Syndax Pharmaceuticals Inc (SNDX) 2023 Q4 法說會逐字稿

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.

Thank you, operator. Welcome and thank you all for joining us today for a review of Syndax Fourth Quarter and Full Year 2023 financial and operating results. Me Sharon Klahre and with me this afternoon to provide an update on the company's progress and discuss financial results. Our 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's 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 10K 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 two potential approvals and commercial launches.

Syndax is firmly on the path to distinguishing itself as a commercial stage mid-cap biotech company and with opportunities to expand well beyond the initial indications for revenue management 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 of our highly selective [men] in 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 KMT2Ar acute leukemia cohort as well as multiple Phase 1 combination trials that demonstrated revumenib ability to safely and effectively combined with standard of care.

In late December, we announced the submission of an NDA filing for recommended under the FDA's real-time oncology review for RTOR program for the treatment of adult and pediatric relapsed or refractory KMT2Ar rearranged acute leukemia.

Submitting the NDA under our RTOR ensures early engagement with the FDA throughout the review process, helping to derisk the submission and provide a potentially expedited time line to repeat to revumenib approval.

We expect to receive a PDUFA action date for recommended this quarter, which should align with a third quarter approval date. For axatilimab, our anti-CS-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 of AGAVE-201 trial presented at a plenary scientific session at ASH in December formed the basis of the BLA submission. And last quarter, we also initiated a Phase 2 double-blind randomized clinical trial for the treatment of idiopathic pulmonary fibrosis or IPF that Neil will later detail in this call.

Financially, we are in a very good position. We strengthened our balance sheet in the fourth quarter with an additional $258 million in cash, and Keith will go into more detail in our financials later in this call.

We continue to prepare for commercialization in 2024. Our first mover advantage is of high strategic importance, and we are busy ensuring that we successfully execute two first- and best-in-class drug launches. For revenue. We are focused on prelaunch activities and we are finalizing our go-to-market strategies for both recommended and axatilamab 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 axatilamab in the United States and provide 30% of the commercial effort has 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 recommended that investigators presented at the ASH Annual Meeting in December. There was significant excitement for every manager in the reaction to the data that investigators presented, which clearly demonstrated revumenibt has 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 in 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 a CR/CRh rate of 23%, 70% of which were MRD-negative. At the time of the data cutoff the median duration of CR/CRh response was 6.4 months based on a Kaplan-Meier estimate with 46% or six patients remaining in response.

Moving to slide 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 proceed to transplant prior to achievement of a CR/CRh. At the time of the data cutoff, 71% of patients who underwent 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 recommend its ability to use 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 recommended 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 to 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 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 were deemed unfit for intensive chemotherapy and would traditionally receive an adequate plus a society.

Our front-line 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 revumenibts.

We started combination development with venetoclax plus azacitidine in front-line 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 in 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 of and initiating a pivotal trial for this combination soon thereafter. On slide 8, is the data from the BEAT-AML trial, a Phase one 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 revumenib of venetoclax and a decided in 28 day cycles.

In an interim look at data from 13 patients, 100% achieved a complete remission for 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 regime.

Turning to slide 9. revumenib was also evaluated in another oral venetoclax combination among patients with relapsed or refractory AML. Interim data from this trial, known as SAVE AML, was conducted by investigators from the MD Anderson Cancer Center and presented at ASH.

The SAVE trial evaluated the all oral combination of revumenib of venetoclax and a fixed dose combination of decitabine and cedazuridine in relapsed or refractory AML or mixed-phenotype acute leukemias.

In the interim presentation, nine patients with either NPM1, KMT2A or NUP98 mutations were enrolled into the trial. These patients had received a median of three prior lines of therapy and over half of them had received prior venetoclax and prior hypomethylating agents. At the interim assessment, 100% of patients achieved a response and 78% achieved a complete remission.

Importantly, responses were observed across all three patient subsets, NPM1, KMT2A or NUP98. This 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 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 $750 million market opportunity in the US, the annual incidence of KMT2A acute leukemia is about 26 hundred 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 and KMT2A acute leukemia, along with no other treatment options approved in this population and no near term competition, revumenib should become the treatment of choice for patients with relapse or refractory KMT2A acute leukemia.

We expect that our first mover advantage and experienced physicians will gain treating patients with revumenib could extend meaningfully beyond KMT2A and allow us to build a formidable franchise in the next few years, augmented by a second indication in NPM1 AML.

Our market research suggests that if approved, oncologists are likely to prescribe revumenib as either their second- or third-line agent of choice for the treatment of NPM1 AML. We estimate that this population would be slightly larger than the relapsed or refractory KMT2A acute leukemia population and based on our Phase 1 results, we also believe overall efficacy and treatment duration will be consistent between the KMT2A and NPM1 relapsed or refractory populations.

Having two distinct market segments in acute leukemias available to us, KMT2A and NPM1 would create a total accessible population of somewhere between 5,000 and 6,500 patients in the relapsed refractory setting and an addressable market oppurtunity (technical difficulty) and 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 beta-catenin driven tumors. We are following these patients and expect to provide an update on the progress of the dose escalation phase of the trial in the second quarter of 2024, we would perceive single agent activity reflected as responses or prolonged stable disease as encouraging in this third-line patient population.

Let me now turn to axatilimab, our monoclonal antibody targeting the CSF-1 receptor beginning on slide 11. As noted earlier, we're thrilled that the BLA for axatilimab in adult and pediatric patients with chronic GVHD after failure of at least two prior lines of systemic therapy has been given a PDUFA action date of August 28, 2024, by the FDA.

Data from the global pivotal AGAVE-201 trial 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 three dose groups.

The overall response rate was 74% at a dose of 0.3 milligrams per kilogram administered every two weeks. The responses were durable, with a median duration of response not yet reached at the time of data cutoff and 60% of responders were still responding at one year. Axatilimab was well tolerated in the trial with a low 6% rate of discontinuations. The most common adverse events for consistent with the on-target effects observed in prior trials.

Axatilimab is differentiated from other approved therapies for chronic GVHD. In that it is the first investigational chronic GVHD treatment to target inflammation and fibrosis through the inhibition of disease associated macrophages.

On slide 12, you will note that responses, including CRs, were seen across all organs involved and notably in fibrosis dominated organs, including esophagus, joints, fascia and lungs. Over 85% of patients reported a reduction in chronic GVHD-related symptom burden in AGAVE-201, which supports the potentially pronounced impact this mechanism can have on patients suffering from chronic GVHD.

These results reinforce its potential as a first- and best-in-class CSF-1R monoclonal antibody in chronic GVHD. I'll now turn the call over to Neil 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.

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 fibrosis lung disease for which there are limited treatment options. When the two drugs have been approved. And both have only been shown to slow without 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 US prevalence of IPF growing to over 180,000 people by 2026. There is an increasing need for new, well-tolerated and effective medication. There are several reasons why we are excited to pursue fibrotic disease outside of chronic GVHD and why we have confidence that axatilimab may provide meaningful benefit in IPF.

There is al growing understanding of the important role of macrophage that macrophages play as a master regulator of the fibrotic process. There's a wealth of preclinical and clinical data indicating that the CSF1R signaling pathway may play an important role in the development of pulmonary fibrosis.

One such preclinical dataset 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 normal lung with extensive flight 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-R-antibodies.

Even more encouraging are the clinical data for axatilimab in patients with pulmonary manifestations of chronic GVHD, for clinically notable improvements in lung function have been observed. The panel on the right shows the date originally presented at the American Thoracic Society meeting last year from patients in the Phase 1/2 chronic GVHD trial of axatilimab who have chronic GVHD-related bronchiolitis obliterans syndrome or BOS.

As you can see, most patients experienced improvement or slowing of decline of pulmonary function, which is very unlikely to occur spontaneously. These data in conjunction with the organ specific data from the agave to a one 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 is a 26-week double-blind, placebo-controlled and multi-center trial, which aims to include 135 patients, randomized 2-to-1 to receive 0.3 milligrams per kilogram of axatilimab every two weeks are placebo on a background of standard of care.

The primary endpoint is the annualized rate of decline in forced vital capacity or FVC. Key secondary endpoints include disease progression, quality of life specific to patients with destructive airways disease and others. We believe this study is robustly designed to demonstrate proof-of-concept for axatilimab in IPF, thereby enabling us to advance the molecule into phase three pivotal development potentially.

Let me now turn the call back to Michael.

Thank you, Neil. For 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 for disease manifestations that aren't wholly address 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 a 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 and currently approved therapies.

Addressing inflammation and fibrosis in one mechanism of action is a key differentiator and also supports moving axatilamab 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 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 into other high-value indications could build significant additional value for axatilimab over the next few decades. We're looking forward to the insight led initiation of additional trials of axatilimab, including a Phase 2 combination trial with Jakafi and a Phase 3 combination trial with corticosteroids, which is expected to commence in mid-2024.

I'll now turn the call over to Keith to review our financial results.

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 the Syndax potential from both existing as well as new high-quality institutional investors. For $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 axatilamab 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 expense expects research and development expense to be $56 million to $62 million and total operating expenses to be $82 million to $88 million.

For the full year 2024, the company expects research and development expenses to be $240 million to $260 million and total operating expenses to be $355 million to $375 million, including approximately $43 million of non-cash stock compensation expense.

So with that, let me now turn the call back over to Michael.

Thank you, Keith. As you have heard during the call, 2023 was a landmark year for growth and execution, as evidenced by our positive pivotal trial readouts and two regulatory submissions for our two lead drug candidates, both of which are first and potentially best-in-class treatments. This is only the beginning of what's to come for Syndax.

We are in a significant transition into a fully integrated biopharmaceutical company serving multiple patient populations of high unmet need. Both programs offer the potential for broad franchise opportunities beyond their initial registration indications adding to Syndax is 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 that.

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. And 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) Peter Lawson, Barclays.

Hi, this is Shay (inaudible) Peter. Congrats on all the progress. But as for axatilimab, can you comment on expectations for your launch in 3Q and related to that it sounds like you're still expecting the 3Q potential approval for the menin inhibitor. Are you expecting that to be potentially positioned for sales in 3Q and potentially dependent on (technical difficulty) in 3Q? Thank you.

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

Yeah. Sure. So thanks for the question, Shay. This is Keith. So for axatilimab third quarter, we have the PDUFA. When the FDA actually approves the drug is still a question. As we’ve laid out earlier in the year, we’ve opted into the co-promotion, and as Michael said earlier, the co-promotion of axatilimab. So we’ll be ready with our sales force prior to the approval of either product.

So as you can see by looking at LinkedIn and are looking at our website in the career section, we're currently recruiting for all of the territory managers. So that's public knowledge, will have them onboard and trained up prior to approval of either product.

With respect to your question around, the timing of the initiation of revenue net of revenue. We'll have to wait until later this quarter when we received the PDUFA date -- PDUFA action date from the from the agency and I think at that time we'll have a better idea of when do you expect the initiation of revumenib revenues. Does that answer your question?

Anupam Rama, JPMorgan.

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 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?

Hey 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 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.

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 to produce imminently for revumenib as well. So we have -- we'll be ready well in advance of some 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, you want to handle the second one?

Yeah, so Anupam, with respect to your question on SG&A expense, and we gave guidance today on total OpEx for the year $355 million to $375 million. That includes non-cash stock comp and then for R&D, the $240 million to $260 million.

So based on that, you can assume 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 you the reps, I think you can assume we're recruiting now. I think it would be a reasonable assumption to assume they're definitely onboard for the second half of the year in advance of both launches. I'll take a 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, up from $66 million, $67 million this year to 100 next year. And given the fact that we've given for first quarter guidance of total OpEx and R&D expenses as well.

But, yeah, definitely the second half of the year will be the additional commercial field force. We have the G&A infrastructure in place from HR, finance, IT that infrastructure is well in place. It’s going to be the reps plus the A&P to go with that.

Thanks so much for taking our questions.

Thanks, Anupam.

Phil Nadeau, TD Cowen

Good afternoon. Thanks for taking our questions and congrats on the progress. A couple on the ASH data and then a follow up on axatilimab. So in terms of the ASH data, there are two controversial aspects that we keep debating with investors and curious to get your thoughts on those.

First, in SAVE AML, I know you said that there was no additive toxicity by having adding revumenib to the background revumenib. Not everyone agrees. So could you address the neutropenia rates that you would expect. I think you showed 56% at ASH. What would ASTX727 do alone?

And then second on BAML, again, there’s some concerns about the combinability, particularly the dose of revumenib going forward in light of the SIP interaction that ven/aza. How will you determine the Phase 2 dose through BAML and what type of dose adjustments would you anticipate once that Phase 2 dose is found?

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

So I think the first thing to remember is that the trial -- the SAVE trial accrued a very heavily pretreated population. So two-thirds of patients had failed prior to ven. One-third have been or half -- over half of them had been transplanted. So this is a patient population with a 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 ven and oral side to cytopen in that particular patient population.

I mean, if there's been some comparison to a less heavily pretreated population that that may be in people's minds, that's just not a valid comparison. 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 started the cytopenia rate was consistent with what would be expected from the backbone.

In terms of BAML, I'm not sure that I understand that why you think that there's a challenge around dose selection botho just to. 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. BAML 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 BAML trial there were newly diagnosed, SAVE we’ve just discussed, they were heavily pretreated with relapsed/refractory and in AUGMENT-102, they were heavily pretreated with relapsed/refractory patients. And in all three trials, the dose limiting toxicity windows for both doses were cleared, okay.

So and in -- with respect to BAML, D&L on board the group is now doing is expanding those cohorts to further refine what the RP2D would be for a Phase three trial. And we stated many times publicly that it is our intention to proceed with our Phase 3 by the end of the year.

So just one final point, those two doses, 113 milligrams and 163 milligrams is the presumptive monotherapy full dos,e when administered with a strong support CYP3A4 inhibitor, okay? And 113 milligrams is also highly active.

Also you have to recall that venetoclax and and azacitidine in the BAML 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 two settings, it’s clear.

That's very helpful. Makes it clear. And then last question, just on axatilamab 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 uninformed question, you said 30% of FTEs. How are the marketing efforts? How is 30% of marketing efforts defined? Is that specifically 30% of the fees or are there other metrics that this index needs to deliver as well, such as some touch points with physicians or call points or something else?

I turn it over to Keith.

Yeah, thanks for the question. So apologies if I wasn't clear, 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 don'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% of the cost of that 30% of it 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 of joint P&L and the joint -- bottom of that joint P&L, call it, the commercial profitability of the product is split 50-50.

(multiple speakers)

Bradley Canino, Stifel.

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

Brad, thanks for the question. I think maybe a little early to start speculating about the sales ramp and projection, and we'll reserve ability to give a little bit more guidance 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 are in a clinical trial. So we’re talking 2,600 patients overall, probably, about 2,000 of which are treated in the relapse/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 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 future discussion.

Michael Schmidt, Guggenheim.

Thanks for taking my question. I had one on the first-line setting for every minute in combination with 7+3. In your opinion, what is the right way to come to view our front-line 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 said 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?

And Michael, thanks for the question. An important one, certainly to get a handle on. I think the seven plus three revumenib, 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 a relapse that happens with most of those patients. Things to look for beyond just 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 relapse refractory patients. Now we're moving it would be moving to frontline and you'd expect to see some 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? And 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 up to us to kind of set the trend for what the bar looks like there.

But certainly from a CRM perspective, from a safety perspective, you kind of know what you want to see relatively clean, relatively clean profile and highly effective, but you need to continue on and should see deep durable responses as well there. Neil, do you want to.

I think yes, 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 are MRD-negative CR is not as certainly an endpoint of it 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 down as we move closer to having now initiated our dose-ranging trial as we move closer to initiating our Phase 3 trial.

And then the only other add that out that I would make would be if you look at the 7+3 trials that have been conducted really over the last, yeah sort of 10 years to 12 years going back as far as my discipline, they've all included maintenance phases and you could assume that any 7+3 trial that we would conduct would also include the maintenance season.

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 remained on therapy for protracted periods of time speaking to the tolerability of revenue manage in a relapsed refractory setting.

And therefore, we anticipate that as we move towards the newly diagnosed setting that patients who would be, for instance, given monotherapy maintenance after induction consolidation therapy would probably -- would most likely a tolerated medicine very well as well or the molecule of it.

Okay. Thank you.

Thank you, Michael.

Yigal Nochomovitz, Citi.

Hi, guys. This is Ashiq Mubarack on for Yigal. Thanks for taking my questions. I had a few on axatilimab. I guess first, congrats on the PDUFA date. I'm just wondering how involved you are in the regulatory process from this point out.

Obviously, we know Incyte is leading the proceedings, will it be part of the mid-cycle review? Will you be able to weigh in on label negotiations? How should we think about that?

Yeah. Thanks for the question. Look, we're very involved with, obviously with our 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 some with what's going on so that an exciting development for the company. And obviously, we have great experience with the molecule involved and 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?

No, that's very clear. I wanted to ask another one on IPF. Maybe I'm 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 look best and AGAVE-201.

I'm 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 the disease biology really similar enough that you felt confident enough not to do that? And obviously, we're dealing with a different endpoint here. So just curious what your thoughts are?

Yes. Hi. 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 that you quite clearly the 0.3 milligram dose in AGAVE trial was superior to the other two doses and we don't need to sort of go back over that, it's quite clearly the superior dose 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 everything that it was reasonable to go ahead with one dose in this trial and dose should be 0.3 milligrams. I think one point that you alluded to that there is sufficient overlap from a biological perspective to have made that decision, and that sort of partly led us to that to add decision.

And maybe I'd add onto 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 the 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.

Very helpful. Thanks very much.

Jason Zamansky, Bank of America.

Hey guys, this is Alex Hanab (inaudible) on for Jason. Thanks for taking my question. 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 eight efficacy evaluable AML/MPAL patients with a 12.5% CR/CRH enough to warrant a tumor agnostic label?

And what are your base case expectations on potential safety monitoring requirements for the U.S. and QTc prolongation? Thank you.

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

Sure. Our anticipation is the label, I mean, let me say, appreciate what I am about to say by reminding everyone that we got BTD back in December 2022 for KMT2A AML and ALL adults and kids. So the development program moving forward from there those based on Phase 1 data.

The development program moving forward from there. It was based around our premise that we would have a potential for a broad indication, as you know, we actually pooled Cohort 2A and 2B and the submission for came to a relapsed acute leukemias is based on that pooled analysis, which of course includes AML ALL, it also as well as pediatric patients.

So our anticipation is, of course, the agency has been fully unlocked is sort of coming on that journey with us along the way, including from BTD, before BTD, through BTD and onwards. So that’s the indication that we’re looking for. So not the exact words, but KM22A rearranged acute leukemias in adults and children.

With respect to your second question about safety monitoring. And we don't -- so first of all, from a class perspective, our broad class, meaning targeted therapies in AML, we are we anticipate we would probably anticipate a boxed warning for differentiation syndrome since that is typical of some of these agents in class, right it's on target.

And then what happens is even if the agency knows what happens to us such that. We do not anticipate we anticipate a warning and precaution for (technical difficulty)

Kalpit Patel, B. Riley.

Yeah, hey, good afternoon and thanks for taking the question. 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 second question is, how should we think about the enrollment split between the KMT2A are and the NPM1 population in that combo study, would it be a 50-50 split or are you seeing -- are you anticipating still are you anticipating is skewing of the KMT2A patient as they're more fit.

Yeah, maybe I'll take the second question, I'll give the first one to Neil. 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 there became KMT2A patients overall are more fit than that onset, right? So that's where they skew, whether or not we have, skewing in our population of patients to KMT2A or not. We don't know at this point, but we do expect representation of both.

Neil, do you want to talk about the 7+3 combo, starting dose?

Just one thing to add on. It doesn't really matter the split between came to an NPM1 patients in the first instance, right but we’re actually seeking to demonstrate is the combined ability of revumenib with 7+3 and the -- 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.

We know, based on the comments that we made earlier on and the data that we've presented for, we know that there combinable with chemotherapy and also venetoclax-based HMA therapy.

Justin Zelin, BTIG.

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

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

Yeah, sure. I can start. And Jeet I will preface this by saying that we need a little bit more efficacy data to really hone in what the expectation, but I think we know that, as Neil mentioned on the call, there's two drugs that are approved and though a lot of patients cycled 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 and then need in them 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 either 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 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 perspective on the combo studies you're doing with ruxolitinib and steroids in collaboration with Incyte. And just what should be looking there from an efficacy and safety perspective to move one or both of those forward ultimately?

Anjali, you want to follow on there?

Yeah, sure. So again, it's axatilimab bringing this drug fibrotic affect to bear on patients and hopefully helping to manage the impact of the disease on organs and therefore, potentially shifting the course of the disease is what we're trying to change, with that combination therapies are 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 and 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 time as they do good.

And so if you could 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 prevalence pool is about 14,000 patients. And so you could access a big chunk of that population with good data.

Thanks for taking (inaudible)

George Farmer, Scotiabank.

Hi there. This is Cleo on for George. Thank you for taking our questions. On 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 that next for other indications for revumenib.

Frankly, thank you for the question. So entrance there (technical difficulty) we don't expect that the FDA will hold another deck for. But I think that 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 estimates indicate that we would have no deck.

So I think if you answer your first question. And then secondly, you had asked about prospects for additional indications at present that is outside of leukemia. And as I mentioned in my previous remarks, we are looking at axatilimab or sorry, revumenib. And then in colorectal disease, third-line metastatic colorectal cancer.

As a monotherapy agent, it’s obviously a very difficult disease state and we’re going to have some data in the second quarter of this year to first get at whether there’s sufficient activity there as a monotherapy agent and how the drug performs.

There is this thesis that we’re pursuing, a beta-catenin upregulated tumor type, which is a broadly implicated phenomenon through a lot of different cancers. Colorectal cancer is one and so there could be other cancers that we look to see whether they’re susceptible to revumenib treatment. So, stay tuned. There may be more to come. I think the first step here is certainly the colorectal cancer trial that we’re running.

Okay. Got it. Thank you.

And you will conclude our question-and-answer session. I will now turn the floor over to Mr. Michael Metzner for any additional comments for closing remarks.

Thank you all. We appreciate you joining us 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.