Syndax Pharmaceuticals Inc Q4 FY2023 Earnings Call

Good day, everyone. Welcome to the Syndax Fourth Quarter and Full Year 2023 Earnings Conference Call. Today’s call is being recorded. All lines have been placed on mute to prevent any background noise. After the speaker’s remarks, there will be a question-and-answer session. At this time, I would like to turn the call over to Sharon Klahre, Head of Investor Relations at Syndax Pharmaceuticals.

Great. Thank you, Operator. Welcome and thank you all for joining us today for a view of Syndax’s fourth quarter and full year 2023 financial and operating results. I’m Sharon Klahre and with me this afternoon to provide an update on the company’s progress and discuss financial results are Michael Metzger, Chief Executive Officer; Dr. Neil Gallagher, President and Head of R&D; and Keith Goldan, Chief Financial Officer. Also joining us on the call today for the question-and-answer session are Dr. Peter Ordentlich, Chief Scientific Officer; and Dr. Anjali Ganguli, Chief Business Officer. This call is accompanied by a slide deck that has been posted on the investor page of the company’s website. You can now turn to our forward-looking statements on slide two. 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 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 annual report on Form 10-K, as well as other reports filed with the SEC. Any forward-looking statements made represent our views as of today, February 27, 2024 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.

Thanks, Sharon, and thank you to everyone joining us on the webcast. 2023 was a year of tremendous progress in execution for Syndax, marked by the delivery of positive pivotal data and regulatory submissions for both revumenib and axatilimab. We look forward to continuing this momentum in 2024 with two potential approvals and commercial launches. Syndax is firmly on the path to distinguishing itself as a commercial-stage smid cap biotechnology company and with opportunities to expand well beyond the initial indications for revumenib and axatilimab, we envision creating long-term value with these franchises for years to come. On slide three, let me take a moment to review some recent accomplishments. With revumenib, our highly selective menin inhibitor, we made significant clinical and regulatory progress in the fourth quarter. At the 2023 American Society of Hematology Annual Meeting in December, we presented robust data from the Phase 1 and Phase 2 portions of the AUGMENT-101 trial that included a late-breaking oral presentation highlighting pivotal results from the KMT2A acute leukemia cohort, as well as multiple Phase 1 combination trials that demonstrated revumenib’s ability to safely and effectively combine with standards-of-care. In late December, we announced the submission of an NDA filing for revumenib under the FDA’s Real-Time Oncology Review or RTOR program for the treatment of adult and pediatric relapsed or refractory KMT2A rearranged acute leukemia. Submitting the NDA under RTOR ensures early engagement with the FDA throughout the review process, helping to derisk the submission and provide a potentially expedited timeline to revumenib approval. We expect to receive a PDUFA action date for revumenib this quarter, which should align with a third quarter approval date. For axatilimab, our anti-CSF-1R antibody, I’m excited to announce today that the FDA granted us priority review and a PDUFA action date of August 28, 2024, for the treatment of chronic graft versus host disease or GVHD, after failure of at least two prior lines of systemic therapy. Positive data from the pivotal AGAVE-201 trial presented at a plenary scientific session at ASH in December formed the basis of the BLA submission. And last quarter, we also initiated a Phase 2 double-blind randomized clinical trial for the treatment of idiopathic pulmonary fibrosis or IPF that Neil will later detail in this call. Financially, we are in a very good position. We strengthened our balance sheet in the fourth quarter with an additional $258 million in cash, and Keith will go into more detail in our financials later in this call. We continue to prepare for commercialization in 2024. Our first-mover advantage is of high strategic importance and we are busy ensuring that we successfully execute two first- and best-in-class drug launches. For revumenib, we are focused on pre-launch activities and we are finalizing our go-to-market strategies for both revumenib and axatilimab that we look forward to communicating in the coming months. In January, we exercised our option under our agreement with our partner Incyte to co-commercialize axatilimab in the United States and provide 30% of the commercial effort, as there is a considerable benefit to promoting two products simultaneously to a highly overlapping and targeted physician-prescriber universe. 2024 is shaping up to be a historic year for Syndax as we prepare to launch two first- and best-in-class products, and I am confident that we have the expertise, resources and determination to achieve our goals. Now let’s turn to slide four and I’ll begin a recap of some recent clinical data for revumenib that investigators presented at the ASH Annual Meeting in December. There was significant excitement for revumenib in the reaction to the data that investigators presented, which clearly demonstrated revumenib’s potential to become a cornerstone for the treatment in NPM1 and KMT2A acute leukemia. The data presentations have translated to continued strong enrollment in our clinical trials through additional engagement from the medical community, as well as additional requests for investigator-sponsored trials that could ultimately expand the use of the drug once approved. In the late-breaker presentation for the AUGMENT-101 pivotal trial, we indicated that KMT2A acute leukemia patients achieved clinically significant responses to treatment with a high overall response rate of 63% and responses were observed across all major subgroups. Revumenib delivered a high rate of deep responses with a CR/CRh rate of 23%, 70% of which were MRD negative. At the time of the data cutoff, the median duration of CR/CRh response was 6.4 months based on a Kaplan Meier estimate, with 46% or six patients remaining in response. Moving to slide five, in the AUGMENT-101 trial, 39% of the overall responder population proceeded to a stem cell transplant, which is higher than historical benchmarks in this population of less than 5%. Many of these patients proceeded to transplant prior to achievement of a CR/CRh. At the time of the data cutoff, 71% of patients who underwent a transplant had either restarted revumenib or were eligible to restart as maintenance therapy. A few of these patients had been receiving maintenance treatment for as long as eight months, with several continuing on therapy, highlighting the potential for long-term treatment with revumenib. Physicians with whom we have engaged are impressed by revumenib’s ability to induce rapid tumor clearance in heavily pretreated patients, enabling many of them to undergo a potentially curative bone marrow transplant. Treating physicians have repeatedly told us that they want to use revumenib as early as possible during treatment to bring more patients to transplant and then extend responses by continuing treatment following transplant engraftment. We unanimously heard from KOLs at our ASH investor event and continue to hear from physicians today their belief that continued use of revumenib post-transplant should lead to the best possible outcomes and it is an attractive option for these patients. Turning to slide six, the final pivotal cohort of the AUGMENT-101 trial continues to enroll relapsed or refractory NPM1 mutant AML patients. It is designed to enroll 64 patients and up to 20 pediatric patients. With multiple presentations highlighting the consistency of menin inhibition across NPM1 mutations and KMT2A rearrangements as a monotherapy agent and in combination with standards-of-care, we continue to see the excitement building for revumenib in NPM1. We are quite pleased with the recruitment in the trial and are reaffirming our guidance of expected completion of enrollment in the late first quarter or early second quarter of this year. We expect to report topline data from the trial in the fourth quarter of 2024, and importantly, we continue to look forward to a potential approval in 2025 based on an sNDA filing for NPM1 following revumenib’s anticipated initial approval in KMT2A acute leukemia. The Phase 1 NPM1 data that we’ve reported for revumenib supports our conviction that revumenib could be an important treatment for this AML population. Across monotherapy and in combination, we’ve generated consistent results between KMT2A and NPM1 acute leukemia. In the Phase 1 portion of AUGMENT-101, 50% of NPM1 patients achieved an overall response and 36% achieved a CR or CRH, and importantly, all patients with a CR or CRH were MRD negative. Consistent with the KMT2A population, revumenib also enabled a high percentage of NPM1 responders to proceed to transplant, 43%, and responses have been durable. This is despite many of the patients failing prior venetoclax therapy and receiving prior stem cell transplants. It’s worth noting that revumenib has been well tolerated in patients with relapsed or refractory NPM1 AML. In the Phase 1 results, there were no Grade 4 or 5 QT prolongations, no patients experienced more than Grade 2 differentiation syndrome and no patients discontinued due to treatment-related adverse events. Now turning to slide seven, we believe that revumenib will form the backbone of treatment for patients with KMT2A and NPM1 acute leukemias. Our clinical strategy extends beyond the initial relapse or refractory indications and into the frontline and post-transplant maintenance settings through combinations with approved therapies. In the frontline setting, there are basically two broad categories of patients. Those who are fit and can tolerate intensive chemotherapy, and those who are deemed unfit for intensive chemotherapy and would traditionally receive venetoclax plus azacitidine. Our frontline strategy is to add revumenib onto standard-of-care treatments to show that revumenib can be used effectively in combination, thereby increasing efficacy without negatively impacting the tolerability or safety profile of those regimens. We started combination development with venetoclax plus azacitidine in frontline unfit AML population in the BEAT-AML trial. The trial is expanding to validate the recommended Phase 2 doses and we expect to have an additional data update for this trial later this year. In parallel, we are planning the venetoclax plus azacitidine pivotal trial that we expect to initiate by year end. To address frontline AML patients fit enough to tolerate intensive chemotherapy, we initiated a Phase 1 dose escalation trial of revumenib in combination with standard-of-care induction therapy known as 7+3. Here we also anticipate identifying an RP2D for revumenib and initiating a pivotal trial for this combination soon thereafter. On slide eight is the data from the BEAT-AML trial, a Phase 1 trial being conducted by the Leukemia & Lymphoma Society. In this trial, frontline AML patients who are unfit for induction chemotherapy are dosed with a triplet of revumenib, venetoclax and azacitidine in 28-day cycles. In an interim look at data from 13 patients, 100% achieved a complete remission or CRC, and all patients for whom we had an MRD assessment achieved an MRD negative response. This is significantly higher than what would be expected from venetoclax plus azacitidine alone, based on the results of the VIALE-A trial where patients achieved a 66% CRC rate and only 24% achieved an MRD negative response. Importantly, I’d like to emphasize that there was no impact on the safety or tolerability observed by adding revumenib to this doublet regimen. Turning to slide nine, revumenib was also evaluated in another oral venetoclax combination among patients with relapsed or refractory AML. Interim data from this trial, known as SAVE AML was conducted by investigators from the MD Anderson Cancer Center and presented at ASH. The SAVE trial evaluated the oral combination of revumenib, venetoclax and a fixed-dose combination of decitabine and cedazuridine in relapsed or refractory AML or mixed-phenotype acute leukemias. In the interim presentation, nine patients with either NPM1, KMT2A or NUP98 mutations were enrolled into the trial. These patients had received a median of three prior lines of therapy and over half of them had received prior venetoclax and prior hypomethylating agents. At the interim assessment, 100% of patients achieved a response and 78% achieved a complete remission. Importantly, responses were observed across all three patient subsets, NPM1, KMT2A or NUP98. This triple combination was also well tolerated at both active doses of revumenib in the trial, including the current monotherapy RP2D with no new or increased safety signals observed beyond what would be expected with venetoclax and a hypomethylating agent. Now to slide 10. KMT2A and NPM1 acute leukemias represent up to 40% of all AML patients and there are no FDA-approved targeted therapies for this population. Inclusive of the expansion opportunities, there is the potential to address upwards of 12,000 NPM1 and KMT2A acute leukemia patients across various settings. We believe relapse or refractory KMT2A acute leukemia alone represents a $750 million market opportunity in the U.S. The annual incidence of KMT2A acute leukemia is about 2,600 patients and the majority are refractory to frontline standard-of-care treatments. We estimate a median duration of therapy across the treated population of approximately nine months and we believe the clinical data supports pricing competitively with other targeted therapies in AML, such as the FLT3 or IDH inhibitors. We anticipate that with the only age and disease-agnostic label in KMT2A acute leukemia, along with no other treatment options approved in this population and no near-term competition, revumenib should become the treatment of choice for patients with relapse or refractory KMT2A acute leukemia. We expect that our first-mover advantage and the experienced physicians will gain treating patients with revumenib could extend meaningfully beyond KMT2A and allow us to build a formidable franchise in the next few years, augmented by a second indication in NPM1 AML. Our market research suggests that if approved, oncologists are likely to prescribe revumenib as either their second- or third-line agent of choice for the treatment of NPM1 AML. We estimate that this population would be slightly larger than the relapsed or refractory KMT2A acute leukemia population and based on our Phase 1 results, we also believe overall efficacy and treatment duration will be consistent between the KMT2A and NPM1 relapsed or refractory populations. Having two distinct market segments in acute leukemias available to us, KMT2A and NPM1, would create a total accessible population of somewhere between 5,000 and 6,500 patients in the relapsed or refractory setting and an addressable market opportunity exists to expand to solid tumors. Our proof-of-concept, signal-seeking Phase 1 clinical trial in metastatic colorectal cancer is ongoing. This trial is based on preclinical science that supports the role of menin-KMT2A interaction in beta-catenin driven tumors. We are following these patients and expect to provide an update on the progress of the dose escalation phase of the trial in the second quarter of 2024. We would perceive single-agent activity reflected as responses or prolonged stable disease as encouraging in this third-line patient population. Let me now turn to axatilimab, our monoclonal antibody targeting the CSF-1 receptor beginning on slide 11. As noted earlier, we’re thrilled that the BLA for axatilimab in adult and pediatric patients with chronic GVHD after failure of at least two prior lines of systemic therapy has been given a PDUFA action date of August 28, 2024 by the FDA. Data from the global pivotal AGAVE-201 trial form the basis for this application. The AGAVE-201 trial, which was showcased during the plenary scientific session at ASH, met its primary endpoint of overall response rate by cycle 7, day 1, using the 2014 NIH consensus criteria for chronic GVHD across all three dose groups. The overall response rate was 74% at a dose of 0.3 milligrams per kilogram administered every two weeks. The responses were durable, with a median duration of response not yet reached at the time of data cutoff and 60% of responders were still responding at one year. Axatilimab was well tolerated in the trial with a low 6% rate of discontinuation. The most common adverse events were consistent with the on-target effects observed in prior trials. Axatilimab is differentiated from other approved therapies for chronic GVHD in that it is the first investigational chronic GVHD treatment to target inflammation and fibrosis through the inhibition of disease-associated macrophages. On slide 12, you will note that responses, including CRs, were seen across all organs involved, and notably in fibrosis-dominated organs, including esophagus, joints, fascia and lungs. Over 85% of patients reported a reduction in chronic GVHD-related symptom burden in AGAVE-201, which supports the potentially pronounced impact this mechanism can have on patients suffering from chronic GVHD. These results reinforce its potential as a first- and best-in-class CSF-1R monoclonal antibody in chronic GVHD. I’ll now turn the call over to Neil to speak about the IPF trial that we started in late fourth quarter, as well as the scientific rationale for the use of axatilimab in IPF. Neil?

Thank you, Michael. Turning to slide 13, we’re excited about the opportunity to expand the development of axatilimab into fibrotic diseases such as idiopathic pulmonary fibrosis, where the monocyte macrophage cell lineage plays a key role. IPF is a chronic fibrosing lung disease for which there are limited treatment options. Only two drugs have been approved and both have only been shown to slow but not halt or reverse disease progression. The only opportunity for a cure is lung transplant, which is limited to less than 5% of patients. With the estimated U.S. prevalence of IPF growing to over 180,000 people by 2026, there is an increasing need for new, well-tolerated and effective medication. There are several reasons why we are excited to pursue fibrotic disease outside of chronic GVHD and why we have confidence that axatilimab may provide meaningful benefit in IPF. There is a growing understanding of the important role that macrophages play as a master regulator of the fibrotic process. There’s a wealth of preclinical and clinical data indicating that the CSF-1 signaling pathway may play an important role in the development of pulmonary fibrosis. One such preclinical data set from an in vivo bleomycin pulmonary fibrosis model is shown in the panel on the left. The bleomycin model is commonly used to investigate the potential of therapies to address lung fibrosis, and in this experiment, animals were treated with an anti-CSF-1R antibody or saline control nine days after the administration of bleomycin. The histological section on the top left shows a normal lung with extensive white airspace. Conversely, the bleomycin treated lung has extensive fibrosis, as indicated by the dark colored material. Strikingly, the lung treated with bleomycin and then therapeutically with an anti-CSF-1R antibody on day nine has significantly less fibrosis and markedly preserved white airspace. Analysis of the extent of fibrosis using the Ashcroft score indicates that significantly less damage to the lungs occurs in the presence of the anti-CSF-1R antibody. Even more encouraging are the clinical data for axatilimab in patients with pulmonary manifestations of chronic GVHD, where clinically notable improvements in lung function have been observed. The panel on the right shows the data originally presented at the American Thoracic Society meeting last year from patients in the Phase 1/2 chronic GVHD trial of axatilimab who had chronic GVHD-related bronchiolitis obliterans syndrome or BOS. As you can see, most patients experienced improvement or slowing of decline of pulmonary function, which is very unlikely to occur spontaneously. These data, in conjunction with the organ-specific data from the AGAVE-201 trial presented earlier, strongly support the therapeutic potential of axatilimab in interstitial lung diseases, including IPF. Turning to slide 14, here we lay out the design of a recently initiated multinational Phase 2 trial of axatilimab in IPF. It is a 26-week, double-blind, placebo-controlled and multicenter trial, which aims to include 135 patients randomized 2-to-1 to receive 0.3 milligram per kilogram of axatilimab every two weeks or placebo on a background of standard-of-care. The primary endpoint is the annualized rate of decline in forced vital capacity or FVC. Key secondary endpoints include disease progression, quality of life specific to patients with destructive airways disease and others. We believe this study is robustly designed to demonstrate proof-of-concept for axatilimab in IPF, thereby enabling us to advance the molecule into phase three pivotal development potentially. Let me now turn the call back to Michael.

Thank you, Neil. Turning now to slide 15, which highlights the broad clinical and commercial opportunity for axatilimab. 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 wholly addressed with current treatment. There are no cures for this advanced population of chronic GVHD patients, and patients who are initially treated with corticosteroids are then cycled through a variety of additional therapies. While patients may be treated with any of the approved therapies, the order in which they are used may depend on the physician’s experience with how a given agent may address specific manifestations of the disease. Newer entrants, Jakafi and Rezurock, have had successful commercial launches, which speaks to the unmet need in chronic GVHD and the substantial commercial opportunity for a differentiated agent such as axatilimab. Axatilimab suppresses monocyte-derived macrophage activation and proliferation, which may provide more comprehensive control of the disease than currently approved therapies. Addressing inflammation and fibrosis in one mechanism of action is a key differentiator and also supports moving axatilimab earlier in the treatment paradigm to potentially prevent organ damage before it occurs. Because axatilimab is an antibody, drug-drug interactions are expected to be minimal and axatilimab’s unique mechanism of action may offer the benefit of being an ideal combination partner with standard-of-care therapies currently used for the treatment of chronic GVHD. The opportunity to expand to ex-U.S. markets and into other high-value indications could build significant additional value for axatilimab over the next few decades. We’re looking forward to the insight-led initiation of additional trials of axatilimab, including a Phase 2 combination trial with Jakafi and a Phase 3 combination trial with corticosteroids, which is expected to commence in mid-2024. I’ll now turn the call over to Keith to review our financial results. Keith?

Thank you, Michael. Turning to slide 16. As Michael mentioned earlier, in the fourth quarter, we strengthened our balance sheet, adding $258 million, providing strong validation of Syndax’s potential from both existing, as well as new high-quality institutional investors. The $600 million on the balance sheet at year-end is expected to provide cash runway through 2026. Turning to the income statement. Operating expenses for the fourth quarter were $77.9 million, comprised of $55.1 million of research and development expense and $22.8 million of selling, general and administrative expense, in line with guidance. Looking forward, our financial strength enables us to focus on the execution of advancing our pipeline and achieving an exceptional launch of revumenib and axatilimab later this year. Keeping in mind that we’ve always embraced a disciplined approach to resource allocation, I’d like to provide financial guidance for the first quarter and full year 2024. For the first quarter, the company expects research and development expense to be $56 million to $62 million and total operating expenses to be $82 million to $88 million. For the full year 2024, the company expects research and development expenses to be $240 million to $260 million and total operating expenses to be $355 million to $375 million, including approximately $43 million of non-cash stock compensation expense. With that, let me now turn the call back over to Michael.

Thank you, Keith. As you have heard during the call, 2023 was a landmark year for growth and execution. As evidenced by our positive pivotal trial readouts and two regulatory submissions for our two lead drug candidates, both of which are first and potentially best-in-class treatments, this is only the beginning of what’s to come for Syndax. We are in a significant transition into a fully integrated biopharmaceutical company serving multiple patient populations of high unmet need. Both programs offer the potential for broad franchise opportunities beyond their initial registration indications, adding to Syndax’s long-term growth potential. We have ambitious goals and milestones that I’ve set out for 2024 and that are laid out on slide 17. I’m confident that we have the right plan and team in place to execute on them. As always, I’d like to express my sincere appreciation to the Syndax team, collaborators and most importantly, the patients, trial sites, and investigators involved with our clinical programs. Through your important work, we are getting closer to delivering on our mission of improving the lives of patients with cancer. I’d also like to thank our committed long-term investors who continue to share in our vision and support us in building Syndax. With that, I’d like to open the call for questions. Operator?

Our first question comes from Peter Lawson with Barclays. Please go ahead. Your line is open.

Hi. This is Shay on for Peter. Congrats on all the progress. With PDUFA announced for axatilimab, can you comment on expectations for your launch in 3Q? And related to that, it sounds like you’re still expecting a 3Q potential approval for the menin inhibitor. Are you expecting that to be potentially positioned for sales in 3Q or is it potentially dependent on regulatory issues in 3Q? Thank you.

Thanks, Shay, for the question. So first off, I think you broke up a little bit on the second question. Do you want to take the first question?

Yeah. Sure. So thanks for the question, Shay. This is Keith. So for axatilimab third quarter, we have the PDUFA. When the FDA actually approves the drug is still a question. As we’ve laid out earlier in the year, we’ve opted into the co-promotion, and as Michael said earlier, the co-promotion of axatilimab. So we’ll be ready with our sales force prior to the approval of either product. So as you can see by looking at LinkedIn or looking at our website in the Careers section, we’re currently recruiting for all of the territory managers. So that’s public knowledge. So we’ll have them on board and trained up prior to approval of either product. With respect to your question around the timing of the initiation of revumenib revenue, we’ll have to wait until later this quarter when we receive the PDUFA action date from the agency and I think at that time we’ll have a better idea of when to expect the initiation of revumenib revenues. Does that answer your questions?

Our next question comes from Anupam Rama with JPMorgan. Your line is now open.

Hey, guys. Thanks so much for taking the question. Maybe expanding on Keith’s comments just now, just remind us of where you are in terms of the sales force, sales team build out. What are some of your pre-commercial kind of plans here in the near-term? And then maybe just on expenses, how we think about the growth here quarter-over-quarter looking to 2024, especially on the SG&A line as we think about the launches?

Thank you for the question, Anupam. I’ll address the first part regarding our sales force build-out, and then I’ll let Keith take the rest. As we've previously mentioned, we are expanding our commercial organization to support both the launch of revumenib and our collaboration with Incyte on axatilimab, for which we will contribute up to 30% of the full-time equivalents. The focus is on targeted call points, allowing us to effectively deploy around 40 to 50 representatives across the U.S. to cover both products extensively. We will continue to build out this sales force leading up to the approval of both agents. As Keith noted, we have a PDUFA scheduled for the end of August for axatilimab, and we anticipate the PDUFA for revumenib shortly as well. We’ll be prepared well in advance of both approvals, and our leadership team has already been hired and is actively working on these preparations. Keith, would you like to tackle the second part?

Yeah. Regarding your question about SG&A expense, we provided guidance today for total operating expenses for the year, which is estimated to be between $355 million and $375 million. This figure includes non-cash stock compensation. For research and development, we're looking at a range of $240 million to $260 million. Based on this, you can expect total SG&A to be around $100 million, which is slightly higher than last year when we finished with SG&A of about $67 million, including approximately $22 million in the fourth quarter. I believe we are currently in the process of recruiting representatives, and it's reasonable to expect they will be onboard for the second half of the year ahead of both product launches. By considering the cost per representative annually and adding that to our projections, you can estimate the SG&A increase from $66 million or $67 million this year to $100 million next year. We've also provided first quarter guidance for total operating and R&D expenses. The second half of the year will definitely see an increase in our commercial field force. Our general administrative infrastructure in HR, finance, and IT is already established. The focus will be on hiring sales representatives and increasing our advertising and promotion expenditures.

Thanks so much for taking our questions.

Thanks, Anupam.

The next question is from the line of Phil Nadeau with TD Cowen. Your line is now open.

Good afternoon. Thanks for taking our questions and congrats on the progress. A couple on the ASH data and then a follow up on axatilimab. So in terms of the ASH data, there are two controversial aspects that we keep debating with investors and curious to get your thoughts on those. First, in SAVE AML, I know you said that there was no additive toxicity by having adding revumenib to the background regimen. Not everyone agrees. So could you address the neutropenia rates that you would expect? I think you showed 56% at ASH. What would ASTX727 do alone? And then second, on BAML, again, there’s some concerns about the combinability, particularly the dose of revumenib going forward in light of the SIP interaction that ven/aza. How will you determine the Phase 2 dose through BAML and what type of dose adjustments would you anticipate once that Phase 2 dose is found?

Phil, thanks for the question. I think I’m going to turn it over to Neil so he can make a comment first about SAVE and then he’ll address the question you brought up about BAML. Thank you.

Yeah. The first thing to note is that the SAVE trial included a patient population that was heavily pretreated. Two-thirds of the patients had previously failed treatment with venetoclax, and more than half had undergone transplantation. This population had a median of 3 to 4 prior therapies. Consequently, the observed rate of cytopenia aligns with what investigators and others would expect given the use of venetoclax and oral cytopenia in such patients. Any comparisons made to a less heavily pretreated population are not valid, as it's essential to focus on the specific group involved in the trial. This is why the investigator, and we as well, are confident that the cytopenia rate matches expectations based on the treatment backbone. Regarding BAML, I'm unclear about the concerns regarding dose selection. To reiterate for everyone, there were two doses of revumenib tested in all three combination trials presented at the investor event at ASH, including BAML, which was presented independently as well. The doses tested in all three trials were 113 milligrams twice a day and 163 milligrams twice a day. Each trial involved different patient populations: newly diagnosed patients in BAML, heavily pretreated relapsed/refractory patients in SAVE, and also in AUGMENT-102. In all three trials, dose-limiting toxicity was addressed at both doses. The team is currently working on expanding those cohorts to better determine the recommended Phase 2 dose for a Phase 3 trial, which we intend to initiate by the end of the year. It's important to note that 163 milligrams is the assumed full monotherapy dose when used with a strong CYP3A4 inhibitor, while 113 milligrams is also very effective. Additionally, in the BAML trial, venetoclax and azacitidine were administered at full doses. Therefore, we are confident in the ability to combine revumenib with venetoclax and azacitidine in the newly diagnosed setting, as well as in the other two settings.

That is very helpful and makes it clear. For the last question regarding axatilimab sales and marketing, I believe you mentioned in your prepared remarks that Syndax is responsible for 30% of the marketing efforts. In response to Anupam’s question, you indicated that this refers to 30% of full-time equivalents. How exactly is that 30% of the marketing efforts defined? Does it strictly refer to 30% of full-time equivalents, or are there additional metrics that Syndax needs to meet, such as interactions with physicians or call points?

Yeah. I will turn it over to Keith.

Thank you for your question, Phil. I apologize if my previous explanation was unclear. Our partnership agreement with Incyte allows us to contribute 30% of the promotional efforts. From a sales call perspective, we will be responsible for 30% of that effort. I referenced this in terms of full-time equivalents because I wanted to avoid specifying the number of representatives, but we will indeed be delivering 30% of the sales force effort. It's important to remember that this is a combined profit and loss statement. We will record 30% of our associated costs in the combined P&L, while Incyte will account for 70% of their costs. Additionally, any advertising and promotional expenses incurred by Incyte, as they are leading from that end, will also be included in the joint P&L. Ultimately, the commercial profitability from the product will be shared equally, 50-50.

Perfect. That’s very helpful.

Thank you, Phil.

Our next question comes from Brad Canino with Stifel. Your line is now open.

Good afternoon. You’ve provided peak sales opportunities, but how do you see the KMT2Ar launch playing out this year, things in terms of number of patients that are available in the relapse/refractory setting, where they’re concentrated and what to expect for the pace of uptake?

Thank you for your question, Brad. I believe it's a bit too soon to speculate on the sales ramp and projections. We'll provide more guidance as we approach commercialization. As we mentioned earlier, KMT2A presents a compelling commercial opportunity since we will have a first-to-market, best-in-class product that can help patients even before they enter clinical trials. We're discussing a total of approximately 2,600 patients, with around 2,000 of them in the relapse/refractory setting. We anticipate being able to reach the majority of these patients, who, as we've emphasized before, are in urgent need of therapy. Many might be eligible for transplant, especially with treatment using revumenib and possibly resuming treatment afterward. We see a highly addressable population, and physicians appear quite eager to use the drug. This interest has been reflected in our trials and feedback from doctors. It seems like a very promising opportunity for a drug to enter the market with little competition at this time, which bodes well for a successful launch. That’s our current perspective on projections, launch, and ramp, and we can revisit this in future discussions.

Our next question comes from a line of Michael Schmidt with Guggenheim. Your line is now open.

Hey, guys. Thanks for taking my question. I had one on the first-line setting for revumenib in combination with 7+3. In your opinion, what is the right way to view frontline combo data with menin inhibitors and 7+3? And specifically, given that one would expect very high CR rates, presumably, on top of 7+3 already, what are other benchmarks that you’re looking for in your own study, including MRD status, transplant rates or any other efficacy measures that are important in your opinion?

Michael, thank you for your question. It’s certainly a significant one to understand. The 7+3 regimen, as you know, is very effective for frontline patients. In cases of NPM1 and KMT2A, the initial response rate is over 80%. However, these responses typically do not last long, leading to relapses in most patients. Beyond just complete response rates, we should be monitoring minimal residual disease and transplant rates as well. We have observed high rates for both in relapse/refractory patients. As we transition to the frontline setting, we would expect to see equal or improved rates of minimal residual disease and certainly transplant in earlier treatment lines. Those are critical measures to consider. The duration of treatment with the 7+3 regimen is relatively short, making it important to see if revumenib can help patients maintain remission over a longer period. It's a new landscape, and we haven't seen a menin inhibitor used in combination with frontline 7+3 yet. Therefore, it will be up to us to set the standard for what efficacy looks like in that context. From a complete response and safety perspective, we have a clear idea of the desired outcomes, aiming for a clean profile and high effectiveness. However, we must continue to monitor for deep, durable responses as well. Neil, would you like to add anything?

Yes, I would like to add a couple of points. There might have been a regulatory context to the question regarding potential endpoints, but it’s too early to discuss that. Michael has indicated that MRD negative CR is not necessarily an endpoint of interest, and whether it could be approvable is still uncertain. We will be in discussions with the agency as we get closer to starting our dose-ranging trial and subsequently, our Phase 3 trial. Additionally, historically, the 7+3 trials conducted over the past decade to twelve years have all included maintenance phases. Therefore, it's reasonable to assume that any 7+3 trial we conduct will also incorporate a maintenance phase. Furthermore, we've observed in the relapsed/refractory setting post-transplant that patients who remain on therapy for extended periods exhibit good tolerability of revumenib. Moving forward to the newly diagnosed setting, we expect that patients receiving monotherapy maintenance after induction consolidation therapy will also tolerate the medication well.

Okay. Thank you.

Thank you, Michael.

Our next question comes from Yigal Nochomovitz with Citi. Your line is now open.

Hi, guys. This is Ashiq Mubarack on for Yigal. Thanks for taking my questions. I had a few on axatilimab. I guess first, congrats on the PDUFA date. I’m just wondering how involved you are in the regulatory process from this point out. Obviously, we know Incyte is leading the proceedings, but will you be part of the mid-cycle review? Will you be able to weigh in on labeled negotiations? How should we think about that?

Thank you for the question, Ashiq. We are very engaged with axatilimab and have generated the data through a close collaboration with Incyte. We are actively involved in the regulatory process and are working closely with them to secure approval for this drug across all aspects, including label negotiations. Overall, I would say we are certainly very engaged with everything happening. This is an exciting development for the company, and we have significant experience with the molecule, which reinforces our involvement. Did I address your question, or was there a second part?

No, that's very clear. I wanted to ask another question about IPF. I might be forgetting or don’t remember this from previous calls, but I know you're evaluating the 0.3 mg per kg dose, which appeared to be the most effective in AGAVE-201. I'm curious about what gave you confidence that this is the right dose for IPF. Why didn’t you feel the need to conduct dose optimization work? Is the disease biology similar enough that you felt confident? Since we're dealing with a different endpoint, I would like to hear your thoughts.

Yes, it's Neil. I'll answer your question. We had an extensive internal discussion about the selection of the dose. The 0.3 milligram dose in the AGAVE trial was clearly superior to the other two doses, demonstrating both efficacy and tolerability. Throughout the past year, especially before we shared the details of the IPF proof-of-concept trial, we focused on finding an efficient trial design. The design we discussed today was the most effective in achieving a solid proof-of-concept result in a timely manner. We believed it was reasonable to proceed with just one dose in this trial, which would be 0.3 milligram. To address your point, there was enough biological overlap to justify that decision, which influenced our choice.

I would like to add that we conducted thorough dose ranging during the Phase 1 and pivotal trials. Early on, we also studied healthy volunteers to understand how this antibody functions and its effects on macrophages. This knowledge of the pharmacology gives us confidence that 0.3 milligrams would be the suitable dose, in addition to what Neil mentioned.

Very helpful. Thanks very much.

Thank you, Ashiq.

Our next question comes from the line of Jason Zemansky from Bank of America. Your line is now open.

Hey, guys. This is Alex Hanab on for Jason. Thanks for taking my question. Appreciating somewhat early, so with regards to your regular submission for revumenib, can you provide some color on what you expect to be included in the label? Are the eight efficacy viable ALL and PAL patients with a 12.5% CR/CRh warrant a tumor agnostic label? And what are your basic expectations on potential safety monitoring requirements for DS in QT prolongation? Thank you.

Maybe I’ll turn it over to Neil. He will talk about the label and then maybe talk about any kind of safety.

Sure. We expect that the label will reflect the breakthrough therapy designation we received in December 2022 for KMT2A acute myeloid leukemia and acute lymphoblastic leukemia in both adults and children. The development program moving forward is based on Phase 1 data and aims for a broad indication. We combined cohorts 2 and 2b for the submission for KMT2A acute leukemia, which includes pooled analysis of AML and ALL in adults as well as pediatric patients. We anticipate the agency's involvement throughout this process, which continues from the breakthrough therapy designation forward. Our focus is on KMT2A rearranged acute leukemias in both adults and children. Regarding safety monitoring, from a broad class perspective on targeted therapies in AML, we expect to warn about differentiation syndrome, as it is typical with these agents. The agency is aware of this occurrence. We also anticipate a warning and precaution for QT prolongation, but that will be the extent of our considerations.

Our next question comes from Kalpit Patel with B. Riley. Your line is now open.

Good afternoon and thank you for the question. Regarding the 7+3 combo study, can you share the initial dose of revumenib that you plan to use? Additionally, how should we view the enrollment distribution between the KM22Ar and NPM1 populations in this combo study? Will it be evenly split, or do you expect a higher number of KM22A patients because they are generally healthier?

Sure. I’ll address the second question while Neil can handle the first one. As for the comparison between KM22A and NPM1, we don't have a definite answer right now. However, it appears that patients in the KM22A group tend to be generally more fit. We are uncertain if our patient population will lean more towards KM22A, but we do anticipate having a mix of both groups. Neil, would you like to discuss the starting dose for the 7+3 combination?

It doesn't really matter how we split the KM22A and NPM1 patients initially. What we're aiming to show is the combined effectiveness of revumenib with 7+3. As we mentioned earlier, in all the combination trials we've detailed so far, we tested two doses: 113 milligrams and 163 milligrams. These are the doses we will also evaluate in the 7+3 trial, along with their equivalent doses without the strong CYP3A4 interaction. Based on our earlier comments and previously presented data, we know they can be combined with both chemotherapy and venetoclax-based HMA therapy.

Our next question comes from the line of Justin Zelin with BTIG. Your line is now open.

Great. Thanks for taking our question. This is Jeet Mukherjee on for Justin. Maybe just coming back to axatilimab, I was hoping you could provide a little bit of a sense of the opportunity for axatilimab and IPF, the subset of patients perhaps best suited for this therapy and what you’d be looking for from an efficacy perspective?

Yeah. I don’t know if, Anjali, do you want to take that question? Yeah. Sure. So, again, it’s axatilimab bringing this strong fibrotic effect to bear on patients and hopefully helping to manage the impact of the disease on organs and therefore potentially shifting the courses of the disease is what we’re trying to change with that combination therapy. So, moving up earlier, could you really have a bigger impact on patients and their overall disease profile going forward? We anticipate getting some data out of this trial in the coming years and I think that would govern what the uptake would really look like, but this is something that physicians are telling us they’re really looking for. Right now, the only thing they have is steroids, and unfortunately, those do as much harm as they do good. And so, if you could get strong efficacy out of that combination, could you minimize the use of steroids and bring axatilimab up to an earlier population? I mean, we know the current estimated prevalent pool is about 14,000 patients and so you could access a big chunk of that population with good data.

Got it. That’s helpful. And maybe just one more on axatilimab. Is there any additional color perspective on the combo studies you’re doing with ruxolitinib and steroids in collaboration with Incyte, and just what you’d be looking there from an efficacy and safety perspective to move one or both of those forward ultimately?

Yeah. Again, sorry. I’ll take that one. So, axatilimab is bringing this strong fibrotic effect to bear on patients and hopefully helping to manage the impact of the disease on organs and therefore potentially shifting the courses of the disease is what we’re trying to change with that combination therapy. So, moving up earlier, could you really have a bigger impact on patients and their overall disease profile going forward? We anticipate getting some data out of this trial in the coming years and I think that would govern what the uptake would really look like, but this is something that physicians are telling us they’re really looking for. Right now, the only thing they have is steroids, and unfortunately, those do as much harm as they do good. And so, if you could get strong efficacy out of that combination, could you minimize the use of steroids and bring axatilimab up to an earlier population? I mean, we know the current estimated prevalent pool is about 14,000 patients and so you could access a big chunk of that population with good data.

Thank you, Jeet.

Our next question comes from George Farmer with Scotiabank. Your line is now open.

Hi there. This is Cleo on for George. Thank you for taking our questions. Two from us on revumenib. So, do you have any sense on whether the FDA is intending to hold an ODAC meeting to discuss the approval package in KMT2Ar AML or ALL? And secondly, could you speak to the prospects for other indications for revumenib?

Great, Cleo. Thank you for the question. So, in terms of an ODAC, we don’t expect that the FDA will hold an ODAC for revumenib. From time-to-time for new mechanisms, they do that more as a showcase than they do for any other reason. But we don’t expect and we haven’t received any word from the FDA to indicate that we would have an ODAC. So, I think that’s the answer to your first question. And then secondly, you had asked about prospects for additional indications. I presume that means outside of leukemia. And as I mentioned in my previous remarks, we are looking at revumenib in colorectal disease, third-line metastatic colorectal cancer. As a monotherapy agent, it’s obviously a very difficult disease state and we’re going to have some data in the second quarter of this year to first get at whether there’s sufficient activity there as a monotherapy agent and how the drug performs. There is this thesis that we’re pursuing, a beta-catenin upregulated tumor type, which is a broadly implicated phenomenon through a lot of different cancers. Colorectal cancer is one and so there could be other cancers that we look to see whether they’re susceptible to revumenib treatment. So, stay tuned. There may be more to come. I think the first step here is certainly the colorectal cancer trial that we’re running.

This concludes our question-and-answer session. I will now turn the floor over to Mr. Michael Metzger for any additional comments or closing remarks.

Thank you all. We appreciate you tuning in tonight and we look forward to seeing you at our planned investor events, including the upcoming Cowen and Barclays Healthcare Conferences in March. And with that, I wish you all a very pleasant evening. Thank you.

This concludes today’s conference call. Thank you and you may now disconnect.