All right, so welcome to this fireside chat with Syndax Therapeutics. Fortunate time today to have the team here. So with me, I have Michael Metzger, CEO, Anjali Ganguly, CBO, as well as Neil Gallagher, Chief Medical Officer. So thanks, guys, for joining us today. Thank you. Really appreciate the time. So Mike, I know as we all know, you announced the top-line data yesterday for Revimenib in the NPM-1 AML study. And so just to set the stage, I know we've seen the data, but remind us of sort of the key takeaways from the data, and then I'll have some follow-up questions. Sure. No, thank you, again, for having us. It's great to be with you all. Exciting times for the company as we've had an action-packed quarter so far. Not only did we have top-line data for our NPM1 cohort yesterday, which you're referring to, but we had several other important occurrences with the company, including completing a royalty deal and having some important ASH information to come out in the abstract. So there's a lot of momentum going into the fourth quarter as we await approval of our drug for KMT2A acute leukemia, so our drug being Revimenib. So the question you have around NPM1 is a good one. I think the trial results we thought were not only consistent with what we've seen before, but were highly expected by the company. I think this is a drug that performs now in over 300 patients. We've seen both KMT2A and NPM1 perform very well and very consistently across all measures. Thinking about overall response rate, complete response, or CR, CRh, duration of response, MRD negativity, it's all very similar in terms of efficacy as well as safety across these populations of patients. There are, for NPM1, some differences between those populations. KMT2A is a little bit younger, actually considerably younger. It averages about 35 years of age. And NPM1 is about 65 years of age in our trial. And that's essentially a big difference in how patients can tolerate treatment and what they take before they reach our trial, was impactful in some of these results. But overall, the drug actually performed consistently and robustly, and we feel very, very pleased with what we've been able to achieve with this trial. Right. I mean, and so based on our checks, I mean, the CR/CRh rate and duration clearly exceed what we think the regulatory bar is in AML, so that's great to see. But it was still lower than what you had previously shown in phase one, which was, I mean, super impressive, above 30% CR/CRh. And so can you just comment on why it came down from that? Sure. So in fact, I think we see that. We felt this, we know this, this lands right in the middle. And that's why we've been guiding to 20%-30% CR/CRh all along, because we felt that it was highly likely it was going to fall into this zone, and it did. And so to us, the point estimates look very, very similar, again, for those reasons. So we don't see necessarily a difference. Right. And then I think there was some discussion of the prior venetoclax use in the phase 2 study being a bit higher, for example. And so what do we know about how well Revimenib does subsequent to seeing a patient having seen venetoclax? Right, so right now, we don't have the updated, what the data will be updated at our ASH event, but we're looking to see how the patients do prior to venetoclax as well as post-venetoclax. We do know that patients in general do poorly after they've received and failed venetoclax, and so that is an important distinguishing factor between what we saw in phase 1, which was patients received it, but received it less frequently before they came on the trial in the phase 1 than they did in the phase 2. I think it was about 60% or so in the phase 1 and about 75% in the phase 2, and the reason for that is the use of venetoclax has increased or become more prevalent since for the last few years since its approval. Phase 1 was around about three years ago. Time has moved on, and the use of venetoclax has become more prevalent. Right. And then I know that MRD negativity, negative response rate was fairly high. And so, yeah, can you just speak to the importance of that as we think about practicing physicians or perhaps even patients moving to transplant? Sure. So maybe I'll let Neil address that. Yeah. Yeah, thanks for the question. So yes, you're right. We've been actually extremely pleased with the MRD negative rates across the program with this amount of therapy and in combination. The importance of it is sort of adjunctive to the overall response rate. So if you think about people focus on CR/CRh and duration of CR/CRh, obviously you brought that up, which is really a regulatory endpoint, right? And people focus on it, as you've done, to say, right, is this drug approval? Yes, the drug is approved. We believe that these data can form on the basis of ultimately an SNDA. But if you think about what's actually relevant from a clinical perspective, what's relevant from a clinical perspective is, can you clear the patient's blasts? And how deep can you drive those responses? Because there are pretty good analyses demonstrating that MRD negativity correlates with longer-term outcome. So that if a physician can actually get a patient into response and that patient is MRD negative, they're going to look for an opportunity to potentially transplant that patient. And although in this particular context, the data are still anecdotal, in other contexts, having a patient MRD negative actually predicts for potentially better outcome following transplant. So MRD negativity is really important. Great. And then, I mean, the other thing that stood out to some folks was the slightly higher rate of QTc prolongation in this study compared to your experience in the KMT2A trial. And so, I mean, we've heard from physicians that it's not too concerning as they are used to monitoring QTc with other drugs, especially in AML. But yeah, there were two grade four events. Can you just comment on that? To what degree does that pose a concern? Yeah, sure. Take it. Sure. So thanks again for the question. So overall, the safety profile remains consistent with what we previously reported. So in fact, when we got these top-line results, there was nothing in the dataset that was surprising, right? At least to me or to the team. And there was a slightly higher overall rate of QTc prolongation, which we actually predicted given the median age of this population being 65 compared to what we'd previously observed in the younger KMT2A population. So that was anticipated. The two grade four events, unfortunately, these were patients, unfortunately for the patients, right, that these patients were extremely sick. So in both cases, they were highly confounded by pre-existing conditions and also the disease, the underlying disease itself. So these were sick patients and a lot of confounding variables. If you think about how these cases are reported, the investigator will attribute causality, and that's what they're expected to do. That's what we want them to do, and that's what they did, right? But in really confounding cases, the circumstances are pretty unclear overall. Right. And then, yeah, again, I think you mentioned the ASH event. I know the data itself will probably not be at ASH, but can you talk about what else you'll provide in terms of the data around ASH? Sure. So we have the ASH abstracts, which came out. There's the SAVE ASH presentation, which will focus on patients. And again, this is Ghayas Issa 's trial at MD Anderson, focused on the combination of Rev plus then Inqovi. It's an all-oral regimen given to patients in the relapse refractory setting. And that's a dataset that's been updated from last year's ASH. I think the abstract was 26 patients in this setting. Patients can have either NPM1, KMT2A, or NUP98, so three different subtypes. And so that's one important presentation. The other presentation is an update from our pivotal trial in KMT2A, where we had presented for the NDA 57 efficacy evaluable patients and 94 safety patients. Those patients were followed for longer, for seven months longer since the submission. And the dataset is now 97 in efficacy and 116 in safety. And so that came out as an ASH abstract, and we'll present that as an oral at ASH as well. And then there are a number of other abstracts. Nick Botwood has a number of abstracts. And we'll have an event at ASH on Monday, December 9th, where we reprise all of the data, both information that's going to be presented at the meeting and then information that wasn't available to be presented at ASH itself, as we did last year. Some of that information relates to a frontline dose-ranging trial for Beat AML. So they will provide an update on their newly diagnosed patients, a combination of Venclexta and Revimenib, again, looking at two different doses that we've expanded. So we don't have the exact patient number, but an update will be presented, and patients will be followed for longer than they were at EHA. That was the last update provided. Then we'll, of course, have the data that we had top-lined yesterday. We'll provide an update there with additional analyses and more depth of understanding around the data itself and what important questions to answer, such as how do patients do without receiving prior ven versus post-ven within the trial setting, mutation status, things like that that are important to know. That was actually my question, but. Yes. And then just maybe one more. In the NPM-1 AML category, there is obviously more competition relative to your KMT2A rearranged opportunity. So with this data in hand, how do you feel Revimenib is positioned competitively as sort of the landscape is getting busier in the coming years? Yeah, Anjali. Do you want to take that question? Oh, sure. Yeah, I'd be happy to take it. I think bottom line, we think we're in a very strong position with our dataset. I think we've showcased the best monotherapy data in both KMT2A and NPM1 population from an overall response rate and MRD-negative response rate, CR/CRh rate. And then to Michael's comment about the additional data, we'll have at ASH. I think our combination data is also looking significantly better than the competition. And in the relapse refractory population, we'll have a bolus of patients tested in combination with Venclexta, which I think is a very well-used treatment of choice in relapse refractory population. And so you have the option of using Revimenib as a monotherapy in patients that you think can do better without intensive chemo and/or as a combination with Venclexta in patients where you want to hit as hard as possible. We're not seeing any additive toxicity in that combination, but we are seeing significant benefit on efficacy. So I think we're setting the bar high for anybody that's coming behind us. Right. And so with the potential commercial launch as a monotherapy in KMT2A settings sort of coming up hopefully very soon, just remind us what you said around market potential as a monotherapy in the relapse refractory setting for KMT2A and then also for NPM1. Right. So this is a great setup for us, unusual for a company to have the opportunity to be not only first in class, but really nothing to really compete with as the market emerges. So this is a, as you know, KMT2A is a terrible prognosis. Standard of care medicines don't work for KMT2A. Patients relapse quickly, which for us sets up the opportunity to not have to compete with standard of care therapy. And in terms of pipeline, there's really nothing behind us, as we said. Our competition isn't focused there and doesn't have the ability to be focused there based on their data. So we have what you call white space within KMT2A and the ability to launch into a market, which we project is $750 million in the U.S. based on 2,000 patients that have relapsed that are available for therapy, price point in the $35,000-$40,000 range, which we previously stated, and roughly nine months duration of response, duration of therapy, which could elongate with additional transplant and maintenance, which ultimately will manifest in practice. But this is a market that we think is really set and poised for us in our entry. So that's $750 million, again, in the U.S. in KMT2A alone. And then if you add NPM-1, it's about 4,000 patients available in the relapse refractory setting. And if you think about using the same metrics, duration of therapy is, again, what's most important. How long will patients stay on drug and continue to be receiving treatment? In the data that we showed yesterday, you have roughly two to three months, closer to three months to achieve a response, and then you add roughly five months of time in response, and that gets you to about eight months of time on therapy. And if you use the same metrics of price and the 4,000 patients, it's roughly somewhere between $1 billion and $1.5 billion market size, which, again, will be the first to market and be able to start to really penetrate. So between the two, it's about a $2 billion segment. And again, being first to market is extremely important. And having consistency, I'd say consistency of response and overall efficacy and safety within both populations will be really important for physicians who prescribe. And I'd just like to add on to that. I think there's upside for both of those populations based on this dataset being the first pivotal data being generated in both KMT2A, relapse refractory KMT2A and relapse refractory NPM-1 population. There are no other data to point to to say these are alternatives. And I think the safety, the ease of use, it's a pill that you don't have to come in for infusions. The tolerability and the efficacy can drive physicians to reach for this molecule, reach for Revimenib as a second-line agent. And that will move the needle on both how long patients get, how fast patients get to response, how long they can stay on therapy, and then overall market potential. Right. And then I know the higher rate of transplant is a big factor, especially in the younger KMT2A population. And so how do you expect that to play out in clinical practice relative to the trial experience? And then I know in the NPM-1 study, you also had a few transplants. Do you expect that to be a factor in driving duration in practice once on the market as well? You know, I think that's absolutely. We heard from Dr. Stein yesterday, who was our guest on our call, who talked about the transplantation rate going up even in the NPM1 patients as an older population. In the past, they didn't transplant them as often, but they're becoming more emboldened by treatments such as ours that allow patients to get a response quickly and then potentially even go back on drug in the maintenance setting. We're seeing that in our trial, right? We're seeing patients go to transplant. We had five patients go to transplant. That's on a percentage basis more than you would expect in this population. We saw three patients go back on in the maintenance capacity. That's also something that we think is going to grow. Both things should grow in the real world as physicians become both more emboldened and understand how the drug can work, but want to take older patients to transplant and put them back on therapy. And moving up line, as I was stating, also enhances the likelihood a patient can go to transplant. So you may actually see even higher rates in second line than you see in third line or fourth line. Right. And then I know you just went through the different updates that are coming at ASH, but I know you have committed to starting a phase 3 study, the first phase 3 study in the first-line AML setting in combination with Venclexta. And so, yeah, anything noteworthy there? What data do you have that supports that decision? Are there any critical pieces of information still missing to increase our confidence in successful outcome? Sure. So maybe I'll discuss some of that data and what we're going to be updating at our ASH event relative to Beat AML. Maybe Neil, you could talk about the trial design and how we see this playing out. So at our ASH event, we'll get an update on Beat AML. And this, again, is our Ven/Aza combo with Revimenib in the frontline setting, newly diagnosed patients. We've shown data, or Beat AML has shown data before. And I think that was EHA, 26 patients. And the rates of response, overall response rate is 90%-100%. CR/CRh rate is close to that as well. MRD is close to 100%. So these are patients who are not only getting to very, very high rates of response in combination, but the safety profile looks like the double, right? So these are patients who are not more cytopenic and can stay on drug for a long period of time. The vast majority of patients were still on drug and on the combination 12 months into their treatment. So this is, again, a phase one, two trial to look at dose. And we've explored two doses that we know are active because there are RP2D doses in our earlier trials, the 160 on a strong CYP inhibitor and the 113 on a strong CYP inhibitor. And we've expanded those doses. And I can't tell you exactly how many patients will be presented at our update, but we've now been able to follow patients longer and really kind of pull apart what's the optimal dose for this trial. And then I'll turn it over to Neil. We're starting the trial before the end of the year, and so maybe you want to describe it. Yeah, sure. So the trial is actually based on the VIALE-A design. So VIALE-A was the original phase three trial for Venclexta that got full approval for Venclexta for the treatment of patients newly diagnosed with AML. So our trial design mirrors that. It's Revimenib, Venclexta versus Venclexta. Patients will be randomized one to one. And the primary outcome, the primary objective is to demonstrate that we can extend overall survival. So the primary outcome variable is overall survival, which is the provable endpoint of reference. If you look at the outcome of Venclexta in VIALE-A, the median overall survival on the experimental arm is just under 15 months. It was 14.7 months. And so while we haven't sort of disclosed the overall statistical design of the trial, what we're trying to demonstrate is a clinically and statistically meaningful extension beyond that sort of 15-month-ish overall survival. And let's face it, that's not great survival, right? So these are patients actually on the VIALE-A study. The median overall, the median age was around 74. Those people should expect to live longer than an additional 15 months. So that's the intention. Now, the study is designed around NPM-1 patients, okay? It will include some KMT2A patients, but the statistical design is focused on NPM-1. And the reason for that is that that is the prevalent AML population. So in what's called the unfit population. So these are patients who would not tolerate intensive chemotherapy. So they tend to be a little bit older. AML is roughly split 50-50 between patients who are considered able to tolerate intensive chemotherapy and this population, the other half. So the prevalent population in this age group is NPM-1. KMT2A tends to occur in younger patients. And therefore, the statistical design is focused on NPM1 patients. And we will allow in KMT2A patients, but where we'd be looking for consistency of effects. So assuming the study is positive, we would expect to see at least a consistency of effect in the KMT2A patients as well. Right. And I guess, what percentage of elderly unfit patients are expected to be KMT2A positive versus the young, the other half, the young fit patients? Well, so if you look at the median age, right? So as I alluded to, in VIALE-A, the median age of that population was 74. I think in this study, it may be a little bit lower, right? So let's say our expected median age, our median age is 70. The median age of the KMT2A population was 35. And I think most of the patients, I can't remember the exact range, but most of those patients were under 60. So there will be very few patients. And that's why we focused on the NPM-1 population. Makes sense. Okay, great. And then I know for seven plus three, so the other half of the first-line market, sort of younger patients, I know there has been some investigator-sponsored data that we saw last year, maybe at EHA as well. But I think you got it to initiating company-sponsored phase 1, if I'm not mistaken. Just remind us what are you doing in combination with chemo in the fit patient population before starting or committing to a phase 3. Right, right. So we're doing some dose ranging work there. Obviously, we don't think there would be a very wide range of doses. We've explored doses in lots of different regimens. We've actually looked at chemo combinations in the relapse refractory setting as well. So we feel like we have a very good beat on how the dosing will work. So we're just accumulating patients in that setting in combination with chemotherapy, and we should have data next year before we start our trial in 2025. Right. And so in the chemo combo, so seven plus three plus menin inhibitor, we've heard from docs that the CR rates are already very high with chemotherapy alone. So, looking at CRs, value added in combination, can you assess additive activity, or is it mainly a safety study that you're doing? Oh, yeah, I can. It's primarily going to be a safety study. We will look at efficacy, but you would expect, especially in the NPM1 population, 90%-100% response rates in combination, and with KMT2A, similar 80%-90% response rate. We're just looking to see that it's safe and that you are seeing responses. I think overall, in the trial, you'll be looking for an improvement in survival, maybe MRD negativity. Maybe for KMT2A, you might be looking for a percent of patients going to transplant could increase because that is the goal in that population. Things like that, I think, would be more in the phase 3 trial than in a phase 1. And I'll just add that I think when Revimenib gets approved in the relapse refractory setting, physicians can prescribe it right after they fail chemo. They don't have to wait until they receive other treatment. So it can be immediate after they fail. And they do fail pretty quickly. Right. Maybe just a couple of additional points. So that group of patients, right, is not homogeneous. It's actually quite a complex group of patients. And although a lot of them have NPM1 mutations, they also have co-mutations. They also have other risk factors. So as we think about how we're going to, as we think about our strategy, there are multiple different directions that we can go in terms of where the unmet need lies. You can expect to hear more from us. Great. So we're looking forward to ASH next, I believe. And with that, our time is up. So. So.