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

Great. Thank you. Good afternoon, everyone. My name is Pete Lawson. I'm one of the biotech analysts at Barclays, and welcome to Barclays Global Healthcare Conference. I just wanted to thank everyone for taking time out that day. And we've got management team from Syndax. If you've got questions, institutional investors can e-mail me at [email protected] or ping me on Bloomberg and my pleasure to introduce the management team from Syndax. So we've got the full suite of management essentially. Briggs, Daphne, Michael, and Anjali, and it's my pleasure to speak to you guys today, and thanks for joining. And I guess, just to kick things off.

I guess the question I've been asking today has just been around like the company's differentiation in the oncology space is plenty of oncology companies, what do you kind of view as the differentiation? What are your core competencies in this space?

Yes. Peter, first, thanks so much for having us at the conference. It's been a terrific conference so far. I would say that our operating model is what we generally call license and develop. So our core competencies, we believe, are identifying great molecules that perhaps others have overlooked. That's the license part. And being able to develop those molecules rapidly and efficiently, given the extensive clinical development experience that our company has. So I would say, right now, those are our key differentiating capabilities. As the company progresses, of course, we will need to add on commercial capabilities to be able to show that we can differentially launch successful molecules. But I would say today, our core competency is identifying great molecules that others have overlooked and then creatively efficiently and effectively developing those.

Got you. And then maybe we could start off with 5613, your Menin inhibitor. Just if you could give us an overview, essentially, like talk to the mechanism of action? And what you think is an important target and kind of the patient population in acute leukemia you can address.

Sure. So again, I'll go back to our license and development model. So I think that this was a model -- this was a target that we found extremely interesting, and I'll talk through just a second why we find it so interesting. If we were able to license the program from Allergan, and I think actually one of the competitive advantages we brought to that discussion was our ability to help the drug rapidly, effectively. And I think Allergan saw that in our team. I think others may have missed this target. There may be others now starting to get interested in it because of all the work that we've done to show, and we'll show more data of course, soon, promise of this. The reason we particularly liked it was it's -- the target itself is a fusion protein. And I think if we look across the history of oncology, fusion proteins, starting with the classic Philadelphia chromosome the 9 21 BCR-ABL fusion protein have been great drug targets. And so this fusion protein is -- was described many years ago. There are rearrangements that occur at chromosome 11q23 that result in a fusion protein that drives the leukemic state. And a lot has been learned about the fusion protein itself, how it works, and most importantly, how it can be drugged. All the previous fusion proteins that people have worked on, primarily in oncology heaven kinases. And so what the fusion does is to activate a kinase and the drug that you make turns off the kinase activity of that fusion protein. In this case, the fusion protein is not a kinase. It represents the immuno terminal half of the protein comes from a methyl transferase known as MLL-1 or KMT2A and the carboxy half of the fusion protein comes from a wide variety of transcription factors. So essentially, what you have is a novel transcription factor turning on genes that are involved in leukemia genesis and doing that inappropriately in an unregulated way. In order to do that, the protein has to bind -- the fusion protein has to bind to a protein called menin. And the major advance in this field was when somebody crystallized menin and that we can clear exactly how this fusion protein binds to menin and it became very clear to structural biologists that there was a druggable pocket there that you could make molecules that would bind to menin, displace the fusion protein and thereby give you an antileukemic effect. So that's the basis of our molecules, very, very potent, orally bioavailable, small molecules that bind to menin, block the binding of the fusion protein and lead to an antileukemic effect. Along the way, it turned out that there's another form of leukemia. And so the MLL-r leukemias represent about anywhere between 5% and 15% of AML and ALL. They're called mixed lineage rearrange because they can present as either AML or ALL. And in some cases, actually features both. So that's why they don't want to get your mixed lineage. It turns out that there is another form of leukemia in which the protein NPM1 is mutated and moves from the nucleus to the cytoplasm. Sometimes, it called NPM1c because it's now stuck in the cytoplasm. It turns out that the biology of NPM1 leukemia is very, very similar to that of MLL-r. And a number of scientists have shown that these small molecule Menin inhibitors that block the binding of menin into MLL-1 have very potent antileukemic activities in preclinical models. And so those are the 2 main tumor types that we're studying in our clinical program, the MLL-r fusion protein in either AML or ALL and the NPM1 mutant protein in AML.

The heterogeneity, you kind of see in the MLL patients in the sense of like the rearrangements. Does that in any way change the outcomes of these patients? Or how you could -- how you would have to drug them or treat them?

So the general literature would suggest that the carboxy terminal half, what the fusion is doesn't really seem to drive prognosis. They're all bad prognostic patients. All of them, however, share in common, the immuno terminists that has the MLL-1 binding site that binds menin. So from a drug development point of view, any MLL-r fusion protein, where the [ middle ] half is MLL-1 and the carboxy tremendous transcription factor, all of those are potentially amenable to our therapy. We have studied a variety of different models preclinically. And for the most part, all of them respond to our inhibitors. Sometimes, the time course of response may be slightly different in different models. In the ALL model, so you tend to see hepatosis of the tumor cells. In the AML model, sometimes, we see differentiation where the myeloid leukemias will differentiate into a normal cell before it dies. But essentially, any MLL-r rearranged fusion protein-driven disease should be amenable to our approach.

Is there -- I guess, as we think about the NPM1 mutations, there's a lot of co mutations there. How do you think about the potential range of outcomes you get from those patients?

Yes. So you're absolutely right. There's a 15% of NPM1 patients who do not have a co-mutation, all the rest of them do. In preclinical models that people have studied so far, if you take -- generate a patient-derived xenografts, take a leukemia from a patient and adapt it so that you can go in an animal and study it. In all of the PDXs, it doesn't seem to matter what the permutations are, whether it's up for 3 mutation or DNA-PK mutation or any other mutation. I wouldn't say that it's been exhaustively studied, but every PDX model as long as it has an NPM1 mutation, regardless of the other mutation, it is sensitive to our small molecule Menin inhibitors. Well, of course, have to see if that's true in the clinic as well, but that's the preclinical data.

And then kind of a final question just around the rearranged. Does the rearrangement change the diagnostic test? Or does it make it confusing in any fashion? Or is just your thoughts there?

Sure. So the normal work up, the sort of standard workup for a patient who comes in with a newly diagnosed AML or ALL includes a cytogenetic panel where they're looking for rearrangements. So this 11q23 rearrangement is picked up mainly in that cytogenetics. There are fish probes that you can use to look at which rearrangement they have. So it's 11q23, but then the other partner you have to identify. It's routinely done today in -- and where patients have worked up for newly diagnosed leukemia. There isn't a one size fits all molecular test. So for example, a PCR test that you could pick up every known fusion because the carboxy-terminus is variable, there isn't a one size fits all to pick up all of them. So -- but from cytogenetics and fish, there were timely diagnosed.

Got you. I guess, just thinking about data, you kind of started the -- you outlined it yesterday on your earnings call or quarterly update call. So we get that kind of end of March, beginning of April time frame. And that's not in a medical conference is more. So it's a company-sponsored event. What was the -- what drove that choice of company-sponsored versus medical conference?

Daphne, you want to take that one.

Yes, sure. Thanks, Peter. So the decision here was really driven by the fact that we would like our primary investigator, Dr. Eytan Stein, to present the data. And in discussing with him the best venue, he didn't think that AACR was the best platform to present clinical data and would rather present the clinical data at a medical platform more in line with leukemia and clinical data like ASH or EHA. Having said that, we obviously want to share the data with the investment community in the time frame that we have laid out. And as such, we're going to opt-in to do management hosted event where, again, Dr. Stein will be presenting the data.

Do you think you'll get an opportunity to present to EHA? It's just such an interesting target and drug and so what seems to be so widely followed by invested and also physicians as well? So just kind of your thoughts about the next clinical update or clinical venue.

Yes. I think, Eytan and the academic investigators are having a investigation now or whether they -- EHA data wouldn't be that different from what he presents at the upcoming event. So they may decide to wait for ASH where there's more of an update, but that's something that [ they'll have to tie it ] along with the ASCO.

Got you. Thank you. And then as you speak to physicians, what kind of response rates would they want to see from, say, the NPM1 patients versus the MLL-r patients, if there is a difference?

Yes. Look, I think that if you look at the sort of precedence in this area, right, so you're essentially looking at targeted agents for the treatment of a genetically-defined population of AML and the -- or acute leukemia in general, right? And the precedents here are FLT3 inhibitors, IDH1 inhibitors or IDH2 inhibitors. And I think in all of those cases, the response rate is somewhere in the 20% range. I think that gilteritinib was around 21%, a little bit higher for one our ivosidenib. So I think as we've thought about from a regulatory point of view, what might be an acceptable level of efficacy that allow us to go down this path of approving a drug in relapsed/refractory leukemia, we look at those as regulatory precedents. Obviously, if the response rate is higher than that, all the better, all the more exciting, but we think that's -- should we see a response rate in that range, we think that that, again, would be exciting to physicians because I think the FLT3 inhibitors, IDH1 and IDH2, have been well received as novel targeted well tolerated agents and obviously, we're higher than that, all the better.

Got you. And I wonder if you can share any feedback you've had from physicians around the safety profile and what they want to see and see in the relapsed/refractory setting?

Sure. So again, and part of the reason for having Eytan do the presentation is he is obviously a practitioner and physician, at Sloan Kettering. He sees these patients all the time. He was instrumental in the development of other targeted agents. So I think he has a very good perspective, and we welcome you and others asking him that question when he presents the data. I would say, in general, from our investigators, these are to be very candid. These are life-threatening diseases. If the average survival of these patients is on the order of [ couple of ] month. So the safety of an agent in this disease is probably not paramount in their mind. What's paramount in their mind is, can I control this patient's leukemia? Could I potentially control it well enough that I can get them to bone marrow transplant because that gets me a chance to potentially cure the patient. And from a safety point of view, they really just want to know, can I get the drug in so that I can get the efficacy that I'm looking for. Now there's more to it than just the physician sort of view of these terrible diseases and what do I need to do to get my patient into remissions and potentially going to transplant. I think there's a regulatory overlay on this. And as we develop drugs, we have our sort of standard rules about dose-limiting toxicities. We also have an interest, and I think our investigators are quite interested as well as what is the sort of chronic tolerability? Can I dose this for a prolonged period of time? Because some patients, I'm going to get into remission, I'm going to take to transplant. Other patients, I don't -- they don't have -- they're not transplant eligible. And so I really want to treat them chronically with the drug. And so that long-term tolerability is important to them.

Got you. And it seems with physicians have such high degree of experience with drugs with whether it's QT prolongation or CYP3A4, have you had any kind of pushback around that? Has that caused any concerns from physicians?

No. No. I would say our investigators, as you say, there are other targeted agents for the treatment of AML in other genetically-defined setting, where the drug does have an incidence of QT prolongation and the physicians know how to monitor for that. It's reversible, it's easily monitorable. It is not -- in and of itself is not clinically meaningful. So that has not really been a -- they understand that they have to monitor through that in our Phase I trial, and that's perfectly fine.

Good. Do you think you can -- with drugs like this, you can really push response rates into the 60s, 70s and 80% response rates and cure rates kind of in that 30%, 40% response rate? So where do you think they kind of fall out eventually?

Well, that's a great question. I don't think we know the answer to that. What I would say in preclinical models, as we talked about earlier, for the MLL-r, it's essentially every model we've looked at, they seem to respond. In NPM1, as we talked about earlier, regardless of the commutations, they seem to respond. So there is -- and as I said at the beginning, the fact that as a fusion protein did was intriguing to us because fusion proteins tend to be dominant drivers as you look at BCR-ABL or EML for health or TRK fusions, et cetera. So there's a possibility that the response rates here, particularly in the fusion population, are extremely high. We'll just have to see.

And do you think, ultimately, these drugs end up as monotherapies or combination therapies? What's the rule?

Yes. There were some -- so I think our sense is that the general role in oncology is the sooner you treat a patient in their disease course, the better they do and the longer they stay on the drug. So we would anticipate that if you think 5 or 10 years down the road after we've really done all of the trials and develop this drug, I think you will see it being used at the beginning when patients are first diagnosed, whether it will displace chemotherapy is sort of a high bar, there is this analogy of CML, where we used to always treat CML with chemotherapy until Gleevec came along and then we treat them with Gleevec first only after they have failed their targeted agent, do we then go on to chemotherapy. Same thing happened in lung cancer, where we now treat patients with targeted agents first. And has -- if they fail, then we go on to chemotherapy. We could reach a day where that happens with these agents, where we treat them with a targeted agent first and only if they progress or can't get to transplant, then we then go to chemotherapy. But I think initially, we'll give them a combination with chemotherapy. And once they're in remission, continue the drug in sort of a maintenance phase to maintain that revision. The main goal is when we talk to leukemia doctors, they say, you want to get more patients at your remission, we want to get more patients to transplant because that is the -- today, at least the only way to cure a patient. And once they're in remission, we want to maintain that remission for as long as possible. So I can see these drugs being used to help get patients into remission and then to maintain those remissions for as long as possible.

Got you. So the Kronos had an interesting trial design frontline combination. Interesting kind of endpoints. Did that change the way you thought about moving into frontline? And is that kind of an encouraging signal?

I think it is an encouraging signal. And in the past, the FDA has not been open to MRD negativity as a endpoint in AML trials. It wasn't ALL, but not in AML. And our sense is that much of that had to do with it the operating characteristics of the tests that are used to detect MRD negativity. In the NPM1 setting, there are next generation sequencing approaches that one can use in a methodology that I think is more amenable to the FDA. So our sense is that the approach that Kronos is taking is more about the assay that they're going to use to detect MRD negativity and that that is something that the FDA is now open to. So I think it is -- does open up the opportunity at least in NPM1 disease to think about using MRD negativity as an accelerated approval surrogate endpoint that would then you need to confirm with either event-free survival or overall survival.

Got you. I'd love to spend a few minutes actually -- [ it's a shame ] we just got a few minutes, but just also talk about the GVHD asset. That's just -- just to share ideas there about -- it's been a difficult disease to treat. Certainly, we've got a lot more drugs or, I guess, 2 more drugs coming into that marketplace. Do you think that's kind of encouraging because it kind of changes the way physicians will be thinking about using drugs in GVHD? So just your thoughts around that?

Yes. I mean, look, chronic GVHD is a complication of bone marrow transplantation. It's a bad disease, and there have been a number of agents that have been used steroids, calcineurin inhibitors, various things all used pretty much off-label. And the first drug actually approved for it was ibrutinib. As you just pointed out, we've now seen a Phase III trial from Insight with ruxolitinib and registration program from Cadmin. So I do think there's -- we actually think it's quite encouraging to see agents getting approved, and we'll see how the launches go. But we think this is a potentially very important area of unmet need that, to be honest, people have not been successful in developing drugs for. I think there's now clear endpoints that the FDA accepts. There are trial designs that the FDA accepts. And we think it's a very attractive sort of, in a way, untapped commercial and clinical opportunity.

And then maybe in the last couple of minutes, you could kind of talk through that that kind of niche that you look like you're carving out around the fibrotic manifestation of GVHD, just like how big is that when new patients go through that issue?

Yes. So again, I wouldn't say that we're trying to carve out that niche. I would say that our drug seems to be particularly active in that segment of patients. But again, the Phase I data that we presented at ASH, the drug was quite active across multiple manifestations of the disease in very heavily pretreated patients who already failed 4 or 5 prior therapies. What I think many of our investigators have commented on that is perhaps, in their view, most remarkable, is some of the effects on the fibrotic lesions, particularly some of the skin manifestations of chronic graft-versus-host disease and the pulmonary manifestations. So I think our intent is to fully characterize the potential of the drug in this late line setting and then think about, again, using it earlier. One of it -- obviously, if you think about a patient who got a bone marrow transplant, the preferred solution for that patient is to never develop chronic graft-versus-host disease. And so the question is, could you use this agent early on in the course of a patient soon after their transplant and prevent them from ever developing chronic graft-versus-host disease, that would be, obviously, for the patient much, much preferred to treating it once it's so late in the disease as it is now. But like all of oncology, we start in late-line therapy. We show that the drug works, we show that the drug's safe, and then we move our way up into earlier, just as we talked about for the menin program.

Got you. And just in a final minute, just the data readouts we get, will it be initiations in different indications first? Or will we see kind of interim readouts?

No. So I think the -- for axatilimab?

Yes.

Yes. What we've guided so far is just the final readout from the GVHD trial. And then there is a Phase II expansion cohort that we ran at the 1 milligram per kilogram, that may be presented -- an update on that population may be presented at the end of the year. And then to your point, we are looking at this antifibrotic capability of the drug for other indications beyond the chronic graft-versus-host disease. And there, it would be study starts or agreement from FDA on what those studies would look like.

Great. We are unfortunately out of time. So I just wanted to thank you, Briggs, Daphne, Michael. And it's just absolute pleasure speaking to you as always. And thanks for joining Barclays fireside chat.

Thanks for having us, Peter.

Thanks, Peter.

I wish we could speak for longer. Take care. Thanks so much.