STIFEL 2026 HEALTHCARE CONFERENCE - SYNDAX PHARMACEUTICALS INC

All right, we're going to go ahead and get started. I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and glad to have with us in the next session, Syndex. We have Michael Metzger, CEO. We have Nick Botwood, who is the CMO. We have the new CFO in attendance as well, Aaron Bordry. So we're just going to have a discussion. If anyone has a question, feel free to raise your hand, and we'll get you acknowledging your question and answered. But Mike and Nick, I appreciate you guys coming. And just, you know, any opening statements you might want to make before we jump into Q&A? Well, first, Steve, nice to see you. Thanks for having us, as always. It's great to be here. Yeah, look, I think we're in a great position as a company. I think we've had a commercial effort over the last seven-plus quarters in growth for two products now within the heme space. For Revuforge in KMT2A and NPM1 acute leukemia, the quarterly report showed growth in revenue, growth in new patients, leading in all categories, really a dominant position within the men in class and growing. So we feel very, very good about the trajectory there. And for Nick Timbo, it's a very similar story, growth, 12% revenue. We're seeing patient growth as well as extension duration. So we're pacing very well with both franchises, moving as quickly as we can towards profitability with some very disciplined spending around our portfolio with aspirations to get the front line coming soon. So we're very excited about the commercial business and now the emerging pipeline that we have, as we talked about this summer, an EGFR inhibitor going into the clinic in the fourth quarter, this quarter. And we think that could be a highly differentiated asset with a very significant market opportunity. And then, of course, the next-gen men and going into MF. So we have lots to come. Exciting time coming at ASH as well, which we'll talk about today. and a lot of data to get through. So I generally do not like to start these things off talking about a competitor asset, but there's obviously been a bit of a visceral reaction to the headline efficacy data we saw in the Ash Abstract last week for J&J's BlexiMedib. So let's just get it out of the way. I mean, obviously not a lot of information or context in the abstract itself, but would just be curious to kind of hear your perspective on it and how you've been messaging this to investors. Yeah, well, let me just start off by saying a couple of things, and I'll maybe pass it to Nick for his thoughts on their abstract. Keep in mind that we've been in this market for three years. We're the market leader. We have a dominant position in Relapse Refractory. We've shown more data in combination, which is where this whole field is going. I think it's going to be very hard to beat our profile from an efficacy, safety, tolerability, and breadth standpoint, breadth of data. So I think if it's one abstract, it's a little early. So we're actually very excited about our position and how we go into ASH this year. But just keep in mind that this is you know, a company that's three years behind us. And while it's J&J, we feel we're very well competitively positioned to continue to win here. So, Nick, maybe. No, thank you. Thank you, Steve. Good to see you. Thank you for the invitation and the question. And just to add to what Michael was saying, I would say that the treatment of relapsed refractory AML has been transformed in the last three years. I think it's really important to remember that when we pioneered in this space, you know, three, four years ago, and we did our original Augment study, the treatment of AML was very different from as it is now. So the first thing to say is it's wirklich not any sort of comparison with J&J. It's a completely different paradigm now. And that, of course, is reflected in the demographics of the patients going into the study. It's much less heavily pretreated number of patients. The median may be the same. But if you look at the percentage of patients that had three or four lines plus, in augment, we had patients add to 11 lines of therapy. Many of these patients were sadly, you know, likely on the way to hospice care when they were offered at that point an experimental therapy. And in the three years since we've been on the market, we've really transformed outcomes. Patients are now getting treated in combinations. They're getting treated earlier in their treatment paradigms. They're going to transplant more regularly, and they're going on to maintenance therapy after transplant. And I think that's most likely what you see in some of the competitor data that is reading out now three years after we did our studies. If you actually compare more relevantly, I think, to the two real-world series we will be having and being presenting at ASH, and you look for the CRCRH and the response rates of those patients, both monotherapy and incombination, you'll see it much more comparable to some ofthe competitor data reading out nou. And that's a much more reasonable comparison than the data set that was done three years ago. it. I also think, and people react to an abstract. Abstracts are difficult to make sense of. These are complicated data sets. You really need to understand the totality of the data. You need to understand how the efficacy of valuable population was defined. Many more patients went into some of these competitor studies than were actually included in the efficacy of valuable populations. And that, of course, can impact the numericalism of CRCRH. So we're excited to see the men in field moving forward, of coarse, but we want to make sure that we've really understood the data. The other thing we don't talk about very much but is important for these patients is, of course, the benefit-risk trade-off. We know some of these newer menin molecules actually have very potent profiles. And of course that translates into some of the on-target toxicity issues that you can see, specifically increased rates of differentiation syndrome, sometimes requiring a dose titration up and careful management initially while patients on therapy, and also higher rates of cytopenias. And we know now, because of the pioneering work we did with John Crespino, we may come back to that a little later, that the impact on thrombocytopenia in particular is a non-target effect of men in inhibition. And as you would expect with a potent asset dosed high, you do see very high rates of cytopenias as a monotherapy. So why is that relevant? Well, the field is moving to combinations. That is very clear. Most of our real-world series now are treated technically off-label because physicians want to get high response rate, and they treat in combinations with Venazer or Ven, single agent, or other standards of care. We know that Revumenib combines very readily, and indeed, we'll have three data sets at ASH looking at frontline combinations showing very tolerable regimens and very high levels of efficacy. We haven't seen any combination data from some of the other Menins yet, and I think that's an important question because as the field moves forwards, monotherapy data may very soon be less relevant than combinations, whether that be in newly diagnosed patients or treating patients in the relapsed refractory setting. So we're extremely happy with our leadership and the presence we'll have at ASH. And I think there are a lot of questions and unknowns still to be figured out for some of the new amendments coming through. Yeah, no, I think all good points. So I guess when I look at, you know, what both you and J&J are doing in the frontline setting, right, you both have registrational studies ongoing. I think you both have the Veneza combo and frontline unfit patients. You have an IC combo and front-line fit patients. But there are some nuanced design differences there. So maybe you can just talk about those a little bit, just given the emphasis that we're kind of moving to combinations. And then what's the strategic rationale kind of underlying those differences? Thank you, Steve. And it's a great question. So maybe I would just start, again, by highlighting the data that supports the phase three. And we are in the strongest position to have data that support the design and considerations that go into those phase threes. So look out at ASH for several orals and a poster looking at combinations with Veneza from our BEAT AML. There's been high scrutiny on that study. This is going to be a much more mature data set with higher numbers that supports very high rates of CR and a median overall survival that's going to be in excess of 24 months. And the reason I highlight that, it gives us a very high level of confidence in the probability of technical success of the EVOLVE-2 study in patients unfit for intensive chemotherapy. We'll also have data from our 708 study with intensive chemo, again, showing it's very tolerable. Of course, high rates of CR and ORR, but importantly, high rights of MRD clearance as well. And that's important and likely to translate into durability in due course. So we're very happy with the data set, Steve, and that's really what's informed the design of these studies that I consider very smart and strategic. We've taken two separate phase threes because we consider outcomes in patients that get intensive chemotherapy or VENAs are very different. Different populations, different outcomes, expectations, and it makes sense to do them separately. We've kind of taken the best of both worlds. One of them we are sponsoring directly within Sundax and working with an international CRO, ParXL. That study is a truly international study. We have sites throughout China, Japan, Asia, Latin America, Europe, and, of course, the U.S. Multiple hundred sites now are active and enrolling, and we've got very good momentum in their enrollment. We're feeling very good about it. One of the unique design aspects of that study, I would say, is that it's a two-arm study, and that differs from some of the other menins in the class that have included a third arm to try to isolate the contribution of maintenance. We felt that that was technically an extremely difficult thing to do in a pivotal phase three, and are addressing the maintenance question in a separate prospectively randomized study called Maintain that we're doing in collaboration with the Dana-Farber Cancer Institute. The net result of that is that our study is at least 30% smaller than some of the competitors. If you look at some of The Other Men in Agents, they need to enroll nearly 1,000 patients in the pivotal phase 3s. It's a very challenging number to enroll in a study in a very competitive space. When we're talking about Hovon and the Evolve 2 study, we are this is not under syntax sponsorship it's under the syntax of under the sponsorship of home excuse me and that's a great advantage for us because this is a very well recognized international cooperative group who have led in the past many successful phase threes in the heme space again we've been able to power that study appropriately for not only statistical significance but also keeping an eye on that it has to be clinically relevant this is an add-on to standard of care we didn't want to overpower it such that you could claim statistical significance but not have a clinically meaningful difference in CR or overall survival. So we're extremely happy with the design of these studies. They have great momentum behind them now, supported by very good data that we'll have at ASH. We just focus on executing and are feeling confident about being those studies reading out in a very competitive time frame. The one last thing I would just say is that both of the studies have dual primary endpoints, which is quite an innovative approach. They're independently powered, so the studies can be successful on either of the endpoints. And that gives us the opportunity for an accelerated approval. Again, there's some innovation that I won't go into in too much detail, because obviously this is a very competitive space in terms of the statistical analysis plan. But we're feeling very good about where we are with those studies and the data that supports them. Yeah, I think it's a pretty creative development program in the sense that you've kind of designed the big registrational frontline trials to be you know a bit more nimble and you've kind of supplemented those with a number of other you know phase two studies like you said maintain as opposed to trying to you know burden the frontline studies by trying to ask multiple questions it's exactly right Steven that's exactly how we thought about it and we have those two pivotal studies but I would maybe just mention some of those supportive studies that answer some of the questions you mentioned maintain again that's the first done prospective study actually isolating the contribution of maintenance specifically and it's the cleanest way to do it you randomize patients after they've had a transplant and we're excited about collaborating with dfci on that and the other study we're very excited about which is complementary to that pivotal frontline study and again we're the only company doing this specifically at the moment is the raven study and the ravens looks at patients that would be fit for intensive chemotherapy but actually with kmt2a but actually gives them veneza as a means to get them to transplant because you want those patients to get to transplant because that's their best chance of a durable remission but without all of the morbidity associated with giving them intensive chemotherapy so that is a novel approach building on the data from the paradigm study and amia farti so we'll see how that works out but it supports our pivotal program okay let's talk about the business a little bit right so i know you just reported a 20 sequential increase in new patient starts. I know the reference point there, 2Q, is a little bit of an outlier, but maybe you can just talk about some of the tailwinds that you're seeing driving growth, and maybe also talk about the quarter-to-quarter visibility that you feel like you have into the business at this point, because I know that 2Q outlier was maybe a little but unexpected by investors. Yeah, no, thanks for the question. Look, I think the business, the new patient starts, as you mentioned, rebounded this quarter. We expected that. I mean, there is fluctuation in this market. It's a patient population that is, you need to find the patients, you need to identify them, and you need be vigilant about it because they're not always in the same physician office, you know, quarter after quarter. So, I think the way you go about it, and we do some innovative things to find patients, identify them and obviously get them drugs as quickly as possible, I think we're leading the space in doing that. And that's part of the reason why we're so successful in building this business. But it's not just about new patient starts. And we do expect to continue to penetrate both KMT2A, NPM1, and perhaps even new lesions like NUP98, which is an area where we're pioneering the science in order to give these patients another treatment. But so the patient population is expanding. We have the opportunity to penetrate more and more. As I said, it's a diligent effort, so we believe we'll continue to grow new patient starts quarter to quarter from here. I do think that there's one of the aspects of this business that's so exciting. It's not just about new patient start. It's also about how do you get patients to transplant and how do we put them back on drug and get them to the maintenance setting. So while we're not indicated for maintenance, a lot of our patients are now getting transplanted and getting to maintenance. About 50% of the patients get the transplant, and about 50% to 60% are coming back for maintenance. So that is both KMT2A and NPM1. What we figured out this quarter was NPM1 is actually behaving very much like KMT2A, which is a bit of a surprise to us, since that 40% of the patients who have NPM 1 are going to transplant, and about 50% of those are going back for maintenance. So the benefit of that is obviously that you grow the time on therapy for these patients, keep them in remission longer through maintenance. And that is a tailwind to the revenue on a quarterly basis as we grow. So it's not just one-dimensional how you grow. It's both new patient starts and also the extension of duration of therapy, which is so meaningful on a quarter-to-quarter basis. And the tailwind of that we expect to see more of next year as more patients come back and as we increase the number of patients going to maintenance through more data. And a lot of the things that Nick talked about, we'll talk about it coming at ASH, are so important to the real world and how physicians are utilizing the drug and driving the transplant maintenance dynamic. So it's quite powerful. I think the question we get asked a lot is, you know, when is this longer-term post-transplant maintenance benefit going to reveal itself within the model, right? And I know you're getting, you know, more of these NPM1 patients to transplant than you had originally expected, certainly a lot more than I had expected. But in terms of visibility, right, because I know if you look at some of the real-world data that you've presented, right? There seems to be some variability in termsof when patients restart, youknow, therapy, how long they're on therapy for. And so how does, younow, the fact that you now have these patients kind of exiting the model, right. They're going to transplant. They're coming back on at some variable time point. They're on drug for some variable amount of therapy. How does that then complicate, if at all, this level of visibility that you have here? Right. So the headwind that we experienced with KMT2A during the first, call it, year to two years of launch is starting to come through the model now as we build more and more maintenance. So it was a 50% transplant, 50% come back for maintenance. Now that's extending to 60% comeback for maintenance, so we're starting to exceed the amount of patients that are getting transplanted with maintenance therapy. I think that phenomenon will continue to go through KMT2A as we approach 70% to 80% of patients, and I think we'll start to see more of that, the durable revenue piece of that in 27. I think we're now in the early innings for NPM1 where you're seeing more patients go to transplant and you're starting to see patients come back. That will, again, wash through and continue through the model as time goes on. And I think 27 will be a more meaningful time to see returning patients and how that impacts the revenue bill. Steve, if I could just very quickly add, just highlight three data sets at ASH, which I think are very relevant to this topic. One is by Dr. Brian Ball at City of Hope, largest transplant center in the U.S. He's going to present phase one data looking at maintenance after transplant. First time a study has actually been done to optimize treatment of patients. In that study, his intent is to treat patients out to two years. You'll see some patients on durable treatment out for one year. Some patients he's had at two years don't even want to stop at two years because they're in a durable remission. They're doing well. He just wants to carry on. So that will be very important data. We also have an interesting data set looking at Rovumenib as a bridge to transplant. And interestingly, it's not just patients with CRCRH that go to transplant. It's at least 40% of the patients that go to transplant have less clear responses, so morphological remission and other types of response. And that's really important because we know revumenib gives you very high overall response rates. And then one other interesting data set is by Andrew Wei, the intercept data, where patients are treated with MRD relapse. And that is an interesting early intervention. So it's before patients have formally relapsed but intervening when patients have MRD. First study of its type, very encouraging response rates by treating patients earlier, which again is a support for the concept of maintenance because many of those patients have minimal residual disease after their transplant. And Andrew's data will demonstrate that you can actually eradicate it. So very important data at ASH supporting the evolution of this treatment paradigm that Michael was talking about. Okay. Maybe just in the interest of time, we'll shift to some of the other parts of the story here. I know Nick Timvo, the IPF data, obviously disappointing, but, you know, it still feels like there's a lot of growth runway for this asset here, right? So both in terms of on-label and label expansion opportunities. So maybe you can just talk a little bit about the on-label growth part of it. And, you know, if I look at Resiroc, right, it kind of suggests that we're still probably in the very early innings here. How do you see, you Know, growth partitioning out for Nick Timbo relative to additional share gains, duration of therapy? And then how do you think about the margin contribution in terms of where that can go over time and how that impacts the P&L? Right. So the the the state of play for for Nick Timbo in third line plus GVHD right now, we're at about a third market share there and meaningful in both fourth line, but call it third line. Plus, and of course, the competitor there is Resrock indicated for third line, plus they did about 500 million, a little bit more than 500 million their first four years of sales. and we're tracking very much on top of what they've been able to do, which is it just shows you there's expansion and growth in the category. We expect to further penetrate third line and fourth line, so there's more room to grow. And what's also nice about this in a similar – kind of a similar way to Reviforge, it's about duration of therapy and keeping these patients in remission and doing well for months, if not years, and we've seen that in our trial. So it's the extension of not only new patients, but also penetrating, but also the ability to keep them on drug for many years. And I think the profile of the drug is coming into focus now where skin and lung lesions are a big driver of late line use. And we're seeing physicians reach for the drug even ahead of the competition in order to satisfy their patient needs. So there's a real building rationale for why this mechanism is so impactful for these patients. And that's, you know, I would say very exciting about use in monotherapy. And then we extend the potential use here in combination therapy with ruxolitinib, the JAK inhibitor, Insights product, really looking at that in a phase two trial, which we'll read out in the first quarter next year, which were interested in to see how that looks like and compares to steroids that use in combination could be, you know, a way to spare use of steroids, which physicians are loathe to give in early line treatment. Even though it works, it comes with a lot of side effect and tolerability baggage. So we'll see that data. That could open up the frontline opportunity for us perhaps to get into compendium listing with that regimen. And then, of course, we have a pivotal trial reading out in the first quarter of 28, which is a steroid against steroids and in combination with steroids. So, again, trying to reduce the use of steroids in the front line. So, I think that's the way to expand this product to the 15,000 to 17,000 patients. Right now, we're at about 6,000 patience in third line plus. So, there's a lot more growth, as you say, to do. And we talked about the overall health of the business. Margins are expanding, right? This quarter, we reported we're in the 30% to 35% range where we'll stay for the foreseeable future. but we've kind of grown from 25% to 30% in prior quarters. Now we're expanding the margin, which is great for us. Obviously, it's $22.6 million in net contribution for Rebuforge to Syndac. So I think this is a growing product that has great potential to continue to expand within GBHD. Margins continue to extend, so it's very helpful for our portfolio and obviously helping to reach the profitability. And as we think about the frontline data we're going to see in the first quarter of next year, how are you guys going to be defining success and what is clinically meaningful in terms of benefit that could emerge out of the top line? Yeah, this is a proof of concept study. So it's 120 patient study, three arms. I mean, elegantly designed study. It has a steroid benchmark arm in there. And the primary endpoint is the response rate at six months using strander criteria for GVHD. And the benchmark for that is about 40%. So the study has powered actually to look at a 20% delta for the two active OMS. One is Rux or Rux-Axa. And, you know, we're expecting to see about 60% response on that. In terms of clinically meaningful, always nice to see an improvement response rate. But I think particularly with the addition of axotilumab, it's going to be some of the time-to-event endpoints that are particularly meaningful. So we will, and this partly fed into the reason why we felt it would be helpful and appropriate to present this at a Congress in the first quarter next year in order to be able to see the totality of the data. And that would include those duration response and event-free survival. We know the combination is going to be very well tolerated, at least we anticipate it's going to be, because we presented preliminary data on that at a Congress earlier in the year and showed that discontinuation rates and overall tox for the combination was very good. And the whole hypothesis or premise behind the study is you want to be able to reduce patients and have them exposed to less steroids, which we know come with a lot of associated morbidity. So that's sort of the benchmark estimate we'd like to see that we think could be clinically meaningful. If it is positive, We think it could definitely drive uptake. We know many physicians really don't like to give patients steroids early on in their treatment therapy. If they could avoid doing that by giving them Rux or Axarux, then that would be a definite upside for patients. We're excited to see those data. Yeah. And you emphasize the importance of steroid-free in the frontline. You do have the ongoing registrational study, which is Nictinvo with steroids in frontline. If this data warrants it, I know you talked about Compendia, but would you think that another frontline trial, Nictinvo-Rux, running in parallel to the one you have ongoing now, would make sense for this? Yeah, I think it's absolutely a consideration. I mean, we'll probably see both data sets. I think Axodex offers an alternative treatment strategy. That combination is quite attractive because they target slightly different approaches, so the MOAs are complementary in terms of targeting the immune system. But when we have the totality of the data, I think we definitely think about with some, you know, with thought leader input and what would be a kind of future development plan that would be best for patients. Is it an Axa-Rux combination? Is it the AxaDex? Do you want to avoid the steroids? And I think with all of the Data in Hand, we'll make a decision on that. Okay. I know you guys hosted an R&D day earlier this year and unveiled a couple of new opportunities that you're looking at, one of which is EGFR inhibitor. Maybe talk a little bit about how that's different and how you're hoping to leverage that differentiation within the clinic. Yeah, a lot of excitement around the pipeline. I'll let Nick talk about the EGFRS, which we think is a big opportunity, highly differentiated. It could yield some data pretty early here. Yeah, absolutely. Thank you, Steve. Very exciting. I mean, as a drug developer, this is a somewhat unique opportunity. I've spent 20 years developing drugs in the field of lung cancer, particularly tyrosine kinase inhibitors, which, as you all know, targets the ATP binding pocket from the first generation, second generation. And then all of the newer agents targeting EGFR are really isolated on that catalytic binding pocket. This is a completely novel and different approach coming out of some research that we have been supporting with and working with Dana Farber on over several years, which actually targets the allosteric binding pocket, so it's a completely separate and independent binding pocket which is present in certain types of EGF-R subtypes, so specifically the L858R mutation subtype and some of the other more atypical mutations. This is a drug we very much like, the preclinical profile. We're going to have the IND submitted by the end of the year, and we'll be in clinic next year. We are anticipating, because we have a very innovative kind of precision-targeted phase one approach, that we would see activity quite early on in its development program, because we're anticipating monotherapy activity. The other interesting thing about this asset is it has high CNS penetrance. We know a lot of patients who are on osimertinib and come refractory to osimeltinib progress with CNS mets. We'd be very excited to see a patient respond who had CNS metastases. That's something we'll be looking for in the program as we dose escalate and as we expand. I mean, ultimately, the target product profile for this drug would not be in competition with osimetinib. Initially, we'll look at OC refractory patients. OC is a very valuable drug, huge unmet need for this type of lung cancer. We'll look ATOC refractory, but ultimately, the intent would be to combine with dosimetinib. We think the two are eminently combinable. All of the preclinical work we're doing would support that hypothesis. It's a so-called double drugging where you can drug both the catalytic binding site and also the allosteric site and get what we anticipate will be really profound inhibition of the EGFR axis. So we're very excited to take that asset into the clinic next year and see what it does. Okay. And then I know you also unveiled the next-gen menin inhibitor, which you're going to be positioning in myelofibrosis. You have some you know, kind of parallel proof-of-principle trials that are ongoing with Revu Meta. When might we see data from those proof-o-principle trials with RevU in MF? Yeah, I mean, like Nick talked about, I think we'll start the MF work with Revuforge. That's starting, you know. End of this year, beginning of next year. And then we'll have – we hope to have data in 27, which will line up nicely with our IND filing for the next gen in 27 as well. Yeah, and we're really excited about this. I mean, I haven't got time to talk about the science, but the science that underpinned this got best of ash last year. It comes out of some work we were doing with John Crespino at St. Jude's. A very elegant hypothesis as to why Revuforge has a role to play in MF, which I won't go into now. We are, in addition, working with John Mascarenas and the Mylar Proliferative Neoplasia Research Consortium to do a proof of principle of this hypothesis with Rev. 62122 is an optimized next-year man, and it has an ideal profile, highly potent activity against some of the resistance mutations, no DDIs. It's a very clean molecule. We're excited to take that into the clinic. We anticipate having it in the clinic next year, and we'll be able to accelerate the development plan based on all of the learning we'll get from RevuForge as a proof of principle in myelofibrosis. So this is a novel and differentiated approach to targeting patients that have myelofibrosis. Initially, we'll approach it as a monotherapy and a dose escalate up, and then we'll quickly pivot into patients that have a suboptimal response to JAK inhibitors. And we're excited to be doing that work with John Mascarenas and colleagues at the NPM Research Consortium. Then how do you just think about BD more broadly and whether or not you think there could be any opportunities you could capitalize on over the near term? Yeah, look, it's at our DNA. We brought all of our assets in aside from the next-gen men through BD, so we feel like we're well-positioned to do it. We'll continue to look and keep a very high bar for what's impactful for us. But yeah, we'll be active and looking. We can't speculate on what we'll able to do, but it's a way to build a business going forward beyond where we are today. All right. We're up against time. Anything we didn't cover that you would like to quickly highlight before we wrap it up? Just that we're extremely well positioned. We believe, I think this is a very pivotal time for the company as we grow the commercial business and set up for our next phase of growth into frontline trials and frontline studies and the pipeline emerging. It's a really exciting time. We'll have a lot of data and things in the coming days for Ed Ash and other conferences. So stay tuned for that. Sounds great. Nick and Mike, really appreciate it. Thanks.