Hello again, everyone. My name is Etzer Darout, one of the Senior Biotech Analysts at Barclays. It's my pleasure to have Syndax Pharmaceuticals with us for our virtual fireside chat. With me today, I have Michael Metzger, our Chief Executive Officer, Keith Goldan, Chief Financial Officer, and Nick Botwood, our Chief Medical Officer. Thank you, gentlemen, for joining me. Maybe Michael, just to kick us off, for those less familiar with the story, maybe just provide an overview of Syndax, and then we can jump into Q&A.
Sure, happy to do so. Etzer, thank you for having us. Thank you to Barclays for kind invitation. Syndax is a commercial-stage organization, company focused in oncology, two leading products, one for acute AML and ALL in specific subsets, KMT2A acute leukemia for adults and pediatrics, as well as NPM1 acute leukemia. Together they cover about 50% of the market for acute leukemia, and that's a real step change in terms of what you can target as a modality. This is a menin inhibitor, to remind people, the class of drugs. We are leading the class in terms of being first to market, also have best-in-class profile. Really important setup.
We launched the drug in late 2024, had a banner year last year in terms of sales. The product is growing very nicely through the fourth quarter and into this year. We're excited about the future. We have lots of development to do with the medicine and you know, well-positioned for success. Next we have Niktimvo, which is for chronic GVHD. Another new mechanism for these patients is indicated in third line plus patients, and it's a CSF-1R inhibitor, which introduces something new to the market in terms of being both an anti-inflammatory and anti-fibrotic agent. Broad profile, and also off to a terrific start.
We launched that product in early 2025 in less than a year, $152 million in sales, growing very nicely in the fourth quarter as well. Two growth products within the hematology oncology space, and the leading position in order to take advantage of what comes next, which is development for both molecules. Excited to be here today to talk about this.
Great. On the on-market experience that you've had so far with Revuforj, you talked about the duration of therapy. Obviously, this is a driver for all indications in terms of being able to sort of drive revenue. You've indicated perhaps longer duration in 2026 versus 2025. What are the key leading indicators that you could point to that would help you to, again, as the metric for how that's doing and whether or not you can reach sort of that longer duration of therapy goal?
This medicine has become quickly the standard of care for patients who have KMT2A acute leukemia. Now we have a new indication with NPM1 launching at the end of last year. This will, we believe Revuforj will be the standard of care for NPM1 and relapsed refractory disease as well. Key to both opportunities, of course, is to treat as many patients as possible. To do that, you need to treat them as early as possible because it is a very serious illness. Treating them second and third line, we've seen the majority of our patients get treated there relative to where they were treated in clinical trials, which was mostly fourth and later lines, which is customary of how clinical trials go. Now in commercial practice, we see second, third line. We expect that to continue to build.
The vast majority of patients from here will be treated in second line for both indications. That will allow for patients to get to transplant, stay on drug longer, ultimately do better. When you bring them back, 'cause the key to, at least for KMT2A, is to bring these patients to transplant. Many of them are very young, and you want to be able to bring them to transplant and then put them on maintenance therapy.
Yeah.
That maintenance therapy is a key component to duration of response, and we've seen patients out three years on our therapy. That will be a key part of how this builds over time, and we did talk about four-six months of an average duration in year one, where you have fewer patients being able to experience maintenance because it takes some time to go through your transplant process and then come back for subsequent therapy. We expect that to build in 2026 and beyond. In 2025, it was four-six months, and in 2026, we think it'll be in the 6-12 months once you factor in the impact of maintenance. We're off to a very good start in that regard, but that's. I think treating them earlier is a key component to that and obviously getting them to transplant.
Right. Obviously, another question is competition. As more menin inhibitors enter the space. I think with any drugs, as more, you know, competitors enter the space, physicians now have to kind of triage the decision tree in terms of who gets what. I guess as you know, speak to physicians, how are they feeling about Revuforj? Then where are the touch points that you think are gonna be important or critical to continue to drive uptake of Revuforj?
We have a, you know, wonderful commercial and medical organization who cover the entire universe of physicians. We've had the best data. You know, our label covers all of the indications, adults, pediatrics, AML, ALL, with regard to Revuforj, now NPM1 as well as KMT2A. We have the broadest label with the best efficacy in the class, the ability to bring the medicine to as many physicians as possible and support broadly with new data, right? Bringing combination data, real-world data. We've been able to do that throughout 2025, and we expect to be doing that again and even more, you know, significantly in 2026.
That will allow us to give physicians the full flavor of how they could use it as both monotherapy and also in combination. Then, of course, you need to carry through and really create that partnership with physicians, which we've done so well in the first year. You have the ability to get them the drug in four days. The drug is completely covered on it from a payer perspective, and quickly. We're in a very good position to deliver on the promise of the drug by actually delivering it to the patients. We're in a great place in order to continue to be the product of choice for physicians as they come across any patient in any particular situation.
Great. Maybe a question for Keith. Obviously, you know, capital allocation across, you know, the commercial platform is important, but also sort of thinking about how to leverage that spending versus that of the pipeline and just maybe how you're thinking about, you know, supporting the commercial story, right?
Sure.
Obviously being able to allocate enough resources to the pipeline.
Yeah. I mean, one of the fortunate pieces of our business model is that we do not perform discovery research. Both of our assets, Revuforj and Niktimvo, were both in-licensed. It allows us to keep our operating expenses controllable and relatively low. We've made a commitment to keep our OpEx flat this year at $400 million for SG&A plus R&D. That's consistent with last year. That still allows us to fully invest in maintaining our leadership position in the menin inhibition space, co-promote Niktimvo with our partners at Incyte, and also maintain our leadership position in the race to the frontline in combination for both products, really.
One of the reasons we're able to do that is because, you know, unlike any biopharma mid-cap that I know of our size, we're able to capitalize on two successful launches, and both are quickly contributing really nice gross margins that help to offset the burn in commercial and in R&D.
Great. Maybe some of the combo use that you talked about previously. It seems to us that, I mean, at least anecdotally from the information that you're giving us, that the combination is combo-friendly, if you will. Maybe what features you're seeing with Revuforj in combination use that are, you know, again, advancing this. It seems that sort of ramping up of the combination use of the drug.
Yeah, for sure. I'll let Nick address it. The combinations have obviously been very exciting. Go ahead.
No, thank you, Etzer. Thank you for the invitation. It's nice to be here. Revuforj is obviously approved as a monotherapy, but interestingly, we're seeing a lot of uptake and use outside of its currently approved indication in combination. Obviously, we're not promoting in that setting. I think what we're learning is that there is a clear physician desire to use the drug in combination. You know, we have reported in real-world evidence last year that interestingly, from Moffitt Cancer Center, actually 80% of the patients there were treated in a combination, either a combination with Venclexta or a single agent, you know, combination agent. It's clearly an attractive proposition for physicians and patients.
I think the reason that they want to do that is if a patient is felt they can tolerate it, then you do get higher response rates, you know, upwards of a 70% or 80% response rate, as opposed to around the 50% response rate for monotherapy. It's a desirable thing to do. Now, what makes Revuforj particularly attractive as a combination therapy? The first thing is that we have now established across a variety of different standards of care that you can combine at the currently approved dose. We've established that it's tolerable, and you don't really get any, you know, incremental toxicity by combining them, you know, when it's carefully managed according to current guidelines. And that's, I think, the first consideration that you can combine safely and at the currently approved dose.
The second is that, as I've said, you get these response rates, but you also get these really deep responses. We've reported that in those patients that respond, whether they're being treated with ven or Venclexta combination or an even intensive chemotherapy combination, they get very profound reduction in the minimal residual disease. A lot of these patients become MRD negative, and that allows a greater number for these patients to get to transplant. These are attractive features. It's also, I think, helpful that, you know, in terms of drug-drug interactions, we have a very clear dose modulation for patients on CYP3A4. That's actually very helpful because it allows for, you know, leveling out PK exposure.
Importantly, you don't need to make any kind of adjustment for patients on antacids or PPIs, which are very common, concomitant medications for these patients getting potentially a chemotherapy combination. I think the experience that physicians now have in the real world, the fact we've been on the market for as long as we have, has really supported that use in combination makes it an attractive option.
Great. If you think about combinations, we also think about earlier line use of Revuforj. Think about like the must wins, and as you know, you're executing on your frontline plans. We hear about MRD negativity, event-free survival, transplant, getting the patients to transplant. What do you view as the kind of key wins, if you will, as you think about, you know, the endpoints that we should be paying attention to as data starts to roll out in those frontline trials?
No. Thanks. That's an important question. I mean, the first thing I'd say is that it's got to be safe in combination. We're always focused on safety and making sure the patients are well managed in clinical trials. We've now established across, in fact, four phase I-B studies. Our own 708 study, which was a combination with intensive chemotherapy, a study we're doing with the NCI, and then two studies, SAVE and BEAT AML, respectively, with ven and a hypomethylating agent, that the drug can be combined safely at recommended doses with the appropriate monitoring and guidance. That's the first consideration. We'll ensure both rapid enrollment in the first-line studies, but also that the studies enroll with high quality, and a focus on safety.
Then in terms of endpoints, I think there are a number of endpoints that are important, and we've built these into the phase IIIs. One of the endpoints that's becoming increasingly, you know, thought about and utilized is the concept of complete response rate or in the instance of patients treated with intensive chemotherapy, complete response rate with MRD negativity, which is kind of probably the most stringent criteria that you've eradicated disease. There is increasingly evolving body of evidence that supports if you can get a patient into complete response or in the case of fit patients, to CR with MRD negativity, that's going to correlate very well with time to event endpoints.
The gold standard, of course, for all of these frontline studies is to improve the survival, actually improve the outcome for these patients, hope that they live, you know, better and longer lives. That's the endpoint that we have built into our UNFIT study because we believe it's achievable. We have generated, you know, very encouraging survival data already from our BEAT AML study. Even though the follow-up was really very immature, we've shown over 15 months median overall survival, which compares really somewhat favorably with historical controls, if you accept that those studies have much longer follow-up, and we anticipate updating those data later in the year. Then the other endpoint that we'll look at, which again is an important endpoint, is event-free survival. This is again a surrogate, and you would expect it to track with overall survival.
In the setting of patients that are fit for intensive chemotherapy, demonstrating a survival benefit is quite difficult simply because it takes a long time, and we'll look at it. The dual primary endpoint of that study is event-free survival. This is how we're approaching it in our frontline program.
Great. In the KMT2A study, I guess the RAVEN study, you opt for the lower intensity approach versus sort of high-intensity induction. What's the clinical bar there that you know you think you need to achieve, so that you know, instead of, oh, well, this is just a less toxic combination versus truly one that could be a new standard of care? How are you thinking about the bar there?
Yeah, I'm excited about this study, and it's a very nice complement to our pivotal program because we want to continue to innovate and lead. I think overall, we've presented the most compelling data in combinations for KMT2A. Based on, if you will, the kind of the evolving approach to how these patients are being treated, we felt that this was a very important, as I say, complement to our pivotal program that could generate data that might inform clinical practice and offer a differentiated option to patients that are fit and would otherwise get intensive chemotherapy. Etzer, to your question specifically, the idea of this study is for patients who are fit with KMT2A, and as Michael said, these tend to be a younger, fitter population.
The idea is to get them to transplant, but maybe be able to get them to transplant with less of the morbidity and toxicities associated with giving them intensive chemotherapy. There was a nice study at the plenary session, ASH last year from Amir Fathi, the PARADIGM study that suggested that this might be a reasonable approach. Our hypothesis is that if you add revumenib, you may get even more patients to transplant. Now, the proportion of patients that get transplants in that setting is quite high already. It's probably 70% or so.
We will compare it in an iterative way to a sort of baseline of how many patients are getting to transplant to see if at the very least we can replicate or maybe even improve the number of patients getting to transplant, reduce the amount of toxicity, and then we'll track the number of patients that are then able to go on to maintenance. Ultimately, as we were speaking about earlier, what the event-free survival looks like. These are the criteria that will go into that study, and we really think it could be a really meaningful study for patients and offer a viable, better tolerated therapy with equally good or potentially even better outcomes.
Great. Myelofibrosis, I think, is an interesting opportunity. You've previously highlighted some, you know, encouraging preclinical data around the role menin inhibitors could play in this space. I guess, how are you thinking about the decision points, how to more maybe when to more aggressively pursue myelofibrosis versus the investments you're obviously making in AML?
Sure. Yeah. Maybe the first thing to say, I mean, these are very exciting data that we generated in collaboration with John Crispino and his lab. They got best of ASH. Clearly a lot of interest in the hypothesis of menin and the role of megakaryocytes and its role in myeloproliferative neoplasm. We're really building on that. I mean, these are early days from a clinical perspective. We haven't announced our clinical trial program, but we will be announcing that this year, and we'll be working with some of the leading cancer centers and consortium treating MF because of the interest that's been generated by these data with revumenib, and the fact, you know, everybody's very familiar with revumenib as a leader in the menin space.
We'll talk about the studies, but what I can share with you is that we will be looking obviously at monotherapy initially to see if we can replicate the preclinical findings, the in vivo, the in vitro data that was generated both as a monotherapy, but also interestingly, in combination with a JAK inhibitor. There's a lot of innovation in how you inhibit JAK, and, you know, why the combination should be synergistic. Our clinical program will include, obviously, initially, you know, patients with relapsed MF, but moving rapidly into a more frontline population in combination with current standards of care and potentially other novel targeted therapies because there's a lot of innovation in this space. Then we'll be looking at a series of classical endpoints. We'll be looking if we can improve the symptomatology associated with MF.
You know, tiredness, anemia, weight gain. We'll be looking at splenomegaly and whether we can reduce the splenic volume reduction 35. Then ultimately more disease modifying measures like variant allele frequency. We'll look at JAK2 alleles, we'll look at bone marrow fibrosis scores to see if we're really modifying the disease. Based on the preclinical findings, feel pretty confident this could potentially be a very interesting lifecycle management opportunity and bring a new treatment option for patients with MF.
Great. Maybe spend a few minutes on axatilimab in the remaining time. I think it's fair to say that drug has continued to surprise to the upside. Maybe just initially where you're seeing the drug really work best. I mean, you know, different patients with GVHD, you know, organ involvement, you know, inflammatory, heavy, or fibrosis-heavy patients. Where are you seeing sort of where that drug is working best?
Yeah. This is mostly used now in the fourth line. I think the first year we penetrated fourth line well. We're starting to see great uptake in third line, about 20% as of last quarter. We think this has a lot of growth in the real-life refractory setting, and certainly we're developing it. We have trials ongoing, one pivotal, one phase II trial in combination with Jakafi and also with steroids. We'll have a lot of data coming on the use in combination. As a monotherapy, we've been, you know, really making great headway in terms of bringing this to patients.
I think two areas that seem to be a focus for potentially even using it earlier would be the lung manifestations that we see with GVHD, chronic GVHD, which the drug has demonstrated, you know, very good ability to reverse inflammation and fibrosis in those patients. We've done some work on bronchiolitis obliterans syndrome, which we've published, which shows this effect, and that's been potentially an area of focus. Of course, the sclerotic skin that can be very difficult to treat as well. In GVHD, the drug does well in those patients too. It has a very profound effect across all the lung, all the different organ manifestations. I think in particular, those types of patients seem to be a choice for physicians that they would go into use axatilimab product.
Right. You know, Incyte's running new combination programs with drugs with steroids, I think 2027, 2028 timeframe for readouts. I mean, what defines success for the trials when you think about response rates, you know, deeper multi organ responses, steroid sparing, other areas? Where do you think how do should we predefine success in those studies?
Yeah. Maybe just say firstly that these are very important studies in the lifecycle of axatilimab in GVHD, and really position us very strongly to move axatilimab potentially into earlier lines of therapy. Based on the activity we've seen and the data Michael was talking about, you know, we feel quite confident when you combine them, there's a very high probability that these studies will be favorable and successful. Now, in terms of what specifically we'll look at, they're slightly different in terms of their design. We have a study that's in combination with current standard of care, which is dexamethasone, and this is frankly an unsatisfactory standard of care.
Patients have to receive high-intensity dexamethasone initially, either intravenously or orally, and then they have a tailored response to dexamethasone over sometimes several months, but sometimes it can be out to 18 months, and there are significant sequelae of treating patients long-term with dexamethasone. We have a combination study with axatilimab combined with dexamethasone, which will have a primary endpoint of event-free survival. The hope is we're gonna actually improve the efficacy. The mechanisms are quite complementary in terms of their impact on the immune system. Dexamethasone obviously has you know widespread, but is predominantly, I would say, anti autoimmune through its action on the T cells, whereas axatilimab is more targeted down kind of monocytes and monocyte-derived macrophages. Those potentially are quite complementary, which it may offer a nice option.
We'll look at event-free survival, but we'll also look at whether it's actually possible to tailor patients off their steroids sooner, which would be a huge win for patients because of all of the morbidity associated with long-term dexamethasone. The phase two study, which is a three-arm study, is a very interesting concept because it has three arms, one of which is with Jakafi alone. It asks the question, does axatilimab add to JAK inhibition? You get a kind of contribution question addressed, and then you ask the question, well, does that combination actually offer an alternative to having to give steroids at all? Now, that has a standard response rate criteria that, you know, you can assess response quite quickly at day 28 in GVHD to know whether patients are responding or not.
That's an attractive option to potentially move in terms of guiding clinical practice axatilimab into a frontline setting.
Great. Maybe a couple of questions on IPF. Obviously, it's very topical. Folks wanna get a sense around Barclays and other questions. Maybe first question, assuming phase II success, how should we think about, you know, a potential phase III of design of that study? And as well as what potential role could we see a subcutaneous formulation play in the development of IPF and how we should think about a potential subcutaneous coming online?
Yeah. Nick, go ahead.
Very excited about this phase II study called MAXPIRe 3 at second half of this year. I think given the totality of the science, we have a you know high degree of confidence it may read out favorably. We set the bench quite high in terms of what we'd like to see. That will guide the design of the phase III, to your point. We are planning for success. I mean, we're doing as much as we can to expedite the start of a phase III study should the study read out favorably. Obviously, it's a double-blind placebo-controlled study, so we have no insights into how it will read. You know, given the totality of the evidence, we're optimistic. We are planning for success.
The phase III, as you say, the assumption is we would start a phase III with a subcutaneous formulation. We do have a subcutaneous formulation in development. The size, powering, and the design of the phase III is obviously not finalized. It would be somewhat dependent on what we see in the phase II. More on that to come, but our expectation and ambition would be just, if a favorable outcome, to start the phase III as quickly as we can.
Right. You've outlined, you know, cost-sharing expectations around with Incyte, assuming the phase II study works. Have you talked about specifics around, you know, decision rights, funding responsibilities and the like around that, if, again, assuming success with the phase II?
Well, we have very established ways of operating with Incyte within our agreement and cost sharing, you know, 55% for them, 45% for us for U.S. development. That's all well understood. In terms of going forward, assuming a positive trial, we would assume that we would go forward in working together on the IPF indication, and that means everything from subcutaneous development to phase III to funding. There's a lot of work to do, and we expect to be doing it with our partner under the confines of our existing agreement.
Great. Looks like we're up on our time. Michael, Nick, Keith, thank you so much for your time. Thank you for our listeners for their participation. We'll talk again soon.
Thanks.
Thank you.