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

Welcome, everyone, to the Wednesday morning of the 41st Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at J.P. Morgan. I'm joined by my colleagues, Malcolm Kuno and Priyanka Grover. Our next presenting company is Syndax and presenting on the behalf of the company, we have CEO, Michael Metzger.

Thank you, Anupam. I want to first start off by saying this is our first time presenting as a company at JPMorgan. So we're thrilled to be here. Appreciate the opportunity to do so. Also appreciate the initiation report from Anupam to start '23. It was a great way to begin the year. So with that, this is our forward-looking statements. Of course, I'll be making forward-looking statements today. This is posted on our website. I encourage you to take a look at it. It's also in our presentation. So 2023 is shaping up to be a, what I would call, a very special and exciting year for the company. As many of you know, we have 2 late-stage programs, both in pivotal trials, addressing high unmet medical need. We expect to have data for both programs this year, pivotal data this year for both programs. And importantly, we expect to have 2 filings for -- 1 for each of the molecules. They address, as I mentioned, high unmet medical need, multibillion-dollar markets. We expect to be first and best in class for both, and they afford us opportunities to expand into multiple markets beyond the early initiation of the registration indications. Importantly, we added to the balance sheet in the fourth quarter. We now are sitting with roughly $500 million in balance sheet cash, which enables us to get through all of our clinical and regulatory milestones over the next year or more and also potentially to launch these programs into the markets, which I'll outline for you. In addition to that, we also selectively look at business development opportunities to build the pipeline, which, of course, these are targeted therapies within the -- in the hematological oncology space. And so, we'll look to potentially add to the pipeline in that capacity as well. So let me just first start off by talking about revumenib, which is our first-in-class, potentially best-in-class menin inhibitor addressing 2 distinct segments of the population in acute leukemia. First is KMT2A, acute leukemia. Rough incidents of 5,000 to 7,000 patients globally addresses perhaps 10% of all AML and ALL. It's a very poor prognosis for patients who have KMT2A leukemia, less than 3 months of survival in the later lines of therapy. And so this is a very high unmet medical need for the field. We recently received breakthrough therapy designation based on the Phase I data that we presented at ASH, which I'll get into in a minute. So this is a very important segment of disease. And a separate segment of disease, NPM1 mutant AML addresses approximately 30% of all AMLs, the most frequent genetic alteration in AML. Together, they comprise about 40% of AML and ALL. So this is perhaps, the largest segment to be targeted by a therapy of its kind. It is first -- potentially first of its kind to do that. There are no approved therapies for either KMT2A or NPM1 acute leukemia. Important to mention that both are -- both of these types of mutations are addressable or at least, I should say, identifiable at the time of diagnosis by physicians through cytogenetic testing. So just a simple cartoon on the mechanism of action for revumenib. KMT2A and NPM1 are addressed through the same mechanism of action. Menin is a scaffold protein interacts with another protein called KMT2A, which turns on transcription through upregulation of hox and meis genes, which leads to leukemia. When you introduce a small molecule, a very specific inhibitor fits right in the binding pocket of menin, it displaces KMT2A, turns off hox and meis genes, which leads to differentiation in apoptosis. So this is our depiction of our Phase I trial, which we recently had data on, and I'll talk about that in a moment. The Phase I is the Phase I component of AUGMENT-101 and a Phase II component, which is the pivotal trials. The Phase I component was a dose escalation. We've arrived at a recommended Phase II dose. In fact, we had a few doses in both Arm A and Arm B of the trial that met the recommended Phase II dose. These are adult and pediatric patients, relapsed/refractory KMT2A or NPM1 acute leukemia patients. And we had presented -- we'll present this data in a moment. Phase II section -- segment of the trial is an ongoing trial, AUGMENT-101, 2A, 2B and 2C separated and individually enrolling patients, KMT2A ALL, KMT2A AML and then, of course, NPM1 AML. Primary endpoint of all 3 trials, which again, enroll separately is the same at CR/CRh rate and 64 patients per arm, up to 10 pediatric patients in addition to the 64 adult patients. So this is the baseline characteristics of the AUGMENT-101 trial. The patients were heavily pretreated and have a poor prognosis, as you know. Again, KMT2A and NPM1 patients, median age is 42.5 years comprised in this trial, AML, ALL and MPAL patients. Important to point out, these are patients who have large part failed prior stem cell transplant and venetoclax, which are 2 important modalities of treatment. So they're very late-line patients, average of 4 lines of -- essentially, this is their fifth line of treatment. Many of these patients are co-mutated which also complicates their prognosis as well. This is a -- these are the tables that list our adverse events. On the right, I'll just highlight for you the dose-limiting tox for this drug is QTc prolongation. We've known this since early on in development where we test for QTc prolongation. It's a simple EKG that's administered at the beginning of treatment and throughout treatment. Important to point out, we identified 10% of patients have great QTc prolongation, which again is easily identifiable. What we do when a patient has a prolonged QT is we drop the dose. They continue on. They don't even stop dosing. They keep -- they continue on treatment. And many of these patients have gone on to have complete responses, go to transplant and do very well in the drug. QTc has not -- the prolongation has not led to arrhythmias or torsades or anything other than a lab abnormality. So patients have done really, really well. It's important to point out as physicians are very familiar with QTc prolongation, they've seen it with other targeted therapies. With our particular drug, it has a reasonably short half-life and does not accumulate. So as we drop the dose, the Cmax comes down from the drug. Patients continue on, they don't see additional QT, it's controlled. So easily identifiable, controllable. We administer some other potential calcium and potassium and other oral supplementation to help control and blunt the effects of QT, which is pretty much standard of care. So this, again, is a very easy to manage phenomenon. The only thing that physicians see is a lab abnormality. We do see some differentiation syndrome. I know this has been the subject of some of our competitors, all Grade 2 and not of significance with this drug. So this is the data from the Phase I that we updated at this year's ASH. It continues, we believe, to support the best-in-class thesis around this molecule. 60 patients in the efficacy population of the 60 patients, 32 had responses, complete responses or otherwise known as CR, CRh, CRp or MLFS. So that's 53% of the population had a clearance of leukemia which is a, we think, a very strong result. MRD negativity was especially high in the patients who had received CR/CRh, 78% of the patients had achieved an MRD negative response. And as we look at breakdown between KMT2A and NPM1, both at the RP2D had 27% CR/CRh, which again is a, we think a very positive result. I'll point out the median duration of response, which we updated in this data set was at 9.1 months as well as the fact that patients are receiving a response very quickly, 1.9 months median time to response. And overall survival, this data set allows us to look at first the first time overall survival. And as you may know that patients who are at this late line generally have 3 months or fewer overall survival. And in this particular study, we saw 7 months overall survival, again, what we think is a pretty impressive result. So the second presentation that was done at ASH is shown here. These are 12 patients -- these are the 12 patients that went on to transplant from the Phase I. As you'll notice, many of them have MRD negative status, which is not a surprise. That's a marker and important indicator for physicians that their patients are eligible to go to transplant and do potentially well in transplant. And so, 92% of the patients achieved an MRD negative response. Many of these patients remained in remission as of the data cutoff, many in excess of a year. And I'd say that the important -- one of the important aspects of this trial was the follow-up that we did relative to compassionate use, where we were able to put patients back on therapy following engraftment, which is, we think an emerging thesis for this drug, patients staying on drug for longer than a year post -- in addition to having their transplant. So again, patients are able to do very well on this drug, get to a complete response, go to transplant, go back -- potentially go back on drug and stay in remission for quite a few months, maybe unspecified number of months at this point, but very, very encouraging. So the question is, so we're going to get -- hopefully get this drug approved in the relapsed/refractory setting, which is AUGMENT-101. But where do we go from here? It's an important question and I think we have aspirations for this drug to take it not only and combine it with other standard of care therapies, such as chemotherapy, which is the subject of AUGMENT-102. That's a company-sponsored trial, which we've started and we'll have -- hopefully, we'll have some data for before the end of this year. We have a front-line trial that's ongoing with the Leukemia & Lymphoma Society, Beat AML, which is a combination of our drug with venetoclax and azacytidine. In the front-line setting, this is in the unfit patient population. And then an important question about maintenance. We're exploring that at first, of course, with AUGMENT-101 in the Phase II, where you can put patients back on drug after engraftment, which I just described. We think that's an important indicator of what patients may be able to do in the front-line setting when you get to them earlier in treatment. And that is, in part, what we're looking at with the INTERCEPT trial, which is a collaborative group trial, looking at converting naive patients from MRD positive to MRD negative disease. So all in all, this is a group of trials that we're hoping to get -- some of them are up and running, and we're starting other ones. We'll be designing additional trials, both to get at the chemotherapy combination in the front-line setting as well as looking at maintenance and other front-line combinations, really to address all aspects in all segments. And that's what's shown here. I think the exciting aspect about -- of this drug is that we can address up to 40% of all AML and ALL through these 2 mutations. And relapsed/refractory is about 5,000 patients worth of that. We're looking to push this in the various lines of therapy all the way to potentially up to 12,000 patients worldwide. So it's a value proposition that has really not been seen with other targeted therapies. And we think we can explore based on the profile of this drug and also the segments that we target with this agent. So that was revumenib. Let me turn our attention to axatilimab, which is our second drug, but equally important in a sense that this is a first-in-class, we believe, best-in-class agent a CSF-1R antibody, specific antibody addressing, first indication being chronic graft-versus-host disease. For those of you who are not familiar with chronic graft-versus-host disease, it develops at approximately 40% of patients who have gotten a stem cell transplant. So that equates to about 14,000 patients in the U.S. It is an immune-mediated systemic disease that affects multiple organs through an inflammatory response and then a follow-on fibrotic response as well. As I mentioned, it affects multiple organs. The mechanism of the disease, CSF-1R depletes macrophage -- the macrophage lineage, which ultimately intercepts the formation of fibrosis, which of course, is the hallmark of disease for chronic graft-versus-host disease. So this is the trial that we ran. It's a Phase I/II trial, highlighting the therapeutic benefit of axatilimab in these relapsed/refractory patients. First, the Phase I was 17 patients, where we did a simple dose escalation. It sometimes happens with targeted therapy, you tend to have quick responses. We actually saw responses throughout the dosing continuum. So this is very exciting from the very beginning when we started to see responses. The Phase II was an expansion at the 1 milligram per kilogram. We're administering once every 2 weeks. This is what we believe to be one of the doses that we hope to get into the label, we'll see how the Phase II works out. But this is 23 patients, and the overall response rate is the -- based on NIH criteria, that is the endpoint for the trial. These data were presented at 2021 at ASH recently published in JCO. So this is the baseline characteristics. I'll just point out that this is a little bit older population than what I presented with revumenib. Medium prior lines, 3.5%. So this is a very sick population. Many of the patients who came on our trial had failed ibrutinib, ruxolitinib, and belumosudil, the most recent agent that Sanofi launched. So these are patients who have seen prior therapies. I'll point out that this mechanism of action affecting the macrophage. This is the only drug of the approved agents. This is the only drug that affects the macrophage, all the others are more targeted towards the B cell. So potentially, what does that mean? That means that we could have a profound effect not only on fibrosis, but we could affect through combinations, other aspects of the modality as well. And this is the AE table. I'd point out that the -- it's a very well-tolerated drug, safe and well tolerated. I think we have seen some serum elevations -- serum enzyme elevations related to the on-target effect of the drug on Kupffer cells, which for macrophages. These are transient effects, things that physicians watch out for. But there's no end-organ damage that we see no myositis or pancreatitis associated with the enzyme elevation. So overall, the drug has been extremely well tolerated. And as you can see, based on the data on this page, 82% of the patients, we see an overall -- got an overall response by criteria based on cycle 7, day 1, measurement. 77% of the patients had failure-free survival at 12 months, also an impressive result. And again, not unlike revumenib, the drug works quickly. In 4 weeks, we're getting time to response. In the middle panel here, the responses were long lived for many of these patients. They are on drug for 6 months or more. We have patients out 2 years. So they're doing quite well on the treatment. And as you look at what this drug does, you want to see that it actually has an effect across organ systems. As I mentioned before, it's a multi-organ system failure and problem. We're having both complete responses and partial responses across all the organ systems, including those that are hard to treat like lungs and skin. So it's a, we think, very impressive data set going into the Phase II. Before we get there, I'll talk about the Lee Symptom Scale for a second. This is the assessment of symptoms and symptom burden on patients. 58% of our patients were evaluable and a 7% or 7-point scale improvement, which is an impressive result. Importantly, you want to be able to take down the dose of steroids that these patients get, which is standard of care. And by introducing our drug, we're able to reduce, at least in this trial, we're able to reduce the use of steroids, which is really important to physicians. They often identify that as a key driver to how they prescribe. So this is the Phase II pivotal trial that I was mentioning. It's a robust trial looking at patients who have had 2 prior lines or more. As I mentioned in the Phase I/II, we looked at slightly sicker patients, third line plus. Most of them are fourth-line. So I think if you look at this trial, it's a 3-dose randomized trial, 1:1, 0.3 milligrams every 2 weeks, 1 milligram every 2 weeks or 3 milligrams every 4 weeks was just more of a convenience dose. The top line data for this trial, which has already been enrolled. In fact, we overenrolled the trial to 240 patients. Top line data is expected at mid-2023 and BLA filing by the end of '23. I will mention that we have a partner Incyte for this program. We did that collaboration in 2021. We're very excited to be working with Incyte. They're a known commodity in the space. They've had ruxolitinib and they've launched an acute and now chronic graft-versus-host disease. It's important to note that their drug actually has a different mechanism, as I mentioned earlier. And the ability to potentially combine these agents is one advantage that we think is key to the partnership as well as the fact that they have commercial infrastructure and really understand how to promote in this space. We'll be combining this drug in a front-line trial, which will be starting in the first quarter. Actually, Incyte will be leading that trial, and it's an exciting way to potentially expand the opportunity. And speaking of expansion, this is just a depiction of what we plan to do beyond chronic graft versus host disease, which I mentioned we expect to submit the package in '23. Hopefully, get the drug approved in '24 and launch it in '24. We'll also be looking at front-line trials, the combination I just mentioned. Also, Incyte will lead commercialization outside the U.S. So that further expands the pie to those patients. And then, we're going to be starting an IPF trial this half to look at the drug in that indication as well, which, of course, could be a very large upside to this program. There may be other indications that we pursue in addition to these with Incyte to be determined down the line. Just a bit on our financial guidance. As of September 30, we had $337 million on the balance sheet. I mentioned our follow-on financing that we did in December. $161.5 million net adds to about $500 million, which is a healthy balance for us. Shares outstanding 69.2 million. The R&D budget, which we'll update on our quarterly call, $145 million to $155 million has been the guidance. We adjusted that as of last quarter. And so we are -- with the cash on hand, I think it gives us ample opportunity to pursue all the things that we talked about today and hit all of our clinical and regulatory milestones as well as selectively add business development opportunities. With that, I will pause. I think it's an exciting year for the company. I hope that came through to you today. And we're happy to answer questions and get into anything in particular.

[Operator Instructions] So we do have a question in the portal actually, which is, how do you handle transplant in the DOR calculation? And if these patients get censored at the time of transplant, can you still show durability over 6 months?

Yes. It's a good question. We -- actually, point of clarification. We do not censor at the time of transplant. That's based on FDA guidance. So if you look at the guidelines, the 2021 AML guidelines, they're pretty specific. There's not censoring for patients. So the measurement of duration of response is literally time to relapse. So actually are calculating through the time that they get their transplant. The opportunity for us will be, in some ways, different in the sense we can put patients back on in the pivotal trial would be able to put patients back on drug post engraftment, which I explained. So that we've shown 9.1 months of median duration in the Phase I that we updated at ASH. We expect that could potentially lengthen with the addition of drug back -- at the back end of treatment.

Maybe expanding on this question a little bit. But in the ASH '22 update, you had 40% of patients that went to transplant, right? And so, how are you thinking about the revumenib as a maintenance therapy post-transplant? And I guess, what evidence is there to date on this setting?

Yes I mean, I think we'll have some evidence in the Phase II. I think this is an emerging -- as I like to talk about, it's an emerging paradigm for revumenib. The application is patients will get drug, go back on after engraftment. As you said, it's a high percentage of patients who get to MRD negative response and do very well, and we're hoping that we can hold them in response for months, if not years. But these are relapsed/refractory patients. These are patients who are fifth-line and they have limited capacity to potentially respond long term. We think we're doing quite well in that setting. We're going to have that data as part of the Phase II, but the opportunity is really to get into what we call maintenance in the front-line setting, where you access patients earlier and you're able to treat their disease, get them to a complete response MRD negative response, either get them transplanted or not, but keep them on therapy to keep their disease at bay for who knows how long. But that is a paradigm that we think we can exploit based on the properties of our drug. And the data that we've seen sort of bears that out at this point, but we'll see more in the Phase II.

We have an e-mail question here as well, which is, can you explain the CR versus CRh rate in NPM1? And you had 2 doses, how do you think about efficacy by dose?

Right. So we had -- what we had shown in the data at -- maybe I could flip to it here. The data that I showed here, that's shown here. So I think the question is referring to the CR/CRh rate for both NPM1 and MLLr. We broke it out for the first time at the RP2D. This is the analysis that FDA asked us for relative to how we do it. So these are -- pool all the data at the RP2D. So that means you would exclude some patients that got dosed above the RP2D or below the RP2D. And so that analysis is what we've done here for both MLLr or known as KMT2A or NPM1 and both of them, as you see, yield 27%. So our view is longer term, we expect the response rates of both NPM1 and KMT2A patients to be roughly the same.

Questions from the audience? Malcolm?

So maybe it's too early to tell that in the maintenance portion of AUGMENT. Would you expect safety to hold up post-transplant in patients?

It's a great question and an open question. I think -- look, I think the best indicator we have when patients get MRD negative CRs that means that they have very deep responses. That means that all the leukemia is gone and their count recovery is either fully there or close to being fully there. And so their bone marrow is recovering as well. And so after they engraft to go back on drug, it's a very -- it seems to be a very well-tolerated drug with side effects at a minimum. So as long as the fitness of the patient remains we should be able to -- we would hope to be able to contain their leukemia as well. So that will be borne out in the Phase II, but that's the promise.

We actually have -- let me see if there's any questions from the audience. Another question is, have you ever broken down the efficacy by AML and ALL for the, I guess, you should say, MLLr portion? And will these indicate -- will this and other indications be part of the submission?

Yes. So we have not broken out AML versus ALL at this point. In the Phase I, it was about -- I believe, 11 patients were ALL. So it's a small segment. I think the best indicator of how these look like so far is based on what the FDA has asked us to do for our breakthrough therapy designation. They ask us to pool the data, cut the data, look at it different ways, adults, pediatrics, AML, ALL. And we did, based on the RP2Ds, and they gave us a very broad designation covering adults, pediatrics, AML and ALL. So to them, it looks sort of like one disease, which is an exciting and a big advantage for us. But specifically, we haven't broken that out for the reason that these are small patient sets. The Phase II, as I kind of went through is 3 separate trials, right? So it's KMT2A AML, KMT2A ALL and NPM1 AML. So they're separate. They're enrolling separately. So we'll see that data specifically in the completion of the Phase II trials.

Questions from the audience? So on AUGMENT-101, the pivotal portions are supposed to start reading out in the third quarter. Have you ever provided any cadence on the readouts of 2A, 2B, 2C? How do you think about that?

Yes. It's a good question. We haven't yet given guidance which of the 3 will read out first, second or third. I think the new element of this is, of course, the FDA giving us breakthrough therapy, and we'll have more discussion with the agency about how we might have an advantage of putting maybe 2 of the cohorts together around KMT2A to have 1 filing. So we'll have more to say about the cadence of which will be first and second or third as we go a little bit longer into the quarter. But yes, I think the guidance remains first cohort will be delivered for enrollment by the end of the first quarter, and then we'll have data in the third quarter and a filing by the end of the year.