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

Good afternoon, and thank you all for joining us. This is Konstantinos Aprilakis. I recently joined the health care equity research team here at Stifel, as a senior biotech analyst. It's my pleasure to introduce Dr. Briggs Morrison, CEO of Syndax. The Syndax team have kindly prepared a brief corporate presentation for us. Please note that this session will not feature a live Q&A. We ask that you submit any questions for the company directly to our corporate access team via e-mail that can be reached at stifelcorporateevents@stifel.com. That's all one word, stifelcorporateevents@stifel.com. And with that, I'll turn it over to you, Briggs.

Thanks so much, Konstantin. Pleasure to be here today to tell you -- bring you up-to-date on where we are in our corporate journey. Let me start with our forward look statement. Again, you can reference our SEC documents to see all the various risk factors that come with investing in Syndax. Our pipeline right now, we have 2, we think, really exciting projects making their way into potential registration programs quite soon. The first is 5613, a small molecule inhibitor of the interaction of menin with MLL1. This is being developed for treatment of acute leukemias. We have a -- some Phase I data that was presented at AACR, which I'll talk about a little later in the presentation, which we think validates this as a new and important target for acute leukemias. We anticipate starting Phase II for this program early in 2021 with a pretty clear potential fast-to-market regulatory path. Our second molecule is an anti-CSF-1R antibody. Being developed for diseases that are driven by the monocyte macro based lineage. We already have proof-of-concept data for the treatment of chronic graft-versus-host disease. We've put out an abstract for the ASH session a week or 2 ago. And we'll have an oral presentation at ASH in a couple of weeks. We're all geared up and ready to start our pivotal trial by the end of this year. And we think that molecule potentially has activity in other fibrotic indications, which we're continuing to explore. Our business approach has been a license and development company. And so we continue to look for additional molecules that we can bring into our pipeline through acquisitions. So let's start with 5613, our menin inhibitor. The -- what we really like about 5613 and about the whole story here is that and I'll walk through the target, we believe, has very strong target validation and allows us to precisely treat the patients who we believe will benefit 2 different forms of acute leukemia. Because you know the patients who are potentially going to benefit, you could potentially see a large effect from the treatment in small number of patients, validating the target and giving you a fairly rapid regulatory path. As I said, the science behind this has been accomplished quite extensively. Our collaborations with Scott Armstrong's lab resulted in a cancer cell published the end of last year, which went through the biology around men in M&L interaction for MLL-r leukemias. And then earlier this year, there was a patient -- a publication in science that went through all the preclinical work, validating this target for NPM1 acute myeloid leukemia. These 2 leukemias are where our key focus is initially MLL-r acute leukemias result from a specific chromosomal translocation that I'll talk about in a second, represent about 5% to 10% of AML and about 10% to 15% of ALL. In infants, if you ever hear of an infant developing ALL, about 80% of those are driven by these or rearrangements. And it's fair to say that these patients have a very bad prognosis. And so we're hopeful that our agent will improve prognosis for these patients. NPM1 mutant AML is perhaps the most common mutation in adult AML, represents about 30% of all AML patients. And in and of itself, if you have an NPM1 mutation alone, it's actually a slightly better prognosis than the typical AML patients, AML that has NPM1 with additional co-mutations is a poor prognostic group that, again, is in need of abdominal therapies. So the story here around -- starts with MLL-r. And so MLL-r is a what they call mixed lineage leukemia rearranged. And it's driven by a fusion protein, which is shown in the panel on the left-hand side here. The fusion protein, the right -- at the left-hand version format of the fusion protein or the amino terminus always comes from a protein called MLL1. And in the right-hand portion of the fusion protein or the carboxy-terminus, comes from a variety of different fusion partners. The fusion partners are themselves generally transcription factors. And so you end up with a fusion protein that acts as a transcription factor. The key insight in developing drugs for this fusion protein was the observation that in the immuno terminus in the left-hand portion of the molecule, it binds to a protein called menin. And it needs to bind to menin to transform cells. If you mutate the fusion protein, so it can't buy into menin, it's non transforming. If you block in any way, it's interaction with menin, it's non transforming. And on the right-hand side of the slide, is a crystal structure of menin showing MLL binding to menin. And we now understand this at very high-resolution of exactly which amino acids of MLL1 bind to menin and in that way, make small molecule inhibitors that sit in that pocket and displace MLL1 from binding to menin. So 5613 is a rationally designed small molecule that sits right in that pocket and displaces MLL1 for binding to menin. And this cartoon sort of shows you schematically, why this matters to the leukemic cells. The MLL fusion protein in the panel on the left-hand side binds to menin and brings with it, a whole host of other proteins that are involved in activating transcription. And what we see is transcriptional activation genes in the HOX family and in the MIES family, both of which are known to be involved in leukemogenesis. If you add 5613 in the panel on the right-hand side, it binds to menin exact same spot that MLL1 wants to bind, and it displaces MLL1, the fusion protein and all the other associated proteins from the place on the chromosome where they want to act. And since they've all been displaced, all that transcriptional activity in HOX and MIES is turned off, the cells differentiate and eventually die. On this slide, I show a little bit of preclinical data validating this mechanism in MLL-r leukemias, perhaps the one that is most compelling is the panel on the right. This is a patient-derived xenograft from a patient who had MLL-r leukemia that xenograft is injected into mice where they develop a leukemic state. And then you can see at the very top, we treat these animals only for 28 days with one of our inhibitors. This is not a development candidate. This is SNDX-469, a tool comp and that we've used in all our preclinical models. But you can see we treat for 28 days, the animals that are received vehicle essentially are all dead within 2 weeks. The animals that received a low dose of the compound a 30 MPK their survival is dramatically improved. And the animals that received the higher dose, the 60 MPK, essentially all of them or 90% of them, are cured despite the fact that we only treat for 28 days. So we see really profound single-agent treatment benefit in multiple preclinical models of MLL-r. On the next slide is to show you a little bit of data, which comes from our work done with Scott Armstrong's lab looking at NPM1 AML. So NPM1, as I mentioned earlier, is the most frequent molecular alteration in AML. And again, depends on genes known to be sensitive to the menin MLL interactions. Patients with NPM1 leukemia are identified routinely today through a next-generation sequencing. And patients with MLL-r are identify today through routine karyotyping of patients with AML. So both populations of patients are routinely identified, physicians know who these patients are. On the panel on the right is again, a preclinical patient-derived xenograft an AML sample that has an NPM1 mutation, but also has a FLT3-internal duplication. Similar to what I showed you previously, in this experiment, we treat only for 90 days after the leukemia is established. And the -- and the mice who have -- get vehicle, you can see they quickly die. And the mice that get the full dose of the inhibitor appear to be cured from their leukemia, even though you only treat for 90 days. So again, a very potent anti-leukemic effect preclinically, both in NPM1 and in MLL-r. We've then gone on to do some detailed PK/PD experiments, giving various doses of the drug to mice, in this case, with [indiscernible] 13 MLL-r leukemia trying to figure out exactly what exposures we would need to see efficacy and see if we can use that as a bar for when we enter the clinic. And on the panel on the right, you see various PK curves for different dose exposures in the mice. We've then taken this and correlated that to efficacy in mouse experiments. And through that analysis, we have sort of a target PK profile that we think if we can achieve these types of exposures, maintain the steady-state level above the IC 95 for most of the dosing interval, keeping that semen above the IC 90 and AUC in the 30,000 range. That, we predict, would be sufficient for giving efficacy in patients. And so we've been looking at the PK exposures as we conducted our Phase I trial. The Phase I trial started just about a year ago, actually, standard, fairly standard dose escalation program single patient cohorts initially until we see Grade 2 toxicity and then expand to a 3+3. There have been a couple of changes in the protocol as we've gone along. Initially, it was an all comers population, any patient who had relapsed or refractory acute leukemia, either ALL or AML. We've now focused that program in on patients who have NPM1 and AML rearranged leukemias. And again, the key endpoints of the Phase I trial is really around safety, pharmacokinetics and picking a recommended Phase II dose. Once we have that completed, and we anticipate completing that over the next -- in the near term. We would go into Phase II expansion cohorts. One cohort is patients with MLL-r ALL, the second cohort of MLL-r AML, and a third cohort of NPM1 mutant AML. These are essentially parallel Phase II trials that run independent of each other, but all within one protocol. And the primary endpoint there would again be the CR rate, how many patients develop a complete response. We anticipate presenting the full Phase I data and initiating these Phase II expansion cohorts early next year. As I mentioned earlier, at the AACR this year, back in the Spring, it seems like a long time ago, given the lockdown we've all been living through. But back in the spring, we presented a small amount of data, the initial 6 patients who have been treated on our Phase I trial, and 3 of those patients had neither NPM1 or MLL mutations. 3 of them had MLL-r mutations. And sort of quite gratifyingly, I think the second patient enrolled in the trial, the first patient enrolled who had an MLL-r rearrangement had a complete response. And so I think that's given us confidence that this mechanism is relevant, at least for the patients who have MLL-r. Additional data will need to be generated in the clinic to validate the NPM1 mutant aspect of this. But we also presented AACR, all of the preclinical data describing the general features of our molecule, it's biopharmaceutical properties. And as I talked about here, all monotherapy activity in preclinical models. So at this stage of the game, we're, as I said earlier, prepared to present our Phase I data, complete Phase 1 program and start Phase II early in 2021. We then are thinking already about what do we do beyond this relapsed/refractory population, the standard, I think, in developing drugs for leukemias to show you have activity in your relapsed/refractory population. And then think about other places to go. So we think of the relapsed/refractory is a fast-to-market regulatory path with subsequent approvals prioritized sort of medical need and commercial opportunity. We're looking at frontline trials both in MLL-r and in NPM1, AML as well as in all. And as I mentioned earlier, the pediatric population an area of keen interest for us as well. So we're looking at front line trials, both in AML and ALL and pediatrics. Let me now turn to our anti-CSF-1R antibody, axatilamab. Axatilamab is a potentially best-in-class CSF-1R antibody that binds to CSF-1R and blocks ligand binding of both ligands, CSF-1 and IR-34. We have Phase I data that's going to be featured in oral presentation during the ASH virtual meeting next month. The abstract had about 12 patients at the presentation, there will be about 15 patients with refractory chronic graft-versus-host disease treated in our Phase I trial. And we are quite pleased to see both the overall response rate and the safety profile of the drug that we think portends, this could be a quite useful agent for the treatment of these patients. And as I mentioned earlier, based upon what we're seeing in GVHD and some of the underlying science of why the molecule work in GVHD, we think there could potentially be a broader utility for this in other fibrotic diseases. This next cartoon illustrates why we think this works. There are monocytes that come out of the bone marrow that differentiate into macrophages and cause the fibrotic reaction you see in chronic graft-versus-host disease. And that can be blocked an antibody against CSF-1R. CSF-1 is Colony Stimulating Factor I is a critical growth factor for these monocytes and for their differentiation. Chronic graft-versus-host disease disease is an immune-immediated disease that comes in patients who've undergone bone marrow transplant. It shows up as an inflammatory fibrotic disease in multiple organs, the scan in the lung being some of the more difficult on to treat. And preclinical data with surrogate antibodies has shown that CSF-1R could potentially be an important therapy for chronic graft-versus-host disease. That's what led us to undertake our Phase I trial. About 40% of patients will develop chronic graft-versus-host disease after their transplant. The prevalence in the U.S. is about 14,000 patients. We, again, did a sort of standard dose escalation trial in patients with chronic graft-versus-host disease who had to have failed at least 2 prior therapies, could be down to a minimum of 6 years of age. And this slide shows the doses that we have studied. Again, the Phase I -- the results from this Phase I trial will be presented as an oral presentation next month at ASH. What I can highlight that we -- the initial abstract that came out for ASH showed that in 7 of the 12 patients, we had an objective response, and we saw responses in multiple organ systems there'll be additional data presented in the oral presentation that was not in the abstract itself because the oral presentation is further updated. The patients had received a median of 5 prior therapies, including some of the agents that are now making their way into usage in this disease, including ibrutinib, ruxolitinib and KD025. Importantly, we think the drug was actually quite well tolerated at -- as we did the dose escalation, the 1 milligram per kilogram has been expanded into a small Phase II, and that seemed to be quite well tolerated. In this slide, on the far right, you can see sort of a graph -- a pictorial representation of the efficacy of the drug. This is a patient who had terrible skin graft-versus-host disease as you can see in the picture on the top with a lot of inflammation and open ulcerated wounds that would not heal. Unfortunately, this core patient had these lesions for over a year. They were treated with our -- with axatilamab and you can see the picture on the bottom that the inflammation has essentially completely resolved and the ulcers are on their way to resolving. And it's this type of observation that has us really quite excited that this molecule could potentially both be an agent for the treatment of chronic graft-versus-host disease, and particularly, in hard-to-treat organs like skin, but may also have opportunity as a broad anti fibrotic. We now have agreement with FDA to go into a registration trial in chronic graft-versus-host disease. It will be a trial done in patients 6 years or older, who have recurrent or refractory active GVHD, having received at least 2 prior lines of systemic therapy. We're pretty much ready to start the trial by the end of this year, patients we randomized to one of 3 dosing regimens and doses. The first 2.3 mg per kg and 1 mg per kg are given every 2 weeks, the 3 mg per kg is given every 4 weeks. So potentially, we could have a more patient-friendly, once a month dosing regimen. We're testing that, obviously in this trial. The primary endpoint is overall response rate using the standard NIH GVHD criteria with other endpoints, looking at duration of response improvement in quality of life using the so-called Lee symptom score. So this trial, as I said, should start by the end of the year. Our guidance at this point is data in 2023. I will just again mention that our business model is what we call license and develop, so we continue to look for molecules. We believe this is a core capability of our company. And we've been able to license in, we believe, 2 very exciting programs. We have very good relationships with many sources of potential molecules. And hopefully, we'll be able to bring in additional ones as well. Finally, for our financial highlights in our fourth quarter financial guidance. We finished the third quarter with about $170 million in cash, 44 million shares total fully diluted shares outstanding, and we've guided in the fourth quarter of this year for R&D expense to be about $15 million to $20 million. Total operating expense is somewhere been $20 million and $25 million. We believe that the cash we have will take us into 2022 and through critical milestones for the company. So again, a very, very exciting time. We think to be at the company 2 really exciting programs is if all the stars align, both of them will be in registration trials in the first half of next year. With that, I'll stop. Go back to you, Konstantin, and see if there are any questions that have come in over the wire.

That was a great overview, Briggs. I'll remind our listeners, any questions for Briggs and his team, you can submit via e-mail at stifelcorporateevents@stifel.com. Many thanks to Briggs and Syndax for your participation and to the audience for your attention. Thank you, and have a great rest of the conference.