Syndax Pharmaceuticals - Q4 2023

Transcript

Operator (participant)

Good day, everyone, and 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. If you would like to ask a question during this time, simply press star followed by the number 5 on your telephone keypad. If you would like to withdraw your question, press star and the number 5 once again. At this time, I would like to turn the call over to Sharon Klahre, Head of Investor Relations at Syndax Pharmaceuticals.

Sharon Klahre (VP of Investor Relations and Corporate Communications)

Great. Thank you, operator. Welcome, and thank you all for joining us today for a review 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 27th, 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.

Michael Metzger (CEO)

Thanks, Sharon, and thank you to everyone joining us on the webcast. 2023 was a year of tremendous progress and 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 mid-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 3, 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 de-risk 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. 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 historical 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 4, 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 6 patients remaining in response. Moving to Slide 5. 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 6. 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 top-line 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 leukemias. 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/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 7. 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 8 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 CR/CRh, 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% CR/CRh 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 9. Revumenib was also evaluated in another all-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 all-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, 9 patients with either NPM1, KMT2A, or NUP98 mutations were enrolled into the trial. These patients had received a median of 3 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 triplet 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 relapsed or refractory KMT2A acute leukemia alone represents a, a $750 million market opportunity in the US. 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 relapsed or refractory KMT2A acute leukemia. We expect that our first-mover advantage and the experienced physicians we'll 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, 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 approaching $2 billion in the US. Beyond acute leukemia, we are also investigating the opportunity 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, and β-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-1R 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 formed 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 seven, day one, 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 mg/kg, 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 lung. 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?

Neil Gallagher (President and Head of R&D)

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 medications.

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 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 our recently initiated multinational phase 2 trial of axatilimab in IPF. It's a 26-week, double-blind, placebo-controlled, and multicenter trial, which aims to include 135 patients randomized 2 to 1 to receive 0.3 mg/kg of axatilimab every 2 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 obstructive 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 3 pivotal development, potentially. Let me now turn the call back to Michael.

Michael Metzger (CEO)

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 treatments. 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-US 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 Incyte-led initiation of additional trials of axatilimab, including a phase II combination trial with Jakafi and a phase III 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?

Keith Goldan (CFO)

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-$62 million, and total operating expenses to be $82 million-$88 million. For the full year 2024, the company expects research and development expenses to be $240 million-$260 million, and total operating expenses to be $355 million-$375 million, including approximately $43 million of non-cash stock compensation expense. With that, let me now turn the call back over to Michael.

Michael Metzger (CEO)

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?

Operator (participant)

At this time, I would like to remind everyone, in order to ask a question, press star, then 5 on your telephone keypad. If you would like to withdraw your question, press star and 5 once again. We'll pause for just a moment to compile the Q&A roster. Our first question comes from Peter Lawson with Barclays. Please go ahead. Your line is open.

Shayan Mitra (Assistant VP)

Hi, this is Shayan for Peter. Congrats on all the progress. With PDUFA announcement 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 revumenib inhibitor. Are you expecting that to be potentially positioned for sales in 3Q, or is this potentially dependent on U.S. priority review? Thank you.

Michael Metzger (CEO)

Thanks, Shayan, 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?

Keith Goldan (CFO)

Yeah, sure. So thanks for the question, Shay. This is Keith. So, for axatilimab third quarter, you know, 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, into the co-promotion of axatilimab. So we'll be ready with our sales force, you know, prior to the approval of either product. So as you can see by looking at LinkedIn or looking at our website in the career 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, and we'll have to wait until later this quarter, when we receive the PDUFA date, 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. Did that answer your questions?

Operator (participant)

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

Anupam Rama (Managing Director and Senior Equity Analyst)

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 your sort of 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.

Michael Metzger (CEO)

Anupam, thanks for the question. Maybe I'll take the first part in terms of sales force build-out, and then I'll leave the rest to Keith to answer. So I think, as we've said in the past, we're, you know, building out our commercial organization to accommodate both the launch of revumenib, and now we've opted into the co-promote with Incyte around axatilimab to provide up to 30% of the FTEs for that effort. You know, it's a overlapping, as I said, my remarks, overlapping and highly targeted call point. And so the opportunity here is with, you know, roughly 40-50 representatives to cover the U.S., you know, quite extensively, and also cover both products.

So that's the build-out of that sales force will continue until the time of right up until we have approval on both agents, which, as Keith mentioned, we have a PDUFA at the end of August for axatilimab, and we expect the PDUFA imminently for revumenib as well. So we have. You know, we'll be ready well in advance of both of those to put the sales force in place, and leadership has been hired and is doing extensive work to get ready. Maybe, Keith, do you want to handle the second point?

Keith Goldan (CFO)

Yeah. So Anupam, with respect to your question on SG&A expense, you know, we gave guidance today on total OpEx for the year, $355-$375. That includes non-cash stock comp. And then for R&D, the $240-$260. So, you know, based on that, you can, you know, it's circa 100, slightly higher in total SG&A for the year. You know, last year, we ended the year, SG&A totaling about $67 million, and about $22 million of that was in the fourth quarter. So, you know, the reps, I think you can assume, you know, we're recruiting now.

I think it would be, you know, a reasonable assumption to assume they're definitely on board for the second half of the year in advance of both launches. You know, take a reasonable cost per rep per year, you know, and add that on. And I think you can pretty simply kind of work out the math of the SG&A growth for the year, you know, from $66-$67 million this year to $100 million next year. And given the fact that we've given first quarter guidance of total OpEx and R&D expense as well. But, yeah, you know, definitely the second half of the year will be the additional commercial field force. You know, we have the G&A infrastructure in place from, you know, HR, finance, IT.

That infrastructure is well in place, so it's going to be the reps plus the A&P to go with that.

Anupam Rama (Managing Director and Senior Equity Analyst)

Thanks so much for taking our questions.

Michael Metzger (CEO)

Thanks, Anupam.

Operator (participant)

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

Phil Nadeau (Managing Director and Senior Biotechnology Research Analyst)

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 adding revumenib to the background regimen. Not everyone agrees, so could you address, like, the neutropenia rates that you would expect? I think you showed 56% at ASH. What would ASTX727 do alone? And then second, on Beat AML, again, there's some concerns about the combinability, particularly the dose of revumenib going forward in light of the CYP interaction that ven has.

How will you determine the phase II dose through Beat AML, and what type of dose adjustments would you anticipate once that phase II dose is found?

Michael Metzger (CEO)

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 Beat AML. Thank you.

Neil Gallagher (President and Head of R&D)

Yeah. So, I think the first thing to remember is that the trial, the SAVE trial, accrued a very heavily pretreated population. So, you know, two-thirds of patients had failed prior ven, a third had been... Or half of, over half of them had been transplanted. So this is a, you know, patient population, a median number of prior therapies of 3-4.

... and therefore, the cytopenia rate that was observed is, you know, according to, you know, the investigators and not only the investigators in the study, but others, entirely consistent with what you would expect with ven and oral decitabine, you know, in that particular patient population. I mean, if there's been some comparison to, you know, a less heavily pre-treated population that may be in people's minds, that's just not a valid comparison. Like, you have to look at the patient population that was included in the trial, and therefore, that's why we can... You know, the investigator has stated with confidence, and we agree with him, that the cytopenia rate was consistent with what would be expected from the backbone.

In terms of Beat AML, not sure that I understand why you think that there's a challenge around dose selection. Both. So just to reiterate for the entire audience, there were two doses of revumenib tested in all three of the combination trials that we reported out at the investor event at ASH, right? Or was also reported at ASH itself, SAVE AML was presented independently of our event as well. So the two doses that were included in all three combination trials were 113 milligrams twice a day, and 163 milligrams twice a day. Different patient populations, obviously, in the Beat AML trial, they were newly diagnosed.

As we've just discussed, they were heavily pretreated relapsed refractory, and in AUGMENT-102, they were heavily pretreated relapsed refractory patients. And in all three trials, the dose-limiting toxicity windows for both doses were cleared, okay? So, in with respect to Beat AML, what the group is now doing is expanding those cohorts to further refine what the RP2D would be for a phase III trial. And we've stated, you know, many times publicly, that it is our intention to proceed to that phase III by the end of the year. So, you know, the... Yeah. So, just to and just one final point, those two doses, 113 and 163.

163 mg is the presumptive monotherapy full dose when administered with a strong CYP3A4 inhibitor, okay? And 113 mg is also highly active. Also, you have to recall that venetoclax and azacitidine in the Beat AML trial was administered at full dose. So there's, you know, the, there's no question in our mind that the combinability of revumenib with venaza in the newly diagnosed setting, as well as in the other two settings, you know, it's clear.

Phil Nadeau (Managing Director and Senior Biotechnology Research Analyst)

That is very helpful, makes it clear. And then last question, just on axatilimab sales and marketing. I think in your prepared remarks, you said, Syndax is responsible for 30% of the marketing efforts. In the answer, I think, to Anupam's question, you said 30% of FTEs. How are the marketing efforts, how is 30% of marketing efforts defined? Is that specifically 30% of FTEs, or are there other metrics that Syndax needs to deliver as well, such as, touchpoints with physicians or call points or, or something else?

Michael Metzger (CEO)

Yeah. I'll turn it over to Keith. Go ahead.

Keith Goldan (CFO)

Yeah. Phil, thanks for the question. So apologies if I wasn't clear or if we weren't clear. So the our partnership agreement with Incyte stipulates that we have the ability to contribute 30% of the promotional effort. So from a sales call point perspective, we'll be delivering 30% of that effort. So I mentioned it before in FTEs because I didn't want to speak, like, in the number of reps, but we will be delivering 30% of that, of that salesforce effort. But don't forget, it's a combined P&L, right? So we'll put our 30% the cost of that 30% effort into the combined P&L.

Incyte will put their 70% of the cost of their effort into the P&L, and then any advertising promotion expenses incurred by Incyte, because they are taking the lead from that perspective, would go into that joint P&L. That joint P&L, the bottom of that joint P&L, called the, you know, commercial profitability of the product, is split 50/50.

Phil Nadeau (Managing Director and Senior Biotechnology Research Analyst)

Perfect.

Keith Goldan (CFO)

We pick up 50%, they pick up-

Phil Nadeau (Managing Director and Senior Biotechnology Research Analyst)

Thanks for taking our question.

Michael Metzger (CEO)

Thank you, Phil.

Keith Goldan (CFO)

Thanks, Phil.

Neil Gallagher (President and Head of R&D)

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

Brad Canino (Equity Research Analyst)

Good afternoon. You've provided peak sales opportunities, but how do you see the KMT2A launch playing out this year? You know, things in terms of number of patients that are available in the relapsed refractory setting, where they're concentrated, and what to expect for the pace of uptake.

Michael Metzger (CEO)

Brad, thanks for the question. I think, maybe a little early to start speculating about sales ramp and projection. And we'll reserve the ability to give a little bit more guidance as we get closer to to commercialization. I think, as we stated in our remarks, we think it's a KMT2A is a really, I'd say, compelling opportunity commercially, in the sense that we'll have a first-to-market, best-in-class product to address patients even earlier than they were tested in the clinical trial. So we're talking 2,600 patients overall, probably about 2,000 of which are treated in the relapsed refractory setting. We believe that we'll have the opportunity to address the vast majority of those patients. And as we've pointed out in previous discussions, that these patients are in dire need of therapy.

Many of them can go to transplant, hopefully, through the use of treatment with revumenib, and then potentially back on treatment in a post-transplant setting. So there is, we think, a highly addressable population. Physicians seem to be quite motivated to use the drug. And so we've seen that in our trials, but we've also heard that from physicians. So I think this sets up as a really interesting new opportunity for our drug to come to market with really no competition at this current point to get in the way of, you know, a very successful launch. So that's how we see it today in terms of projections and launch and ramp. We'll maybe preserve that for a future discussion.

Operator (participant)

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

Michael Schmidt (Senior Managing Director and Senior Biotech Analyst)

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? You know, what are other benchmarks that you're looking for in your own study, you know, including MRD status, for example, transplant rates or any other efficacy measures that are important in your opinion?

Michael Metzger (CEO)

Yeah, Michael, thanks for the question. Important one, certainly to get a handle on. I think the 7+3 regimen, as you know, is highly effective, in frontline patients, NPM1 and KMT2A patients initially respond, upwards of 80% of patients respond, to those treatments. However, they don't usually respond for long, so there's relapse that happens with most of those patients. Things to look for beyond just CR rates, CR/CR rates, of course, would be MRD and transplant rates, which we would be looking for. Obviously, we've seen, you know, high rates of both, in relapsed refractory patients. Now we're moving to we would be moving to frontline, and you'd expect to see, you know, equal or better rates of MRD and certainly transplant in earlier line settings.

I think that's the—those are some really important measures. Duration of treatment, of course. 7+3 is a short course. The ability to treat with revumenib and keep patients in remission for an extended period of time is obviously something that we'd want to see. Of course, it's new days, right? We haven't—you haven't seen a menin inhibitor perform in the frontline 7+3 as of yet. So I think it would be, you know, up to us to kind of set the trend for what the bar looks like there.

Certainly from a CR perspective and a safety perspective, you kind of know what you'd want to see, a relatively clean profile and highly effective, but you need to continue on, and you see deep, durable responses as well. Neil, do you want to add anything?

Neil Gallagher (President and Head of R&D)

Yeah, maybe just two things I would add to that. And I think there may have been a regulatory context to the question about what the potential endpoint could be. It's certainly too soon to talk about that. I think Michael has mentioned you know, MRD-negative CRs, and that is certainly an endpoint of interest. You know, whether or not it could be an approvable endpoint remains to be seen, and we will, of course, be engaging in discussions with the agency you know, as we move closer to having now initiated our dose ranging trial, as we move closer to initiating our phase III trial.

And then the only other add that I would make would be, you know, if you look at the 7+3 trials that have been conducted, really, you know, over the last, you know, sort of 10-12 years, going back as far as 2011, they've all included maintenance phases. And you could assume that any 7+3 trial that we would conduct would also include a maintenance phase. And in support of that, what we have seen. Recall that what we've seen in the relapsed refractory setting, post-transplant, is patients who've remained on therapy for protracted periods of time, speaking to the tolerability of revumenib in a relapsed refractory setting.

Therefore, we anticipate that as we move toward the newly diagnosed setting, that patients who would be, for instance, given monotherapy maintenance after induction consolidation therapy, would probably most likely tolerate the medicine very well as well, or the molecule rather.

Michael Schmidt (Senior Managing Director and Senior Biotech Analyst)

Okay, thank you.

Michael Metzger (CEO)

Thank you, Michael.

Operator (participant)

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

Ashiq Mubarack (VP of Biotechnology Equity Research)

Hi, guys. This is Ashiq Mubarack on Yigal. Thanks for taking my questions. I had a few on axatilimab. I guess, first, congrats on the, on the PDUFA date. I'm just wondering how involved you are in the, in the regulatory process from, 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 label negotiations? How should we think about that?

Michael Metzger (CEO)

Yeah, so thanks for the question. Look, we're very involved with, obviously, with axatilimab. We've generated the data, and it's been a very close collaboration with Incyte, and so we are involved in the regulatory process, and are working with them closely to get this drug approved in all facets. So, things you're thinking about, label negotiations and things like that. We are, I'd say, suffice to say, very involved with what's going on. So that's an exciting development for the company, and obviously, we have great experience with the molecule, and we want to think that we're involved. So that's certainly what it is. Was there a second part to your question, or was that - did I cover it?

Ashiq Mubarack (VP of Biotechnology Equity Research)

Nope, that, that's very clear. I wanted to ask another one on IPF. Maybe I'm-

Michael Metzger (CEO)

Sure.

Ashiq Mubarack (VP of Biotechnology Equity Research)

Just forgetting or simply, just don't remember this from prior calls. But, we—I know you're evaluating the 0.3 mg per kg dose, which was obviously the dose that looked best in AGAVE-201. But I'm just wondering what kind of gave you confidence that's the right dose, specifically for IPF? I guess why, why didn't you need to do dose optimization work, or is the disease biology really similar enough that you felt confident enough not to do that? Obviously, we're dealing with a different endpoint here, so just curious what your thoughts are.

Neil Gallagher (President and Head of R&D)

Yeah. Yeah, it's me. Hi, it's Neil. I'll take the question. So, no, it's a good question. We did have a long, you know, a long discussion internally about the dose selection. So a couple of things. The, you know, quite clearly, the 0.3 milligram dose in the AGAVE trial was superior to the other 2 doses. And, you know, we don't need to you know, sort of go back over that. It's quite clearly the superior dose in terms of efficacy as well as tolerability.

And, you know, what we have talked about a number of times, over the past year, and particularly before we announced the details of the IPF proof of concept trial that we talked about today, was that we were looking for an efficient trial design. And therefore, the most efficient trial design, which would get us to a sort of robust proof of concept answer, you know, efficiently, meaning efficiently in terms of the design of the trial, but also in the time to execute the trial, was the one that we've described today. And we felt that on the balances of, you know, the balance of everything, that it was reasonable to go ahead with one dose in this trial, and that dose should be 0.3 milligrams.

I think to one point that you alluded to, yes, I think that there is sufficient overlap from a biological perspective to have made that decision, and that sort of partly led us to that decision.

Michael Metzger (CEO)

Right. Maybe I'd add on to that, that you probably know that we did extensive dose ranging in the course of the phase 1, as well as the pivotal trial. We've also looked at, early on, we looked at healthy volunteers. We know how this antibody behaves and so, and the effect that it has on the macrophage. And so I think understanding the pharmacology here, and therefore how we think it would translate to patients in IPF, kind of gave us some, you know, I think, some good confidence that 0.3 would be the appropriate dose in addition to what Neil has added.

Ashiq Mubarack (VP of Biotechnology Equity Research)

Very helpful. Thanks very much.

Michael Metzger (CEO)

Thank you.

Neil Gallagher (President and Head of R&D)

You're welcome.

Operator (participant)

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

Alexandra Hammond (VP of Biotechnology and Pharmaceuticals)

Hey, guys, this is Alec Hammond on for Jason. Thanks for taking my question. Appreciating it's somewhat early, but with regards to your regulatory submission for revumenib, can you provide some color on what you expect to be included in the label? Are the eight efficacy evaluable ALL and AML patients with a 12.5% CR/CRh enough to warrant a tumor-agnostic label? And what are your basic expectations on potential safety monitoring requirements for DS and QTc prolongation? Thank you.

Michael Metzger (CEO)

Right. Maybe I'll turn it over to Neil. We talked a little bit about the label and then maybe talk about any kind of safety.

Neil Gallagher (President and Head of R&D)

Sure. Well, our anticipation is that the label, I mean, let me just presage what I'm about to say by reminding everyone that we got BTD back in December 2022 for KMT2A, AML and ALL, adults and kids. So you know, the development program moving forward from then, that was based on phase 1 data. The development program moving forward from there was based around a premise that we would have a potential for a broad indication. As you know, we actually pooled cohorts 2A and 2B, and the submission for KMT2A relapsed acute leukemia is based on that pooled analysis, which of course includes AML, ALL, adults, as well as pediatric patients.

So our anticipation is, and of course, the agency has been fully in lock, you know, sort of coming on that journey with us a lot, you know, the whole, the whole way, including from BTD, before BTD, through BTD and onwards. So that, that, that's the indication that we're looking for. So not the exact words, but KMT2A rearranged acute leukemias in adults and children. With respect to your second question about safety monitoring, we don't, so first of all, you know, from a class perspective or a broad class, meaning targeted therapies in AML, yeah, we anticipate we would probably anticipate a box warning for Differentiation Syndrome, you know, since that, you know, is typical of these agents in class, right? It's on target. You know, it happens.

You know, the agency knows it happens, so that's that. We do not anticipate. We anticipate a warning and precaution for QT, but that's it.

Operator (participant)

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

Kalpit Patel (Senior Biotech Research Analyst)

Yeah. Hey, good afternoon, and thanks for taking the questions. Maybe a couple on the 7+3 combo study. Can you give us some color on what dose of revumenib you're planning to start with? And then, the second question is, how should we think about the enrollment split between the KMT2A-R and the NPM1 population in that combo study, would it be a 50/50 split, or are you skewing, you know, are you anticipating a skewing of the KMT2A patients as they are more fit?

Michael Metzger (CEO)

Yeah, maybe I'll take the second question. I'll give the first one to Neil. Yeah, so I think that's. I think you just said it. In terms of KMT2A versus NPM1, we don't really know, but I think it's, you know, they're the KMT2A patients overall are more fit than unfit, right? So that's where they skew. Whether or not we have, you know, a skewing in our population of patients to KMT2A or not, we don't know at this point, but we do expect representation of both. And, Neil, do you want to talk about the 7+3 combo, starting dose?

Neil Gallagher (President and Head of R&D)

Yeah. So just one thing to add on: It doesn't really matter how, you know, the split between KMT2A and NPM1 patients in the first instance, right? What we're actually seeking to demonstrate is the combinability of revumenib 7+3. As we mentioned a little bit earlier on in the call, in all of the combination trials that we've described thus far, there have been two doses tested, 113 milligrams and 163 milligrams. And those are the doses, or the equivalent doses, without CYP3A4, that strong CYP3A4, that we will be testing in the 7+3 trial as well.

I mean, we know, we know based on the comments that we made earlier on and, you know, data that we've presented before, we know that they're combinable with both chemotherapy and also low-intensity HMA therapy.

Operator (participant)

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

Jeet Mukherjee (VP and Biotechnology Analyst)

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

Michael Metzger (CEO)

Yeah, I don't know. Anjali, do you want to take that question?

Anjali Ganguli (Chief Business Officer)

Yeah, sure. I can start. And Jeet, you know, I will preface this by saying that we need a little bit more efficacy data to really hone in the expectations. But I think we know that, you know, as Neil mentioned on the call, there's two drugs that are approved, and though a lot of patients cycle through both of them and sometimes see them added onto one another, all they do is slow the decline. They're not actually treating the disease, and so there is still a huge unmet need in the marketplace. There are a very large number of IPF patients out there today, even in the US alone, and we would expect to be able to...

You know, we're doing the trial to add on to standard of care, so we'd be looking at a second- or third-line utilization. I think you know, we would expect, based on positive data, to get significant uptake in that population, because of the large unmet need.

Jeet Mukherjee (VP and Biotechnology Analyst)

Got it. That's helpful. And maybe just one more on axatilimab. Just any additional color or 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, you know, one or both of those forward ultimately?

Michael Metzger (CEO)

Yeah, Anjali, you want to follow on there?

Anjali Ganguli (Chief Business Officer)

Yeah, sure. So, you know, 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. This 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, you know, 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.

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.

Jeet Mukherjee (VP and Biotechnology Analyst)

Thanks for taking our-

Operator (participant)

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

Chloe Zhang (Manager of Provisions Financial Reporting and Planning)

Hi there. This is Chloe 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 KMT2A-r AML, or ALL? And secondly, could you speak to the prospects for other indications for revumenib?

Michael Metzger (CEO)

... Great, Chloe, 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 axatilimab, or sorry, revumenib, in colorectal disease, third line metastatic colorectal cancer, as a monotherapy agent.

It's obviously a very difficult disease state, and we're gonna 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 types, 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 or 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.

Chloe Zhang (Manager of Provisions Financial Reporting and Planning)

Okay, got it. Thank you.

Michael Metzger (CEO)

Thank you.

Operator (participant)

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.

Michael Metzger (CEO)

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.

Operator (participant)

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