Morning, everyone. I'd like to welcome everybody down to H.C. Wainwright's 20th Annual Investment Conference. My name is Andres Maldonado. I'm a Senior Biotech Analyst here at the firm, and it's my pleasure to introduce you. Next on the docket is Syndax Pharmaceuticals, and it's my pleasure to welcome CFO Keith Goldan and Chief Medical Officer Nick Botwood, and Head of R&D. Welcome, gentlemen.
Thank you.
For investors less familiar with the Syndax story, how should they think about the company today from the two commercial franchises to the next wave of pipeline assets?
Yeah. First, I want to thank Andres and H.C. Wainwright for having us here. It's been a great conference yesterday and today. I feel like this is a really great time for Syndax, to use a motor analogy, really hitting on all cylinders. We are a small company, but we have two commercial assets, both in their second year of launch. The first is Revuforj. We own global rights, long IP out to 2040-ish. Right now, we have two indications that we sell the drug for, KMT2A-r acute leukemia, that includes AML, ALL, pediatrics and adults, as well as NPM1 mutated AML, also adults and pediatrics. Promote that with our own field force and annualizing well over $200 million, just six full quarters into our launch. Second drug is axatilimab, known commercially as Niktimvo. We co-promote that with our partners at Incyte.
They report net revenue, we report collaboration revenue. That drug is indicated for third-line plus chronic cGVHD. Also annualizing well over $200 million, actually closer to $240 million. Both these drugs, which I'm sure we'll get into, both these drugs have extensive life cycle management programs in place, with actually a couple near-term readouts coming out here in the fourth quarter for axatilimab, two phase III trials, which are really important to us. Beyond that, we have a pipeline of two preclinical assets that we rolled out at an R&D day earlier this summer, which I'm sure we'll talk about as well, SNDX-4321, an allosteric EGFR for non-small cell lung cancer, as well as SNDX-62122, which we are developing for MF. Exciting times at Syndax, for sure.
Great. So digging a little deeper into the launch of revumenib. Now that it's been used commercially across both KMT2A-rearranged and NPM1 mutated diseases, what have you learned about the real world AML treatment journey that you didn't fully appreciate initially when it launched?
You want to comment on the treatment journey?
Yeah. Firstly, thank you for having us. It's a pleasure to be here and appreciate the opportunity to talk about our programs at Syndax. It's an exciting time in the treatment of AML. This has always been a difficult area of drug development. We're making real progress now, and I would say really transforming the paradigm and the treatment of AML. And we're proud to be leading the field of menin inhibition, driving the scientific leadership and to be the first menin inhibitor approved. And as we're seeing that evolution in the treatment of AML, it's exciting to see treatment practice evolving alongside it. Obviously, our approval is in relapsed/refractory AML covering NPM1, KMT2A. Also very proud of our indication that includes pediatrics, also ALL.
What we're learning now in clinical practice, and we've been the first to publish a series of real-world evidence, is actually sort of augmenting what we actually see in the label, just as a function of clinical practice and what clinicians are seeing. The first observation is that increasingly, patients get treated earlier in their treatment journey. I think that's important because once they've progressed on their first-line therapy, you really want to come with the next best available therapy to them, and people see that as Revuforj. That's number one. Number two is increasingly we see patients getting treated in combination. Again, our current indication doesn't cover that, but we have published compelling data now in combination with readily available standards of care, which significantly improves the response rates for these patients.
In the real-world series that we have presented from Moffitt and other leading cancer centers across the U.S., we do see up to 80% of patients potentially being treated in combination. One of the impacts of that is we see increasing numbers of patients actually going on to get stem cell transplant. That's really important for patients because that gives them the best possible chance of a long-term remission and a favorable outcome. Potentially even some patients, maybe we're even talking about cure, and that would be very exciting. The last piece in the treatment journey that is very important for patients and a big driver for uptake of Revuforj is the use of Revuforj after patients have had a transplant.
We're seeing now nearly 50% of patients going on to get a transplant, which is very different from what we experienced in our original pivotal study AUGMENT-101. Increasingly, we're seeing patients going back onto therapy after they've had a transplant. Up to 70% of patients are offered and will then receive Revuforj as a post-transplant maintenance, which gives them, we believe, the best possible chance of a durable remission. I think those are the big drivers of clinical practice and clinical uptake.
Great. Very helpful. Maybe just to reexamine and double-click on this point. As you've stated just now, new patient starts and treatment duration is the two fundamental growth drivers of Revuforj. As the launch matures, talk a little bit more about your expectations for those dynamics. Which becomes the bigger growth driver, particularly as the pool of patients, as you said, receiving longer-term therapy after transplant continues to build.
Yeah.
from where we are now?
It's a good question. I think clearly,
t he biggest driver of revenue longer term is going to be that stacking effect you see from patients coming back on revumenib. Let's just take KMT2A-rearranged acute leukemia, for an example. The incident population is about 2,000 patients per year in the U.S. So new patient starts are always going to be important to add to the top of the funnel. But over time, as Nick mentioned, we're getting about 50% of those patients to transplant, and we're seeing already 50% of those patients who go to transplant coming back on Revuforj maintenance therapy, and they could be back on for six months. They could be back on for two years.
That recurring revenue piece from that stacking effect, it's already making up the majority of the revenue in any given period, whether it's a week, a month, or a quarter today, and it's only going to continue to build.
Great. And maybe going a little deeper into the KMT2A population. Roughly half of those patients, as you said, who undergo transplant have resumed Revuforj. What is your fundamental expectations on what has to change in clinical practice to close the gap, and how quickly can you think that behavior can evolve there, and how that extends-
Well, our commitment is to generate data to support physicians and patients in making an informed choice for their treatment to give them the best benefit risk. That's our significant commitment. As the leaders in the menin inhibition field, we have significant efforts with our data generation and clinical trial programs to help inform that decision. Now, currently, we do see uptake of the drug. Clearly not something we promote on. We're happy to educate physicians on the data we have, but we really feel it's beholden on us to generate data that better informs the benefit risk profile, who's going to benefit, how they should be optimally managed, and for how long. So we have a big commitment with our real-world evidence to collect data from patients that have been treated in the maintenance setting that will help inform patients make an informed decision.
We also, and I'm very proud of this, we have the first prospectively randomized study actually addressing this question directly. It's called the MAINTAIN Study. This is a collaboration we have with leading cancer centers, primarily the Dana-Farber Cancer Institute in Boston, working with Corey Cutler and co-collaborators. This is a study for patients that actually have a transplant and then randomizes patients to receive revumenib or placebo. It will really help inform how revumenib can help eradicate minimal residual disease. It will help inform time to event endpoints like event-free survival. It will support the optimization of dosing, because patients, after they've had a stem cell transplant and after they've been given a period of time for engraftment, they're still quite prone to certain side effects like low platelets.
The marrow is still quite sensitive, and we want to be able to optimize those patients through that potential period of thrombocytopenia, and revumenib is very well-positioned to do that because it does allow for some flexibility in dosing. We will be presenting some data later this year from Dr. Brian Ball, who's a leading hematologist, and transplants are based out of City of Hope, which is the biggest transplant center across the U.S. And those are going to be very important to help inform and make sure that physicians and patients are making the best decision for their care.
Great. Very helpful. So maybe turning to more of the frontline opportunity. With both EVOLVE-2 and the REVEAL studies designed to support accelerated and full approvals, the ultimate question becomes: what would a truly practice-changing frontline data set look for revumenib? If you can comment on, is the signal higher CRc, deeper MRD clearance, or any of those metrics there?
Well, I think all of the above, and our program is committed to that, and we've already generated, I would say, quite compelling data from both an efficacy and a tolerability perspective in combination with venetoclax. Then an oral HMA IN QOVI, which was the SAVE study, and those data look very encouraging for that combination. We seem to have particularly effective combinations with venetoclax combinations, and we're excited about that pivotal phase III, which is called EVOLVE-2, and then also with intensive chemotherapy for patients that are fit enough to receive intensive chemotherapy with an NPM1 mutated AML. I think all of the endpoints you've raised will be important. Both of those pivotal phase III studies have surrogate endpoints that we believe could support accelerated approval.
In the incidence of EVOLVE-2, the surrogate endpoint is complete response rate, which has been used before to support accelerated approvals. In the fit patients who get intensive chemotherapy, we're looking at CR but complemented by MRD negativity, and actually assessed in the bone marrow. The reason we selected the bone marrow is it's probably the most sensitive place to confirm that you have truly got minimal residual disease. We think the baseline for that is just under half of the patients, and we want to be able to see if we can improve that by the addition of revumenib intensive chemotherapy. We believe if we're able to demonstrate a big enough difference between the active and the control arm, that could also serve as an accelerated approval endpoint. So very exciting frontline program. The focus of the teams at the moment is executing those studies.
We have great momentum behind them. They're going very well. We look forward to those studies maturing and reading out and hopefully changing the standard of care in frontline newly diagnosed AML. Very exciting time, actually.
Great. In the interest of time, I want a few questions on Niktimvo. Obviously, the successful collaboration with Incyte and graft versus host, but there's a hidden catalyst here in IPF. Maybe walk us through expectations there for the MAXPIRe study.
Yeah. This is one of the most exciting things in our program and a lot of interest in idiopathic pulmonary fibrosis, and I think that's based on the compelling biology and science that supports CSF1R in diseases that are characterized by inflammation and fibrosis, and IPF is clearly one of those. Interestingly, axatilimab was originally conceived as a drug that would be very effective in idiopathic pulmonary fibrosis, and then because of the biology, it was taken into GVHD, but IPF has always been on our minds. It is characterized by a disease that is underpinned by monocyte-derived macrophages. They come in two varieties, one of which is more associated with driving inflammation, and the other that characterizes the fibrosis. In our AGAVE study in GVHD, it's a multisystems disease, and one of the characteristics of it is that you get a syndrome called bronchiolitis obliterans syndrome or BOS.
We saw a 50% response rate in those lung manifestations of GVHD. We presented at our R&D day with Toby Maher, who is one of the leading pulmonary fibrologists in this field, believes that the pathology underpinning the lung symptoms of GVHD and idiopathic pulmonary fibrosis are very similar. They just affect slightly different compartments of the lung. We have this MAXPIRe study. It's reading out next quarter, Q4. We're really close to it now, and it's a very robustly designed phase II. You look at two things when you look at the probability of success of a phase II. One is the biology and the science underpins it, and we feel very confident about that. The second is, well, is the study well-designed?
We have taken all of the learnings of phase IIs within IPF that didn't go well or didn't translate into phase III, and we've put a kind of belt and braces around it. We're very rigorous in the definition of the primary endpoint, which is forced vital capacity. It's a well-powered study. It's been executed very well. We have very low rates of discontinuations. We'll wait and see how it reads out, but we're feeling good about that, and it could be very important for patients and for Syndax because if it's positive, this would be a very quick catalyst for us to transition into phase III and execute a phase III in IPF, which remains an area of extraordinary high unmet need. These patients are highly symptomatic. They have rapidly progressive disease, and unfortunately, even their survival is often impacted.
The mortality associated with IPF is still quite severe. To bring a new class of agent targeting what we believe is foundational in IPF is very exciting for us.
Great. Maybe a granular question on MAXPIRe, digging into a little bit of the weeds. MAXPIRe allows for patients on nintedanib, pirfenidone, or no background anti-fibrotic therapy. Although the trial is not powered to compare those strata, when the data does read out, what is the magnitude and consistency of FVC benefit that would give you confidence that axatilimab is generally an additive agent to existing therapy?
Well, great question, and we love the weeds, so thank you for that because these are important considerations. You are absolutely right. We allowed for background on anti-fibrotics. We actually stratified by those three strata, so no anti-fibrotic, pirfenidone on nintedanib. We actually think, I mean, just going back to the biology, we actually think axatilimab is particularly well-suited for combinations with the currently approved anti-fibrotics. Most of the currently approved agents are targeting through different mechanisms, but they are primarily targeting fibroblasts. We believe these monocyte-derived macrophages are sort of upstream of that and really the foundational pathology, so quite complementary. Your question specifically, when you look at this phase II, again, when we look at the validity or the integrity, I should say, of the outcome, we will want to look at consistency across these groups.
Traditionally, you would expect the biggest magnitude of benefit to be in those patients that are not receiving an anti-fibrotic. I think we would look to see, are you seeing considerable benefits over and above currently available anti-fibrotics and in our phase III, potentially even more newly approved anti-fibrotics just because of the complementary mechanisms of action. We will look across all of those subgroups. What I would say is that our phase II is very representative of a potential phase III population. By far, the majority of patients are on a background anti-fibrotic. It is a relatively small proportion who are on no anti-fibrotic. Nonetheless, we will look across this three groups for consistency of outcome. It is a great question.
Great. In the interest of time, I want to give some light to some of the earlier and newer studies that you have unveiled during your recent R&D day. Starting with SNDX-4321, I guess give us just a quick primer on the key points of differentiation between CNS penetration, atypical mutations, and where this fits in the EGFR paradigm.
Yeah, extremely exciting, and we've been working on this for a while, but only publicly talked about it six weeks ago at our R&D Day. We were very happy to talk about it, and this comes out of a collaboration, again, with the Dana-Farber Cancer Institute. I personally have been collaborating with some of the leads there for over 20 years, and they have been really shining a light on this particular subset of EGFR mutated lung cancer, and they have been developing this allosteric inhibitor. The reason allosteric inhibitors are exciting is because they've never really been tested in the clinic in EGFR mutated lung cancer. Just to provide some context, all of the current EGFR inhibitors directed towards the ATP binding site, the catalytic binding site, and then chasing some of the resistance mutations that developed there, originally the T790M, which was where osimertinib came in.
Now there's a C797S, and many so-called fourth-generation ATP binding site TKIs are being developed. Now, 4321 is completely different. It breaks the model. There is an allosteric binding pocket on the receptor that this drug uniquely and very potently attacks, and that offers the opportunity to double drug the receptor. Because it's in a separate binding pocket, you could combine it with osimertinib and really provide very profound blockade. And the preclinical and cell line models that we have looked at suggest that it is extremely potent in patients that are refractory to osimertinib who have the C797S resistance mutation. And we know that this allosteric binding pocket is present in all L858R and other atypical mutations. You don't see it in exon 19 mutations, so we know that, and there's a structural reason as to why that's the case. So we're excited.
It's progressing very well through its IND-informing studies. We're going to have that asset in the clinic next year. We will know very quickly whether we're able to replicate the preclinical findings. We will anticipate seeing tumor shrinkage. If it's active, we'll very quickly get to therapeutic level doses, and we'll be particularly interested to look at whether patients with brain metastases respond, because we know from our animal experiments that we get very high CNS penetrance. And that's really important for patients because one of the most common patterns of relapse is CNS.
Great. Moving to SNDX-62122. You're using revumenib as clinical proof of principle experiment in myelofibrosis before advancing to a more potent optimized molecule. Can you talk a little bit about your efforts there?
Yeah, very briefly, and it is an exciting time to be at Syndax because we could have four really potentially differentiated and two approved agents in the clinic in 2027, and that's very exciting for the company and for our R&D organization. This is another extremely exciting opportunity based on compelling science that came out of John Crispino's lab, who we work with very closely, that highlighted the opportunity for menin inhibition to have a pivotal role in the normal process of megakaryopoiesis and megakaryocyte precursor cells. We know that that's one of the driving pathologies that underpins myeloproliferative neoplasms like myelofibrosis. So we have this next generation menin inhibitor, 62122, that is optimized for a number of characteristics that we want to take into myelofibrosis.
While we are progressing that through its IND, we will do a proof of principle with revumenib in MF, and we're working with John Mascarenhas and the MPN Research Consortium to generate proof of principle data. We'll learn a lot about menin inhibition in MF that will catalyze our next generation menin inhibitor through that collaboration. We're excited to have that. That study should be starting this year, and it will be very informative and potentially really bring a new therapeutic option, either a monotherapy or perhaps more importantly, as a combination with Jakafi.
Because again, the mechanisms targeting megakaryocyte precursors and the JAK-STAT signaling pathway could work very well in combination. It remains an area of high unmet need. So we're extremely excited about that asset, and we're extremely excited about the progress we have made with our pipeline and with axatilimab and Revuforj in the clinic helping patients now.
Great. And maybe in the last 30 seconds, can we just summarize for the investors, where should their focus be in the next 6- 12 months for Syndax?
Sure. I think we talked about some of the really near-term catalysts. We have two phase II readouts coming up in the fourth quarter. The first is the phase II IPF readout in the trial called MAXPIRe. Also have a phase II readout of axatilimab in combination with ruxolitinib in the frontline cGVHD setting. Continue to look forward to sales growth for both products, and a really fun time to be at Syndax.
Great. So on behalf of myself and the whole H.C. Wainwright family, it was a pleasure hosting you guys. Congrats on the progress, and we look forward to future updates.
Thank you very much.