Syndax Pharmaceuticals, Inc. (SNDX) Earnings Call Transcript
May 18, 2022
Earnings Call Speaker Segments
Okay. Great. Welcome, everyone, to the Targeted Oncology panel. My name is Yigal Nochomovitz. I'm one of the biotech analysts here at Citi. It's my pleasure to have with me 4 CEOs from important Targeted Oncology companies. From Ideaya, Yujiro Hata, who's the Co-Founder and CEO; from Oric, Jacob Chacko, President and CEO; and from Rain, Avanish Vellanki CEO; and finally, from Syndax, Michael Metzger, also CEO. So gentlemen, welcome all of you. Thank you very much for taking a bit of time out of your super busy schedules to chat. So I think to start out to level set, if you wouldn't mind just for each of you running through very, very quickly 1, 2 minutes, just a very brief introduction to the company, the key pipeline levers. And then as well, please just mention the catalysts that are coming up for your pipeline in the next 6 to 18 months. That would be great. Maybe if you could just go down the list starting with Yujiro.
Sure. First, thank you, Yigal, for the invitation, and thank you for -- to Citi for the opportunity to participate this year. So IDEAYA Biosciences was founded just over 6 years ago. Our core focus is to build the leading synthetic fatality focused precision medicine oncology. We did have a recent earnings update. We do have approximately $350 million of cash on the balance sheet. We believe that's sufficient to take us in 2025. And that does not include potential milestone payments, we believe, could be potentially near term with GSK. In terms of our clinical pipeline, we have 2 programs in the clinic. First is dorobosiritib. This is a Phase I/II protein kinase C inhibitor. We've been doing 2 combination studies with Pfizer. The focus there is on crizotinib. The second clinical program, IDEAYA 397 is in Phase I dose escalation. We are now preparing for the expansion phase as well as combinations and here the patient selection biomarkers, MTAP deletion. And then behind that, we have 2 fairly late-stage preclinical programs. First is PARG, there we're targeting IND in the fourth quarter. And then the second program, [indiscernible], with our partner, GSK, we're on track for a candidate selection this quarter. Behind that, Yigal, as you know, we have a very broad platform as well as pipeline behind that. And that's really the summary of the company.
Awesome. Thanks, Jacob?
Yigal. Thank you for having us in here. It's exciting to talk today to the group. So ORIC Pharmaceuticals stands for -- ORIC stands for overcoming resistance in cancer. And that in a nutshell is the mission of the company. We essentially are focused on 2 areas within cancer resistance that -- one would be precision oncology, the other is hormone-dependent cancers. In either case, we're essentially searching for key tumor dependencies that we can then drug, either as a single agent or in combination. One of the unique things about the way we put together the pipeline is that we have a pretty big internal discovery group with all preclinical functions represented inside the company. But we've paired that up with opportunistic and selective business development along the way. So as you look at the pipeline, it's a mix of drugs that were developed -- discovered totally in-house and also a few that were in-licensed externally. And they all adhere to the themes that I mentioned to you upfront. We like to think of the pipeline as a mixture of first-in-class targets where there's novel biology that we're exploring. Obviously, quite a bit of risk that is entailed with unvalidated targets but more white space for us to explore versus competitors there. And then we've matched that up with a few that are best-in-class opportunities where we think it's a validated target where the biology is easier to understand, but the chemistry is where we think we've got a differentiated approach to a best-in-class opportunity. So as you look at the pipeline today, we have 3 clinical stage programs. One is a CD73 inhibitor. It's a small molecule, orally available. CD73 inhibitor, that's in itself is quite rare to be able to have a small molecule orally available, CD73 inhibitor. But beyond that, we're exploring that as a single agent in multiple myeloma, which also, again, is a differentiated clinical development path we competitors in the CD73 and the medicine space. Our next program is an EGFR exon 20 inhibitor. This is, in particular -- one of the important characteristics is that it is brain penetrant and that is a key differentiating insight into the way that, that molecule was developed, and we believe will carve out some white space for us in what is otherwise a crowded field that is mostly occupied by non-brain-penetrant inhibitors. And then the final program is an allosteric inhibitor of EED. Many folks know the EZH2 target. There's actually another subunit of the PRC2 complex called EED, which is sort of the approach of the second-generation inhibitors. That's one that we are -- we in-licensed from Mirati and are developing in prostate cancer initially. So each of those 3 programs hit the clinic in the first half of this year, we expect initial data sets publicly available data sets for those to be available in the first half of 2023. Again, those are all single-agent approaches. And then beyond that, we have several other programs that are in lead optimization or earlier stages. One that we most recently revealed is in lead optimization for an inhibitor of PLK4, which is a synthetic lethality approach to -- essentially that's relevant to both breast cancer and neuroblastoma. The cash position, we went public in April of 2020, and then we're fortunate to top up the balance sheet a couple of times after that. And so after the most recent quarter ended with approximately $260 million of cash that provides us runway into the second half of 2024 comfortably. And so we feel like we're well capitalized to be able to flip over the data cards on multiple of these programs before that. Thanks for having us.
Okay. You're welcome. Awesome. Next up, Avanish, you want to tell us about RAIN?
Absolutely. Again, Yigal, thanks for having me. I'm noticing a familiar group here, so I think we should all kind of get together after these events. It's a pleasure to be here. RAIN is a small molecule world precision oncology company. And we're about 5 years old, incorporated back in 2017 and IPO-ed in April 2021. The primary value driver for the organization is our lead program, milademetan, in Phase III trials enrolling around the world in a pivotal liposarcoma study. We have over 70 sites in U.S., Europe and Asia enrolling, and we expect to have that pivotal data in the first half of 2023. So I think the most important thing that I'll focus in on is the opportunity for near-term commercial program and is a potentially revenue-generating asset. The critical inflection points coming up about 6 to 9 months, 6 to 12 months away from the Phase III trial, and we think milademetan rather differentiated from the historical class of MDM2 inhibitors given its tolerability profile. MDM2 inhibition is not new. There have been various programs prior to milademetan and certainly big pharma has invested a heavy degree of capital into this mechanism. However, the problem has historically been a specific set of on-target toxicities with MDM2 inhibition that has prevented patients from staying on therapy. So the Grade 3/4 cytopenias has been the big problem to solve for. And the milademetan program, which we licensed from Daiichi Sankyo demonstrated from a very large Phase I data set, a level of tolerability that we think is best in class. And ultimately, we think could be applicable to a wide variety of tumor types, whereas liposarcoma could be the first indication that enables this program to get to market. So we're very excited about that. We're very excited about the probability of success for this program in the Phase III trial, giving that the comparator arm and the standard of care is unfortunately equivalent to placebo. So very low [ hurdle ] success in the Phase III trial, we believe. In terms of our cash position, we have $123 million or so on the books as of the last quarter, which we said is sufficient through the first half of 2024, and certainly sufficient to finance the entirety of the Phase III program and potentially through a submission to the FDA.
Great. And last, but certainly not least, Michael Metzger, who recently took the CEO job at Syndax.
Thanks, Yigal. Great to be part of this group and great to be invited. Thank you. So Syndax is a development stage pharmaceutical company focused in the area of oncology. We utilize a license and development business model. So we do BD transactions to acquire what we think are promising technology at the earlier stages of the development, and then we use our expertise in translational medicine and clinical development to optimally develop the pipeline. We are currently developing 2 first-in-class, best-in-class targeted agents within the heme space. They're both -- both agents are in pivotal trials with data and potential regulatory filings in 2023, followed by approvals potentially in 2024. Both are addressing what, we would say, are multibillion-dollar market opportunities. The first drug is -- what we refer to as Revumenib, is also known as SNDX-5613, the small molecule inhibitor of the menin-MLL1 interaction that targets specific patients who have MLR acute leukemia or NPM1 acute leukemias. These 2 distinct lesions account for roughly 40% of AML patients, and this would be the first drug to specifically target these mutations. The second agent in the pipeline is axatilimab. It's an antibody targeting the CSF-1R receptor. We're currently developing a chronic graft versus host disease. And we'll be starting a trial in idiopathic pulmonary fibrosis at the end of the year. We recently entered a collaboration with Incyte to co-develop and co-commercialize axatilimab on a global basis. And the partnership is pretty significant in that it brings resources and complementary expertise of who we think is the best partner in insight to help us fully exploit the potential of the franchise. And so we're excited to work with them as our new partner. We're capitalized with roughly $400 million in the balance sheet, gives us cash into the second half late into 2024, and importantly, funds us through all of our key clinical and regulatory milestones that enables us to build out our commercial organization as we prepare to launch both of these products and do what we say is selective business development transactions to feed the early pipeline. So in summary, I think it's a really exciting time at Syndax. We're building the organization and preparing to get 2 drugs approved in the next few years, and launched. Thank you.
Okay. Great. Well, we'll come back to more pipeline and company specifics a little bit later in the conversation. But I wanted to get the dialogue and discussion going. It's sort of a high-level question that I think will generate a lot of good discussions. So the question is what makes a big target worth exploring? How do you make the call to take that target into Phase I? And then obviously, on the flip side, how do you make the call to abandon a particular target despite potentially early promising preclinical data? So whoever wants to jump in and go for it? I think we should have a lot to say there.
Jacob, why don't you lead us out here?
Sure. I'm happy to lead off. I'm not sure it's a -- so I hope it's not a particularly controversial question for the group to answer. From our perspective, Yujiro, we are looking, ultimately, as I mentioned, for key tumor dependencies. And so in the preclinical work that we do, whether this is an internally discovered target or one that we're looking to in-license, we do a lot of preclinical work to first and foremost validate whether in preclinical models, we believe that there's a key tumor dependency where there's an addiction of sorts of the tumor to a particular pathway where we can come up with a selective and potent inhibitor to shut down that pathway. That's kind of the first thing that we look for. The other thing that we're looking for ideally preclinically is also a hypothesis as to how we're going to be able to select patients. Now we don't generally want to select patients in the Phase I dose escalation. We actually think that part of the validation of the target and our selection approach entails enrolling a broad array of patients that we can figure out whether the selection hypothesis is working or not. And then I think the third thing is that we're looking for preclinically, a target that we can actually measure whether we're able to downregulate or inhibit that clinically. Because that's another piece in terms of picking dose and trying to figure out whether we're getting target engagement and testing the hypothesis correctly in the clinic. So those are all the things that we're looking for preclinically. I think all bets are off kind of once you get in the clinic because in some cases, the preclinical models don't translate into the clinic. And in some cases, it's harder to measure the things that I just mentioned once you get in the clinic. But that's generally the things that we're looking for. I think from a macro perspective, there's always a debate on what makes a good target of first-in-class versus best-in-class. And that's kind of what I mentioned upfront that I think what we're probably all searching for is areas where we have white space to compete versus other competitors. But I think that almost inherently means you're going after an area of unvalidated biology, unvalidated targets. So there is some risk inherent in that. But on the flip side, if you're going to focus on validated targets only, you're going to find yourself competing with a dozen other companies going after the same thing. So -- that's a bit of a balance. I'm sure every company has a different approach on that. In our case, we've decided to go after both, both first-in-class targets as well as best-in-class targets.
Okay. Yujiro, do you want to expand on that?
Yes. I mean I think that was a very comprehensive answer. So maybe just a few things additional I would add. I think for us, the 2 core pillars are how much confidence do we have in the biomarker. And I think that's a fairly large body of data we need to generate preclinically. But I would say that's very key for us. Second is also just around combinations. Have we identified what we think are compelling combinations that will give us opportunity for success in the clinic. I think several additional -- as Jacob mentioned, I do think, especially in the targeted oncology space, having a robust pharmacodynamic marker is critical because -- especially in dose escalation to know that you're hitting the target appropriately prior to -- let's say, before you start seeing an efficacy signal. We think that's quite important. So -- and then I think lastly, as we've seen and different -- especially if you're in the novel target biology space is when you hit these targets, does the tumor care? And are you seeing stasis or are you seeing regression not all targets from that perspective are created equal. So I think those are several of the key parameters for IDEAYA.
Okay. Avanish or Mike, do you want to add anything?
Yes -- go ahead, Avanish.
No, sorry, I'm not sure I can add a lot incremental to what was already said. I think one of the issues that we're certainly trying to grapple with is understanding the degree of our dependency and certainly we, in our own context, looking at amplification of a certain gene. What level of amplification matters, right? So amplification is unlike a mutation which in comparison to either having it or not having it. What level of amplification actually matters for a tumor and picking that cut point that's actually going to be most relevant. One of the things I think Jacob and I talked about last time in this call was the approach to the Phase I clinical trial strategy of either enrolling everyone broad patient set versus kind of slicing and dicing from the get-go. We've kind of approached it the opposite way and we've actually kind of select in Phase I with a very stringent degree of patient selection and then dialing it down from there. So if we see activity where we'd expect to see activity, great. And then we can broaden from there. If we don't see activity where we expect to see activity, then it's probably not going to work in multiple other opportunities. So we've kind of approaching it a little bit more of a stringent way of selecting patients at Phase I.
Yes. And I would just add, in our particular case, we're looking to identify targets, so there's a clear connection between the target and the tumor biology. I think others have said something similar. With our menin program, you see that with MLLR, where the fusion is clearly the driver of the disease and removing its ability to initiate tumor genesis. This leads to a complete response in patients. So even the most heavily pretreated late-line settings, you're seeing really good responses from these patients. And so I think when you see this type of activity with monotherapy early in development, it's pretty reassuring that the target is a good one and that it's the key driver of the disease. So essentially, the advantage of targeted therapy, right, you generally know really early whether you have something or not.
Got it. And I think all of you have already touched on some of these themes in my next question. But in terms of sort of thinking about what's most challenging in developing a targeted oncology therapeutic, my list is the following: Patient selection, target coverage, whether you can find a good biomarker, med chem challenges, and then having enough single-agent activity without having to rely on combos. So -- is it all of the above? Or are there certain aspects of that? Or are there other things on that, that you'd like to add to that list that make it challenging to develop targeted oncology therapeutic.
Yes. Maybe, Yigal, I'd add -- just maybe one additional there is, I think you asked a question earlier about bridging preclinical data and then when you go in the clinic, how do you sort of think about that? So I think additional item I would add there is probably just the importance of translational research. I think oftentimes, you can find disconnects as we have seen from preclinical to clinical. And I do think the translational research one does could be that critical gap. So as an example, are there certain just compensatory mechanisms that identify once you go into patients that you may see different variability from histology to histology as you enter into the clinic. So I do think that's another critical piece, so you can understand why some of the differences may be occurring. And then that just enables you, right, how to make the corrections in the clinic, whether that's certain combination strategies, perhaps how you're thinking about the biomarker or areas like resistant mechanisms that perhaps didn't surface preclinically.
Okay. That makes sense. I guess shifting topics a little bit in terms of FDA and regulatory. I'm just wondering if you guys agree that the FDA has been moving away a little bit from surrogate endpoints to support accelerated approval and shifting emphasis a bit towards survival-based outcomes? I'm not sure if you agree with that, but I'm curious of your thoughts. And then how would that impact your drug development strategy? As obviously for targeted oncology products, they have traditionally benefited from the accelerated approval path typically via ORR.
I don't have chime in here and say I think, yes, we certainly are seeing some. It's hard to see if the comments from the FDA are consistent with the underlying mission statement of ensuring a greater degree of support for overall survival endpoints. I'll tell you we're concerned by that because I think overall survival endpoint is now in an era where there's so many more drugs in clinical trials that are going to influence the OS endpoint for a patient population, which may not be equally split amongst all patients in study could influence the outcome in an unequal manner. So for example, with so many unique combinations that are now being tried, and many of those combinations not being really accessible from all patients equally, it's quite conceivable that subsequent therapies dramatically affect the overall survival endpoint for a given agent. So I'm a little less confident that overall survival is kind of giving the data that the FDA wants to see. So I guess it's not really a question you're asking, Yigal, in terms of what the FDA is looking for. But I guess I'm very concerned if that was true, if it's actually predicting, it's the right predictor of success for a molecule.
Interesting. Anyone else want to chime in on that topic?
Yes. Maybe I'll take a stab at it as it's related to our particular situation. So I think we're pretty fortunate that in AML, the FDA has published got real good guidance on developing drugs and biologic products. And so there's a -- and there's also a regulatory precedent for our approach, getting our drugs approved. And the team -- our team has worked really closely with the FDA, agreement on our registration program, 3 -- consisting of 3 separate arms and the endpoint of CR/CRh and the primary endpoint, it's all acceptable. And importantly, it's acceptable as a full approval program. So it's not accelerated approval, which is sort of, I think, part of your question here. And so secondary endpoints will include the durability of response and safety of the normal secondary endpoints. And so although I think there have been some suggestions about new approaches to accelerated approval at the FDA. That evolving landscape doesn't really apply to what we're doing in AML. But I do imagine it has -- it could have a profound effect on how others are thinking about survival-based outcomes and how it affects the trials that you're running.
Makes sense. Yes.
And maybe, Yigal, I'll sort of add a few points to that. I mean obviously, it's -- I think it's maybe a kind of a target-by-target basis. I know there was a recent just guidance around the PI3K space, where, as you know, the surrogate endpoint didn't necessarily connect with the survival, and I think there was a broader risk benefit question there as it relates to that. But at least our sense was that, that was more specific to that specific target. So the question is, does that apply more broadly? I mean, I do think -- for accelerated approval, I do think surrogate endpoints are still acceptable, whether that's ORR or medium PFS. Obviously, OS is still the gold standard. But I think they're -- if you're doing it under accelerated approval, I think perhaps the more critical piece there is more perhaps a greater desire to see certain randomization designs. But again, there, I do think that's more indication-specific depending on what the unmet medical need and what is there available in terms of randomization. So again, I think there, that would be more likely case by case. There's obviously been some more recent initiatives from the FDA that I think is also influencing some of these pieces, including, as you know, project front runner, something that we're thinking about quite hard in terms of the FDA, trying to encourage sponsors to do more frontline studies. And I know would not note they specifically called out randomization. But again, that assumes that there is a standard of care in frontline, which may not always be the case. And then lastly, I think probably impacts all of us, which is around project optimist, right? And so depending on what you've done in the early trials, if you've not really dose optimized or looked at multiple doses then I think there could be a question for the randomization design, might you get asked to do more than 1 dose. You've been under an accelerated approval design. So I think that will be important to just continue to follow and how that unfolds.
Yes. Yigal, I'll just add a thought or 2. I think Yujiro covered it nicely, that I think our internal view is that it very much relies on the target in terms of the FDA's approach. We certainly do feel in the conversations with FDA that there's more of an emphasis on holding sponsors' feet to the fire in terms of the confirmatory trials and eventually doing those confirmatory trials that's something that's always been on our radar. I think the bigger thing for us or the bigger consideration is what Yujiro highlighted at the end, which is project optimist. And how are you proving that you optimize dose? How big is a big enough data set to show that you've optimized dose because one of the things, especially for us all as small companies, is the ability to move quickly. As Michael highlighted with these targeted therapies, you can see signal quite early. But I think the real question will be exactly how much data does the FDA want to see improving that you've optimized dose in your initial Phase I dose escalation before you've moved into potentially registrational Phase II studies. To the extent that somewhat -- there's a clear sign that you've got the efficacy safety trade-off nailed with 1 dose over another, I think it's maybe an easier question to answer. But one thing that's on our mind and I'm sure others minds is that you may or may not see a very clear trade-off on efficacy versus tox at 2 different dose levels. And if you don't see that trade off then how much proof is going to be necessary to convince FDA.
Makes a lot of sense. One more macro question, and then we can move into our company-specific lightning round, so to speak. So just on companion diagnostics, I'm just curious for all of you, when does this become a helpful or important approach? When perhaps is it not necessary? And if necessary, how early in the development path do you need to start working on the companion diagnostic to make sure you're ready for launch?
I'll jump in. So as to say, how early the one -- should one ought start working on it. I'll give you our example, which is our Phase II basket study in MDM2-amplified patients to milademetan. We have not started work on a companion diagnostic yet, and we won't until we start seeing a signal. If we see a signal that we think is close to where the FDA cut point is going to be with the threshold for success, then we will certainly start working on it at that point. So I think this is scrutinizing cash spend and spending only when you think there's going to be success. If we say we work on a companion diagnostic, I think it's because we like what we're seeing. We've also identified a central diagnostic partner in Tempus for our strategy that would be effectively a built-in diagnostic partner if we see if we're going down a favorable realm. So -- but I don't think you would -- I don't see a situation where companies start developing the [ pain ] diagnostic ahead of seen activity.
Okay. That makes -- that makes a lot of sense.
And I think -- Yigal, I think there's, I think, several elements to that question. I think one is purely from a regulatory perspective, and then there's obviously more just commercial aspects as well as others. But for example, MTAP is a good example. We can capture patients through NGS. We can capture patients through a CLIA certified IHC assay. We believe, moving forward, ctDNA is also going to be a potential option through liquid biopsy. So I think as just noted by Avanish, I think initially, you want to see a signal. I think there is likely a point at which as you should start moving towards mid-late-stage development from a regulatory perspective to have a companion diagnostic just to ensure that the actually diagnostic platform is not generating variability or data, right? So when you look at the PARP inhibitors, as we know, the different companies and molecules did pick specific platforms, right? So one picked Foundation, the other picked Marriott. And we know that, that actually did make somewhat of an impact. So I think I would think from a regulatory perspective, there could be advantages just so you know that you've removed that variability, that your core data set that's being reviewed is off of a specific selection platform. As we know, the diagnostics space has advanced quite a bit. So it's somewhat become, I think, fairly ubiquitous. So I think post approval, is not going to need to be likely selected through that one specific diagnostic platform. They'll get enrolled, it would be my guess. So -- but I think that's also a pretty fast evolving situation. But I do think still that at some point, picking a companion diagnostic in a platform from a regulatory perspective would likely have value.
Makes sense. Okay. Well, let's move on to some more company-specific questions. And I apologize in advance for sort of going one by one here and leaving the other 3 on the sidelines, but we'll try to get to everybody and hopefully get 1 or 2 questions in for each of you on the pipeline. So Yujiro, maybe just starting with you. You already mentioned the Elite asset, IDE397, the MAT2A inhibitor for MTAP dilutions. Obviously, this is synthetic lethal with MTAP deletion. And so is the other target, PRMT5. And there's a lot of data on the PRMT5 inhibitor. So I'm curious if you could spend a few minutes just comparing and contrasting targeting PRMT5 versus MAT2A given the both synthetic people with MTAP?
Yes. Sure. Yes. I would say in a high level, both PRMT5 and MAT2A, through the various synthetic label screens that have been done, including our own, I would see are the top hits in terms of synthetic lethality with MTAP deletion. They are both in the similar broader pathway of PRMT5. The mechanisms are different, so MAT2A you're deleting -- sorry, you're depleting a key enzyme called SAM. And we know that SAM is involved in the specific -- it's the key substrate for protein methylation of PRMT5. With PRMT5, obviously, you're directly hitting the target but there has been several generations of efforts, sort of generation 1 versus 2, and I'll be brief on this. But generation 1 bounded in the fashion to PRMT5 in that it displays the normal binding of MTAs who cannot benefit from the synthetic lethal. And the second generation efforts are able to bind to PRMT5 in a fashion while MTA is present and elevated. And then it's the view that it's the elevated MTA that's caused by MTAP is what really drives the synthetic lethal. In short, Yigal, our view with these 2 targets is that they're more complementary than competitive that there are 2 different nodes in the pathway. We and others have generated quite a bit of preclinical data about also the potential combination opportunity of these 2 nodes. So I think looking -- moving forward, I think this will be an exciting space to follow and how these 2 targets could potentially interplay for the field of MTAP deletion more broadly. Okay. Got it. And then, Jacob, for you, you mentioned at the top, the CD73, the ORIC-533, as you know, and we've done work on this ourselves, CD73 is a very interesting space. It's getting more and more crowded as the days go by. But you're one of the only, if not the only, company developing a CD73 for myeloma, which, as everyone knows, is a pretty large indication. So very curious to understand a little bit more about the thought process in terms of choosing myeloma. And then as we look forward to the Phase I data in the first half of next year, tell us at least maybe qualitatively what type of monotherapy data you would like to see there to be comfortable taking this forward.
Sure, Yigal. Happy to. So ORIC-533 is one of the only small molecule oral inhibitors of CD73. We've done a lot of profiling preclinically of that molecule and presented that at multiple scientific conferences previously, and all of that has shown superior potency, picomolar potency and much better differentiated than multiple of the other adenosine pathway antagonists, whether that's CD73, CD39 or the A2A receptor antagonist that in addition to the picomolar potency, it also has a slow off rate and essentially in a high adenosine environment as you can see in these tumor microenvironments, it was retaining its potency orders of magnitude better than the other competitor molecules that are out there. So -- we've always felt very, very good about the preclinical differentiation and profile of ORIC-533, but the -- where we really sort of pushed internally was -- in -- as you said, what is otherwise a very crowded field, how do we also differentiate on the clinical development plan. And this is dating back a couple of years, but we were connected in through one of our investors into Ken Anderson, Dr. Anderson at Dana Farber has really led a lot of the groundbreaking work within multiple myeloma. And essentially, this investor was aware that Dr. Anderson and his lab, through their proprietary ex vivo multiple myeloma assays had stumbled upon a mechanistic hypothesis around CD73, potentially having single-agent activity in multiple myeloma. And that they were quite excited about the potential for CD73 development as a single agent and then eventually as a combination in multiple myeloma. So we got connected to Dr. Anderson's lab through those dialogues, ran ORIC CD73 inhibitors in those same -- or I should say his lab ran those in the same proprietary extevo assays and saw compelling single-agent activity. So better than multiple approved classes of agents that we have tested in those assays and on par or better than daratumumab, anti-CD38. And so all of that is what got us excited that while everybody else in that area is doing -- essentially large combination IO studies and those take years and lots and lots of patients and then people argue till they're their blue in the face about which one of them looks better than the other, we figured we would go into somewhat white space there on the clinical development side. And that's what led us to choose myeloma. Now I think as folks who are familiar with myeloma now, there's a tried and true development path in that space, which is we'll start as a single agent in a highly refractory population. These patients be triple-class refractory, in many cases, quad and penta-refractory in terms of total number of therapies. And if we can see even modest single-agent activity with ORIC-53. so to your question, call it, 10% to 15% single-agent activity that would be enough to get us excited to then move quickly into combination studies with the traditional classes. So the imid, the proteasome inhibitors and the anti-CD38. And that's what we'd be looking for. Now to the earlier conversation around accelerated approvals, if we saw something north of what I just mentioned, so the 10% to 15% would get us excited about doing the combinations. But if we're able as a single agent, to see 20-plus percent response rate, call it, 20% to 25% response rates then -- and of course, we'd also pursue a single agent accelerated approval pathway there as well in addition to the combinations that I just mentioned.
Very interesting. We're definitely looking forward to that. Avanish, you have a huge Phase III catalyst coming up in the first half of next year. In fact, you just narrowed the guidance on that, the mantra trial for milademetan in liposarcoma. So I've been telling investors that I have a lot of confidence in this trial working. I'd love to hear from you what gives you the confidence that mantra Phase III is going to be a successful trial?
Yes, absolutely. So I think to put it simply, and unfortunately for patients, the standard of care in the comparator arm in our Phase III trial is abysmally low. And so in terms of median progression-free survival with the standard of care, which is the control arm, it's a ongoing randomized Phase III study, median progression-free survival in 2 months is, as shown by other company trials, equivalent to a placebo show. So it's a very low hurdle to be. We IPO-ed off clinical data, so monotherapy efficacy data with milademetan in a comparable patient population of triple to quadruple that of a standard of care. So it gives us a lot of room margin for error, we believe. The trial is powered for a hazard ratio of 0.5. So when doubling a progression-free survival versus the competitor arm, so that gives us a great degree of comfort and confidence that in terms of the efficacy endpoint, we could achieve the primary endpoint. Further -- and again, what we said repeatedly is liposarcoma is the initial indication is certainly not while we license the program. We licensed a program because of what the tolerability profile of this molecule has shown. MDM2 inhibition is not new, MDM2 inhibition has been tried before. I always equate this to version 2.0 or versus 3.0 of any technology, but now we know what the problem is that we're trying to solve for. In the MDM2 landscape, they are trying to solve for the tolerability issue, and this is the thrombocytopenia, neutropenia, et cetera. And so now knowing that, that's the problem to solve for and to keep patients on therapy, the prior sponsor of this molecule, Daiichi Sankyo, did a fantastic job of optimizing this regimen for a schedule that can be maintained over a long period of time. So ultimately, this efficacy that we've seen, long PFS from their prior Phase I study, is because of its tolerability. It's because unlike any other -- many of the other MDM2 inhibitors, patients didn't need to dose reduce or discontinue therapy. So in terms of our confidence on the program, the tolerability gives us confidence that there's not going to be a significant deviation dose, that we're not going to see a high grade 3 or 4 thrombotic neutrophil issues. We already have single age efficacy data, 7 to 8 months for a comparable patient population as the control arm had in their published pivotal study. So there's -- it's not a big gamble in our view at this point because we're basically off of a full published clinical data. So that's the reason for the confidence.
Makes a lot of sense. Syndax, Michael Metzger, so obviously, you've demonstrated very meaningful monotherapy proof of concept for the menin inhibitor, revumenib in relapsed/refractory AML and ALL with MLL rearrangements and NPM1 mutations. So now you're enrolling in the pivotal cohorts. So you'd be able to file for approval, I believe, as soon as next year. So tell us a little bit more about what you'd like to see from these pivotal cohorts. And to the extent possible, what can you comment on regarding your ongoing regulatory discussions?
Yes. Thanks, Yigal. So I think you probably know agents have been approved for the treatment of relapsed/refractory AML with CR/CRh rates in the range of 20% to 30% and the median duration of 4 to 6 months, which is in the case of gilteritinib. This includes the follow-up for patients that also received the stem cell transplant. So at ASH, we showed data that revumenib had a 24% CR/CRh rate overall and the MDR was not -- so 50% of the patients with a CR/CRh responded for more than 6 months. We have a very high MRD rate among our responders, especially those who have achieved CR/CRh response. And we're seeing patients go on to successful stem cell transplant potentially curative therapy, as you know. And in the Phase II, we'll also allow patients to come back on study drug, and we'll continue to monitor them for benefit on drug. And we anticipate this will serve to enhance the median duration of response among treated patients. We don't think there will be a difference between response rates or the durability of patients who have either of these 2 mutations based on the preclinical data that we've seen and what we've also seen in Phase I. And so in terms of regulatory interactions, we continue to have an excellent collaboration with the agencies and interact with them regularly. We -- I think as we've reported, FDA has agreed to our dose that we're testing in the pivotal trials as well as the design and endpoints of our trial. So the collaboration is continuing to be productive there.
Okay I'm going to try to squeeze in 1 more question for each of you and the round 2 here, so just try to keep your answers tight since we have about 8 or 9 minutes left. So Yujiro, back to you. So for IDE397, you're going to be submitting the option package to GSK very soon. If they opt in, you're going to get $50 million, I believe, as a milestone. So tell us a little bit more about how the development strategy would change for 397 if GSK chooses to opt in?
Yes. So I mean right now, for the monotherapy expansion [indiscernible] proceed independently, our focus will be on lung cancer expansion as well as in gastric esophageal. There are several additional cohorts that we don't explore as well in monotherapy in the scenario that there's a GSK opt-in. For the combination portion, there are 2 combinations we've already gotten clearance from the FDA to initiate, and that will be [ oxinecombo ] as well as pemetrexed. There is a third combination we've not disclosed yet. And I would say there are several business discussions ongoing there. So we're also committed to do that independently and our understanding is in a scenario of the GSK opt in, that would be consistent as well. So the way I would think about it all is in either scenario. Our plan is to have a robust Phase II expansion as well as combination program and just maybe more of a global scale clinical development effort at GSK side by side with us.
Got it. Okay. Jacob, we talked about 533, but you have 2 other interesting assets, ORIC-114 as well as the PRC2 inhibitor, ORIC-944. So very quickly, just tell us how these 2 are differentiated? And what type of data should we be expecting to see in 1 half '23.
Yes. So for the 114, the ED-20 inhibitor, I think it all hinges on CNS penetrant. So I think every other month, there is the announcement of a new exon 20 inhibitor. Our firm view is that for the 2 approved agents, the leading clinical agents and then every other exon 20 inhibitor out there, they don't have CNS penetrants, CNS activity, they're out of the game. And that's a very, very, very short list of inhibitors that actually do have CNS penetrants. So these have shown it preclinically and no one has shown it clinically. So for us, with ORIC-114, that's the key hook as to why we think that that's going to be a best-in-class inhibitor, and why it will be differentiated in an otherwise crowded space. For PRC2, again, here, I mentioned upfront that most folks know EZH2 is a target. I think EZH2 is sort of famous for core drug properties as a target and most of the EZH2 inhibitors, including tesmetostat, the approved one, have poor drug properties. The reason why we like this is that Mirati came up with -- actually synthesized EZH2 and EED inhibitors, put them all through the preclinical phases to pick which one met a high-bar target candidate profile, and it was this, the EED inhibitor, that won. And there's also biological reasons to believe that EED ought to be better at [ shutting down ] PRC2 complex than EZH2, not have the same issue with in the acquired or bypass resistance that the EZH2 inhibitors could have. So we're developing that one in prostate cancer. Both of them will have their first data sets in the first half of next year. It will be largely -- we're obviously dose escalation right now, but we think that the reason we waited until presented data in the first half of next year, we think we'll have enough patients treated at clinically efficacious doses that we ought to be able to see what whether we're seeing early signs of signal or not, according to the signs of differentiation that I just talked about.
Perfect. Avanish, well, we didn't talk about the other trial, the MANTRA 2, the Phase II basket study, you're going to have some data in the fourth quarter of this year. I know it's not going to be a lot of patients. But I'd be curious as to what type of response would you view as meaningful and worthy of advancing into further studies.
Yes. So I think what we said was if we're in the ballpark of a 30% response rate and the duration of response north of 5 months, then that's the trigger to start having conversations with the regulatory buyers on what type of trial expansion could be appropriate for to make this Phase II registration [ in a room ] study. So of course, there's a lot of complexity to that situation given the diversity in heterogenetic tumor types we're going to be enrolling. And so if we start seeing a bucketing of responses by tumor type that will affect our thinking, but from a tumor-agnostic perspective, 10 patients is not an immense amount of patients. We're looking for that early hint of the signal to trigger much of what you asked about before, companion diagnostic development, other regulatory conversations. But we would see, broadly speaking, if we can reproduce or if we could produce in the ballpark of a 30% response rate from a larger tumor agnostic approach, that makes it very interesting.
Got it. And Mike, you get the final question. So obviously, as you know, revumenib isn't the only menin inhibitor out there. There are some others from other companies like [indiscernible]. Just curious, tell us a little bit more about how you see revumenib as differentiated from those other assets, both in terms of its inherent properties as well as how you've differentiated in terms of clinical strategy.
Thanks for the final question, it -- so look, I think we're in a fortunate position to have presented a considerable amount of clinical data on revumenib recently at ASH. This is sort of juxtaposed, you mentioned the competition who are sort of far behind us at this point. I haven't really presented much of anything meaningful which to compare our molecule. I'd say what energizes us is the positive physician feedback that we've received on how well patients are responding to and tolerating our drug. And we're extremely proud to be pioneering the mechanism of action for patients. And based on our data, which is high response rate, deep MRD responses, MRD-negative responses, promising durability extending beyond 6 months in a heavily appreciated population, we believe our drug will not only be the first menin inhibitor in market but potentially best-in-class as well. And so we're pretty confident we've set a high bar for the competition, and we're going to be aggressively going forward and building a strong foundation in multiple settings within AML and ALL. The fact that there is competition, especially from large pharma, should probably reinforce for investors that this is a pretty considerable market opportunity in acute leukemia and perhaps solid tumors as well. And we didn't talk about solid tumor today, but we are starting some work in that area to expand the program. And I'd say from my vantage point, no other company is better positioned to take advantage of the current landscape that we're in with the menin inhibitors. Being first to market with our drug, revumenib is going to be a pretty important differentiator in terms of the market positioning and ultimately, the long-term potential franchise value. So that's how we -- that's our view.
Awesome. Well, again, thank you all so much for the time. Much, much appreciated, and very much looking forward to following all of the clinical pipelines over the next year and beyond. Thanks again.
Thanks, Yigal.
Thanks so much all.
Bye-bye.
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