Syndax Pharmaceuticals Inc
NASDAQ:SNDX
Earnings Call Analysis
Q4-2023 Analysis
Syndax Pharmaceuticals Inc
Among the highlights for potential investors is the company's focus on acute leukemia treatments, centering on two gene mutations: NPM1 and KMT2A. With no FDA-approved targeted therapies for this group, the drug revumenib could fill a significant void, addressing an approximate patient population of 12,000 and potentially owning a $750 million market for relapsed or refractory KMT2A acute leukemia alone in the U.S. This first-mover advantage may see revumenib become the treatment of choice and pivot the company towards building a formidable franchise.
The company is not resting on its laurels with leukemia but is actively expanding into solid tumors. Ongoing clinical trials in metastatic colorectal cancer explore the inhibition of menin-KMT2A interaction, with updates on this exciting work expected in the second quarter of 2024. This diversification could potentially further increase the company's market presence.
Another promising drug in the pipeline is axatilimab, which targets chronic graft versus host disease (chronic GVHD) following two failed systemic therapies. The drug has demonstrated an impressive 74% overall response rate and tolerability in trials. Anticipating FDA approval, the company expects to kick off further trials, aiming to address a substantial part of the 14,000 patient market suffering from chronic GVHD in the U.S.
Further to their portfolio is axatilimab's use in treating interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF) -- a significant move given the drug's ability to target fibrosis and inflammation. With a Phase II trial underway, the company is optimistic about the molecule's potential and is projecting expansion into Phase III pivotal development.
In terms of financial footing, the company raised $258 million in the last quarter, leading to a strong cash balance expected to provide runway through 2026. For the full year of 2024, it projects research and development expenses between $240 million to $260 million, with total operating expenses estimated at $355 million to $375 million, factoring in approximately $43 million of noncash stock compensation expense.
The company executives discussed the commercial prospects of revumenib, recognizing it as a first-to-market, best-in-class product with potential to address the majority of the estimated 2,000 patients treated in the relapsed/refractory setting annually. Anchored by strong clinical trial results and physician support, revumenib stands as a formidable new therapeutic option with substantial commercial opportunity.
Looking beyond the current trial indications, combination studies aim to enhance patient outcomes. For axatilimab, trials combining it with existing treatments such as ruxolitinib and corticosteroids could significantly impact patient disease profiles and address a broader population earlier in their treatment cycles. Positive data from these trials in the coming years could solidify axatilimab's position in the market and improve disease management for the 14,000 patients with the current prevalent pool.
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Good day, everyone, and welcome to the Syndax Fourth Quarter and Full Year 2023 Earnings Conference Call. Today's call is being recorded. [Operator Instructions]At this time, I would like to turn the call over to Sharon Klahre, Head of Investor Relations at Syndax Pharmaceuticals.
Great. Thank you, operator. Welcome, and thank you all for joining us today for a 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 2. Before we begin, I'd like to remind you that any statements made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors, including those discussed in the Risk Factors section in the company's most recent annual report on Form 10-K as well as other reports filed with the SEC. Any forward-looking statements made represent our views as of today, February 27, 2024 only. A replay of this call will be available on the company's website, www.syndax.com, following its completion.With that, I am pleased to turn the call over to Michael Metzger, Chief Executive Officer of Syndax.
Thanks, Sharon, and thank you to everyone joining us on the webcast. 2023 was a year of tremendous progress 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 2 potential approvals and commercial launches. Syndax is firmly on the path to distinguishing itself as a commercial-stage SMID-cap biotechnology company. And with opportunities to expand well beyond the initial indications for revumenib and axatilimab, we envision creating long-term value with these franchises for years to come.On Slide 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 I and Phase II 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 I combination trials that demonstrated revumenib's ability to safely and effectively combine with standards of care.In late December, we announced the submission of an NDA filing for revumenib under the FDA's Real-Time Oncology Review, or RTOR program for the treatment of adult and pediatric relapsed or refractory KMT2A rearranged acute leukemia. Submitting the NDA under RTOR ensures early engagement with the FDA throughout the review process, helping to derisk the submission and provide a potentially expedited time line 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 2 prior lines of systemic therapy. Positive data from the pivotal AGAVE-201 trial presented at a Plenary Scientific Session at ASH in December, form the basis of the BLA submission. And last quarter, we also initiated a Phase II 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 2 first and best-in-class drug launches. For revumenib, we are focused on prelaunch 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 2 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 2 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 preceded 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 have been receiving maintenance treatment for as long as 8 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 I 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 I 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 I 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 2 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 received venetoclax plus azacitidine.Our frontline strategy is to add revumenib on to 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 II 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 I 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 I trial being conducted by the Leukemia & Lymphoma Society. In this trial, frontline AML patients who are unfit for induction chemotherapy are dosed with a triplet of revumenib, venetoclax and azacitidine in 28-day cycles. In an interim look at data from 13 patients, 100% achieved a complete remission or CRC and all patients for whom we had an MRD assessment achieved an MRD-negative response. This is significantly higher than what would be expected from venetoclax plus azacitidine alone based on the results of the VIALE-A trial where patients achieved a 66% CRC rate and only 24% achieved an MRD-negative response. Importantly, I'd like to emphasize that there was no impact on the safety or tolerability observed by adding revumenib to this doublet regimen.Turning to Slide 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 3 patient subsets; NPM1, KMT2A or NUP98. This triple combination was also well tolerated at both active doses of revumenib the trial, including the current monotherapy RP2D with no new or increased safety signals observed beyond what would be expected with venetoclax and a hypomethylating agent.Now to Slide 10. KMT2A and NPM1 acute leukemias represent up to 40% of all AML patients, and there are no FDA-approved targeted therapies for this population. Inclusive of the expansion opportunities, there is the potential to address upwards of 12,000 NPM1 and KMT2A acute leukemia patients across various settings. We believe relapse or refractory KMT2A acute leukemia alone represents a $750 million market opportunity in the U.S. The annual incidence of KMT2A acute leukemia is about 2,600 patients, and the majority are refractory to frontline standard of care treatments.We estimate a median duration of therapy across the treated population of approximately 9 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 will gain treating patients with revumenib could extend meaningfully beyond KMT2A and allow us to build a formidable franchise in the next few years, augmented by a second indication in NPM1 AML. Our market research suggests that if approved, oncologists are likely to prescribe revumenib as either their second or third-line agent of choice for the treatment of NPM1 AML. We estimate that this population would be slightly larger than the relapsed or refractory KMT2A acute leukemia population. And based on our Phase I results, we also believe overall efficacy and treatment duration will be consistent between the KMT2A and NPM1 relapsed or refractory populations.Having 2 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 [Technical Difficulty] and we're also investigating the opportunity to expand to solid tumors. Our proof-of-concept signal-seeking Phase I clinical trial in metastatic colorectal cancer is ongoing. This trial is based on preclinical science that supports the role of menin-KMT2A interaction and beta-catenin driven tumors. We are following these patients and expect to provide an update on the progress of the dose escalation phase of the trial in the second quarter of 2024. We would perceive single-agent activity reflected as responses or prolonged stable disease as encouraging in this third-line patient population.Let me now turn to axatilimab, our monoclonal antibody targeting the CSF-1 receptor beginning on Slide 11. As noted earlier, we're thrilled that the BLA for axatilimab in adult and pediatric patients with chronic GVHD after failure of at least 2 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 7, day 1 using the 2014 NIH consensus criteria for chronic GVHD across all 3 dose groups.The overall response rate was 74% at a dose of 0.3 milligrams per kilogram administered every 2 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 1 year. Axatilimab was well tolerated in the trial, with a low 6% rate of discontinuations. 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?
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 who reach their limited treatment options. Only 2 drugs have been approved and both have only been turned to slow, but not halter 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 the lung fibrosis. And in this experiment, animals were treated with an anti-CSF-1R antibody or saline control, 9 days after the administration of bleomycin. The histological section on the top left shows the normal lung with extensive white air space. 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 in day 9, has significantly less fibrosis than markedly preserved white air space. 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 I/II chronic GVHD trial of axatilimab, who had chronic -- who had GVHD-related bronchiolitis obliterans symptom or BOS. As you can see, 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 II trial of axatilimab in IPF is a 26-week double-blind, placebo-controlled and multicenter trial, which aims to include 135 patients randomized 2:1 to receive 0.3 milligrams per kilogram 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 III pivotal development potential.Let me now turn the call back to Michael.
Thank you, Neil. Turning now to Slide 15, which highlights the broad clinical and commercial opportunity for axatilimab. Approximately 14,000 U.S. patients suffer from chronic GVHD, 50% of whom require treatment beyond second line due to disease progression in adequate 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 U.S. markets and into other high-value indications could build significant additional value for axatilimab over the next few decades. We're looking forward to the [ 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?
Thank you, Michael. Turning to Slide 16. As Michael mentioned earlier, in the fourth quarter, we strengthened our balance sheet, adding $258 million, providing strong validation of Syndax's potential from both existing as well as new high-quality institutional investors. The $600 million on the balance sheet at year-end is expected to provide cash runway through 2026.Turning to the income statement. Operating expenses for the fourth quarter were $77.9 million, comprised of $55.1 million of research and development expense and $22.8 million of selling, general and administrative expense, in line with guidance. Looking forward, our financial strength enables us to focus on the execution of advancing our pipeline and achieving an exceptional launch of revumenib and axatilimab later this year.Keeping in mind that we've always embraced a disciplined approach to resource allocation. I'd like to provide financial guidance for the first quarter and full year 2024. For the first quarter, the company expects research and development expense to be $56 million to $62 million and total operating expenses to be $82 million to $88 million. For the full year 2024, the company expects research and development expenses to be $240 million to $260 million and total operating expenses to be $355 million to $375 million, including approximately $43 million of noncash stock compensation expense.With that, let me now turn the call back over to Michael.
Thank you, Keith. As you have heard during the call, 2023 was a landmark year for growth and execution. As evidenced by our positive pivotal trial readouts and 2 regulatory submissions for our 2 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 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 Instructions] Our first question comes from Peter Lawson with Barclays.
This is [ Shay ] on for Peter. Congrats on all the progress. [ PDUFA announced ] that for axatilimab, can you comment on expectations for your launch in 3Q? And related to that, it sounds like you're still expecting a 3Q potential approval for the Menin inhibitor, are you expecting that to be potentially positioned for sales in 3Q? Or is this potentially dependent on [Technical Difficulty].
So first off, I think you broke up a little bit on the second question. Do you want to take the first question?
Sure. This is Keith. So for axatilimab third quarter, we have the PDUFA, when the FDA actually approves the drug is still a question. As we've laid out earlier in the year, we've opted into the co-promotion and as Michael said earlier, the co-promotion of axatilimab. So we'll be ready with our sales force prior to the approval of either product. So as you can see by looking at LinkedIn or looking at our website in the 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. We'll have to wait until later this quarter when we received 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. Does that answer your questions?
Our next question comes from Anupam Rama with JPMorgan.
Maybe expanding on key comments just now. Just remind us of where you are in terms of the sales force, sales team build out. What are your -- 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.
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 building out our commercial organization to accommodate both the launch of revumenib, but now we've opted into the co-promote with Incyte around axatilimab to provide up to 30% of the FTEs for that effort. It's an overlapping, as I said in my remarks, overlapping and highly targeted call point. And so the opportunity here is with roughly 40 to 50 representatives to cover the U.S. 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 -- 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?
Yes. So Anupam, with respect to your question on SG&A expense, we gave guidance today on total OpEx for the year, $355 million to $375 million, that includes noncash stock comp. And then for R&D, the $240 million to $260 million. So based on that, you can -- it's [ circa 100 ] slightly higher in total SG&A for the year. Last year, we ended the year SG&A totaling about $67 million and about $22 million of that is in the -- was in the fourth quarter.So the reps, I think you can assume we're recruiting now. I think it would be a reasonable assumption to assume they're definitely on board for the second half of the year in advance of both launches take a reasonable cost per rep per year 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 from $66 million, $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 yes, definitely, the second half of the year will be the addition of commercial field force, we have the G&A infrastructure in place from 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.
The next question is from the line of Phil Nadeau with TD Cowen.
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 2 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 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 combined ability, particularly the dose of revumenib going forward in light of the SIP interaction [ that have enhanced ]. 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?
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 wrote up about BEAT-AML.
Yes. So I think the first thing to remember is that the trial -- the SAVE trial accrued a very heavily pretreated population. So 2/3 of patients had failed [ prior van I've heard ] have been -- or half of -- over half of them have been transplanted. So this is a patient population of median number of prior therapies of 3 to 4. And therefore, the cytopenia rate that was observed is according to the investigators and not only the investigators in the study, but others entirely consistent with what you would expect with [ Zen and oral ] decitabine in that particular patient population. I mean if there's been some comparison to a less [ heavily pretreated ] population that maybe 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 -- the investigator has stated his confidence and we agree with them that the cytopenia rate was consistent with what would be expected from the backbone.In terms of BEAT-AML, I'm not sure that I understand -- 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 2 doses of revumenib tested in all 3 of the combination trials that we reported out at the investor event at ASH, right? Or was also reported at ASH itself [ BEAT-AML ] was presented independently of our event as well. So the 2 doses that were included in all 3 combination trials were 113 milligrams twice a day and 163 milligrams twice a day. Different patient populations, obviously, in the BEAT-AML trial that were newly diagnosed. SAVE, we've just discussed, they were heavily pretreated relapsed refractory. And in AUGMENT-102, they were heavily pretreated relapsed/refractory patients.And in all 3 trials, the dose-limiting toxicity windows for both doses were cleared, okay? So -- and 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 stated many times publicly that it is our intention to proceed to that Phase III by the end of the year.So just -- and just one final point. Those 2 doses, 113 and 163 -- 163 milligrams is the presumptive monotherapy full dose when administered with a strong CYP3A4 inhibitor, okay? And 113 milligrams is also highly active. Also, you have to recall that venetoclax and azacytidine in the BEAT-AML trial was administered at full dose. So there's -- the -- there's no question in our mind that the combinability of revumenib with ven/aza in the newly [ diagnosed setting ] as well as in the other 2 settings, it's clear.
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 was 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 touch points with physicians or [ co-points ] or something else?
Yes. I'll turn it over to Keith. Go ahead.
Yes. So apologies if I wasn't clear, if we weren't clear. So the -- our partnership agreement with Incyte stipulates so 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 sales force 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 and that joint -- the bottom of that joint P&L called the commercial profitability of the product is split 50-50. [indiscernible] they pick up.
Our next question comes from Brad Canino with Stifel.
You've provided peak sales opportunities, but how do you see the KMT2A launch playing out this year, 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?
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 guided because we get closer 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 a drug to come to market with really no competition at the current point -- at this current point to get in the way of a very successful launch. So that's where we -- how we see it today in terms of projections and launch and ramp, we'll maybe preserve that for a future discussion.
Our next question comes from the line of Michael Schmidt with Guggenheim.
I had one on the first-line setting for revumenib in combination with 7+3. In your opinion, what is the right way to view frontline combo data with menin inhibitors and 7+3? And specifically, given that one would expect very high CR rates, presumably on top of 7+3 already. What are other benchmarks that you're looking for in your own study, including MRD status, for example, transplant rates or any other efficacy measures that are important in your opinion?
Important one, certainly to get a handle on. I think the, 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 treatment. However, they don't usually respond for long. So there's a relapse that happens with most of those patients.Things to look for beyond just CR rates, CR/CRh, of course, would be MRD and transplant rates, which we would be looking for -- obviously, we've seen high rates of both in relapsed/refractory patients. Now we're moving to -- would be moving to frontline and you'd expect to see equal or better rates of MRD and certainly transplant in earlier line settings. And so 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 front line, 7+3 as of yet. So I think it would be up to us to kind of set the trend for what the bar looks like there. But 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?
Yes, maybe just 2 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 MRD negative CRs and that is certainly an end point of interest, 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 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, if you look at the 7+3 trials that have been conducted really over the last sort of 10 to 12 years going back as far as [indiscernible] 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. And therefore, we anticipate that as we move towards the newly diagnosed setting, the patients who would be, for instance, given monotherapy maintenance after induction consolidation therapy would probably -- would most likely tolerate the medicine [ very well as well, the molecule of that ].
Our next question comes from Yigal Nochomovitz with Citi.
This is Ashiq Mubarack on for Yigal. I had a few on axatilimab. I guess, first, congrats on the PDUFA date. I'm just wondering how involved you are in the regulatory process from this point out. Obviously, we know inside is leading the proceedings, but will we be part of the mid-cycle review? Will you be able to weigh in on label negotiations? How should we think about that?
Look, we're very involved with -- obviously, with axatilimab, we 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 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 another -- second part of your question? Or was that -- did that cover it?
No, that's very clear. I wanted to ask another one on IPF. Maybe I'm just forgetting [ or simply, I 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. Just wondering what kind of gives you confidence that's the right dose specifically for IPF? I guess why didn't you need to do dose optimization work? Or is it disease biology really similar enough that you felt confident enough not to do that. And obviously, we're dealing with a different end point here. So just curious what your thoughts are.
Yes, it's Neil. I'll take the question. So no, it's a good question. We did have a long discussion internally about the dose selection. So a couple of things. Quite clearly, the 0.3 milligram dose in AGAVE -- in the AGAVE trial was superior to the other 2 doses. And we don't need to sort of go back over that. It's quite clearly the superior in terms of efficacy as well as tolerability.And 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 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 balance of -- the balance of everything that it was reasonable to go ahead with 1 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.
Maybe I'd add on to that, you probably know that we did extend the dose ranging in the course of the Phase I 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 the understanding the pharmacology here and therefore, how we think it would translate to patients in IPF kind of gave us some, I think, some good confidence that 0.3 would be the appropriate dose in addition to what Neil has added.
Our next question comes from the line of Jason Zemansky from Bank of America.
This is Alex Hammond on for Jason. Appreciating it's somewhat early, but with regards to your [ regular submission ] for revumenib, can you provide some color on what you expect to be included in the label? Are the 8 efficacy [ evaluable AML and PAL ] patients with a 12.5% CR/CRh not warrant a tumor-agnostic label? And what are your base expectations on potential safety monitoring requirements for [ CS and QTc ] prolongation.
Maybe I'll turn it over to Neil. He talk a little bit about the label, and then maybe talk about any kind of safety.
Sure. Well, our anticipation is that the label -- I mean, let me appreciate what I'm about to say by reminding everyone that we got BTD back in December 2022 for [indiscernible] to a AML and ALL adults and kids. So the development program moving forward from them, those based on the Phase I data. The development program moving forward from there was based around that premise that we would have a potential for a broad indication. As you know, we actually pulled Cohorts 2a and 2b, and the submission for KMT2A relapse to keep leukemia that 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 -- it's sort of coming on that journey with us the whole way, including from BTD, for BTD, through BTD and onwards. So 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, from a class perspective, our broad class meaning targeted therapies in AML, we anticipate we would probably anticipate a [indiscernible] differentiation syndrome since that is typical of these agents in class, right? It's on target. It doesn't happen -- the agency knows it happens, so that's that. We do not anticipate -- we anticipate a warning of precaution for [ Q2 ], but that's it.
Our next question comes from Kalpit Patel with B. Riley.
Maybe a couple on the 7+3 combo study. Can you give us some color on what goes of revumenib you're planning to start with?And then the second question is, how should we think about the enrollment split between the KMT2Ar and the NPM1 population in that combo study? Would it be a 50-50 split? Or are you anticipating the skewing of the KMT2A patients as they're more fit?
Yes. Maybe I'll take the second question, and I'll give the first one to Neil. Yes. 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 -- the -- the KMT2A patients overall are more fit than unfit, right? So that's where they skew, whether or not we have 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?
Yes. So -- and just one thing to add on. It doesn't really matter the split between KMT2A and NPM1 patients in the first instance, right? What we're actually seeking to demonstrate is that is the combined ability of revumenib 7+3. And the -- as we mentioned a little bit earlier on the call in all the combination trials that we've described thus far, there have been 2 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 based on the comments that we made earlier on and data that we've presented before, we know that they're combinable with both chemotherapy and also venetoclax-based HMA therapy.
Our next question comes from the line of Justin Zelin with BTIG.
This is Jeet Mukherjee on for Justin. Maybe just coming back to axatilimab, I was hoping you could provide a little bit of a sense of the opportunity for axatilimab in IPF, the subset of patients, perhaps best suited for this therapy and what should be looking for from an efficacy perspective?
Yes. I don't know if Anjali, do you want to take that question?
Yes, sure. I can start. And Keith, I will preface this by saying that we need a little bit more [ SEC ] data to really hone in the expectations. But I think we know that, as Neil mentioned on the call, there's 2 drugs that are approved, and though a lot of patients cycle through both of them and sometimes see them added on to 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 U.S. alone, and we would expect to be able to -- we're doing the trial to add on to standard of care. So we'd be looking at a second or third line utilization. And I think we would expect, based on positive data to get significant uptake in that population because of the large unmet need.
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 one or both of those forward ultimately?
Yes, Anjali, do you want to follow on there?
Yes, sure. So again, axatilimab bringing this strong fibrotic effect to bear on patients and hopefully helping to manage the impact of the disease on organs and therefore, potentially shifting the courses of the disease is what we're trying to change with that combination therapy. So moving up earlier, could you really have a bigger impact on patients and their overall disease profile going forward. We anticipate getting some data out of this trial in the coming years. And I think that would govern what the uptake would really look like. But this is something that physicians are telling us they're really looking for. Right now, the only thing they have is steroids and unfortunately, those do as much harm as they do good. And so if you could get strong efficacy out of that combination, could you minimize the use of steroids and bring axatilimab up to an earlier population. I mean we know the current estimated prevalent pool is about 14,000 patients. And so you could access a big chunk of that population with good data.
Our next question comes from George Farmer with Scotia Bank.
This is [ Kelly ] on for George. Two from us on revumenib. So do you have any sense on whether the FDA is intending to hold an ODAC meeting to discuss the approval package in KMT2Ar AML or ALL? And secondly, could you speak to the prospects for other indications for revumenib?
Great. 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 going to have some data in the second quarter of this year to first get at whether there's sufficient activity there as a monotherapy agent and how the drug performs.There is this thesis that we're pursuing, 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 whether they're susceptible to revumenib treatment. So stay tuned. There may be more to come. I think the first step here is certainly the colorectal cancer trial that we're running.
This concludes our question-and-answer session. I will now turn the floor over to Mr. Michael Metzger for any additional comments or closing remarks.
Thank you all. We appreciate you tuning in tonight, and we look forward to seeing you at our planned investor events, including the upcoming Cowen and Barclays Healthcare Conferences in March. And with that, I wish you all a very pleasant evening. Thank you.
This concludes today's conference call. Thank you, and you may now disconnect.