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

Good morning. Welcome again to the 19th Annual Morgan Stanley Healthcare conference. I'm one of the biotech analysts here. My name is David Lebowitz. Before we get started, let me read the requisite disclosures. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. And with that, I'm going to begin. For the next session, I have from Syndax Pharmaceuticals, CEO, Briggs Morrison; President and COO, Michael Metzger; and CFO, Daphne Karydas.

I guess if we just start out, can you just give a top line description of Syndax, where you've been and where you're going?

Yes. David, thanks very much for inviting us to the conference. So our mission as a company is to realize a future in which people with cancer live longer and better than ever before. And we hope to achieve that by identifying breakthrough medicines that can improve the lives of people with cancer. We have 2 programs in clinical development today that we believe have the potential to address really important unmet medical needs. And we anticipate presenting exciting clinical data as we finish out this year on both 5613, our best-in-class Menin inhibitor and axatilimab, our first and best-in-class antibody against CSF-1R. For 5613, we anticipate sharing both safety and tolerability data from the Phase I portion of AUGMENT-101 for at least 50 patients, and we're excited to be able to provide, I think, a rich breakdown of the efficacy data that's generated to date, including overall response rate, CR/CRh rate, MRD-negative rate, and importantly, a first look at the durability of response. Given the number of patients we've treated, we anticipate an initial look at key efficacy parameters for each of the genetic lesions, both MLLr and NPM1. In terms of clinical data for axatilimab, we anticipate sharing safety, tolerability and efficacy data for about 40 patients from our Phase I and II experience. And we think that this will be quite relevant to the ongoing pivotal trial potentially be an important derisking event for axatilimab. Looking out longer term, we anticipate both of our programs to be in registration trials this year. And potentially, within 2 years, we could potentially have both agents, each of which we think are potentially $1 billion opportunities are approved in the U.S. So it's a very exciting time for the company. We have 2 really important molecules. I think it's also clear that the areas that we're working in our high interest to pharma companies. We recently saw one of our competitors, Kadmon, get acquired for their chronic GVHD program, again, validating that GVHD is an important area of interest of pharma companies, and we know that already for menin. So very exciting time to be at the company.

Thanks for that update. Now let's move on to the assets themselves. You have a Menin inhibitor, SNDX-5613, you're studying it in relapsed/refractory MLLr and NPM1 acute leukemias. You presented Phase I data earlier this year. And I guess, could you recap that data for us? And why did The Street find it so exciting?

Right. So let me first just recap the design of the Phase I trial. So this was a sort of standard Phase I dose escalation trial, initially started out with the trial enrolling any patient who had relapsed/refractory AML or ALL. They did not have to have a specific genetic lesion. Fairly quickly, as we were progressing through the trial, we went back to the agency and indicated that we were starting to see efficacy in the populations that we were interested in. And importantly, we're not seeing efficacy in the populations that didn't have one of these genetic lesions. And so we focused the trial to only enroll patients who had MLLr or NPM1 genetic regions. The data we presented earlier this year was a total of 43 patients from that Phase I trial who are evaluable for safety and then 31 patients who had one of the 2 genetic lesions that we're interested in. That was the efficacy population. I'll point out, again, to your question of why people were excited. This was a Phase I trial. Patients had a meeting of 3 prior lines of therapy for their leukemia. About 37% of them had progressed after a bone marrow transplant, a very, very bad prognostic sign. 60% of them had received prior venetoclax. So it's a very heavily pretreated population. In terms of safety, the drug was well tolerated. There were no discontinuation of the drug due to treatment-related adverse events. Patients were able to stay on the drug without significant toxicity in the data we presented for up to 9 months. We saw a good dose proportional PK. We saw exposures that we thought would be associated with efficacy. And I think the excitement was, indeed, we did see efficacy. Even in this Phase I trial with heavily pretreated patients, we saw clear evidence of monotherapy activity. There's -- as you know, David, we've seen a number of combination trials being read out by other companies that sometimes are a little more challenging to interpret. This is clear monotherapy activity in patients who have relapse or refractory acute leukemia, either MLLr or NPM1. We saw a 48% overall response rate. 2/3 of the responders achieved an MRD-negative status, which means by the most sensitive test we have available today, there was no evidence of leukemia. The CR/CRh rate stands at about 23% as of our last update. So really, overall, quite promising, both efficacy and safety data. The goal of Phase I was to define a recommended Phase II dose, and we've now finalized our selection of that dose that we're going to be taking forward into Phase II. And as I mentioned in my introductory comments, we're looking forward to updating the data from the ongoing Phase I at a medical meeting at the end of the year.

Now these specific populations, MLLr and NPM1 exactly, how prevalent are these particular leukemias?

So the MLLr represents about 10% of leukemia, and the NPM1 is about 1/3. So when you put them all together, it's somewhere around 40% of patients with AML. The -- in ALL, again, if you look at infants, if you've ever heard of an infant, 20-month-old, for example, being diagnosed with leukemia with ALL. About 80% of those are these MLLr rearrangements. And although the treatment of pediatric leukemia is really one of the great success stories of the oncology investigative enterprise, it's the MLLr patients who still do quite poorly. So that's, again, an area of very high unmet need that we'd like to address.

Now how are these patients currently treated? What is the current standard of care? And when you look at the monotherapy of SNDX-5613, how does it -- how do you look at them in comparison?

Sure. So the unfortunate news is the patients that we're getting, these are patients who, as I said, on average, have had 3 prior lines of therapy for the leukemia. There probably isn't a standard of care. The standard of care, unfortunately, is to put them on a clinical trial. Because if you treat them with conventional chemotherapy, their response rate is quite low, probably less than 10%. And some of them will -- I think, over half of the patients that have come on to our trial were actually refractory to their last therapy. So they got whatever the best therapy was available, and it didn't do anything. So unfortunately, in this relapsed/refractory population, they really don't have a lot of options. And so that's why, again, back to your question, why people are so excited to see a 48% overall response rate in a population of patients who their best option is to go on a clinical trial because standard of care really won't offer them anything, is really quite exciting.

Now in the studies, the adverse event of QT prolongation did pop up in the dose escalation study. What are the strategies for managing this, number one? And number two, how attuned are these particular physicians to this particular type of adverse event?

Yes. So I think it's -- first, to emphasize that the drug was overall very well tolerated, really the only drug-related adverse event that we saw was this QT prolongation and it is -- it's dose-related. At higher doses, we see it. At lower doses, we see much less of it. At the dose that we're taking in as our recommended Phase II dose to go into Phase II, we think the incidence of clinically significant Grade 3 QT prolongation will be less than 10%, probably somewhere in the 5% to 7% range. So not at all that common. Certainly, something that physicians have to keep an eye on. But the work that we've done with both academic and community-based physicians who treat AML is that they're already quite comfortable and experienced with this because this toxicity has been seen with a number of other targeted agents for the treatment of AML. So they know how to manage it. They know how to dose reduce it. We don't anticipate the management of this for 5613 will be any different than it is for what physicians are doing today. And again, I want to emphasize that the QT prolongation does not appear to limit clinical efficacy. We've seen a number of patients -- or a couple of patients who did bump into the Grade 3 QTc. We dose reduced them. They went on to have a very nice durable responses without a recurrence of their QT prolongation.

Thank you for that. Now in the Phase II trial, you are actually increasing the dose versus what was done in the Phase I study. Could you tell us about the decision to do that, number one? And number two, considering you're winding down the Phase I, have you had an end of Phase I meeting with the agency yet? And have they, I guess, been seeing your plans about going into Phase II with a different dosing regimen?

Right. So the goal of the Phase I trial was to identify the maximum dose that met our prespecified recommended Phase II dose criteria. So we had prespecified in the protocol that what we were looking for is a dose where we would see a limited number of dose limiting toxicities where patients could stay on the drug for multiple cycles and where we got adequate PK exposure, and the way the protocol is written is the goal of the recommended Phase II dose was to identify the maximum dose that would meet all of those criteria. So the so-called intermediate doses that we talked about recently that is, in our opinion, the maximum dose to meet those criteria. We have a meeting coming up this quarter, this month with FDA to confirm with them the recommended Phase II dose that we have selected. And based upon all the analysis we've done around PK/PD, efficacy, safety, I think, our team feels quite confident that we have a strong support for the dose that we've selected. We have strong support from our investigators. And we'll know when we have this meeting with FDA this month if they concur.

Will we hear an update after the meeting? And I guess, are you going to wait for the minutes before that update is provided?

Yes. I think our base assumption would be we would simply cover this off in our next standard quarterly call.

Got it. Got it. Now you indicated that you're going to present additional data later this year, could you elaborate on the specifics of what we could see vis-a-vis the various mutations, the different types of leukemias that are being investigated? And if we might see some of the before and after with QT elongation patients being adapted as far as to improve their tolerability.

Sure. So as I said in my intro comments, I think, we'll be presenting at least 50 patients worth of safety data. Some of those patients don't have one of the 2 mutations, so probably at least 40 patients' worth of efficacy data in a Phase I trial, heavily pretreated patients. But because that sample size is now getting pretty appreciable, we will be able to, as I said, cover off both the overall response rate, the CR/CRh rate, the MRD-negative rate, and importantly, I think, for people to first look at durability of response. We have not previously been able to really look at that. The data has been maturing. And given the number of patients that we've treated, we should be able to look at both MLLr versus NPM1. In terms of the different types of leukemia, most of the patients that have been enrolled in the trial have been AML. There are less patients with ALL. So the information on the use of this agent in ALL will be more limited. But we think there's a very rich data set. And again, David, I think, you and I have joked about this before. Phase I is the new Phase II. So even though this is a Phase I trial, where the goal is to identify a recommended Phase II dose because we conducted the trial in patients, obviously, we're getting a quick -- an early look at efficacy. And we're excited to be able to present that at a medical conference at the end of the year.

That sounds great. As far as pediatric patients, how much insight do we expect to get in those populations? I imagine it's not very much at this stage of the game.

It's not very much at this stage of the game. The trial, I should have mentioned this as well. We also did amend the trial so that actually patients from the age of 1 month onwards as young as 1 month can go into the trial. And when we presented the data back in the spring, I think, the youngest patient on the trial was 16. So we are seeing some younger patients come into the trial. But as I mentioned at the beginning, the infant ALL, our experience there is quite limited at this point.

Got it. Looking forward, you're going to initiate some chemo combo and frontline leukemia studies as well. Could you tell us your thoughts on that?

Sure. So I think that the -- obviously, as I pointed out, the Phase I trial is being conducted in relapsed/refractory patients who've had on average 3 prior therapies. As I pointed out, many were refractory to the last therapy that they got. So very difficult patients to treat. And we're super excited to see that the drug is working. But as we've learned over the years in treating cancer patients, the earlier in their course that you treat them, the better they do and the longer they stay on therapy. So it does make sense at this point to start asking, well, how would this drug work in the first-line setting for newly-diagnosed patients. And so the first trial that we just recently announced that will be undertaking is to combine our drug in the first-line setting with what is emerging as a standard of care for these patients in the combination of venetoclax, plus azacitidine. And so the initial portion is really just the Phase I portion to identify the dose of 5613 that we can safely combine with ven/aza. As I've pointed out, 5613 has been quite well tolerated, and we think it will combine quite well, quite easily. We anticipate that we'll be able to get full doses of all 3 drugs, but that's, obviously, the purpose of the Phase I trial to be able to answer that. Because we are, of course, want to still be able to offer increased benefit to patients with relapsed/refractory disease, those patients when they become relapsed/refractory, will initially get chemotherapy. And so we also want to ask, will 5613 add to standard chemotherapy regimens that are used in the relapsed/refractory setting for both ALL and AML. So we're starting a Phase I trial to, again, look at the safety of 5613 with those regimens.

Thank you for that. And now just to remind investors who are watching, feel free to use the Q&A portal. I've already actually asked one of the questions that came in from the portal during this presentation. I guess let's jump over to axatilimab, looking at chronic GVHD, tell us a little bit about that asset. And frankly, the space itself, which is undergoing a great deal of transition. People are becoming much more aware of -- with new therapies that are coming on board.

Yes. So let's just start with the disease. So graft-versus-host disease is a complication of bone marrow transplant. So we were just talking and when we're talking about 5613 that there are patients who undergo a bone marrow transplant as a potentially curative treatment for their leukemia. And there is a complication where if we take bone marrow from one person and put it into another person, the bone marrow actually recognizes the host as foreign, and you get what's known as graft-versus-host disease. And it's a complication of bone marrow transplant. There's probably about 14,000 patients a year in the U.S. who are suffering from this chronic graft-versus-host disease. There aren't any real standard treatment algorithms for this. And historically, physicians have really used sort of off-label agents to try to manage the condition. Most of the -- it doesn't work particularly well, and most patients will succumb to the disease within 3 to 5 years. So the new data that's being generated in various lines of treatment for specific manifestations are starting to help to define some of these treatment regimens. And so we've seen data from Jakafi, we've seen data from REZUROCK and ibrutinib. I think the acquisition of Kadmon around REZUROCK, as I pointed out earlier, supports that this is an area of unmet need in that when you have an agent that is starting to address that, that's attractive to the pharma companies. Axatilimab is unique in that. It is the only drug in development for chronic graft-versus-host disease that targets the monocyte macrophage population, and it does so by blocking the CSF-1 receptor. CSF-1, colony stimulating factor 1, is a growth factor for monocytes and macrophages. And if you block the receptor, then those cells decrease, and we've represented some data already showing that this mechanism works for chronic graft-versus-host disease, and we're now in a registration trial, which we'll talk about, I'm sure.

Well, yes. You just foreshadowed the next one. Tell me about the registrational trial, how the trial is designed and what you expect to learn.

Right. So let me first just say, we did present some Phase I data at ASH last year. Which was, again, a dose escalation in heavily pretreated patients who had multiple prior therapies, and we saw an overall response rate of about 57% across multiple organ systems, chronic graft-versus-host disease can affect your gut, your skin, your lungs, joints, fascia, eyes, and we saw efficacy across all of those. And the drug was, again, quite well tolerated. So based upon that, we opened up a registration trial, which we call AGAVE-201. This is a pivotal trial for approval of axatilimab in chronic graft-versus-host disease. The trial is currently enrolling, enrolling well. It's a randomized trial to test 3 different doses and dose regimens. So there are 2 doses that are given every 2 weeks and one dose that's given every 4 weeks to see if we can find a more convenient dosing regimen for patients. It'll enroll a total of 70 patients. The primary endpoint is the objective response rate as defined by the so-called NIH GVHD criteria and then there's some key secondary endpoints like duration of response and improvement in their symptoms using the lease symptom scale. So that's the AGAVE-201 trial that's ongoing. The one other thing I would just mention, David, is, as I -- in my introductory comments, we have an update on data that, again, we'll be at a medical meeting at the end of the year. And this will be about 40 patients with some good -- again, good follow up. So we can see both efficacy, safety and durability of response. Somewhere between 25 and 30 patients who are being treated at the 1 milligram per kilogram dose, which is what we think will be our label dose. So I think that data, too, will give people -- should help de-risk the ongoing pivotal trial.

Now the treatment paradigm is shifting as you're in development here, how does it affect the design of your study with new drugs coming on board? What are you using for the control?

So in the pivotal trial, it's a -- there is not a placebo-controlled. There is a dose, as I point out, there are 3 dose regimens. One of the doses is a 0.3 mg per kg, which based upon all of our PK/PD modeling, we think, will be effective, but not maximally effective. So it's -- that I think will help us show where we are in the dose response curve and does sort of act as an internal control for the program, but there's not a placebo control. In terms of the emerging changes in standard of care, well, we've -- the trials designed that patients must have failed 2 prior therapies. At this stage with the approval of REZUROCK, it is possible that patients will have failed REZUROCK before they come on to our trial, we already have data from our Phase I trial that we've seen patients like that who have progressed on REZUROCK and have responded to axatilimab. So there's no requirement that they have to have failed REZUROCK. And it is a global trial. So there'll be sites open around the world where REZUROCK is not available. So I think we'll see a mixture of patients and be able to get quite a good handle on the populations that benefit best from our drug.

Got it. Now your mechanism is fairly distinct from other therapies that are out there right now. How does that impact the potential for combinability with these other therapies?

Yes. No, I think, it's a wonderful opportunity. Again, similar to menin, I mentioned, it's well tolerated. So it should combine well with other things. We think the same is true for axatilimab, it's been well tolerated, should combine well with, for example, ruxolitinib, which is used in this disease. So we're quite interested in starting some of those combination trials.

Excellent. Now you've had a great history as a company. We're coming up towards the end here. And with your business development efforts, these are both assets that were brought in along the way. Tell us about what you're doing now and where you might be looking going forward.

Yes. Michael, did you want to take that question, if you...

Yes, sure. Yes, thanks, David, for acknowledging the business development we've done. I think proof is in the molecules and how well they're progressing, and we're excited to continue the trend here brining great molecules. I think we continue to hunt. I think it's an area in oncology, where single-agent activity, targeted therapy really kind of speaks to us. And so we continue to look in all pockets of where we could find anything from an early kind of lead stage through early clinical stage molecule where we can then add our expertise and develop aggressively and optimally to drive value and elucidate the profile of any of these agents. So I think we'll continue to kind of push on those themes, and hopefully, in the near term, can add meaningfully to the portfolio and obviously, align with the resources we have on hand to develop those assets. So it's really an important focus for us in the coming months.

And then what's the situation with respect to cash and runway going forward?

Thanks, David. So again, at the end of the second quarter, we had $253 million of cash on the balance sheet. As I made in the prepared remarks, that takes us into 2023 and importantly, covers all of the activities that we have ongoing for both axatilimab and menin to their first registrations.

Excellent. And with that, we've come to the end. Thank you very much for your time this morning, and look forward to speaking with you again soon.

Yes. Thanks for inviting us, David. We enjoyed it.

Thank you, David.

Thanks, David.

Bye.