Syndax Pharmaceuticals Inc Q3 FY2024 Earnings Call

Good day, everyone, and welcome to the Syndax Third Quarter 2024 Earnings Conference Call. Today's call is being recorded. All participants are in listen-only mode. You'll have the chance to ask questions after the presentation. Now, I would like to hand 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 as we review Syndax's third quarter 2024 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; Steve Closter, Chief Commercial Officer; 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 Strategy Officer. This call is accompanied by a slide that has been posted on the Investor page of the company's website. You can now turn to our forward-looking statements on Slide 2. Before we begin, I'd like to remind you that any statements made during the 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 quarterly report on Form 10-Q, as well as other reports filed with the SEC. Any forward-looking statements made represent our views as of today, November 5, 2024, only. A replay of this call will be available on the company's website, www.syndax.com, following its completion.

Thank you, Sharon. Good afternoon, everyone, and thank you for joining us today. We made remarkable progress in the third quarter. We delivered on multiple important milestones that demonstrate our ability to bring novel medicines to patients. In doing so, we marked our transition from a development organization to an integrated commercial-stage company with an extremely bright future. With the announcement of yesterday's $350 million royalty agreement for Niktimvo with Royalty Pharma, we have strengthened our balance sheet significantly, and now have the capital to fund Syndax through profitability, ensuring strong launches for revumenib and Niktimvo and solidifying our commitment to their continued development and expansion of the pipeline overall. Importantly, this deal further highlights how vastly underappreciated the value of Niktimvo is in the market and why it remains a critical element of our long-term strategy. Let me now dig into some third quarter milestones. In August, we received FDA approval for Niktimvo, the first and only CSF-1R antibody approved for the treatment of chronic graft-versus-host disease, or GVHD, after failure of at least two prior lines of systemic therapy in adult and pediatric patients weighing at least 40 kilograms. Shortly after we received FDA approval, the positive pivotal AGAVE-201 trial results were published in the New England Journal of Medicine, and Niktimvo was added to the latest NCCN guidelines, two achievements that highlight the significance of this dataset and the important role of Niktimvo in the treatment armamentarium. With Incyte's deep understanding of the cGVHD market and long-standing relationships with key stakeholders, we are thrilled to partner with them to bring this much-needed new option to patients. Later in the call, Steve will provide more color on our plans for the commercial launch. We believe the approval of Niktimvo represents the initial opportunity to make a major impact for patients by targeting the CSF-1R pathway. Together with Incyte, we are advancing a robust clinical development program, investigating the potential for Niktimvo in frontline chronic GVHD in combination with standard-of-care therapies and in other diseases marked by fibrosis and inflammation, such as idiopathic pulmonary fibrosis, or IPF. In addition to making tremendous progress with Niktimvo, we've also continued to make excellent progress advancing revumenib, our selective menin inhibitor that we anticipate will receive FDA approval this quarter in relapsed or refractory KMT2A rearranged acute leukemia. With a PDUFA date of December 26, 2024, and compelling clinical data across the treatment continuum, we believe revumenib is poised to become a first-in-class and practice-changing therapy for KMT2A and NPM1 acute leukemia. In addition to the anticipated approval of revumenib, we are also looking forward to the topline readout from the pivotal cohort of patients with mutant NPM1 AML, our AUGMENT-101 trial this quarter. In recent months, we've executed on multiple initiatives that we believe laid the foundation for a strong revumenib launch and successful long-term franchise growth across both KMT2A rearranged and mutant NPM1 acute leukemias. In September, we published the pivotal data from the AUGMENT-101 trial supporting the use of revumenib in relapsed or refractory KMT2A rearranged acute leukemia in the Journal of Clinical Oncology. This publication is raising awareness of revumenib's compelling profile and potential utility once approved and will be instrumental in gaining rapid acceptance into the NCCN guidelines. As you saw from our press release earlier today, we have multiple presentations at ASH that highlight the clinical data supporting our two assets, including additional revumenib data in KMT2A rearranged acute leukemia from the Phase 2 portion of our AUGMENT-101 trial and new combination data from the investigator-sponsored SAVE trial. These data, which are consistent with our previously reported data, continue to show remarkable responses that are deep and durable in heavily pretreated patients. Furthermore, in both monotherapy and combination, revumenib continues to demonstrate a tolerability profile that allows patients to benefit significantly from continued therapy. Beyond the conference presentations, we will also have the opportunity to discuss the latest data supporting our pipeline at ASH and our event on Monday, December 9th. And with that, I'm going to turn the call over to Neil to review the latest data in the ASH abstracts and review our revumenib clinical development program.

Thanks, Michael. It's great to be here today to discuss the latest data from our clinical development program for revumenib, focusing on treating adults and children with KMT2A rearrangements or mutant NPM1 acute leukemias. Through a strategic mix of Syndax-sponsored and investigator-sponsored trials, we are quickly generating data supporting the use of revumenib, both alone and in conjunction with standard treatments, in frontline as well as relapsed/refractory contexts. I will now go over the recently released ASH abstracts that present the latest information from various ongoing trials and provide a brief overview of the revumenib clinical development program. At ASH, we will present an updated analysis that adds more patients to the pivotal Phase 2 portion of the AUGMENT-101 trial involving revumenib for relapsed or refractory KMT2A rearranged acute leukemia. These new findings are very much in line with the previously reported data that supported our NDA application. With data up to February 2024, the updated safety population includes 116 patients, which is 22 more than previously reported, and the efficacy population comprises a total of 97, 40 more than in the earlier analysis. The median age of patients was 35 years, with 24% being under 18. Patients had received a median of two prior therapies, with 44% having undergone three or more treatments, 63% previously treated with venetoclax, and 51% having had a stem-cell transplant. The efficacy results from this broader analysis align closely with earlier interim findings, showing an overall response rate of 64%, a CR/CRh rate of 23%, and a composite complete remission rate of 42%. Out of the 62 responders, 21, or 34%, went on to receive allogeneic stem cell transplant, and nine patients resumed revumenib as maintenance therapy post-transplant. The median duration of CR/CRh was 6.4 months at the time of the data cutoff. Among evaluable patients, 61% of those in CR/CRh and 58% of CRc patients achieved MRD negativity, which is an important clinical milestone that may correlate with improved long-term outcomes. The consistently high MRD-negative rates seen with revumenib indicate its strong potential. Revumenib continues to be generally well-tolerated, with only 5% of patients stopping treatment due to treatment-related side effects. Side effects were consistent with previous reports. The updated analysis also looks at response durability for the 13 patients who achieved CR/CRh in the prior interim analysis presented at ASH 2023. The median duration was 6.4 months at that point, but in this updated analysis, the median has increased to 13 months following seven additional months of follow-up. At the latest data cutoff, five of the 13 patients remain in follow-up without relapse. Now, turning to the investigator-sponsored Phase 1b trial SAVE, led by Dr. Issa at the MD Anderson Cancer Center, this trial assesses an all-oral combination of revumenib, venetoclax, and oral azacitidine in children and adults with relapsed or refractory AML or mixed-lineage acute leukemias. At last year's ASH meeting, Dr. Issa presented promising results from the first nine patients in this study. This new abstract features data from 26 patients with a median age of 35. Of these patients, 42% had KMT2A rearrangements, 38% had mutant NPM1, and 20% had NUP98 rearrangements. The median number of previous therapies was three, with 65% having received prior venetoclax and 42% having undergone stem-cell transplant. The combination treatment was well-tolerated, with a safety profile consistent with what is expected for venetoclax and hypomethylating agents alone. Notably, two-thirds of these patients had failed previous treatment with venetoclax. The overall response rate was 88%, with a 46% CR rate and a 12% CRh rate. Among MRD evaluable patients with CR/CRh, 93% achieved MRD negativity. Additionally, 12 patients, or 46%, went on to receive stem-cell transplant, with three resuming revumenib after the transplant. The six-month relapse-free survival rate was 59%, and overall survival reached 74%, with the median duration of CR/CRh yet to be determined. As of the data cutoff, two patients have completed maintenance treatment post-stem cell transplant and remain in remission. These findings further support the combination of revumenib with venetoclax and hypomethylating agents, and we anticipate sharing more data from this trial soon, including from a frontline cohort now open for enrollment. As I mentioned, the trials I just highlighted form critical parts of our comprehensive clinical development program exploring revumenib throughout the treatment continuum. Additionally, we will present preliminary results from INTERCEPT at ASH, another investigator-sponsored platform trial managed by the Australasian Leukaemia & Lymphoma Group. This trial is assessing innovative therapies, including revumenib, to combat measurable residual disease or early relapse in AML patients. Patients are enrolled while in remission, and their MRD status is tracked. Those who become MRD positive or experience early relapse are assigned treatment. At the data cutoff, nine patients with MRD relapse—eight with mutant NPM1 and one with KMT2A rearranged AML—were enrolled in the safety cohort and treated with revumenib. Three had prior exposure to venetoclax, and six had undergone stringent chemotherapy. Preliminary results for those with mutant NPM1 indicate promise, as five of eight achieved a reduction in measurable residual disease, three of whom became MRD negative within six cycles. We are eager to see further data from this trial. BEAT AML is another ongoing investigator-sponsored trial led by the Leukemia & Lymphoma Society. It explores the combination of revumenib with venetoclax and azacitidine for frontline patients with NPM1 or KMT2Ar AML. Recent data presented at the European Hematology Association meeting showed a CRc rate of 96%. We look forward to the next update, expected in the fourth quarter of 2024. Outcomes from this trial have influenced the design of the pivotal frontline Phase 3 study, which we aim to initiate by year-end. Next, you'll see an overview of the Phase 3 trial design. This pivotal frontline study will investigate revumenib in combination with venetoclax and azacitidine in newly diagnosed adults with mutant NPM1 or KMT2A AML who are not candidates for intensive chemotherapy. The trial will be a randomized, double-blind, placebo-controlled study conducted with the HOVON network, and we are excited about this partnership, given HOVON's extensive experience with Phase 3 AML trials. The trial aims to enroll around 400 patients randomized to receive either placebo plus venetoclax and azacitidine or revumenib with venetoclax and azacitidine. The primary endpoint is overall survival for patients with mutant NPM1 AML, while secondary endpoints include event-free survival, CR/CRh rates, and response rates without MRD. We expect the first site to open for enrollment by year-end. Before our topline readout from the Phase 2 cohorts of patients with relapsed/refractory mutant NPM1 AML from AUGMENT-101, I want to highlight the unmet needs for these patients. NPM1 mutations are prevalent in AML, found in about 30% of adults with the illness. While they can lead to favorable outcomes in specific frontline populations, the prognosis for those who have relapsed or are refractory to treatment is poor, with a median overall survival of around six months or less following three or more lines of therapy. Compared to patients with other genetic alterations like KMT2A rearrangements, NPM1 AML patients are often older and less fit to undergo intensive chemotherapy or proceed to transplant. In the Phase 1 trial of revumenib for relapsed/refractory mutant NPM1 AML, we observed a strong response rate. The efficacy and safety profile for these patients align closely with findings in KMT2Ar patients. Based on historical data from other AML therapies, we believe that a CR/CRh rate of 20% to 30% with a median duration of response in the four- to six-month range would signify a meaningful enhancement over the current standard treatment and could potentially lead to regulatory approval. We look forward to sharing topline data for the ongoing NPM1 cohort in AUGMENT-101 later this quarter. With that, I’ll hand it over to Steve, who will update us on our commercial progress.

Yeah, thank you, Neil. Starting with Slide 10, we are thrilled that Niktimvo is now FDA-approved and included in the latest NCCN guidelines as a recommended treatment for chronic GVHD after failure of at least two prior lines of systemic therapy in adult and pediatric patients weighing at least 40 kilograms. We anticipate that this new medicine will be available to patients no later than early in the first quarter of 2025. Addressing the needs of patients who have progressed after at least two prior lines of therapy is an attractive commercial opportunity. For example, in the three years since the launch of belumosudil or REZUROCK, another drug indicated for the same line of treatment as Niktimvo, net sales continue to grow in the high double digits and suggest that the drug is now annualizing at over $500 million in US sales alone. With the new mechanism and clinical data showing that Niktimvo can provide both rapid and durable responses in heavily pretreated patients, including results in difficult-to-treat organs, we believe that we will be able to capture a significant portion of the $1.5 billion to $2 billion estimated total addressable market for third line or later chronic GVHD treatment in the US. This will be a targeted launch as there are roughly 200 important transplant centers in the US. The Syndax team will provide 30% of the sales effort for Niktimvo and our partner Incyte will provide 70%, leveraging their existing field force that is already deeply engaged with the chronic GVHD community through their work with Jakafi. The key transplant centers that we will be targeting fall squarely within the larger group of accounts that are also important for revumenib, creating opportunities for commercial synergy. In addition to preparing for the launch of Niktimvo, we and Incyte are also continuing to advance clinical trials evaluating Niktimvo in earlier lines of chronic GVHD treatment and other diseases. Incyte is now enrolling patients in a Phase 2 trial of Niktimvo in combination with Jakafi in patients with newly diagnosed chronic GVHD, and we continue to enroll patients in a Phase 2 trial on top of standard of care in IPF with topline data expected from that trial in 2026. Turning to Slide 11. Revumenib has the opportunity to transform the treatment paradigm for certain genetically defined acute leukemia patients who currently have no targeted options. There are several important factors that differentiate our program and position Syndax to establish a successful menin franchise. First, we're set up to secure first-mover advantage. We have built a highly experienced commercial organization that is already engaging with key stakeholders and is ready to launch revumenib as soon as we receive the anticipated FDA approval before the end of the year in relapsed or refractory KMT2A rearranged acute leukemia. We believe that physicians' familiarity with revumenib will expand quickly because patients with these alterations have an urgent need for new treatment options as no drugs are currently approved for this population or under investigation in late-stage trials. With today's standard-of-care therapies, the median overall survival for patients who have received more than two prior lines of treatment is less than 2.5 months, a truly devastating prognosis for patients. Given this is a high-risk population, centers are already routinely testing for KMT2A rearrangements. Further, with compelling data across both KMT2A and NPM1 alterations as well as adults and pediatrics, we expect to have a broad future label that drives a strong competitive advantage. Last but not least, we have a near-term opportunity for a unique launch trajectory with pivotal topline data in relapsed or refractory mutant NPM1 AML expected in the same quarter as our anticipated FDA approval in KMT2A. Positive data would enable us to file a supplemental NDA in the first half of 2025. And if approved, we'd be positioned to launch into a second indication, leveraging an already established commercial effort. We estimate that the two distinct market segments in acute leukemias, KMT2A and NPM1, equal a combined accessible population of 5,000 to 6,500 patients in the relapsed or refractory setting and an addressable market opportunity that approaches $2 billion in the US. In summary, I'm very excited about positively impacting the lives of patients and the commercial opportunities we have with Niktimvo and revumenib. I'm confident that we are well-prepared to successfully launch both of these drugs. With that, I'll pass the call to Keith to talk about our financials.

Thanks, Steve. Turning to Slide 12. We expect that the $399.6 million in cash, equivalents, and short- and long-term investments on our balance sheet as of September 30, plus the $350 million in cash received from the royalty funding agreement for Niktimvo, will provide sufficient cash for Syndax to reach profitability. Under the terms of the royalty funding agreement, Syndax received $350 million in exchange for a 13.8% royalty on US net sales of Niktimvo. Royalty payments to Royalty Pharma are capped, which preserves the upside longer term for opportunities, including treatment of frontline chronic GVHD and IPF. Our financial strength allows us to fund the commercialization of Niktimvo as well as the anticipated launch of revumenib while also appropriately investing in our pipeline to fuel continued growth and value creation. Turning to the income statement, operating expenses in the third quarter were $102.1 million and included $71 million of research and development expense and $31.1 million of selling, general, and administrative expense. For the full year 2024, the company is narrowing its guidance and now expects research and development expenses to be $245 million to $250 million and total expenses to be $365 million to $370 million. Note that the guidance range for operating expense for the full year 2024 includes an estimated $41 million of non-cash stock compensation expense, which is down from our previously estimated $43 million, and that research and development expense guidance includes any milestones earned or expected to be earned by our partners upon potential approvals. With that, let me now turn the call back over to Mike.

Thank you, Keith. As you heard today, we have built remarkable momentum heading into another exciting period filled with several near-term, value-generating milestones that can be seen on Slide 13. Building on the FDA approval of our first novel medicine in August, we are confident that revumenib will also be approved this year and launched soon thereafter. We believe this first anticipated approval in relapsed or refractory KMT2A rearranged acute leukemia will be just the first of several potential approved indications for revumenib, and we are extremely focused on leveraging our first-mover advantage to build long-term franchise value. This quarter, we will be presenting the first pivotal NPM1 dataset, which gives us the opportunity to further solidify our position in the emerging menin space. So, stay tuned. Finally, I want to take a moment to thank our dedicated Syndax team, collaborators, and most importantly, the patients, families, investigators, and trial sites who have participated in our clinical trials and made it possible for us to advance our mission. I'd also like to thank our committed long-term investors who continue to share in our mission and support our work building Syndax into a leading oncology company. And with that, I'd like to open the call for questions. Thank you.

The first question will come from Anupam Rama with JPMorgan. Your line is now open.

Hi, guys. This is Priyanka on for Anupam. Just a quick question from us. Post the potential approval of KMT2A and pending positive NPM1 data for revumenib, can you remind us of the process to get into guidelines and potential timeline considerations we should be thinking about?

Sure. Thanks for your question, Priyanka. The timing to get into the guidelines involves first having an approved drug and then compiling data for publication. We plan to publish that data promptly and subsequently submit for guidelines. The NCCN guideline panels typically meet twice a year but can also convene on an ad-hoc basis, allowing for timely approvals as we anticipate engagement with the guidelines. We experienced a similar situation with axatilimab; following its approval and simultaneous publication of the data in the New England Journal, we were able to be included in the guidelines within two to three weeks. Our objective is to proceed quickly into the guidelines.

Thank you so much for answering my question.

The next question will come from the line of Brad Canino with Stifel. Your line is now open.

Thank you. Lots to talk about, and I look forward to asking more at ASH, but two topics for me for now. For AUGMENT-101, in the updated data, you noted nine of 21, or 43%, of transplanted patients restarted revumenib maintenance. Is that a maintenance percentage rate you expect in the commercial setting, or could it be higher? And also, what have you seen so far on durations? And then, congratulations on the HOVON collaboration for frontline AML. I think you do point to BEAT AML updates in 4Q '24. Help us understand what you're looking for in those data to finalize and initiate that pivotal trial? Thank you.

Yeah. Thank you, Brad. So maybe I'll take the first question, and then I'll pass it over on the BEAT AML trial to Neil. So, in terms of the AUGMENT-101 trial, we did note that there were certain patients that went back on maintenance, and that is a trial-driven result. Physicians were allowed to put their patients back on therapy post-engraftment. Many physicians elected to do so. We do expect that that phenomenon will continue to advance once the drug is approved, and we'll have the opportunity to have many more patients treated. Of course, that could lead to potentially the opportunity to have patients not only go to transplant, but get back on therapy and stay on therapy for an extended period of time. So, I think we'll continue to build the data in the real world, but we are encouraged by what we've seen thus far in AUGMENT-101 in that regard. And then, for BEAT AML, I think I'll turn it over to Neil in terms of what we expect on an update.

Sure, thanks, Brad. What I think everyone should expect is an increase in the number of patients treated, specifically at dose level one. This involves the combination of 113 milligrams of revumenib with venetoclax and azacitidine, along with a higher number of patients than what was reported previously. Just to clarify, this is not a limiting factor for us. We are currently in the process of applying for health authority approval to start the study, which is why we are still on track to potentially begin the Phase 3 study by the end of the year. These activities are progressing simultaneously.

Thank you.

The next question is from the line of Peter Lawson with Barclays. Your line is now open.

Great. Thanks so much. Just with the sale of some of the royalty strength of Niktimvo, does that accelerate any programs under development?

So, Peter, I think the setup with the royalty agreement, which was extremely positive for us, does bring in $350 million of cash onto the balance sheet and pro forma lands us at somewhere around $800 million. So, I think we have a very strong balance sheet to execute on. I think we're set up extremely well for all the trial initiations that we have planned for frontline trials, pivotal trials, and several additional trials. We haven't named yet, but that will be in support of the utilization of our drug in other settings. So, I think it's definitely helps us aggressively move forward with plans for revumenib and for axatilimab, Niktimvo. It advances the portfolio overall and gives us the opportunity to expand the portfolio with other molecules as well. So, it's a very happy, very healthy balance sheet. Pro forma, I think I said approaching $800 million, it's about $750 million, actually, just to correct myself. Thank you, Brett...

Perfect. Thank you.

Thank you, Peter.

Can you clarify the timing of the NPM1 data? Is it expected before or after a publication? How should we approach that, and will it be included in the direct NCCN guidelines or considered supplemental?

So, I believe the sequence of events is that once you receive approval for your molecule, we will also have crucial data for NPM1 around the same time. This data for NPM1 needs to be published. The data for KMT2A has already been published. Therefore, we could potentially incorporate KMT2A into the guidelines following its approval. However, for NPM1, the process involves publishing the data first and then submitting it for guideline inclusion, which can happen separately from the approval process. Our goal is to expedite getting it into the guidelines, and this would likely occur before the approval for NPM1.

Got you. Okay. Perfect. Thank you so much.

Thank you.

The next question is from the line of Chris Shibutani with Goldman Sachs. Your line is now open.

Great. Thank you very much. I think many of us are beginning to turn to 2025, and I realize that with important data readouts coming out, that's a factor. But can you give us any sense early in terms of how we should be thinking about the trajectory of an initial commercialization of Niktimvo? And what we can think about how the results from the NPM1 data may impact the level of spending that you have, particularly from the SG&A aspect? Thank you.

Great. Thanks so much, Chris. So maybe I'll turn it over to Steve to talk a little bit about the, as you say, the early launch trajectory and that question related to 2025.

Good question, Chris. Regarding the trajectory, the market is ready, and there is an unmet need. We have observed significant market growth, which is promising. For example, REZUROCK, a drug I mentioned earlier, is generating over $500 million annually and is in its third year of promotion. Market research indicates that while some patients are satisfied with their treatment, many are not, highlighting the demand. Additionally, we have had some extra time to prepare, and fortunately, we are collaborating with Incyte, who has essentially developed this market. They are currently engaging with important customers across nearly 200 transplant centers nationwide, with 35 of those centers accounting for half of the patient volume. They are already profiling within this targeted group. We plan to ramp up our efforts as everything is in place for a successful product launch. There is often a small surge of patients eager for new options right after launch, and we believe we have a strong molecule with compelling features that will appeal to clinicians. We are fully prepared to move forward once we receive the go-ahead.

Right. And so, maybe you want to make a comment on revumenib as well?

Yes. And on revumenib, I think we're in the same place in terms of the trajectory. We've had the gift of time. We've had a little bit of delay. I think what that's enabled us to do from a preparedness standpoint is to be ready. The market is ready. We've been able to focus on menin inhibition as a mechanism of disease. The awareness is high. We've got a very talented team that's been put in place. They started calling the customers back in the June timeframe. We've got about 2,000 accounts that we call in for revumenib. There's about 200 that cover two-thirds of the patient opportunity. We've prioritized them. So, we've taken a very talented, experienced sales team. It's got over 20 years in the space. Many of them have launched products, averaging about six. They came in with pre-existing relationships. So, we know a lot about our accounts and how they think about AML and ALL, and the role that KMT2Ar will place. Testing is very high. We're understanding how to pull things through. And then, on the payer side, we've been calling in customers for well over a year. So, goal is to get on to formulary as close to approval as we can. It generally takes about nine to 12 months. All the activity we have placed against payers, we think we can truncate that to the six- to nine-month frame. We've also got a really great group of specialty pharmacies and distributors in place that are the best at what they do. So, they'll be able to pull through prescriptions really at launch, getting through the medical exception process. So, I think for that drug, there's not much of a bolus. Patients are too sick. I think I mentioned the prognosis for patients with relapsed/refractory KMT2Ar is about 2.5 months, and customers are incredibly eager for this drug to get approved. We think once the drug is available, we'll get some immediate utilization.

And then, Chris, this is Keith. Regarding your question on SG&A spending, as Steve mentioned, we are fully established from a commercial standpoint. If you look back at our third-quarter spending of just over $31 million for combined SG&A, that will increase as advertising and promotion costs rise following approvals and the launch of these drugs. However, you should expect this growth to be incremental rather than a sharp increase, because as Steve stated, this field force, market access, medical affairs, and so on, are already fully built out.

That's helpful context. Thank you.

Thank you, Chris.

The next question comes from the line of Kelly Shi with Jefferies. Your line is now open.

Congratulations on the impressive progress in the quarter and the upcoming busy Q4. I would like to hear your thoughts on the clinical benchmark for the CR/CRh rate regarding the pivotal NPM1 data. Additionally, how should we assess the relationship with overall survival benefit, and what are the expectations for overall survival benefit in relation to the KMT2A subgroup? Thank you.

Thank you, Kelly. I appreciate your kind comments. Regarding the clinical bar for NPM1, we have maintained a consistent approach. The data for KMT2A and NPM1 across various trials, both monotherapy and combination, has been very consistent. Based on previous precedents, we can expect a CR/CRh rate of 20% to 30% as the threshold for approval, with 20% likely sufficient. We have shown data within that range for NPM1, even exceeding it, as our Phase 1 data was at 36%. We are very confident that the results will fall within that range and will be very positive. There is a question of approval, but we believe the data will align well with our previous findings and meet the expectations of physicians. Naturally, higher results are preferable. As for your second question about OS benefit, I’ll have Anjali provide some insights.

Yeah, sure. So, Kelly, I think in the historic data analyses that have been published, we've seen with KMT2A, with increasing lines of therapy, you have shorter and shorter survival expectations getting down to between two and three months by the time you're treating a third-line patient. It's similar for NPM1, but maybe the decrease isn't as steep. And they start off as a more favorable prognosis, but over time, they will also, when they relapse, get down to a shorter survival benefit. And I think in third-line, it's something like four to five months benefit expectation.

Thank you, Kelly.

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. Two questions from us. So first, the updated KMT2A AUGMENT-101 data that we saw in the abstracts today, is that the most recent analysis that the FDA has? Is that what was submitted to the FDA? And is that what the FDA is reviewing? That's first. And then second, we noticed on your slides describing the pivotal trial in combination with ven/aza in the frontline, there was no revumenib dose listed. Have you determined with the FDA's input what that dose is likely to be? Thanks.

Thank you, Phil. Regarding the KMT2A update, we generally refrain from commenting on the FDA review specifics. As I mentioned earlier, the agency requested additional information concerning the clinical trial later in the review process, which resulted in a three-month PDUFA delay, now scheduled for December 26th. I won't confirm or deny if this is the specific information they were seeking, but I can state that it strongly supports approval. We previously noted that the submitted information was also highly supportive of approval, which gives us and others significant confidence. You can see that we essentially doubled the dataset from 57 patients and obtained similar results. It's worth mentioning that for the 57 patients followed for an additional seven months, we observed an extension of the median duration of response to 13 months. There are some encouraging signs, and the data is robust, which I know investors and others were keen to see. We're eager to provide this update, and the agency has access to all our information. While I won’t confirm or deny anything, we feel quite confident that the data is supportive. Now, regarding the pivotal trial, I'll pass it over to Neil for his comments. Please go ahead, Neil.

Yeah, sure. So, Phil, thanks for the question. I mentioned a little earlier, the health authority approvals are currently in process. In fact, several of the submissions have been made in several countries, and we're initiating the study on 160 milligrams.

That's very helpful. Thank you.

You're welcome.

Thank you.

The next question is from Michael Schmidt with Guggenheim. Your line is now open.

Hey, guys, thanks for taking our questions. Two from us. Just on the KMT2A data on the 13-month duration of response that you've disclosed today in the ASH abstract in AUGMENT-101, would you expect a similar duration in NPM1-treated patients once you have longer follow-up from that cohort? And then, as we think about the menin inhibitor competitive landscape, there's been greater focus recently on differences in drug product characteristics as investors are looking to project how combinable the different agents are, particularly on PK or drug exposure metabolism. And as we continue to look at the emerging combo data at ASH, are there any learnings you can highlight where you feel confident about potential advantages for revumenib over others in the field? Thanks so much.

Thank you, Michael. I appreciate it. Regarding the duration of response, I noted the 13-month extension on the follow-up, which I believe is an interesting and significant finding. The follow-up may sometimes extend duration, especially when the upper limit hasn't been reached and time is adjusted. I cannot comment much on the NPM1 data at this stage since we don't have that information yet, so we will have to wait and see how it presents. However, we are encouraged by the KMT2A data. Patients who underwent transplants typically show extended time on therapy, which might influence duration. There may be differences in KMT2A patients who get transplants compared to NPM1 patients, and we'll observe how that unfolds. I cannot speculate further at this point. As for your second question regarding the combination data and the differences between the drugs, the ASH abstracts were released today, and we might draw some conclusions, though it may be a bit early. We will need to wait for more follow-up at ASH regarding overall presentations. From our own data, the SAVE data is quite promising, particularly among fourth-line patients who have undergone multiple stem-cell transplants and previous venetoclax treatment. We observed a high overall response rate of 58% in terms of complete responses, and the treatment has shown excellent tolerability and duration, with patients being followed for over six months and mostly remaining on the drug. This regimen has proven to be well-tolerated and effective in 26 patients, indicating strong results compared to the previous update from ASH last year. We are hopeful for an update during our investor event on the BEAT AML trial at ASH, which will provide an expanded dataset, as Neil mentioned earlier. We have observed excellent safety, tolerability, and efficacy when combining with the doublet in frontline patients. Overall, our profile is appearing increasingly distinct compared to others in their trials, and we are the most advanced in both relapsed/refractory and frontline settings, particularly regarding ven/aza combinations.

Thanks. Really appreciate.

Thank you, Michael.

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

Hi, this is Ashiq filling in for Yigal. Thank you for taking my question, and congratulations on all the recent updates. I wanted to follow up on the earlier questions about maintenance settings for revumenib. In the AUGMENT-101 KMT2A cohort, nine out of 21 patients received maintenance therapy, while three out of 12 did in the SAVE study. I'm curious if there were any differences in how those studies were conducted, or perhaps differences in physician awareness regarding the use of revumenib in a maintenance setting. Additionally, how aware are you of the factors that influence physicians' decisions on when or how to use revumenib in maintenance, and what decision-making processes are currently in place? Thank you.

Thank you, Ashiq. I believe this is still evolving. As I mentioned previously, maintenance is a fascinating concept. We're referring to relapsed or refractory patients who have undergone multiple prior treatments, including stem-cell transplants and often venetoclax as well. Their treatment is somewhat delicate. Physicians are considering this on an individual basis. There is nothing in the two protocols that prohibits them from receiving maintenance; it ultimately depends on the physician’s judgment about whether to start maintenance and the duration. As I mentioned earlier, I think this will develop over time, and as physicians gain more experience, they will better understand how to administer it and how long to keep patients on. It’s encouraging to see that sometimes over half of the patients are receiving maintenance, which may vary from these early trials, but overall, we are in a good position. Neil, would you like to add something?

I’d like to add that we’ve observed patients remaining on treatment for extended periods, some for three years or more. Physicians understand this as well. As mentioned by Michael, the decision to conduct a transplant is complex. However, doctors recognize that the drug is well tolerated as a standalone treatment during post-transplant maintenance for long durations. Many have publicly expressed their readiness to adopt this treatment approach, acknowledging the drug's tolerability in that context.

Got it. Can I just ask one more?

Sure. Go ahead, Ashiq.

I have one more quick clarifying question on the frontline revumenib plus ven/aza study: it appears that the primary endpoint is overall survival specifically in the NPM1 population. I'm curious why the focus is solely on NPM1. Is this related to population dynamics or another reason? Thank you.

Yeah, Neil, just take that.

Yes, that is correct. The study I mentioned in the script is specifically designed for the NPM1 population. This population consists of older patients who are not suitable for intensive chemotherapy, and the predominant mutation in this group is NPM1. We expect the median age of these patients to be around 65 or older. For comparison, the median age in our KMT2 population from AUGMENT-101 was 35 in the updated analysis we discussed. KMT2A is more common in older patients, but NPM1 is overall more prevalent and especially more common than KMT2A in older individuals. In fact, KMT2A is quite rare in this age group. Therefore, the study is designed accordingly. Does that make sense?

Yeah. Makes a lot of sense. Thanks very much, and congrats again.

Thanks, Ashiq.

Thanks, Ashiq.

The next question comes from Jason Zemansky with Bank of America. Your line is now open.

Great. Thank you. Good evening. Congrats on the quarter and thanks for taking our question, as well as the additional color on ASH. Maybe two quick ones from me. For NPM1, curious as what you're thinking about the potential for breakthrough therapy designation. Have you requested this? Has FDA given you any indication, particularly given they awarded it in KMT2A? And then, maybe just to circle briefly back on your previous answer regarding the NPM1 efficiency range or efficacy range. Certainly, you mentioned for physicians higher the better, but is that 20% floor you mentioned necessary for approval? Does that still apply, or is that higher? Thanks.

Thank you for the question, Jason. Regarding NPM1 and the breakthrough therapy designation, we had 14 patients at the recommended Phase 2 dose during Phase 1, but that number is insufficient for a submission for breakthrough status. We lacked the necessary data for that designation, so we did not apply at that time. We are currently conducting a trial, and if the data supports it and we believe applying for breakthrough would assist our submission, we can consider it then. Having breakthrough designation for the first indication is very important, which we achieved, benefiting us with KMT2A. Having it for a second indication is less significant. To clarify, we did not apply because the Phase 1 data at the correct dose did not meet the requirement, which is at least 20 patients’ worth of data. Regarding your second question about the 20% threshold for NPM1, as I mentioned earlier, a complete response or complete response with partial hematologic recovery rate of 20% or higher, along with a duration of response of four to six months, would signify a meaningful improvement over the current standard of care and could support regulatory approval. We look forward to sharing topline data from the ongoing NPM1 cohort in AUGMENT-101 later this quarter.

Great. Thanks.

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

Hi. Good afternoon. Thanks for taking my questions. I really appreciate your decision to disclose the additional KMT2A data. A question on this 6.4-month duration that you showed in 97 patients with the February cutoff. Are you going to be showing anything more mature than that? And is it possible that we could see something closer to the 13 months that you reported from the first 57 patients?

Thank you, George. I don’t expect that we will update the data set again. We have an approval coming and need to focus on NPM1 data. Analyzing a data set requires significant effort, and we are eager to get this drug approved. In real-world scenarios, we will be able to evaluate its performance across various measures, such as patient adherence and maintenance. The 6.4-month duration appears consistent, and the 13-month extension data from the first 57 patients was a positive outcome. As I mentioned earlier, this gives us hope for a longer duration with continued follow-up. At this point, we do not plan to update the data set beyond what we have already shared.

Okay. And then, the HOVON trial, when do you anticipate that concluding and to be reporting on data? Maybe I missed that in your primary comments.

We haven't provided a specific timeline for the conclusion yet. There are general parameters for trials similar to VIALE-A, which lasted about four years. This is an overall survival-driven endpoint, so it will take time to gather results. We plan to start the trial at the end of the year and will provide more guidance as we progress.

Okay. And then one more, if you don't mind. With the Royalty Pharma deal, were they looking at the potential of Niktimvo in IPF by any chance when they were contemplating the term?

Yeah. So, we're very excited about Royalty Pharma's partnership with us and how they really looked at the opportunity for the drug over many years, not just in GVHD, but potentially beyond that. I'll note that there is a cap on the transaction. In other words, we are paying them back 2.35 times what they've put into the transaction, which supports and the drug forecast seemed it will support that. Then some, we believe that they looked at all of the indications and potential indications, both in GVHD as relapsed or refractory frontline as well as the extensions in IPF included to arrive at a forecast that supported the deal on their end, and it aligned very closely with what we believe, right? It really was quite a robust forecast, which is different, of course, than what the market has believed up to this point. So, we feel that the partnership is well aligned, and the value that we were able to attain in this deal for Syndax is quite helpful and supportive long term of our objectives.

Okay. Good. Thanks very much.

Thank you.

The next question is from Kalpit Patel with B. Riley Securities. Your line is now open.

Yeah. Hey. Good afternoon, and thanks for taking the question. Just one more follow-up on that overall survival endpoint in the frontline triplet trial. I guess I understand the rationale for just including NPM1 patients in that analysis, but is there a minimum efficacy threshold that you need for the KMT2Ar patients to make sure that they will be included on the label? Or do you just need to hit the primary endpoint for NPM1 patients?

Thank you for the question. As I mentioned, the study is designed to test the hypothesis in NPM1 patients. The statistical power is based on that population. The approximate number of patients that has been publicly disclosed includes some KMT2A patients. While we will evaluate the consistency of the effect in the KMT2A patients, the study is not structured to test a statistical hypothesis in those individuals. I cannot comment on potential regulatory developments in the future, but the main goal of conducting the study is to gain approval for the drug in combination with ven/aza specifically for NPM1 patients.

Okay. Got it. And then, at ASH, I guess what sort of additional analysis should we expect for the KMT2Ar patients from the pivotal cohort, if any, anything at all? I think a lot of investors have been wondering what the efficacy analysis is like for patients based on the number of priors and the types of priors and just looking at a baseline demographic.

Yeah. Look, we've been pretty busy. We're focused on getting the abstract in as it stands. You can expect to see additional analyses, additional data presented at ASH, but we haven't been specific about exactly what those details are. But you can expect to see more detail around it at the ASH presentation. Sorry, I can't be more specific.

Okay. Got it. Thank you very much.

Thank you very much.

The next question comes from Justin Zelin with BTIG. Your line is now open.

Thanks for taking our question, and congrats on the progress. So, on the revumenib filing, I understand that patients are regularly tested for KMT2A status, but do you expect you'll need a companion diagnostic for approval?

Thank you, Justin, for your question. We haven't really discussed what will be required for regulatory approval yet, but there is a precedent for companion diagnostics being needed post-approval. At this point, we feel confident in our ability to get the drug approved, and there may be requirements for companion diagnostics in the future. For KMT2A, there are existing diagnostics that ensure robust testing. While there's more to share after the approval, we are confident that we are on track to get the drug approved, and we will provide further updates on that.

Okay. Great. Thanks for taking our question.

Thank you.

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

Thank you, operator, and thank you all. We appreciate you tuning in today to discuss our recent progress and the transformative milestones that we have ahead. We look forward to seeing many of you at the upcoming Guggenheim, UBS, Stifel, and Jefferies conferences in November, as well as our ASH event in December. And with that, have a great evening.