ classes. So that's the -- that's the -- the hypothesis of the MOA, which is now, of course proven clinically.

Right. So maybe coming in a [indiscernible] here. As you think about the mid-'23 readout, what do you think is the bar for both the kind of primary endpoint of objective response rate and duration of response in this third-line GVHD population?

Yes. Anjali, do you want to take that?

Sure. Yes. Thanks, Madhu. What we've seen in the last couple of years, 2 different drugs get approved in chronic graft versus host disease. Jakafi in the second-line setting with a response rate around 70% and REZUROCK, similar level of response in the third-line setting, we feel that anything above 60% would be competitive in that population and definitely approvable. In terms of duration of response, the primary endpoint is response at cycle 7, day 1. So after 6 months or by 6 months of treatment. And I think physicians are looking for optionality for these patients. As Neil said, this mechanism treats both anti-fibrosis and anti-inflammation seen in GVHD, which isn't something that's addressed by the current standards of care, or the current therapy is approved. And so, it gives both physicians and patients some optionality. We've seen efficacy across all organ systems tested, and we believe there's some potential benefits from -- that axatilimab could bear on the extent of fibrosis on these organs that we aren't seeing with other agents.

Maybe following up on that. I mean [indiscernible] comes up a lot in discussions is the fact that axatilimab in its current form is an IV formulation versus many of the novel therapies in GVHD or oral. How do you think about how that influences not just the kind of -- in a post-approval setting, the kind of utilization of axatilimab relative to these other novel agents?

Why don't you continue?

Yes, sure. I mean, I think it all comes down to efficacy and what these patients need. A lot of times when the disease is out of control, they are going to see their physician on a regular basis to maintain control of their disease and axatilimab is IV, but it's a 30-minute push infusion. It's not a difficult process and they can do it in the office. So it actually, in some cases, physicians like the fact that they know their patients are compliant. We have in the AGAVE trial allowed patients after 6 months of treatment, the -- well, the physicians the choice to translate to a once-monthly dose. So that will be data that we'll have and may enable real-world use. I think also that we're working on a subcu formulation that could also enhance the benefit of axatilimab. But I think it's really about the efficacy. And if you're able to control the disease, I think it will be a compelling opportunity. A lot of the agents that are used today besides these oral ones that were recently approved, are even more onerous than what we're talking about for axatilimab. So it's not a new paradigm for this class of disease.

I'd also say that just to follow on what Anjali said, I mean, the enthusiasm by investigators has been high. And I think the trial was intended to enroll 210 patients or so, I mean, well, 240 patients. There's just been a lot of interest in what we're doing, and the unmet need is there. So I think as Anjali said, it's about efficacy. By controlling patients, it's about making sure that you're not making their quality of life worse than it was before, of course, but they want to see these patients and interact with them. And I think it's -- a treatment like this fits in very well with their paradigm.

I guess kind of more and more focusing in on kind of -- are there certain manifestations of graft versus host disease where you think there's a specific utility specific benefit to axatilimab relative to other agents? I mean we take particularly the lung, which is the reason that you guys plan on ATS. How do you think about kind of like specific organ involvement that could kind of more meaningfully drive uptake for axatilimab versus other agents?

Do you want to talk a little bit about the lung?

Sure. So I guess it's [indiscernible], but just to reiterate the point that several of us have -- I think we've all made is that the drug is active across all affected organ classes, right? That's important. With respect specifically to the lung, data that we presented at ATS, it was in a subgroup of patients with bronchiolitis obliterans, so had an extremely severe manifestation or a consequence of chronic graft versus host disease amongst others, where the lungs are severely affected. Now it's a subgroup of patients from the study because -- it was a subgroup of like 9 patients who had at least one post baseline pulmonary function assessment. So baseline and 1 -- at least 1 post-baseline. And what we showed in the poster is that 5 of those 9 patients actually had improvement in their FEV1, which is pretty remarkable, right? And the other 4 had stabilization of pulmonary function. So that, in particular, is highly encouraging.

Okay. So a couple of weeks from now, well, we've seen a bit of our computer is [ blue ], press release, top line data from axatilimab and graft versus host dose disease. What should we expect to see from the top line in a few weeks' time versus kind of later more fulsome data presentation?

Yes. It's always a tricky question, right? So look, I think the objective here in presenting top line data is always to give people, stakeholders an understanding of what the drug can do, and the profile differences relative to competition. I think you want to get as much out there into the hands of physicians as well as investors to understand kind of the profile you're dealing with. Having said that, I think we're going to obviously try to present this data at a medical meeting. So we would want to hold back some elements of what -- of what's available to us, and we'll continue to do analyses that will make that a robust presentation at a medical meeting. But I think we'll have enough in the top line. Without giving you specifics, I think there'll be enough in the top line to fully assess the -- and characterize the activity.

Okay. Maybe let's shift gears over to revumenib in KMT2-rearranged, NPM1 mutant leukemias. Why don't we start before we kind of get into some of the more mechanistic data. Remind us what the kind of treatment unmet need is in these 2 types of leukemias in KMT2A arrangements and NPM1 mutant disease?

Neil, do you want to take that?

Yes. So for the KMT2A population, the patients in particular, that we've been treating in the study have been meeting the 4 prior lines of therapy. And for these patients, there really is no treatment alternatives, right? They are end-stage patients. And therefore, the kinds of responses that we've alluded to a little bit earlier on our observing has been pretty -- pretty special, right, patients who are actually close to end of life suddenly actually responding and having extension to [ their lives ] are even going on to transplant. So for those patients, it's a particularly severe form of the disease, and there's really very little that works, right? They're -- very poor prognosis group in general. For NPM1, it's a little bit different. NPM1 represents a sort of intermediate risk factor in -- when they're nearly diagnosed. But I think we also have to put that -- you have to put that into context, right? AML overall, is not a great disease, right, in terms of overall prognosis. So the fact that there's a large subgroup of patients fall into an intermediate-risk population, at least at initial diagnosis. We shouldn't -- we should be careful how we interpret that. However, once patients relapse, then that good -- or that intermediate or better prognostic associations lost, right? So once an NPM1 patient relapses, then they begin to assume a much more high-risk profile, right? How they're currently managed is somewhat different because they still may respond to existing therapies to chemotherapy. If they've got co-mutations such as FLT3 or IDH mutations, and particularly FLT3, there may be -- even if they've been previously treated with FLT3, they may be re-exposed to FLT3 where an alternative for FLT3 therapy is available. And then as they fail subsequent lines of therapy, second line, third line, then they become higher and higher, higher risk. So -- yes, go ahead.

That's okay. We're going to come back to that later on. So -- with all of that in mind, can you walk us through, again, the rationale for targeting menin-MLL interaction in these 2 genetically defined subsets of leukemia?

Yes, sure. So -- so the menin -- let's start with menin KMT2A rearrangement. That -- the KMT2A rearrangement in association with menin has been shown to drive HOX, MEIS gene expression, okay? The genes that are driven by those particular transcription factors are associated with maintenance for the chemical state, right? So in other words, it's beneficial to have that complex, the KMT2A menin complex, KMT2A menin complex driving these pro-survival genes, right? They maintain the cells in a primitive state closely called blast and the cells continue to replicate, right? So they're like parasites on the human body. What happens when you switch that off by basically giving revumenib and breaking apart that complex is that the genes stop being transcribed and the cells start to differentiate into something that approximates normality. And once that happens, then various complex -- various processes in the cells, apoptosis and associated -- apoptosis is programmed cell death kick in, right? So the genes have been preventing that. And once those processes kick in, then the cells realize -- the internal machinery of the cells realize that actually, there's something wrong here and the cells die, okay? The -- the mechanism is quite similar with NPM1, where NPM1 is also associated in conjunction with menin KMT2A in driving HOX, MEIS gene expression. So the same pro-survival signals for the cells, pro-leukemic signaling for the cells. And again, once the -- once that signaling is broken up, same thing happens, which is the cells begin to differentiate, their internal machinery kicks in and realize that actually, they're not -- they shouldn't be alive, and they undergo programmed cell death.

Okay. Great. So with that rationale in mind, can you walk us through briefly the existing clinical results for revumenib is in the Phase I portion of the AUGMENT-101 trial?

Right. So in brief, I think many of you know the results -- most recently presented at ASH was our Phase I results in 60 patients who either have the KMT2A or NPM1 mutation. And response rates of what we track for the primary endpoint is CR/CRh, and that was 30% between the 2 populations, 27% at the recommended Phase II dose. The median duration of response was 9.1 months. We had up to -- I think it was about 40% of patients going on to transplant who responded, which is a very high number. MRD rate of close to 80% in these patients. So these are patients who have achieved minimal residual disease by a very sensitive measure, which is what you generally required to go to transplant for physicians. And so that's what's led to a very high transplant rate. And what we've seen is patients have stayed on, as I said, for 9.1 months. Many patients had asked to go back on -- or physicians had asked to put their patients back on transplant -- rather back on drug post-transplant, and that was not allowable in this trial, but we've been able to do that in our pivotal trial. Time to respond is very quick, less than a cycle. So patients are actually getting drug going to response -- getting to response very quickly, which is important, especially in a disease like leukemia, where patients are at sort of the end of their journey and need something to intervene quickly. So that's the general reprise of the data.

Okay. Great. So kind of with those results in hand, can you walk us through the Phase II portion of AUGMENT-101? And -- more kind of practically what the cadence of data updates could be from the cohorts in that study?

Right. So I think we've mostly covered this, but I'll kind of tease it out again. So we have 3 cohorts of -- in the pivotal trial. There's an AML KMT2A cohort and ALL KMT2A cohort and an AML NPM1 cohort. All -- each of the cohorts are 64 patients, adult patients, up to 20 pediatric patients can be enrolled as well. The statistics drive off of the 64 adult patients. We had said that we're pooling the KMT2A cohorts together. So that will be the first analysis that comes out that will lead to our first filing. And the NPM1 will be available. We'll have that fully enrolled this year and then data next year.

Okay. So maybe let's come back to again like -- really coming back to KMT2A. As we think about this data coming, potential approval and kind of use case, where do you think this drug fits in relative to the kind of regimens of care that exist in KMT2A rearranged leukemia?

Yes. I mean I think simply stated that these patients don't have anything specifically for their mutation, for their rearrangement. So these patients typically in the frontline setting, get chemotherapy and then they relapse rather quickly. And so, there are sort of out of options. Again, the idea of being you would love to be able to get them to a transplant as quickly as possible, but you have to get them into an MRD-negative CR, and that's where our drug comes in. And so, it could be as early as first relapse, even with this first indication where they're going to get our -- get revumenib and hopefully get them to a CR and get them to transplant. And then, as Neil mentioned earlier, the emerging paradigm in relapsed/refractory disease is to be able to put them back on -- these patients back on treatment once they've been grafted post transplant. And so that's the idea being you can get them to a complete cure -- durable remission and keep them on for hopefully many, many months.

So that actually gets to the kind of eternal optimists versus the eternal pessimist conundrum that this drug works so well in getting you to mineral -- as you get the transplant, you don't have to take the drug anymore. How do you think about the kind of path effectively? So in the trial, you're running the option of maintenance therapy post transplant. But how do you feel like the kind of regulatory path to getting on label use of post-transplant maintenance on revumenib in KMT2A population?

Right. So I'll maybe handle the first part of it, which is, you're right. This is a trial we're running that is not intended to have a label for maintenance. I think that's an important distinction here. It will have -- we will have experience in the maintenance setting in relapsed/refractory disease, and that experience, I think, will influence physicians. That is, in fact, an important piece of how they should practice medicine, the idea being that these patients are extremely fragile, right? They're at risk of relapse and anything that can keep them in relapse. And in fact, our drug actually help them get to a CR, an MRD-negative CR, you would like to keep them in that state. So a transplant is important. But actually, keeping the cancer at bay is equally as important. That's why you want to put them on a drug that actually doesn't have a heavy side effect burden. In fact, the drug is extremely well tolerated. So that opportunity is not lost on positions. So -- while we won't have a frank label for maintenance coming out of this first registration trial, I think the experience will speak volumes to physicians, and that will probably influence them quite a bit. I think maybe Neil handle -- could handle the -- what are we going to do about maintenance, maybe in the frontline setting, which is important.

Yes. So Michael is right, and just maybe to add on to that. It's important to remember as well that the physicians asked us, right? So the investigators are very keen for us to have the option to include patients to be able to retreat patients post transplant on study. And whilst we don't have an indication, we will have language in the label describing how the study was conducted, right? And that was part of the experience. So we can expect -- I mean, we're not going to get into detail of the labeling, but I would anticipate that, that will be the case. Then in the earlier setting in the fit patients, we're currently about to start dose ranging with 7+3, which is a standard chemotherapy for patients that could go on to SIP meetings that they could be eligible for -- not just for intensive chemotherapy, but also subsequently for transplant. So our anticipation is that we will start dose ranging soon. We haven't really discussed publicly what the pivotal study design could look like in that space, but we're certainly getting ready to position ourselves to be able to do a study potentially in that space.

Okay. Great. So maybe coming back to the different flavor of the question we asked earlier for axatilimab. Third quarter data from AUGMENT-101 -- I'm going to France second half of August, so hopefully, it's not then. But let's say, [ blue ] e-mail, top line data for revumenib and KMT2-rearranged leukemias, what should we expect to hear then versus potentially in a more fulsome data presentation later in the year?

Yes. No. Thanks, Madhu. I think it's -- again, it's an equally challenging question to give you much detail, but I think people have seen how we presented data and what's important for revumenib in terms of endpoints. We had talked about CR/CRh, we had talked about duration. I think we are challenged with -- we want to make sure that everybody has a fulsome understanding of the data set and that can make a judgment on that, but at the same time, obviously, maintain our optionality around presenting the data in more detail at a medical meeting. But look, I think we've been -- in our disclosures, we've been very detailed to kind of break out the key measures that would influence whether a drug can get approved. And I think that -- this will be the first opportunity to do that. So I think it will be consistent with what we've shown in the past.

Okay. So then maybe one last question specifically around the monotherapy studies. How do you think about risk benefit on some of the kind of tolerability considerations seen within the cloud? So obviously, for you all, there's QT prolongation as an observed AE for other drugs or differentiation syndrome as a kind of like AEO-focused, how do we think about that kind of tolerability profile for your drug and the future use of it in treatment of [indiscernible] leukemias?

Yes. Look, I think the data suggests with our drug, I mean -- again, every drug has its own AE profile. But I think for us, the drug has been extremely well tolerated. Low rates, I think are -- dose-limiting tox, people know is QT prolongation. We've seen some Grade 3 at a low level, about 10% or less of Grade 3 QT which is easily identified, managed through dose adjustment. You don't have to stop dosing patients. Patients don't actually even know that they have a QT event, asymptomatic. So it's the lab abnormality, and it goes away within the next dose. So it's a very easily managed side effect, which a lot of other AML drugs have. So we're -- we've sort of been through that and physicians are very comfortable in how to manage that. We've seen differentiation syndrome at lower levels, Grade 3. So this is part of -- as you said, these are differentiation agents. So you'd expect to see some, and we expect to see some, easily managed again and others in the class have seen differentiation syndrome of more severe variety, and they have to go to more heroic measures to manage that with their physicians -- to manage it with their patients. So again, there's some differences in the profile and more will emerge over time. I think this as a class seems to be a very efficacious and I would say, more benign side effect profile relative to AEs than perhaps other targeted agents that have come down the pike. So I mean -- we're excited. I think there's -- I don't know if there's anything else to add on the AE side of the equation.

No, I think you had -- I think, a very manageable safety profile.

Okay. So maybe one last one on the kind of recent data you all have put out and we'll kind of get into more big-picture discussions. Obviously, I think there's a lot of investor discussions has been your publication about resistance mutations and how resistance mutations read to other drugs versus not. Like where do you kind of sit in thinking about kind of MEN1 resistance mutations for revumenib versus other drugs and where you kind of see them leading for the class?

Anjali, do you want to take that?

Sure. Yes. Thanks, Madhu. I think one place to start is just the publication that we had -- that was put out in nature based on the work Scott Armstrong has done to really profile how do Menin inhibitors work? And what are ways that the tumor can get around Menin inhibition? And to do that, they looked very carefully in very sensitive methodology to try to understand what is the -- what are the realm of possibilities and that's what they published in the science paper. And so, they've identified 3 mutation sites within the binding site where the inhibitors across the Class 1 set of all of the agents that are currently in the clinic are susceptible to where you can push out the ability of those agents to bind but maintain binding of MLL1 to menin. And so, that was what then was published also at AACR in April. And you can see that different inhibitors because of their different chemical structure have different levels of sensitivity to these mutations in the active site. But I think most prominently, all of them are susceptible to one or more of these mutations and the protein will find a way to get around it. And I think that was the basis of these resistance publications. And I think it's not surprising for a targeted therapy is what we've seen across all of these ALK inhibitors, EGFR inhibitors that's what happens with cancer biology. And I think what we're -- what we've shown in our Phase I data is despite the presence of these mutations, we've got very robust response rates, very durable results, 9 months of durability. And we're getting a transformational effect for these patients. And again, just to reiterate, these are patients who are fifth-line patients, very unstable -- in a very unstable disease. And so, as we move into frontline therapy in combination with chemo, if we can get patients to an MRD-negative disease, perhaps these resistance pathways won't be an issue anymore.

Coming to that, we briefly walked through the AUGMENT-102, Beat AML INTERCEPT trials kind of briefly described them and kind of walk through when we might see some initial data from those studies. And how should we think about initial data from those combination studies?

Sure. Yes. So as part of that process, we're looking at combinations with standard-of-care agents. So ven/aza is a frontline treatment for the unfit patient population. We're looking at that combination. We should have safety data in a recommended Phase II dose at the end of this year, and the goal would be to then start a pivotal trial with that triplet to understand and to get approval in combination for the unfit population for AML. We also are looking at combinations with chemotherapy in the relapsed/refractory population. This is to address how physicians like to treat with standard of care if patients can tolerate it, especially in the pediatric population. Again, we hope to have some safety data and recommended Phase II dose by the end of the year. And then in collaboration with the Australasian Leukemia & Lymphoma Group, we're doing a maintenance trial, monotherapy, revumenib after -- after CR to see if we can to patients from MRD-positive to MRD-negative state and keep them in response for longer. So that has started, and we haven't guided on when we'll see data on that one.

Just one last -- we'll add -- we'll have a 7+3 trial will start before the end of the year. That's in the unfit -- I'm sorry, the fit patient population, yes.

Great. Well, as ever with the question we're asking every company at the conference and it's kind of a silly one, given the context of this whole conversation. What is the reason to own Syndax stock in the next 12 months?

Look, I think -- as I think we said, we have very unique situation here at Syndax, where we have 2 drugs that will have pivotal data in the coming weeks for being first and best -- potential best-in-class agents with really high unmet medical need areas with big expansion opportunities. And where we're valued today, I think you could potentially get there on axatilimab alone, let alone what revumenib will bring in terms of value. So it's a tremendous setup for the rest of the year. We will also have filings that will solidify that before the end of the year. So exciting times for Syndax.

Right. Great. Well, thanks so much, team Syndax for joining us this afternoon. So...

Right. Thank you, Madhu.

Thank you.

Thank you.