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

Good morning, and thank you for joining us today. My name is [ Andrew Lang ], and I'm an analyst in JPMorgan's health care group. Before I introduce you to our presenters today, I want to call your attention to the blue ask a question button on your screen. This is where you'll submit questions that will be addressed at the end during the Q&A session. With that, I am pleased to introduce you to the Syndax team here today. Briggs Morrison, CEO; Michael Metzger, President and COO; and Anjali Ganguli, CBO. I know they're very excited to tell you a little bit more about their story. So we'll turn it over to them.

Great. Thank you so much, Andrew, and welcome and thank you to those of you joining us on the line this morning for a summary of our current corporate priorities as we strive to realize a future in which people with cancer live longer and better than ever before. I'm Briggs Morrison, CEO of Syndax. This call is being accompanied by a slide deck that you will be able to advance on your own. So I would ask you to please turn to our forward-looking statements on Slide 2. Before we begin, I'd like to remind you that any statements made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act. Actual results may differ materially from those indicated by these statements as a result of various important factors including those discussed in the Risk Factors section in our company's most recent quarterly report on Form 10-Q as well as other reports filed with the SEC. Any forward-looking statements represent our views as of today, January 12, 2022 only. And a replay of this presentation will be available on our website. So we turn to Slide 3. Slide 3 provides a high-level summary of our intent to grow our company through pipeline development and continued in-licensing. When our kids look back on the history of Syndax, I believe that last year, 2021 will be remembered as a transformative year for our company. We now have 2 registrational programs ongoing for 2 first-in-class and potentially best-in-class medicines for 2 areas of important unmet medical need. SNDX-5613 is our selective menin inhibitor. And we have pivotal trials ongoing for patients with relapsed or refractory NPM1 and MLLr leukemias. Notably, we were the first to demonstrate clinical validation of targeting menin for acute leukemias. And now ours is the first program to advance into registration-oriented trials. Importantly, we are poised to expand beyond the relapsed/refractory population and have trials starting this year that will position us for both first-line and maintenance indications. Axatilimab is our antibody against CSF1R, and enrollment is ongoing in our pivotal AGAVE-201 trial for patients with chronic graft versus host disease, whose disease has progressed despite 2 prior therapies. Importantly, we now have Incyte as a fabulous partner to maximize the value of this important program by expanding into earlier lines of therapy. And we anticipate starting a POC trial in IPF later this year. Thanks to the support of our many committed investors, we are well financed to vigorously pursue both of these existing programs and to aggressively look for additional opportunities to bring targeted oncology drugs into our pipeline. Let me now briefly summarize our 2 ongoing programs. I will note that both programs were presented in oral sessions at ASH in December of last year. So I will briefly summarize the data that was presented. And I'll remind investors that the full presentations are available on our website. On Slide 4, I'd like to introduce the first 2 diseases that we intend to address with SNDX-5613, our selective menin inhibitor. On the left panel, we summarize mixed lineage acute leukemias, which represent -- can present as either AML or ALL. There are currently no FDA-approved medicines that specifically target MLLr acute leukemias, which have a global incidence of about 5,000 to 7,000 patients per year and have a particularly grave prognosis. On the right panel, I summarize NPM1 acute leukemias. NPM1 mutations are the single most common mutation in AML occurring in about 30% of newly diagnosed patients. And many of these patients similarly have a poor prognosis. Both of these mutations are routinely diagnosed today. And physicians are looking for an effective and well-tolerated agent for their patients with these diseases. On Slide 5, I briefly summarized the mechanism of action of SNDX-5613. Briefly, it has been shown that the interaction of MLL1, either the MLLr fusion protein in the case of MLR leukemias or the native protein in the case of NPM1 leukemias is required for transformation. As diagram in the left panel, when the MLL complex is tethered to chromatin via be its binding to menin, specific genes are turned on that cause leukemic transformation. And as diagram in the right panel, SNDX-5613 binds to menin, displaces the MLL complexes turning off this leukemic gene transcription leading to either differentiation or death of the leukemic cells. On Slide 6, I summarize our Phase I/II first-in-human clinical trial. Again, all of the details of this trial and the results to date were presented at ASH in December of last year by Dr. Eytan Stein with the Memorial Sloan Kettering Cancer Center. The trial began as an all-comers trial in adult patients with any relapsed or refractory leukemia. But as the trial progressed, the trial focused enrollment only on patients with either MLLr or NPM1 genetic abnormalities. Enrollment of pediatric patients was also allowed as the trial progressed. The objective of the Phase I portion was determined the maximum tolerated dose and a recommended Phase II dose as well as to characterize PK, PD and efficacy. Slide 7 shows the baseline characteristics of the full 59 patients that were enrolled in this Phase I trial. You can see that the patients are heavily pretreated with a median of 4 prior therapies. 42% of the patients had at least one prior stem cell transplant and about 60% of patients had received prior venetoclax. Most of the patients in this Phase I trial had relapsed or refractory AML. Slide 8 shows the treatment-related adverse experiences with the table on the left showing all grades and the table on the right showing only Grade 3 or higher adverse experiences. We did see some cases of differentiation syndrome, but all were Grade 1 or 2 and easily managed with standard therapies such as hydroxyurea or steroids. The one other adverse experience of note is QTC prolongation. These tend to occur early in therapy and have been asymptomatic ECG findings. About 7% of patients had Grade 3 QTC prolongation at the recommended Phase II doses, all of which resolved with dose reduction. But overall, I think it's important to note how well tolerated SNDX-5613 has been so far, which bodes well both for chronic monotherapy dosing and for being able to use full doses in combination with other antileukemic agents. If you turn to Slide 9, you'll see the impressive efficacy that we have seen to date in this heavily pretreated population of patients. We have focused the efficacy analysis on the 51 patients who had either NPM1 or MLLr genetic abnormalities. The overall response rate was 55% and 24% of patients met the FDA regulatory endpoint of CR or CRh. That is complete response or a complete response where their blood counts come back to at least half normal. Remarkably, of the 12 patients who had a CR or CRh, 92% of those responses were MRD negative. And then the broader CR/CRh, CRP population, 84% of the responses were MRD negative. The CR, CRh rate was comparable between NPM1 and MLL genetic abnormalities. And indeed, all 3 of the NPM1, CR, CRh responses were MRD negative. So it appears from this Phase I data that the drug is quite active in both NPM1 and MLLr populations. Slide 10 is a Kaplan-Meier plot of durability of response in the 12 patients who had a CR or CRh. I will note that the median duration of response has not yet been reached and the Kaplan-Meier estimate of continued remission at 6 months currently stands at 70%. Given this promising Phase I data, last year, we progressed into 3 Phase II registration trials as illustrated on Slide 11. There are 3 independent pivotal trials in patients with either relapsed/refractory MLLr ALL, MLLr AML, or NPM1 mutant AML. In each pivotal trial, patients are dosed with 5613 and 163 milligrams twice a day with any strong CYP3A4 inhibitor. The primary endpoint is the rate of CR/CRh, with duration of response and other measures as secondary endpoints. Importantly, should a patient have a response on SNDX-5613 and go on to get a bone marrow transplant, the patient can go back on 5613 after transplant. We expect the fastest enrolling cohorts to be the AML cohorts but anticipate that all 3 cohorts should complete enrollment by the beginning of next year. I mentioned in my opening that we are poised to expand beyond the relapsed/refractory population and have trials starting this year that will position us for both first-line and maintenance indications. Those trials are shown on Slide 12. The panel on the left illustrates our first-line trial combining 5613 with venetoclax and azacitidine. The middle panel illustrates our first trial testing 5613 in combination with chemotherapy. And the panel on the right shows a very innovative trial to test the activity of 5613 in patients who are in morphologic remission, but still have MRD-positive disease. These patients are at very high risk of relapse. This last trial could provide a path towards a maintenance approach with 5613. So as you can see, we are aggressively capitalizing on our leadership position in the menin space to expand our growth opportunities. Let me now turn to Slide 13 and introduce axatilimab, our first-in-class and best-in-class anti-CSF-1R antibody. We are developing axatilimab for patients with chronic graft versus host disease, a disease that develops in about 40% of patients who undergo allogeneic stem cell transplant. Preclinical data had indicated that bone marrow-derived monocytes, which are dependent on CSF-1, could mediate the inflammatory and fibrotic components of this multi-organ disease. On Slide 14 shows our Phase I and Phase II trial design. Again, the full data from these 40 patients were presented by Dr. Stephanie Lee at ASH last month. And that full presentation is on our website. So I will briefly summarize the data. The Phase I component led us to take 1 milligram per kilogram every 2 weeks and 3 milligram per kilogram every 4 weeks into our registration trial. And the Phase II expansion cohort enrolled an additional 23 patients using that 1 milligram per kilogram every 2-week regime. Slide 15 shows the baseline characteristics of the full 40 patients, the Phase I and Phase II. We again see a very heavily pretreated population of patients who have suffered with their chronic graft versus host disease for a median of greater than 3 years. Slide 16 shows the overall safety summary profile that we saw in these 40 patients. Again, the drug was very well tolerated. The panel on the left shows all treatment-related adverse experiences regardless of grade. And the panel on the right shows the adverse experiences that were Grade 3 or higher. Mechanism-based adverse experiences, including LFT normalities and periorbital edema were observed, but were rarely dose limiting. Slide 17 summarizes the efficacy seen in this heavily pretreated population. The overall response rate approached 70% with many responses ongoing well beyond 6 months. And the median time to response was a rapid 4 weeks. Based upon these promising early clinical data, we have initiated a registration trial outlined on Slide 18. This trial is the axatilimab for a graft versus host disease trial, which we call AGAVE-201. The trial is enrolling patients with chronic graft versus host disease, whose disease has progressed after 2 prior therapies. Patients must be at least 2 years of age and have met our overall entry criteria. And this is a pivotal dose-ranging trial in which patients will be randomized to 1 of 3 treatment groups, each investigating a distinct dose of axatilimab given either every 2 weeks or every 4 weeks. The primary endpoint is overall response rate using the 2014 NIH consensus criteria for GVHD. And secondary endpoints will go duration of response and validated quality of life assessments using the lease symptom scale. Enrollment of this study is well underway, and we're on track to deliver top line data in 2023. Now as I said in my introduction, Syndax and Incyte have entered into a broad long-term global collaboration that we believe brings together 2 companies with a solid track record of innovation to accelerate and maximize the development of axatilimab. So to briefly recap the agreement summarized on Slide 19, the deal provided Syndax $152 million upfront, $117 million in cash. And notably, a $35 million in equity at a 30% premium, which we believe is a strong endorsement of our company and its overall value proposition. The 50-50 profit split in the U.S. enables us to retain significant upside and actively participate long term in the franchise build-out. The 45%, 55% cost sharing mechanism limits our downside and extends our cash. And the opportunity for co-commercialization in the U.S. will allow us to participate in the launch of an important product alongside a strong commercial partner. Outside the U.S., we will rely on Incyte to develop and launch the product in all the major markets to maximize its full potential as a global brand. The economics to Syndax over the course of the collaboration are enhanced with key regulatory and sales milestones, covering multiple indications throughout the world. And those payments total an additional $450 million. Syndax also receives double-digit royalties on the ex-U.S. Also important to highlight is the development plan, which calls for the partners to design novel combinations with axatilimab and Incyte's JAK inhibitors with the goal of establishing axatilimab in earlier settings within GVHD and expanding its market opportunity. As we previously mentioned was our intention, Syndax will initiate and fully fund a proof-of-concept trial in IPF, the first expansion outside of establishing chronic graft-versus-host disease as a beachhead into other fibrotic diseases where we believe axatilimab could have a significant impact. Successful development in IPF could lead to an additional approval in a very important indication of considerable value and would provide support for axatilimab in other fibrotic-driven diseases that the parties could explore over the course of the collaboration. Slide 20 summarizes the transactions that led to the acquisitions of the menin MLLr and axatilimab programs. We believe these transactions underscore our robust capabilities to evaluate and identify high-value differentiated assets as well as the clinical development expertise to bring these compounds through key value inflection points. We anticipate that we'll be able to continue to expand our pipeline through product acquisitions or in-licensings of quality, differentiated assets, and we expect to remain among the preferred partners of such transactions. Our focus is for early-stage molecules, those that are perhaps 12 to 18 months to IND or in a Phase I, where we think we can add tremendous value given our proven expertise in translational medicine and our proven expertise in rapid, high-quality clinical development. Slide 21 provides our financial highlights. I show both the cash and short-term investments as audited and disclosed at the end of the third quarter as well as the pro forma cash and short-term investments on hand as of the end of 2021. The pro forma number includes the proceeds from our collaboration with Incyte as well as the proceeds from our December 2021 offering. I also show the total shares outstanding, again, as of the end of the third quarter and the pro forma shares as a result of the shares issued to Incyte and the shares sold in our recent offering. Importantly, we believe we have cash on hand that should fund the company well into 2024 and through the approval of both of our molecules. So thank you very much for your time and hearing our update today. I think, Andrew, I'll turn things over to you for questions.

Great. Thank you, Briggs. Thanks so much for the presentation. It's definitely very informative. And congrats on the success to date.

So I guess the first question we have is, could you talk a little bit about the SNDX-5613 data that you just presented at ASH? Do you believe it derisks the potential that the ongoing Phase II registrational studies could lead to an approval in each of the acute leukemia indications being studied?

Yes, sure. Thank you, Andrew. Thanks for that question. So the short answer is, yes, we do think it derisks the potential for approval. Going into ASH, there were 2 major questions, I think, that we're circulating around 5613. One is does the drug work in both MLLr and NPM1. We had presented data early in 2021 that I think was quite strong on MLLr, but we had less data on NPM1. And the second question that people were interested in was the durability of responses because durability of response is an important regulatory consideration. And I think the data that we presented at ASH answered both of those questions. Again, as I went through in my presentation, the response rate, and importantly, the regulatory endpoint of CR/CRh responses is generally similar between NPM1 and MLLr. So I think it does look like the drug is active in both populations. And importantly, the durability that I showed you in the Kaplan-Meier plot, I think, again, suggests that the median duration of response will be more than 6 months, which, again, we think is more than adequate for regulatory approval. So short answer to your question, yes, we think the ASH data does significantly derisk the probability of approval for both MLLr and NPM1 leukemias.

Great. And then, I guess, when would you expect or anticipate those trials reading out? And what is the expectation around a subsequent NDA filing?

Right. So as I pointed out in my presentation, there are essentially 3 independent Phase II trials. If any one of them is positive, we could file with just one. If two of them are positive, we can file with two. If all three are positive, we can file all three. And we can file at different times for -- if they happen to enroll at different rates. We believe that the AML populations will enroll faster than the ALL simply because there's more innovation going on in ALL with a lot of competing studies. We anticipate that one or more of the AML trials could complete enrollment this year with data in 2023. As I said in my presentation, we think all three trials, we should have data -- in all 3 trials, we should have data in 2023.

Great. And next question, what are your plans for developing SNDX-5613 beyond its monotherapy use in relapsed/refractory MLLr or NPM1 acute leukemias?

Right. So thanks for the question. The -- what I think I pointed out on multiple occasions is in this Phase I trial, we're treating very, very heavily pretreated patients. And that's just the nature of oncology drug development. You start with patients who have no other options. And we're seeing really, I think, quite impressive activity in patients with heavily pretreated disease. What we've learned over the years in all of oncology is the earlier in a patient's disease course you treat them, the better they do and the longer they stay on therapy. So our goal is to get this drug into first-line therapy where the patients can benefit from the power of the drug early in the course of their disease. So the first trial, as I mentioned, is a combination with venetoclax plus azacitidine, which is quickly becoming a standard of care for patients who are not candidates for intensive chemotherapy. So that trial will start the first half of this year. And then we are working on a trial in which we combine our drug with so-called 7+3, the standard chemotherapy induction for patients who can get chemotherapy. We'll have more to say about that as the year progresses. And then I think the third point, which you -- and your question is the maintenance setting. So again, in some of these diseases with intensive chemotherapy, we can get patients into remission, but those remissions don't last very long. And the important point is how can we maintain that remission so that the patient's leukemia does not come back. As I indicated in my presentation, in our relapsed/refractory populations in the registration trials, if a patient goes into remission, again, as a result of taking 5613 and they go on to bone marrow transplant, they can go back on 5613. And all of our investigators have been asking for this in the Phase I trial because here's a drug that, despite how bad the prognosis was for this patient got them into remission, got them to a transplant, the doctor would love to put them back on the drug to try to maintain that remission. And so we're doing that in the relapsed/refractory population. And we're in the process of designing a formal maintenance trial where we will formally prove that, that maintenance therapy does, in fact, maintain remissions longer than not getting maintenance.

Great. And I guess if we switch gears a little bit to axatilimab. How does the data you presented for axatilimab in chronic graft versus host disease at ASH helped derisk the ongoing AGAVE-201 trial?

Right. So the AGAVE-201 trial, again, as I pointed out, there are 3 arms. There's a low-dose arm, 0.3 mgs per kg; the 1 milligram per kilogram, which I'll talk more about; and then the 3 milligrams per kilogram every 4 weeks, which is really an attempt to try to find if there is a regimen that's a little more patient-friendly than the every 2-week regimen. Because we have such a large amount of data on the 1 mg per kg every 2 weeks, that's what was presented at ASH, I think that significantly derisks that arm of the trial and gives it a high probability that we will be able to achieve the regulatory hurdles for the 1 mg per kg every 2 weeks. The 0.3 mgs per kg was put into the trial, essentially to try to identify what's the lowest dose that gives maximal efficacy. We do believe the 0.3 mgs per kg will be active, but not as active as the 1 mg per kg. And I think we have some data on those lower doses in the ASH data. But I think the most important piece is that 1 mg per kg, having more than 20 patients' worth of data showing nice response rates, good tolerability and good durability significantly derisks AGAVE-201.

Very helpful. And so I guess, what is the expectation for completing enrollment for the AGAVE-201 study and filing for approval in refractory chronic graft versus host disease?

Right. So we anticipate completing enrollment this year and filing the NDA next year.

Great. And then what are your plans for developing axatilimab beyond its monotherapy use in refractory chronic graft versus host disease?

Right. So as I said, the wonderful collaboration we have with Incyte allows us to do combinations with their JAK portfolio. Again, trying -- same concept that I talked about for AML. The earlier in the course of therapy you treat a patient, we think the better they'll do and the longer they'll stay on therapy. So it's -- one of the things we like to do is to start earlier-line therapies in combination with a JAK inhibitor to see if potentially we could identify a steroid-sparing regime. The first-line treatment for chronic graft versus host disease is steroids, which carries with it its own toxicity. So if we can come up with a steroid-sparing regime, we think that will be quite beneficial for patients. So those -- that work we -- as I said, we've kicked off our collaboration with Incyte. And we'll have more to say about those study designs and when all that will start relatively soon. And then the second piece is extending beyond chronic graft versus host disease. So as we've pointed out, the -- some of the data that we saw in the chronic graft versus host disease patients strongly encourages us that this molecule has anti-fibrotic effects. And so we spent quite a bit of time working with scientists who are studying interstitial pulmonary fibrosis. And we think there's very good rationale for testing the drug in that disease. That trial should start the second half of this year. And again, if that were to -- if we could show not only slowing of the disease of interstitial pulmonary fibrosis, but potentially actually reversal of the disease and improvement in FEC, I think that would be just a major accomplishment for that. So those are the two places where we're starting now going into earlier lines of chronic graft versus host disease and the proof-of-concept trial in IPF.

Great. And I guess, turning a little bit to COVID and Omicron. Has there been any kind of impact in regards to clinical development or supply chain?

Not to date, no. Again, I think that in the setting of acute leukemia, patients just need to be treated. And if anything, what we have heard a little bit from some of our investigators is because our therapy is a oral outpatient therapy that, that is actually -- that type of trial is less impacted because the patient's not coming into the hospital and -- which are overwhelmed with other COVID activities. So the fact that they can treat the patient as an outpatient and have them come in periodically for examinations is actually a plus there. Axatilimab, I would say we ran into a little bit of slowdown at the beginning of 2021. That has now resolved and we haven't seen any impact currently. Again, we'll see how the enrollment numbers come in January, February, but so far, things seem to be going well.

Great. That's great to hear. And I guess just a final question from me. What is the team most excited about in 2022?

Yes, I would say the team is most excited about finishing enrollment in our 2 pivotal programs. I mean, it's actually if you -- as we look at our project plan for the company, both axatilimab and 5613 are sort of running in parallel. They could complete enrollment in their pivotal -- in the pivotal trials roughly about the same time. We could be preparing 2 NDAs at roughly the same time. So it's a lot of work, but it's incredibly exciting for a company of our size to have this kind of portfolio, 2 programs. So I'd say the big excitement for '22, finish enrollment and get ready -- brace yourselves for 2 NDAs next year.

Great. Well, we'll definitely be on the lookout for that. And I guess, that was it for me. So thanks again for the time. And thank you, everyone, for joining our session and best of luck in 2022.

Thanks so much, Andrew. I really appreciate the opportunity to present. And any other questions that investors have, please feel free to give us a call.