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

Good day, everyone, and welcome to the Pivotal AGAVE-201 Top Line Axatilimab Data Conference Call. Today's call is being recorded. At this time, I would like to turn the call over to Sharon Klahre, Head of Investor Relations at Syndax Pharmaceuticals.

Thank you, operator. Welcome, and thank you all for joining us today. I'm Sharon Klahre, and with me this morning to provide a review of top line results from the pivotal AGAVE-201 of axatilimab in adult and pediatric patients with chronic graft-versus-host disease, following two or more prior lines of therapy, are Michael Metzger, Chief Executive Officer; and Dr. Niel Gallagher, President and Head of R&D. Also joining us on the call today for the question-and-answer session are Dr. Peter Ordentlich, Chief Scientific Officer; Dr. Anjali Ganguli; Chief Business Officer; and Keith Goldan, Chief Financial Officer. This morning, we issued a joint press release with Incyte, reporting top line data for the pivotal AGAVE-201 of axatilimab, which can be found on the Investors page of Syndax' website. Please turn to our forward-looking statement disclosures on Slide 2. Before we begin, I'd like to remind you that any statements made during this call are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. 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 the company's most recent quarterly report on Form 10-Q as well as other reports filed by the SEC. Any forward-looking statements made on this call represent our views as of today, July 24, 2023, only. A replay of this call will be available on the company's website, www.syndax.com, following its completion. With that, I am pleased to turn the call over to Michael Metzger, Chief Executive Officer of Syndax.

Thank you, Sharon, and thank you all for joining the webcast on this very exciting day for Syndax. This morning, we are thrilled to announce that all three cohorts in the AGAVE-201 pivotal trial of axatilimab, our monoclonal antibody targeting the CSF-1 receptor, met their primary endpoint of overall response rate in patients with refractory chronic graft-versus-host disease. These responses were durable and accompanied by a reduction in symptom burden in a notably advanced and heavily pretreated patient population. Furthermore, axatilimab was generally well tolerated, and the most common adverse events were consistent with on-target effects and prior trials, and we feel confident that these results will provide the necessary data for optimal dose selection. With these positive results now in hand and pending agreement from the regulatory authorities, we, along with our partners at Incyte, continue to expect to submit a BLA by year-end, with potential commercial launch in 2024. We and Incyte are extremely excited to be one step closer to bringing axatilimab to patients suffering from this devastating underserved condition. Before we turn to the trial results, let me just remind you on Slide 4, why we believe axatilimab will bring an effective and differentiated option for the 14,000 patients in the U.S. that suffer from chronic GVHD. Axatilimab has the potential to be the first approved treatment for chronic GVHD to target the disease-modifying macrophage. The slide -- the graphic on Slide 4 clearly demonstrates how the activation, proliferation and survival of these macrophage populations is regulated through the CSF-1 receptor. Through its ability to directly bind the CSF1 receptor, axatilimab is designed to decrease the proliferation and function of CSF-1R-dependent monocytes and their associated macrophages and has now demonstrated robust monotherapy activity in heavily pretreated patients. We believe axatilimab's differentiated mechanism may also offer the advantage of being an ideal combination partner with standard of care therapies available for the management of this disease. Axatilimab's ability to suppress macrophages allows it to have a significant impact on both anti-inflammatory and anti-fibrotic pathways, both of which are involved in driving the progression of chronic GVHD. Axatilimab is administered as a short 30-minute infusion in the clinic, allowing clinicians to have control over compliance as well as better treat patients experiencing any absorption issues, such as those with gastrointestinal manifestations. Based on its compelling clinical profile, which Neil will go through in the following slides, and supported by the positive feedback we have received from numerous key opinion leaders and treating physicians, we firmly believe that if approved, axatilimab will become an important addition to the chronic GVHD treatment armamentarium. I will now ask Neil to walk us through the AGAVE-201 trial results. Neil?

Thank you, Michael. Turning now to Slide 5. The global pivotal AGAVE-201 trial enrolled 241 adult and pediatric patients at 121 sites across 16 countries. The trial evaluated the efficacy, safety and tolerability of axatilimab in patients with active chronic graft-versus-host disease, whose disease has progressed after these two prior therapies. The primary endpoint of the trial was overall response rate by cycle 7 day 1, C7 D1, using the 2014 NIH consensus criteria for chronic GVHD. Patients were randomized to one of 3 treatment groups, each investigating a different dose of axatilimab. These were 0.3 milligrams per kilogram every 2 weeks, 1 milligram per kilogram every 2 weeks and 3 milligrams per kilogram every 4 weeks. Patients were treated until progression, but after 6 months on trial, patients at the 0.3 milligram per kilogram and 1 milligram per kilogram doses had the option to switch to an equivalent once-monthly dose. Patients were stratified at baseline based on prior exposure to ibrutinib, ruxolitinib or belumosudil as well as by disease severity. Because macrophages play an essential role in maintaining physiological homeostasis, these regimens were chosen to allow time for recovery of the macrophage population, thereby potentially minimizing adverse events, while maintaining robust efficacy. The demographics on Slide 6. Here, we present key baseline demographic data for patients included in the trial. The median age of patients enrolled in the trial was 53 years. The median time since diagnosis of chronic GVHD was 4 years. 54% of patients had four or more organ systems involved at baseline, including 45% of patients with lung manifestations. Patients had received a median of four prior lines of therapy, frequently consisting of recently approved therapies, as demonstrated by the fact that 74% of them had received prior ruxolitinib. 31% had received ibrutinib and 23% had received belumosudil. 80% of patients enrolled were classified as having severe chronic GVHD based on the NIH criteria. Now turning to Slide 7. The AGAVE-201 trial met its primary endpoint of ORR by cycle 7, day 1 across all dose cohorts, represented by the teal-colored columns on the chart. The response rate was assessed using the 2014 NIH consensus criteria for chronic GVHD for each dose. A cohort met the primary endpoint of the trial if the lower bound of the 95% confidence interval exceeded 30%, which corresponds to meeting or exceeding an approximate 40% ORR for an 80-patient-sized cohort. The overall response rate by cycle 7, day 1 was 74% in patients treated at 0.3 milligrams per kilogram every 2 weeks, 67% in patients treated at 1 milligram per kilogram every 2 weeks and 50% in patients treated at 3 milligrams per kilogram every 4 weeks. As you can see, the lower bands of the confidence intervals for all cohorts exceed the minimum requirement. In addition, we have included the best overall response achieved on trial represented by the dark blue columns. These results further support the consistency of effect observed within each dose cohort. The response rates were higher in the 0.3 milligram per kilogram and 1 milligram per kilogram cohorts than in the 3 milligram per kilogram every 4-week cohort. The highest overall response rate was achieved in the 0.3 milligram per kilogram cohort at 74%, as I mentioned a little earlier. While we have not yet analyzed exposure response relationships, these data may support our belief that lower doses provide a greater opportunity for macrophage function recovery between dosing intervals. And this may be key to higher response rates and improved tolerability, particularly at the 0.3 milligram per kilogram dose level. I would like to reiterate that patients enrolled in the AGAVE-201 trial had a longer time since diagnosis of their disease, 4 years; received more lines of -- prior lines of therapy for chronic GVHD and a higher proportion of lung disease involvement than patients included in prior pivotal trials for approved agents. Although the trial was initiated early 2021, before either ruxolitinib or belumosudil have been approved for the treatment of the disease, a high percentage of patients in the AGAVE-201 trial have previously received these therapies. This highlights the robustness of the clinical activity of axatilimab that observed in the study and the value of targeting this disease directly by inhibition of macrophages rather than through targeting T or B cells. On Slide 8, there were several secondary end points included in the study, including duration of response, validated quality of life assessments using the modified Lee Symptom Score scale, percent reduction in daily steroid use and organ-specific response rate. Slide 8, we include positive results from some of these secondary end points, and we look forward to presenting the full set of data that rather speaks to the robustness of the outcome of the AGAVE-201 trial at a future medical meeting. At the time of the data cutoff in April 2023, the median duration of response based on the Kaplan Meier estimate, defined as the time from initial response until progression, or DAP, have not been reached in the 0.3 milligram per kilogram cohort. Among responders treated with -- at 0.3 milligrams per kilogram, 60% of patients maintained response at 12 months. Importantly, clinical responses were also accompanied by a reduction in chronic GVHD symptom burden, with 55% of patients treated in the 0.3 milligram per kilogram cohort experiencing a clinically meaningful improvement in symptoms as measured by at least a 7-point improvement in the modified Lee Symptom Scale score. Additionally, responses were observed in patients previously treated with ruxolitinib, belumosudil and/or ibrutinib, which is meaningful, as physicians will want to understand the outcome for real-world treatment for their patients with refractory chronic GVHD. Moving to Slide 9. Axatilimab demonstrated a manageable safety profile in this refractory and heavily pretreated population. Most common adverse events observed were consistent with on-target effects of CSF-1R inhibition and prior results from axatilimab trials. Amongst the patients treated at 0.3 milligrams per kilogram, 18% experienced a Grade 3 or greater treatment-related adverse event, and only 6% of patients discontinued treatment due to an adverse event. Fatigue was the only adverse event of any grade that occurred in over 20% of patients. On Slide 10, we showed the adverse event profile for all patients treated in the trial. A higher proportion of patients discontinued therapy at the higher doses. And overall, a high proportion of patients at higher doses experienced adverse events of any grade. Laboratory adverse events that occurred in over 20% of patients included expected on-target events, such as increases in enzymes, aspartate transaminase -- aminotransferase, blood creatinine phosphokinase, lipase, blood lactate dehydrogenase and alanine aminotransferase, as well as fatigue. Overall, the safety profile of axatilimab was as expected. In summary, the data for the AGAVE-201 trial demonstrate the robust clinical activity and manageable safety profile of axatilimab in patients with recurrent or refractory active chronic GVHD and confirm our belief of axatilimab with its differentiated profile and unique mechanism of action is poised to provide a meaningful benefit to patients and change the paradigm of the treatment of chronic GVHD, if approved. I'll now turn the call back to Michael.

Yes. Thank you, Neil. Slide 11 provides an overview of the chronic GVHD market. We estimate that approximately 14,000 U.S. patients suffer from chronic GVHD, 50% of whom require treatment beyond second line due to disease progression, inadequate response or disease manifestations that aren't fully addressed with current treatments. Further, this population is expanding due to a rising prevalence of blood cancers as well as an increase in the number of stem cell transplants and is expected to continue to grow beyond the $2 billion to $2.5 billion market estimate for 2022. There are, unfortunately, no cures for this advanced population of chronic GVHD patients. So following initial treatment with corticosteroids, many patients are cycled through a variety of additional therapies. We believe there is a broad clinical and commercial opportunity for axatilimab. As outlined on Slide 12, the treatment paradigm for these patients is evolving with the recent approvals of therapies specifically for the treatment of chronic GVHD. Until recently, most chronic GVHD patients were managed with off-label generic agents. However, Jakafi and Imbruvica are now approved second-line treatments for chronic GVHD, while Rezurock is approved as a third-line agent. Despite these approvals, there remains a significant unmet medical need for a disease-modifying treatment, and chronic GVHD continues to cause significant morbidity and mortality among patients following transplant. Importantly, the successful commercial launches of Incyte's Jakafi and Sanofi's Rezurock speak to the unmet need in chronic GVHD that translates to a large commercial opportunity. Chronic GVHD can manifest very differently across patients, and there is no one-size-fits-all therapy for these patients. As physicians gain experience with the recently approved drugs for chronic GVHD, they may choose their treatment option based on ability of a given agent to manage specific disease manifestations. We believe axatilimab's unique mechanism of action and clinical and safety profile will provide a differentiated option for the treatment of chronic GVHD, if approved. On Slide 13, I want to reiterate a few key points that we covered in the presentation. First, axatilimab is the only investigational agent to target disease-causing macrophages and impact fibrosis and inflammation as a way to treat chronic GVHD. We believe the data shows that axatilimab has a best-in-category profile at the 0.3 milligram per kilogram every 2-week dose. In the AGAVE-201 trial, patients experienced a high overall response rate, which was durable and accompanied by a meaningful reduction in symptom burn as measured by the modified Lee Symptom Score. Axatilimab is a monoclonal antibody. So it is less likely to cause drug-drug interactions than small molecule competitors, and it has been very well tolerated throughout the chronic GVHD clinical experience, especially at the 0.3 milligram per kilogram dose. We feel confident that this trial reflects real-world treatment, given how many patients were treated with recently approved standard of care agents prior to entering this trial. Axatilimab's ability to target monocyte-derived macrophage development activation and proliferation may provide a more comprehensive control of the disease as compared to targeting of individual enzymes or signaling pathways. This could be a key differentiator and suggests a benefit from moving axatilimab early in the treatment -- earlier in the treatment regimen to help prevent organ damage before it occurs. Combinations in earlier settings, both in adults and pediatrics as well as the opportunity to expand to the ex-U.S. markets, could build significant additional value for axatilimab in chronic GVHD. The impact of axatilimab across all organ manifestations in chronic GVHD, as demonstrated in the published Phase I/II data, also supports expanding into other fibrotic diseases. Specifically, the data we presented in chronic GVHD-related bronchiolitis obliterans syndrome, or BOS, at the American Thoracic Society Conference earlier this year, coupled with the fact that we had a high percentage of patients with lung manifestations enrolled in this trial, provides further support that axatilimab may provide a substantial benefit in other diseases of the lung, where the monocyte macrophage lineage just thought to play a key role, such as idiopathic pulmonary fibrosis, or IPF. Slide 15 lays out the near-term milestones that we anticipate will enable us to realize the full potential of axatilimab for patients and maximize growth for Syndax. First, we expect to present the full data set from AGAVE-201 at a future medical meeting, which would allow us to further present on axatilimab's compelling clinical profile and the overall benefit it can bring to chronic GVHD patients. Next, along with our partners at Incyte, we intend to discuss these data with regulatory authorities and pending agreement, to submit a BLA for axatilimab in relapsed or refractory chronic GVHD by the end of 2023. While Incyte will be leading these regulatory activities, we will be collaborating with them closely to ensure timely and successful submission. Third, we are looking forward to the initiation of two clinical trials by year-end 2023. In chronic GVHD, we expect that Incyte will initiate a Phase I/II combination trial of axatilimab with Jakafi in treatment-naive patients. Moving axatilimab earlier in combination could potentially reduce steroid use and benefit morbidity and mortality. In IPF, we plan to initiate a Phase II trial, with the goal of generating proof-of-concept for axatilimab, on top of standard of care treatments, along with clinical information to better guide the long-term development in IPF. In parallel, we remain keenly focused on preparing for potential commercialization of axatilimab with Incyte, a clear leader in the GVHD space. We -- they bring significant experience and expertise that will help to appropriately message and position axatilimab in the evolving treatment landscape using its differentiated mechanism of action and the positive results from AGAVE-201 to delineate axatilimab's value proposition to both physicians and patients. The positive AGAVE-201 pivotal data that we reviewed today continues to support our belief that axatilimab will be a differentiated, effective and practice-changing intervention for this underserved population. This is an exciting time for Syndax. I look forward to providing future updates on the axatilimab program as well as top line data for our AUGMENT-101 pivotal trial of revumenib in patients with KMT2A rearranged acute leukemia later this quarter. Before we turn it over for questions, I would like to take a moment to extend our gratitude to the patients, their families, the investigators and site staff who participated in AGAVE-201 as well as earlier axatilimab trials. We would not be at this exciting juncture today without your valuable contributions. Additionally, I would like to thank the team at Syndax and Incyte for all of their hard work and collaboration, which made this trial and the positive data readout possible. With that, let's open the line for questions.

[Operator Instructions] Our first question comes from Salveen Richter with Goldman Sachs.

This is Matt on for Salveen. Could you just go a little more in detail on the market opportunity in the U.S? You said 14,000 patients, 50% passed beyond corticosteroids. So you have those 7,000 patients. How many passed beyond Jakafi treatment? So how many are you looking at in terms of the third line plus?

Great. Thanks so much for the question. I'm actually going to ask Anjali to take the question.

Yes. Thanks for the question. We actually believe that it's close to 80% to 90% of patients will need treatment beyond Jakafi. And I think there's an evolution of this paradigm that's changing because of the fact that now these physicians have agents that they can really believe will help their patients. And I think they're more likely to try additional treatments rather than potentially give up or send them to hospice. So the ability to move beyond new therapy -- beyond two new therapies: one, something stops working and know what to look for and know what to expect with the -- in terms of safety and efficacy and potentially even specific impact on organ manifestations, I think will really change the game for physicians. And we're really excited to be bringing this novel treatment to the marketplace.

We'll take our next question from Phil Nadeau with TD Cowen.

Congratulations on the data. A few follow-up questions from us. In terms of the better response out of the 0.3 dose versus the higher doses in the in your prepared remarks on the slide, you suggest maybe it was due to adverse spends. It did seem like there were higher dropouts at the 1 milligram dose versus 0.3. Did those dropouts happen early in treatment before the primary endpoint was assessed? What was the time course of the adverse events and when patients discontinued therapy?

Yes, Phil, thanks for the question. I'm actually going to ask Peter Ordentlich, our Chief Scientific Officer, to address that.

Happy to take that question. And I'll start by saying, obviously, the data are new. And we are still in the process of looking at the exposure response and exposure safety analysis, which will address that question and to understand how and when patients are coming off the study. Of course, from the data that we presented, it is a plausible that the adverse event profiles at the higher doses may play a role in the lower response rates observed. But from a scientific perspective, we really do want to emphasize the point that Neil had made in the presentation where our hypothesis is that macrophage recovery in between doses is an important feature of our strategy for blocking CSF-1R. And it's certainly possible and likely that the lower doses allow for a greater recovery period than the higher dose, and that certainly may translate to the differences in response rates and safety and tolerability.

Obtained a response before cycle 7 with discontinued therapy, would that response -- that observation carryforward be carried through cycle 7? Or would that be considered a nonresponse if the patient was no longer on therapy at cycle 7?

Yes. Peter, maybe just a follow-up for Phil on that one as well.

Yes. The primary endpoint of the study is response rate by cycle 7, day 1. And so if a patient had a response and discontinued, that will still count as a response.

Got it. Okay. In terms of the FDA filing, what doses will be filed? Realizing it's early days, would you file just the 0.3-milligram dose or are you contemplating filing maybe others?

Yes. Let me ask Neil to address that.

Yes, thanks for the question. So while we agree that the data at 0.3 milligrams per kilogram are pretty compelling, as Peter alluded to, a, we just got the data; b, we're still in the process of analyzing -- producing full analysis. And of course, any discussion around dose will be dependent on that and subsequent conversations with health authorities. So obviously, we'll keep you informed as that evolves. But overall, we're very excited.

Great. And then last question from us, what is rate limiting for filing? Is it simply preparing all the documents? Or is there anything else that has to be completed?

Yes. Thanks, Phil. As you know, filing is an undertaking. But we're very well prepared, and we're working closely with Incyte to make that a reality. And I think our time line is before year-end that we'll have a BLA filed. And -- so nothing in particular. Now that we have the data, we have work to do to get the filing together, but it's certainly, an exciting time for the company to participate in that.

We'll take our next question from Anupam Rama with JPMorgan.

Congrats on the data. Should we be assuming ASH toward the full medical conference presentation? And what other analyses are planned to sort of highlight differentiation here? And is the medical conference where we're really going to understand sort of your macrophage recovery hypothesis and safety played a role in terms of the dose -- inversed dose response that you're seeing? And I have a question here also. Just can you remind us how long the administration takes for axatilimab?

Sure. Thanks for the question, Anupam. So first off, your question about whether ASH is the conference, we don't -- we have a policy of not speaking about specific conferences and projecting whether or not we'll be presenting at those conferences until we have acceptance of submissions. And so I'm going to hold off in commenting on which medical meeting will present the full data set at, but we're certainly -- there are a number of options, and so we're thinking about that actively as of now. And then in terms of analysis, other analyses that we'll be digging into, maybe I'll ask Peter to address that as well.

Very happy to. So of course, we have a large number of secondary analyses and endpoints that we will be eager to report response by organ class, subset analyses and such that will all help understand our obviously, high response rate and durability. And then, of course, the other areas that we're interested are these questions around exposure response, exposure safety. Those will be key to understanding the differences between the doses. And then we do have a number of photodynamic markers that we'll be also looking at. And I think those will go along with the exposure response analysis to help us understand this dose question.

And Anapam, just to highlight something that Peter had said earlier, I mean these are -- remember, these are different regimens. So we dosed patients at the 0.3 every 2 weeks, the 1 every 2 weeks, and the 3 every 4 weeks. So there's differences in the regimen that -- and as Peter said, the recovery of the macrophage over the period is important to understand better. So I think that's something we'll be digging into. And then relative to administration, the onset of action of the drug is fast. And while I don't believe that we gave specifics around the actual time to best response, we had previously disclosed in our published work at JCO with the earlier trials, Phase Ib, that it was within a cycle or two. And of course, this is an IV administration, 30-minute push, which we highlighted in the presentation.

We'll take our next question from Yigal Nochomovitz with Citi.

Just a few more for me on efficacy. Have you looked at fibrosis yet? Would that be something we would see at a medical meeting? And then with respect to subset analysis, I'm curious what other subset analysis you have conducted or will conduct specifically by a number of prior therapies as well as bispecific organ involvement locations, such as lung versus scleroderma?

Sure. Thanks, Yigal. A long list of questions there. Let me actually ask Peter to address the efficacy and subset analysis question because there is a lot going on.

Yes. Thank you. No, we have not yet looked at fibrosis in the study, or organs and such. And the subset analyses you already mentioned, of course, are top of the list. We are very keen to understand the differences in responses to the prior therapies and by organ class. Of course, we had already presented from our Phase I/II results, suggesting axatilimab has some clinical benefit in patients with their lung GHD involvement, which were presented recently. So we are, of course, interested to see and confirm those in a larger patient subset. And then certainly, the other organ manifestations are, of course, of interest as well. And then, again, just getting back to the question of the dose and such, just to reiterate this question of exposure response and understanding that and the safety and such is one of the key things that we'll look at, and that will go along with each of those types of subsets that we've talked about: baseline demographics, organ subsets, prior therapy and things like that. So we're just so excited to have such a positive study to be able to look at all of those questions in a fairly large patient set.

And then with respect to structuring the label and the discussions with Incyte, obviously, this trial was a meeting of four prior lines. I think the enrollment criteria were two or more prior lines. What are you thinking in terms of how you would frame that on the label in terms of the patient population?

Thanks, Yigal. I'm going to turn it over to Neil to address that.

Well, the study was designed -- I mean the [indiscernible] criteria allowed patients to enter if they had two or more prior lines of therapy. And our intention would be to file or to submit with the objective of getting an equivalent label. In other words, for patients who had failed at least two prior lines of therapy.

Our next question comes from Brad Canino with Stifel.

Congrats on the results from me as well, and thanks for providing some detailed elements in the top line. I do have two additional data questions, though, that I hope can be answered at least qualitatively. The first is, did a lot of the 0.3 mg per kg patients move to the Q4 week higher dose? And in your view, did the increased toxicity impact the durability of response in this trial at all?

Maybe the first part of the question, I think, Brad, I think -- we don't have the data today to suggest or to support the amount of patients who actually went on to the extended dose. Meaning, the -- we're able to switch one stable at 6 months moving on to the monthly dosing. But we do believe that it will be fairly significant in terms of the number of patients who did go onto the monthly dosing. But again, that will be reserved for the future presentation. And maybe the second part of your question, I'll ask Peter to follow up on that.