Syndax Pharmaceuticals Inc Q2 FY2025 Earnings Call

Good day, everyone, and welcome to the Syndax Second Quarter 2025 Earnings Conference Call. Today's call is being recorded. 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's Second Quarter 2025 Financial and Operating Results. I'm Sharon Klahre, and with me today to provide an update on the company's progress and discuss financial results are Michael Metzger, Chief Executive Officer; Steve Closter, Chief Commercial Officer; Dr. Nick Botwood, Head of R&D and Chief Medical Officer; and Keith Goldan, Chief Financial Officer. Also joining us on the call today for the question-and-answer session are Dr. Peter Ordentlich, Chief Scientific Officer; and Dr. Anjali Ganguli, Chief Strategy Officer. This call is accompanied by a slide 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 the statements as a result of various important factors, including those discussed in the Risk Factors section in the company's most recent quarterly report on Form 10-Q as well as other reports filed with the SEC. Any forward-looking statements made represent our views as of today, on August 4, 2025, only. A replay of this call will be available on the company's website, www.syndax.com, following its completion. And with that, I am pleased to turn the call over to Michael Metzger, Chief Executive Officer of Syndax.

Thank you, Sharon, and good afternoon to everyone. Thank you for being here today. Starting with Slide 3, the first half of 2025 has been a transformative time for Syndax, characterized by exceptional execution in both our commercial and pipeline areas. We are strategically positioned for significant growth in the latter half of 2025 and beyond, with two leading therapies offering a combined market potential exceeding $10 billion. Sales of Revuforj and Niktimvo are on the rise, reaching nearly $100 million in combined net product sales in the first half of the year, which greatly surpassed our expectations. Notably, Revuforj's net revenue grew by 43% from the previous quarter to $28.6 million, despite around one-third of patients delaying their treatment to undergo a stem cell transplant. We are on the path to profitability with increasing contributions from Revuforj and Niktimvo, a robust balance sheet, and an operating expense structure that will remain stable over the next few years while fully supporting our strategic initiatives. Looking ahead, our leadership in the menin space places us in a strong position to be first in frontline therapy and to significantly expand the Revuforj brand. We also see a compelling opportunity to introduce Niktimvo to earlier lines of therapy and additional patient populations. Moving to Slide 4, let's take a closer look at Revuforj, the first and only FDA-approved treatment for relapsed or refractory acute leukemia with a KMT2A translocation. The continued growth in usage reflects strong acceptance, the high unmet medical need, and the enthusiasm from physicians regarding Revuforj. Following recent presentations at ASCO and EHA, it has become evident that Revumenib has a standout profile with impressive efficacy across various genetic subtypes, including data in relapsed/refractory mutant NPM1 AML that exceeds any other results within the field. The extensive and robust nature of our clinical data will be crucial to our success in the acute leukemia market, which heavily emphasizes efficacy due to the severe nature of the disease. Looking forward, the outlook appears very promising with several factors expected to further strengthen our leading position and ensure sustained growth for years ahead. I will briefly outline these factors, and the team will provide further details. First, patient identification and uptake have been strong. Since our launch, we have already treated over 500 patients with Revuforj, with around 90% of usage coming from KMT2A patients. In just seven months, we have treated one-fourth of the 2,000 patients diagnosed with relapsed/refractory KMT2A acute leukemia each year. Given the impressive activity we have witnessed in this patient population and the excitement from physicians surrounding the drug, we anticipate the total number of patients treated with Revuforj to grow significantly in the upcoming quarters, particularly considering it is the sole approved therapy for these patients. Second, Revuforj is increasingly being utilized in earlier therapy lines. Emerging claims data shows that this quarter's use in KMT2A is already concentrating in the second line. This trend is particularly significant in oncology because treatment at earlier stages typically results in higher response rates, longer durations of response, and better chances of reaching a potentially curative stem cell transplant. Thus, as Revuforj is deployed earlier, we expect to see an increase in the average time patients remain on the drug. We also believe the rate of patients advancing to transplant will be higher than what we observed in our pivotal trial, which primarily involved a later-line patient population. Early signs already suggest a significantly higher transplant rate in the commercial setting. Third, as more patients receive Revuforj after transplant, it should greatly extend the total duration of therapy. Notably, prescribing physicians have indicated plans to restart patients on Revuforj post-transplant for one to two years. Given the high risk of recurrence, patients and physicians are keen to resume the therapy that previously induced remission, especially considering the drug's excellent tolerability profile. These three factors position Revuforj to shift care for KMT2A patients from an acute treatment approach, where survival is measured in months, to a more chronic disease approach with the potential to extend survival to years. Importantly, relapsed/refractory KMT2A acute leukemia is only the first opportunity for Revuforj. In the near future, we expect Revuforj to be included in clinical treatment guidelines and for the approval of our supplemental new drug application in relapsed/refractory mutant NPM1 AML. The anticipated approval of this application, which recently received priority review, has a PDUFA action date of October 25, 2025, and would expand our treatment population to over 6,000 patients across both genetic subtypes. This would increase the market opportunity for Revuforj in the U.S. relapsed/refractory segment to $2 billion. Importantly, Revuforj is on track to be the first and only menin inhibitor with approval for both mutant NPM1 and KMT2A translocated patients, including both adult and pediatric populations. Based on strong feedback from Key Opinion Leaders, the anticipated breadth of our label will provide a significant competitive edge. Looking ahead, we aim to extend our leadership into frontline settings, with a U.S. market opportunity exceeding $5 billion. Enrollment is ongoing in our frontline trial for patients unable to undergo intensive chemotherapy, and start-up activities are in progress for trials in patients who can receive intensive chemotherapy. With Revuforj's best-in-class profile and a head start in the market compared to potential competitors, we are well-positioned to maintain our leading role in this multibillion-dollar market opportunity. Now shifting focus to Slide 5 regarding Niktimvo, our first-in-class therapy for chronic graft-versus-host disease. I'm excited to report a very successful first full quarter for sales, with our partner Incyte reporting $36.2 million in net revenue, a significant increase from $13.6 million in the initial two months of the launch in Q1. The $50 million in net revenue generated in the first five months of the launch highlights the considerable potential in chronic GVHD. Notably, Niktimvo is already profitable for Syndax, with our 50% share of the Niktimvo product contribution totaling $9.4 million for the second quarter. As sales continue to grow, Niktimvo's cash flow contributions to Syndax will become increasingly significant. The early sales of Niktimvo are aligning with benchmarks set by REZUROCK, another drug approved in the third-line chronic GVHD space, which has now annualized over $500 million in the U.S. within three years of its launch. We are confident that Niktimvo will play a crucial role in our success for many years to come. Before I turn the call over to the team, I want to note that we also enhanced our leadership team this quarter by welcoming Dr. Nick Botwood as Head of R&D and Chief Medical Officer. Nick is a trained medical oncologist with over 25 years of experience in leading the development and global commercialization of new oncology medicines, including blockbuster drugs like Opdivo and Yervoy during his tenure at BMS. I would also like to acknowledge Bill Meury for his seven years of service on our Board and congratulate him on his new role as CEO of Incyte, our partner for Niktimvo. Bill has been an invaluable member of our Board as we developed and launched both drugs, and we look forward to continued collaboration with him and the Incyte team as we realize Niktimvo's value. With that, I will turn the call over to Steve to discuss our commercial progress in further detail.

Thank you, Michael. Let's dive right into our commercial updates on Revuforj and Niktimvo, starting with Revuforj on Slide 6. As Michael said, the launch is going very well with net revenue for the second quarter increasing 43% quarter-over-quarter to nearly $29 million and $56 million generated over the first seven months of the launch. These impressive results are driven by multiple factors, including: a high unmet patient need; a robust stream of new patient starts over the quarter; expanding breadth and depth of prescribing; excellent formulary coverage; and a product in Revuforj that is delivering for patients. Physicians are observing excellent activity in clinical practice; Revuforj is rapidly becoming the standard of care in our indicated population. Over 1,300 prescriptions for Revuforj have been written for more than 500 patients from launch through the end of June. Just midway through the year, we have already penetrated 25% of the annual 2,000 patient incidents and are on track to penetrate 50% by year's end. Next, I'm excited to share some of the emerging data and customer feedback that provide important insights into the population of patients being treated with Revuforj and bolster our confidence that the momentum we have seen since launch will continue well into the second half of the year and beyond. First, Revuforj is increasingly being used to treat patients earlier in their treatment journey. Early claims data show that 70% of Revuforj use has been concentrated in the second and third-line settings, with approximately 50% of use coming from that second line, which we can also call first relapse patients alone. Second, we estimate that one-third of KMT2A patients treated with Revuforj have proceeded to transplant based on our analysis of medium to large academic institutions using Revuforj commercially. In contrast, one out of four KMT2A patients proceeded to transplant after treatment with Revuforj in AUGMENT-101, which enrolled a significant percentage of later line and heavily pre-treated patients. It's important to understand that patients who ultimately proceed to transplant are typically treated with Revuforj for two to four months to ensure complete disease remission before pausing Revuforj for approximately three months to ensure engraftment of the transplant. Notably, physicians tell us they expect to put most, if not all, of their patients back on Revuforj post-transplant for one to two years. In fact, in our clinical trial experience and compassionate-use program, we have already seen transplant patients who have been on Revuforj for one to two years and were still on drug at the time of the data cutoff. Encouragingly, in the commercial setting, we have started to see the first cohort of patients restart Revuforj. Based on a sampling of our accounts, we estimate that at least one-third of transplant patients have already restarted Revuforj, with that percentage expected to grow over time as more patients clear the engraftment period. As Revuforj continues to move earlier in the treatment paradigm, we expect this will translate to a significant increase in the average duration of therapy over time. Specifically, we expect the average treatment duration to build to four to six months in the first year of launch. According to our assessment of patients who started Revuforj shortly after launch, the average time on therapy is already well within the projected four to six-month range, and we expect this duration to expand to an average of six to twelve months as treatment patterns mature in the second year of launch. I'd now like to briefly review some other metrics that underscore the strong position we're in for continued growth in KMT2A and our anticipated launch into relapsed/refractory mutant NPM1 AML. First, we have a broad and growing prescriber base. From launch through the end of June, we've penetrated 65% of our higher-priority Tier 1 and Tier 2 accounts, up from 44% of accounts at the end of the last quarter and continuing to grow into the third quarter. These Tier 1 and Tier 2 accounts are the centers of excellence in the medium to large academic institutions, which represent two-thirds of the patient opportunity. Adoption is also increasing across all other tiers too, including in the community setting. Among all accounts that have ordered, the vast majority have ordered multiple times. Second, we have established excellent market access. Formulary coverage is now complete with more than 97% of all lives covered, including commercial, Medicare, and Medicaid patients. Nearly all prescriptions are reimbursed, with very few patients requiring our patient assistance program. The average time from prescription to first fill is less than four days, significantly faster than typical industry benchmarks. The best-in-class customer service we are delivering will be a key factor for our long-term competitive immunity and brand loyalty. Notably, Revuforj performance is outperforming the early launch benchmarks set by other targeted AML therapies on key metrics, including revenue and prescriptions, patients treated, activation accounts, as well as formulary coverage. Further, all indicators give us confidence that Revuforj is delivering for patients and that we are well positioned to develop this medicine into an industry-leading franchise with a market opportunity exceeding $5 billion across the relapsed/refractory and frontline setting, as outlined on Slide 7. Now turning to key Niktimvo metrics on Slide 8. Since the beginning of the launch, over 4,000 infusions have been administered to an estimated 700 patients, representing approximately 10% of the third-line plus chronic GVHD total market. Of all the patients that had started Niktimvo, approximately 80% to 90% remain on therapy today. More than 80% of all bone marrow transplant centers in the U.S. are using Niktimvo, reflecting solid execution and the strong commercial synergies Niktimvo has with both companies' product portfolios. Importantly, Niktimvo is poised for further growth given the high unmet need in the chronic GVHD space and the positive experience physicians and patients are having with the drug. Physicians are reporting rapid and durable improvements across organ systems, including some of the most difficult-to-treat organs like the lungs and skin. These observations align with the results we demonstrated in our pivotal trial and highlight Niktimvo's unique ability to address both fibrosis and inflammation, hallmarks of the condition. As shown on Slide 9, Niktimvo has a multibillion-dollar market opportunity. Our current indication allows us to target the 6,500 chronic GVHD patients in the U.S. who require three or more lines of therapy. This represents a $2 billion total addressable market, assuming an average treatment duration of 12 months, which could be conservative given the chronic nature of the disease and the tolerability of Niktimvo. Notably, in our clinical trial experience, we have seen some patients stay on therapy for more than three years. To summarize, we are very pleased with the progress we've made with both Revuforj and Niktimvo. Early indicators for both launches drive our confidence in continued growth and expansion with both products. With that, I'll hand the call over to Nick.

It's a pleasure to be on the call today and to have the opportunity to build upon the exceptional work that Syndax has done pioneering two new therapeutic approaches. Starting on Slide 10 with Revuforj or Revumenib, an asset which has the potential to become the menin inhibitor of choice across the breadth of menin-driven acute leukemias. In the second quarter, we advanced our leadership position with a strong presence at EHA and ASCO, including two important publications. At EHA, we and our collaborators presented the latest data from AUGMENT-101 and the BEAT AML trial. I'd like to highlight two key takeaways from these. First, the AUGMENT-101 data demonstrate the breadth of Revumenib activity across relapsed/refractory mutant NPM1, KMT2A, and NUP98r acute leukemias. Notably, in the pivotal NPM1 population, nearly half of the patients achieved an overall response. And in a subgroup analysis, a median overall survival of 23 months was observed among these responders. These data, along with the rate of CR/CRh and duration of CR/CRh, are encouraging results that really stand out in this population. The compelling results are particularly relevant as efficacy is paramount in patients with acute leukemia given the severity of disease and the need for improved outcomes. Data from the pivotal NPM1 population were recently published in Blood, an important milestone that makes these landmark results available to the clinical community. Turning now to NUP98r. Phase I data from the AUGMENT-101 trial show an overall response rate of 60% among five patients with relapsed/refractory NUP98r AML, which is an aggressive difficult-to-treat form of acute leukemia. While the sample size is small, physicians are encouraged by these data, and further trials are underway that will evaluate Revumenib in NUP98r as well as other acute leukemias associated with HOX upregulation. The compelling and consistent results observed with Revumenib across these genetic subtypes highlight the potential for Revumenib to transform the standard of care for potentially 50% or more of all patients with AML. Moving now to the second key takeaway. The BEAT AML data presented at EHA and simultaneously published in the Journal of Clinical Oncology are encouraging. As a reminder, this is a Phase Ib trial evaluating Revumenib in combination with venetoclax and azacitidine in newly diagnosed older patients with mutant NPM1 or KMT2A rearranged AML. The data support the combinability of Revumenib with ven/aza in the frontline setting and the potential for the triplet to provide high rates of complete remission and MRD negativity, two treatment goals associated with improved clinical outcomes. The overall response rate was 88% and the complete remission rate was 67% in the 43-patient intent-to-treat population. Importantly, MRD negativity was 100% by centralized flow cytometry testing. Both the CR and MRD negativity compare very favorably to the historical rates reported in the VIALE-A trial of ven/aza. Looking ahead, we have Revumenib publications and presentations planned at major upcoming medical congresses, including the anticipated presentation of the first real-world evidence before the end of the year. Given the strong clinical interest in real-world evidence, we are thrilled to be working with leading cancer centers and physicians to present outcomes for this new therapeutic class. Turning now to Slide 11, and our further work developing Revuforj and Niktimvo into industry-leading franchises, I want to highlight three key points. First, we are laser-focused on extending our leadership position in menin inhibition into the frontline setting. Enrollment is well underway in the pivotal EVOLVE-2 trial of Revumenib in combination with ven/aza in newly diagnosed patients with mutant NPM1 or KMT2A rearranged AML, who are ineligible or unfit to receive intensive chemotherapy. EVOLVE-2 is a Phase III randomized, double-blind, placebo-controlled trial. This trial will have dual primary endpoints of complete remission and overall survival to support potential accelerated approval and full approval, respectively. While the trial is open to both NPM1 and KMT2A patients for enrollment, the primary efficacy analysis will be based on the NPM1 population. This is the population that is more commonly ineligible for intensive chemotherapy due to advanced age or other comorbidities, unlike the KMT2A population which tends to be younger and fit enough for intensive chemotherapy. We are conducting this trial in partnership with the HOVON Group, a leading clinical trial cooperative known for executing clinical trials that deliver practice-changing data in hematology. Second, in the newly diagnosed fit population, study start-up activities are well underway for two randomized placebo-controlled studies of Revumenib in combination with intensive chemotherapy followed by maintenance. We have named these the REVEAL trials. One trial is designed for patients with an NPM1 mutation and one for patients with KMT2A rearrangements. We expect to initiate in the fourth quarter of 2025. In the NPM1 population, the study will have dual primary endpoints of MRD negative CR and event-free survival, as these are important clinical endpoints in this population and could have the potential to support accelerated approval and full approval, respectively. We expect that high awareness of Revuforj and positive experience in the clinic will drive rapid enrollment across our frontline programs. In support of our trials in the fit population, we are also looking forward to reporting Phase I data in newly diagnosed patients treated with Revumenib and intensive chemotherapy in the fourth quarter of the year. Lastly, I want to highlight the work underway to develop Niktimvo, or axatilimab, for additional patient populations. In partnership with Incyte, several important trials are well underway, including a Phase II trial studying axatilimab in combination with ruxolitinib and a Phase III placebo-controlled registration-directed trial investigating axatilimab in combination with steroids. Beyond chronic graft-versus-host disease, we have an ongoing Phase II placebo-controlled trial called MAXPIRe, which is studying axatilimab in idiopathic pulmonary fibrosis, or IPF. Enrollment is proceeding very well, and we are on track to complete enrollment in the fourth quarter of this year, with top-line data anticipated in the second half of 2026. We are optimistic about the potential for axatilimab in IPF and beyond, given the strong mechanistic rationale and preclinical evidence, along with the remarkable lung response observed in the AGAVE-201 trial. With that, I will hand the call over to Keith to discuss our financials.

Thank you, Nick. Earlier this afternoon, we reported detailed second quarter 2025 financial results, and I'll touch on a few of these key points on Slide 12. For the second quarter of 2025, we reported Revuforj net revenue of $28.6 million. Quarter-over-quarter sales growth was driven by demand, as inventory levels remained stable from the first quarter at 2 to 3 weeks. We expect quarterly growth to meaningfully accelerate over the next year with the potential approval in NPM1, as well as the benefit of a longer duration of treatment in KMT2Ar acute leukemia. Also, in the second quarter, Incyte reported Niktimvo net revenue of $36.2 million, with inventory accounting for less than 5% of sales. Syndax reported $9.4 million in Niktimvo collaboration revenue after deducting the cost of sales and commercial expenses. Importantly, Niktimvo is already a positive cash flow contributor to Syndax in just its first full quarter of sales. We expect the Niktimvo margin contribution, defined as collaboration revenue recorded by Syndax as a percentage of Niktimvo net sales, to be in the 20% to 30% range in the near term, and we anticipate this will improve longer term as sales grow and the partnership leverages a largely fixed expense base. We expect continued sales growth given GVHD remains a chronic disease, where there is a high response rate to Niktimvo and the average patient will likely remain on therapy for years. R&D expense was $62.2 million in Q2, with the increase versus the comparable prior year driven by costs related to ongoing trials and increased activities to support commercialization. SG&A expense was $43.8 million, with the increase versus the comparable prior year driven by costs related to the U.S. commercial launch of Revuforj. With regard to expenses, you can find our guidance for the third quarter of 2025 and full year in the press release we issued today. Notably, we announced today that we expect our operating expenses to remain stable over the next few years. Turning to the balance sheet, we continue to maintain a strong financial position with $518 million in cash, equivalents, and short- and long-term investments as of June 30. As I've said in the past, and I reiterate today, we expect Syndax will reach profitability with current funds on hand. In fact, my confidence is higher today given both drugs are outperforming our original forecasts. We are confident we can execute commercially and also deliver on our integrated clinical development plans for both drugs while keeping operating expenses at today's levels. Our combined cash, with increasing Revuforj and Niktimvo cash flow contributions alongside a fixed expense base, will drive our path to profitability. Turning the call back over to Michael.

Thank you, Keith. Before we move to Q&A, I want to take a moment on Slide 13 to reiterate how well positioned Syndax is as a company. Revuforj and Niktimvo are outperforming expectations as strong physician enthusiasm drives robust adoption. We have a very sizable cash balance that will allow us to control our destiny and achieve sustained profitability with what we know are two dominant products in multibillion-dollar markets. A few key points to recap on Revuforj. Revuforj is the only FDA-approved therapy for KMT2A patients, and we have already identified and treated over 500 patients since launch, with 90% of those being on label. Physicians are treating earlier relapsed/refractory patients, which portends more favorable outcomes. Revuforj is getting patients to transplant at an even higher rate than what was observed in our clinical trials. Physicians are eager to put their patients back on Revuforj post-transplant, and we have begun to see evidence this is happening. Further, all key indicators of demand remain strong in July, which gives us confidence in the continued momentum of this launch. Ultimately, in the future, KMT2A patients on Revuforj and with the aid of transplant will likely remain on drug for one year or more, with the best hope of improved survival. In the near term, we are poised to expand into relapsed/refractory mutant NPM1 AML, pending the FDA's anticipated approval of our sNDA. Additionally, we are extending our leadership position to the front line with enrollment already well underway in our first pivotal frontline trial. It is important to keep in mind that acute leukemia is an efficacy-driven market, and it is clear that Revuforj is a highly effective therapy with a favorable safety and tolerability profile. Finally, I will also note that we've retained worldwide rights to Revuforj, and patent protection continues through at least the late 2030s. Turning to a few key points on Niktimvo. In collaboration with our partners at Incyte, the leaders in GVHD, the Niktimvo launch is off to an exceptional start. It is well positioned for growth in the $2 billion market for third-line chronic GVHD treatments with patent protection extending to the late 2030s. Niktimvo provides a novel option in a market that needs new mechanisms of action. Patients initiating therapy may continue the drug for years. We and Incyte continue to advance development programs designed to bring this drug into earlier lines of chronic GVHD therapy and other diseases, starting with IPF. Niktimvo's financial contribution to Syndax is already profitable in its first full quarter. This will grow materially as sales ramp and operating margins continue to expand. Syndax has never been in a stronger position than we are today, and I look forward to sharing additional progress with you in the months ahead. As always, I want to close by thanking everyone who has supported us on this journey, including, most importantly, the patients and families who have placed their trust in us, as well as our dedicated Syndax employees and long-term investors. And with that, I would like to open the call for questions.

Our first question will come from Anupam Rama with JPMorgan.

Just wanted to ask a question about this path to profitability. Keith, I know you mentioned operating expenses staying stable over the next couple of years. But what are you assuming in terms of the top line, in terms of treatment settings for Revuforj and Niktimvo? Can you get to profitability on sort of the refractory settings alone? Is there some sort of assumptions on frontline expansion baked into getting to profitability? How should we be thinking about that?

Anupam, thanks for the question. We have been pretty consistent since November that we expect to get to profitability with the existing resources that we have today. And I would say the only thing that's changed since then is that we have two launches that are both outperforming our expectations. So the new disclosure that we provided today, stable operating expenses for the foreseeable future, say, the next two to three years, we're doing that because we want to give the buy-side and sell-side, we want to give the street the appropriate data for them to model our business better, so you guys can get to the same answer that we're getting to. We're not giving revenue guidance per se, Anupam, but I will say that given the timelines to get to approval in the frontline setting, you can definitely assume that we are getting to profitability on the relapsed/refractory indications alone. And I think I just want to add, the guidance that we are giving, stable operating expenses, is not to be taken as we are taking our foot off the gas pedal, because we're not. The modeling that we've done allows us to fully invest in the continuing successful launches of two products, executing commercially, but additionally, executing our integrated clinical development plan, as Nick talked about, both for Revuforj and Niktimvo. So, I think we're in a pretty unique position to control our own destiny. We have two launches that are both outperforming and a stable expense base, and the team has worked extremely hard to put ourselves in this position to specifically reward our shareholders for their investment.

Our next question will come from Corinne Johnson with Goldman Sachs.

This is Kevin Strang on for Corinne. I had a quick question on the patients moving on to transplant. After how many cycles is that typically occurring? And for patients that are going back on drug, you said that it was about one-third of patients so far. What are your expectations for the ultimate proportion of patients that will move on to maintenance therapy? And is this something you'll report quarterly?

Thank you for your questions, Kevin. We are very encouraged by the progress we are seeing with patients transitioning to transplant. From the beginning of our drug development, we noted that patients typically respond quickly to Revumenib, often within the first few cycles. This response usually leads to a transplant, which can occur within a couple of weeks, especially for KMT2A patients. Our approach is to get them to transplant as swiftly as possible, typically after two to three cycles of treatment, which allows them to achieve remission. In our commercial experience, about one-third of patients have reached transplant, and we expect that figure to increase. This is due to our strategy of treating patients earlier in their treatment journey. Physicians have mentioned they would place patients on Revuforj in the second line or during their first relapse; however, we are now observing that most patients are being treated in the second and third lines. This is a positive development as it leads to longer drug adherence and improves their chances of going to transplant. We believe the one-third figure could rise and will monitor this as we progress through the early stages of our launch. We plan to report on this metric in the future. Regarding maintenance therapy, patients are indeed returning for maintenance, and we have noted that about one-third have come back so far. This is a promising sign early in the launch. Physicians consistently indicate they expect to place the majority of their patients back on maintenance, which could range from 70% to 90%, depending on eligibility.

Our next question will come from Kelly Shi with Jefferies.

So, after the second full quarter of launch, could you comment on the latest observation of treatment duration for Revuforj in real-world practice? And also, how do you expect the treatment duration to evolve over time, especially now when you have more earlier second lines of patients on the treatment?

Kelly, thank you for the question. So first question, duration in the real world, what are we seeing? I'm going to hand that to Steve to answer that.

Yes. Thanks, Kelly, for the question. And we'd always predicted this first year would be roughly in the four to six-month range for average duration. Based on data that we've been able to see, we're very confident that's the case. We take a look at the earliest cohort of patients, and they're certainly within that range. That will improve over time. I appreciate the mention of the earlier line patients, which were also in our prepared remarks. And that's a real phenomenon, and this happened very, very quickly. The first patients at launch were not these patients. They were likely more third, fourth line patients, but it moved earlier very, very quickly, and that portends well in terms of treatment duration. So a better chance of success of getting to a transplant and more likely, as Michael just described on the previous question, the concept of returning to drug. So that will build over the course of this year. We would expect in 2026 that, that average treatment duration will be six to twelve months and could skew towards the latter end of that as the launch matures and we're able to move patients earlier and physicians gain more experience.

Just one more question, if I may. So on the cost side, how could we expect the change quarter-over-quarter for the rest of the year?

Thanks, Kelly. I'm going to ask Keith.

Thank you for your question, Kelly. Today, we adjusted our guidance approach. Previously, we included noncash stock compensation in our operating expense guidance, but we've received feedback from investors who are more interested in our cash usage. Therefore, we've revised our guidance to focus on operating expenses excluding noncash stock compensation. For the third quarter, we anticipate expenses will be between $95 million and $100 million, and we reaffirm our full-year estimate of $370 million to $390 million. We also provided implicit guidance for the fourth quarter based on our expenses from the previous two quarters. This suggests that our fourth-quarter estimate is nearly equal to the third quarter's guidance for research and development along with selling, general, and administrative expenses, excluding noncash stock compensation.

Our next question comes from Phil Nadeau with TD Cowen.

Congrats on the two successful launches. A couple of questions from us. First, on the KMT2A launch for Revuforj. You suggested, I think, that 25% of patients with KMT2A for one year have initiated therapy in the second quarter, which suggests in the incident population the penetration is probably quite high. Can you give us a sense of where you think the penetration is in the incident KMT2A population here today in Q2 of 2025? And kind of where could that go at peak? I guess we're trying to understand how much growth could be left over the next couple of quarters before the label expansion? And then second, on the NPM1 label expansion, any update on inclusion of NPM1 in the NCCN guidelines?

Yes, Phil, thanks for the questions. The first question related to KMT2A and penetration in '25. I think we're going to clarify that. I'm going to ask Steve to clarify that a little bit.

Yes, Phil, thank you for the question. We've treated over 500 patients since our launch, and we typically measure ourselves against the total available market of 2,000 KMT2A relapsed/refractory AML and ALL patients. Since our launch, we estimate that we've reached about 25% of this population. It's important to note that the 2,000 patients refers to the total over the course of the year, not at any single point in time, so there will be some variability as patients are identified and diagnosed. We are optimistic about our ability to find patients, and Rev is at an early stage of becoming the standard of care. Physicians are actively using diagnostic testing to identify patients. Throughout the quarter, the influx of new patients has been strong, and we anticipate that this trend will continue for the remainder of the year. We expect to end the year having addressed approximately 50% of the identified population, which we believe would represent a successful launch and greatly benefit patients while also building the pipeline for Revuforj in our initial indication.

And then in terms of your second question, Phil, about label expansion NPM1, you had asked about the guidelines. Comment is, we've submitted to the guidelines. We published in Blood. The data is available, very helpful to our medical team to help educate in advance of launch. Guidelines, we don't have perfect information about when the guidelines will be updated. It could be any day. We do expect it before we get approval in NPM1, and that will help aid our launch even more by having the guidelines. I think that's important for payers as well as physicians. So looking forward to that, but everything is all set up and ready for launch. We're just eager to continue to make progress.

Our next question will come from Peter Lawson with Barclays.

Congratulations on the quarter. As we consider the upcoming FDA approval, could you provide any insights on outstanding issues or feedback from the FDA that would bolster confidence in the approval? Additionally, what percentage of patients do you anticipate will eventually be on the maintenance setting?

Yes, Peter, thank you for the questions. First, regarding FDA approval, I'm going to turn it over to Nick. Are we learning anything new?

Yes. Thank you. The submission is progressing very well. We have our PDUFA date. We've been working very closely with the FDA. And so it's a team we know well now, and things are progressing very well according to plan. So we're looking forward to the PDUFA as guided on October 25th.

Yes. Regarding your second question about maintenance, we believe that a significant percentage can be put back on. We've heard from physicians that the vast majority, if not all, of their patients would like to return to maintenance. While not every patient will qualify, the trend of physicians treating patients earlier and focusing most treatments in the second line is encouraging. It suggests that physicians will actively work to take more patients to transplant, which will give us additional chances to reinstate them after they clear their transplant and graft. I can't provide a specific percentage, but it should be quite high for KMT2A patients.

Our next question will come from Michael Schmidt with Guggenheim.

This is Paul on for Michael. I have two on the frontline combo opportunities. So first on the recent EHA updates from BEAT AML. It seems pretty clear that Revumenib is enhancing the CR and MRD compared to ven/aza alone. but would love to get your thoughts on the degree of OS improvement you're seeing and whether or not you plan to provide another survival update in the study with additional follow-up? And then secondly, just looking ahead to the intensive chemo combo, can you sort of talk about how we should think about key CR and MRD benchmarks for that combo and sort of what to expect for the update later this year?

Paul, thank you so much for the questions. I'm going to turn it over to Nick to touch on the BEAT AML piece of this first.

Yes. Thank you for that. And firstly, very encouraged by the BEAT AML study. I mean, this was an important study. We were able to confirm a dose to take into Phase III and show that the dose was tolerable, and also, as you say, report out some early efficacy measures. And I think the efficacy measures that are probably most important in this setting are the complete response rate and MRD negativity because remember, this is a relatively small 43-patient Phase Ib study. So interpretation in that context is quite difficult. And the CR rate and MRD negativity were very high. They were 67% and 100% MRD negativity, which, as I said in the earlier comments, are really a step change above what you expect from historical controls. Now, when you look at the overall survival, you have to remember that the median follow-up is quite short currently. The median follow-up was only around seven months, and it's over 20 months in VIALE-A. So certainly, we expect as those data mature, you'll see some changes in the median OS. There's a lot of steps in the Kaplan-Meier currently, which suggests the median is quite unstable, and it’s therefore very difficult to estimate. Having said that, it's already very comparable or somewhat similar to VIALE-A, which you must also recall is a very heterogeneous group of subtypes of AML with a variety of different genetic mutations. And when you actually benchmark against NPM1, you probably find the median overall survival is a little less than was reported and closer to 10 months. So, in summary, we remain extremely confident in the profile of the combination with ven/aza. And I think it gives us a very high level of confidence that the EVOLVE-2 study that we're doing in collaboration with HOVON will read out well in due course. With regard to the intensive chemotherapy and the MRD negative CR, we think both CR for unfit and MRD negative CR, both plasma and bone marrow are important endpoints in this setting. They've been shown to predict for improved outcomes around event-free survival and OS and believe that they could serve as surrogates to support accelerated approval. Those are obviously discussions we have had with the agency and have refined those. They are built into the protocols as dual primary endpoints, which means that they are independently powered. So you could have either the surrogate CR endpoint or the time-to-event endpoint, whether that be OS or EF, to give a positive study. And we remain quite confident that both of those should read out favorably. As previously indicated, we will be updating data for our combination with intensive chemotherapy for fit patients, specifically the 7+3 regimen from our own sponsored study, the 708 study. And also, we'll likely hear from the study we're doing in collaboration with the NCI, which is also a combination of intensive chemotherapy in the latter part of this year. And those data should both confirm the dose, tolerability, and also early signs of efficacy to support our Phase IIIs with intensive chemotherapy. So overall, we feel very confident about the programs, and we really have very good momentum going into the latter part of this year.

Our next question comes from Yigal Nochomovitz with Citi.

Could you clarify about the patients who have restarted after the transplant and those who haven't? For the two-thirds who haven't restarted, is it that they are not expected to, or are they just not ready to restart, with the expectation that most of them will eventually do so?

Thank you for your questions, Yigal. It's the latter. We've said it's early days, and one-third of the patients have already restarted, which is very encouraging for us. This leaves two-thirds who have yet to restart, and we anticipate a high proportion from that group will also return. We are seeing an evolving situation with patients coming back from transplant to maintenance, and we have not excluded the two-thirds; we are actually waiting for them to return.

And then just can you clarify on the mechanics? Do they need to get a reimbursement approval again when they come back after the transplant? Or is it seamless and they just start Revuforj again without a second need to request the reimbursement?

Yes. Our expectation is that it will be pretty seamless. In this industry, six-month renewals are standard, and that may apply here. Typically, if you are within that window, they will restart without any issues from payers. Even when there is a restart or reinitiation of a prescription, we have not encountered any challenges with that. Payers cover over 97% of formulary coverages, and claims are being reimbursed regularly. Therefore, we do not anticipate any challenges with restarting at all.

Okay. And then lastly, I'm just curious if you could speak in a little more detail about this first wave of the real-world evidence that you're going to have at the end of the year? Can you just expand on that a little, please?

Maybe Nick can take that.

Yes, I'd be happy to. So we're obviously working with leading centers across the U.S. and leading thought leaders, and we're at the point now with the drug being used in clinic from commercial supply that we're getting some interesting series of data from physicians' experience in the real world. So we're collaborating closely with them to collect those data and look forward to presenting those real-world experiences from those centers in the latter part of this year. And I think we're uniquely well placed to be able to do that with this new therapeutic class. We're now available commercially in the clinic and can actually report real-world experience versus just clinical trial experience. So I think those data and how the drug is getting used in the real world will be very insightful, and we're looking forward to those reporting out later in the year.

Our next question will come from Justin Zelin with BTIG.

Congrats on the strong quarter. So looking ahead to the October 25th PDUFA date for NPM1 label expansion, could you walk us through how you're preparing the commercial organization for launch readiness? And do you anticipate a meaningful incremental uptake in the population out of the gate or would it be more gradual?

Yes. Thanks, Justin, for the questions. I'm going to turn it over to Steve to touch on the launch readiness, launch maintenance.

Yes, we're actively preparing for the market launch, and I appreciate the distinction from others entering the space. Regarding our launch strategy, a significant aspect of our success hinges on our current efforts. We are using our market experience with KMT2Ar effectively. Physicians are familiar with how to dose the drug, understand the available dosing options, the initiation of treatment, and managing any possible adverse events during that process. They know what to expect in terms of efficacy and how to introduce the drug as a treatment option. Moreover, our target treatment centers for KMT2Ar are the same ones that handle NPM1. We already have a strong customer-facing team in place, with excellent relationships in the field. They know the landscape well and understand how these treatment centers operate, giving us a significant advantage once we receive the sNDA indication. Another key factor is the quality of our drug. We believe Revuforj has a best-in-class profile backed by our NPM1 data. Physicians consistently emphasize that the most crucial aspect of any treatment is its effectiveness compared to existing options, and we believe we have a standout product in Revuforj. The efficacy data supports this belief, and as Michael may have noted, having multiple indications for our menin inhibitor is significant. This is important not only for treating physicians but also for payers, who see the value in a second indication like Revuforj, making it easier for them to support. In terms of expected uptake, we do anticipate an initial increase. While we currently see small off-label usage, approximately 10%, we believe the most substantial impact will come when we secure the indication grant. That is when we can effectively promote and commercialize the drug, and we expect a significant response at that time since physicians are ready to embrace it.

Yes. I'll just add that adding NPM1, you take your patient population from about 2,000 patients to 6,000 patients, that's a big difference. And so we expect it to be a really important driver, not only starting at the end of the year but going into next year and beyond. It's important to be first. It's important to have the best profile. We have both. So we're in good shape.

Our next question will come from Salim Syed with Mizuho.

Congrats on the quarter. Mike, Keith, we have a question about Niktimvo. I apologize for this math question, but regarding 2026, the current consensus is around $240 million for end-user sales. Considering some figures released by you and Incyte, I believe there were about $45 million in sales, about 4,500 infusions mentioned on their call. You indicated more than 4,000, but they reported 4,500. This suggests a net price of about $10,000 per infusion, assuming a trial duration of 10.3 months. This leads to a projected total of $225,000 for the 22 infusions that would occur if you have around 1,000 patients by the end of this year. Given those assumptions and without factoring in additional inventory impact, penetration, or growth, is it just me, or does that Niktimvo end-user sales number seem quite low based on this math? Am I missing something?

Thanks for the question, Salim. So we're trying to track with your math here. But Keith, why don't you comment?

Yes, trying to track your math. I mean, I think going back to some of the comments that Mohammed and Bill made on the call that Incyte had last week, I think they were asked a question about peak sales, and there was a response that included an estimate of looking at the REZUROCK launch and comparing the Niktimvo launch to that launch. We think that both we and Incyte both think that that could be a low watermark for us. And if you just look forward, Michael made comments in his prepared remarks that third full year of launch, Niktimvo's annualizing over $500 million in the U.S., again, we think looking forward to 2028, when we'll still only have a relapsed/refractory, we don't expect to have necessarily frontline indications by then. But we definitely think this can be several hundred million dollar product in the next few years.

Okay. Yes. I mean they did talk about the $1,000 million sort of at the end of the year from the current $700 million or so. That's sort of the basis for the math. But I understand your point. And just quickly, I guess, on your slides, it looks like you updated your EPi data for the NPM1 from 3,000 to 4,500 just to 4,500. Is there something you guys did on the Epi to make you more confident around the upper end of that range? The one that's $5 billion TAM?

Thank you for the question. We have a lot of factors that boost our confidence. Regarding the EPi, we're primarily treating patients in the second line now, which will help us tap into the higher end of that number as physicians prefer to treat earlier. This gives us the confidence to aim for that upper range. I also want to revisit your question about Niktimvo. You noted a duration of 10 months, but it's worth mentioning that physicians intend to keep patients on this highly effective drug for potentially years. We believe there is significant potential for increasing the duration of therapy, so it's something to consider in your assumptions, and we'll monitor that moving forward. That aspect stood out to me in your calculations that might warrant a closer look.

Yes. And so...