Right, perfect. Thank you so much. Good morning. My name is Peter Lawson. I'm one of the biotech analysts at Barclays. Welcome to Barclays Global Healthcare Conference in Miami. I'm really pleased to have up on stage with me management from Syndax, and I should say as well, if you want to ask questions, raise your hand, or try and be on Bloomberg as well. One of my team members will be, so you can get questions to us multiple ways.
So up on stage with me, I've got Michael Metzger, CEO; Keith Goldan, CFO; and Anjali Ganguli, Chief Business Officer. First question, as always, we're kind of thinking about what's coming up, and I'm sure you'll have to provide some context around the question. Just as we think about the approval for KMT2A, kind of what's the timeline there, and then in particular that NPM1, and how important, how much a delay is there between KMT2A and NPM1 and AML? So big question.
Well, first of all, thank you for having us. It's great to be here at Barclays and to see everybody. Maybe a little context around the program first before we start. Syndax is focused on two programs as of now who have finished their first pivotal trials. The first molecule is revumenib, which is a menin inhibitor. We're looking at it in KMT2A acute leukemia as well as NPM1 leukemia as well. These are AML and ALL patients first treated with menin inhibitor. The first trial that you referenced is a KMT2A pivotal trial which read out last year, and we've submitted our NDA for that program. The timing is such that we submitted last year. We've actually under our RTOR Breakthrough Therapy Designation for this molecule, and we are submitting our program, our NDA, under Real-Time Oncology Review.
So the agency is quite engaged and has been since last October when we announced that. We are waiting for our PDUFA date. We expect to receive that in the first quarter, the action date, and that will mean that we would likely get approval somewhere in the third quarter of this year. We also have the second indication, which we are running a pivotal trial for, the NPM1 AML, and we expect to have that fully enrolled either end of this quarter, beginning of next quarter, so pretty soon. And that's going quite well. We'll have that enrolled, and then we'll have data in the fourth quarter of this year as well. So that will be submitted as our second indication for revumenib, and that will be submitted through an sNDA process and expect to have approval in 2025.
So just to kind of give a little bit of context, this is first-in-class menin compound. It will be our first indication, KMT2A, roughly 2,000 patients. And in the relapsed refractory setting, so these are patients who have received other medicines. The diagnosis or the prognosis for KMT2A is as bad as it is in any subset of AML, actually probably the worst. And we are going to be the first drug specifically targeting those patients. Again, we'll have our first launch in this year, sometime in the third, hopefully the third quarter of this year, followed by a second indication next year.
Gotcha. Thank you. And then as we think about that launch, kind of what should we model it against? What do those initial dynamics look like, and what are the best drugs to compare it to?
Yeah. Do you want to maybe lean on there?
Yeah. No, thanks for that question, Peter. I think it's super important. Excuse me. I do feel like, unfortunately, there aren't the best analogs out there. Yes, there are targeted drugs that have been approved in AML, but these subsets of AML are so different from each other. KMT2A is a significantly younger median population. The median age of patients in our trial was 34 years old versus 68-72 for the other targeted therapies. That changes the dynamics of what physicians are looking to do and how aggressively they treat. I think the other major point of difference is that nothing out there as standard of care today works in the KMT2A population. The unmet need is quite significant. The IDH inhibitors, the FLT3 inhibitors, do respond to venetoclax and 7+3 and salvage chemo. There is a sensitivity there.
So there is none of those were adequately addressed, but there was activity, and there was a lot of comfort with the drugs that were out there with the KMT2A population. Especially, there really is a huge dearth of options for those patients. And I think that changes that also adds to the key point of differentiation for that population. NPM1 is, I think, a little bit more similar to the IDH inhibitors in that there is sensitivity to 7+3. There is strong sensitivity to venetoclax. But we're probably looking to target in the relapsed refractory population the point at which the responses aren't there anymore. So with gilteritinib, with the IDH inhibitors, they enrolled basically a second-line population in their trials. We're talking about third, fourth, fifth-line population and are probably targeting a third-line NPM1 to start.
And so I think there is, and then the fact that there's what we anticipate will be, and what Michael just alluded to, a two-step launch. We'll have the KMT2A out there. Then we'll have data that is potentially actionable because they have the drug available to them and then a launch. And so there will be a two-stage cadence. And we will have data in combination with the drugs that they like to use already available at the time of launch. We've already put out some of that data at the end of last year, and there will be continued updates in 2024. And so there's just a bigger dataset building here for menin inhibitors than there was the other AML agents prior to launch.
Gotcha.
Maybe one more add to that. I think it is important to so the concept of maintenance, and I think it has a lot to do with the patient population that we're treating, KMT2A. Anjali mentioned that these patients have nothing but the ability to get them to a deep, durable response, get them to transplant in high numbers, much higher than they've ever been before, and then maintain them on therapy. This maintenance aspect, going back on therapy post-transplant, is really exactly what physicians want in this setting, to be able to keep them in remission for a long period of time. It's never been possible before revumenib came along, certainly in terms of KMT2A, but we think that's possible for NPM1 as well. That makes this a very different setup for a menin inhibitor like revumenib versus some of the other drugs that came before.
Gotcha. So should we look at the FLT3s, IDH1s as kind of a floor for revenue as opposed to that's not the curve we look at, but that's almost like the worst-case scenario?
Well, it's hard to say that. I think you could say the patient population size-wise is not for KMT2A, is not so different than IDH. But in terms of access to patients and being a drug that's reached for as sort of second-line immediately, it's different for those therapies than it was, as Anjali said, than it is for ours. So from a kind of, call it, number of patients perspective, from a TAMS perspective, it changes because you have the ability to treat them early, get them to a transplant, and keep them on. So it could be quite different, we'd say, significantly higher in terms of overall performance for revumenib and a menin inhibitor than perhaps these others. It's very hard to say exactly what the baseline is.
Just as we think about that gap between KMT2A and NPM1, would you look for NCCN guidelines for NPM1 to start getting used?
That's a possibility. Yeah. I mean, we're generating data, and we've put out data this year in ASH. The combination data that we had includes NPM1 patients, includes KMT2A, but we'll also obviously have our pivotal data, which we'll ultimately get we expect to get that published, and we could utilize that potentially for guidelines as well as for approval.
Okay. And then as we think about those first quarters of launch, are there any kind of puts and takes we should be thinking about, patients that are essentially waiting for therapy or patients that would be on an existing trial where you just can't put them on therapy immediately?
Sure. One guess.
Yeah. I mean, I think there, it's hard to quantitate all of those different opportunities and buckets of patients. But there will be some patients that are on either a compassionate use or an early access program that could roll into paying patients. There is a time period of getting all of that documentation done. There will be patients, as we've seen the trajectory. There's some that stay on a very long time. There's some that go to transplant quickly or come off for a different reason. And so it's hard to quantitate what proportion of each one of those patients will be in that bucket, but we do expect there will be some. In terms of a bolus, I don't think in an acute disease setting that you can really have a stockpile of patients waiting for a therapy.
We don't expect there to be a large pool of patients that will come on on day one. We do anticipate that as physicians identify patients, they will be going on to revumenib very quickly. We've heard very strong support for this drug and the need that this drug addresses. And physicians, despite the fact that our trial enrolled a median of third- and fourth-line patients or actually fourth- and fifth-line patients, they anticipate wanting to use this as a second-line agent. And so that is, I think, a very strong support for how quickly and how strongly they are going to embrace revumenib at uptake. But I don't think there's a bolus that we can anticipate because it's such an acute disease.
Gotcha. Thank you. The NPM1 population, you kind of talked about it as maybe a third-line option. And you're kind of viewing that because there's other options that they can have. But what moves it earlier line into second-line? Is there an option there?
Yeah. Excuse me. I think there are second-line patients that could be available for NPM1. It really depends on the way the patient presents to the physician. So in AML, generally, there are two buckets of patients at initial diagnosis. Those that are deemed fit for intensive care chemotherapy and those that are not. And if they're fit for intensive chemotherapy, they get 7+3. And then depending on right now, if you have a FLT3 mutation, you could also get a FLT3 inhibitor at that time. And so those patients will be treated that way in front line. When they relapse, a majority of patients then see venetoclax because NPM1, FLT3, IDH mutations are all very sensitive to venetoclax, and it's a broadly acting drug. There's not a lot of other drugs that elicit strong efficacy approved.
So even though ven is only indicated for front line, a majority of patients will see it second line. And so we would anticipate revumenib gets to that patient in third line. If that patient was actually unfit, then at diagnosis, they would get ven front line. And then there's not a defined pathway. Each physician can sort of try therapies that they respond to. And so that patient that was unfit could be a second-line patient that receives a menin inhibitor. The other way that we could get earlier use in second line is based on the data that we're generating in combination with venetoclax HMA. And so if a patient has not seen a menin inhibitor, has an NPM1 or a KMT2A mutation, and the physician wants to put them on venetoclax in the second line, perhaps they add revumenib at that time.
So that's another way to move it up if we get that in the guidelines. Because the data was so strong, 100% response rates, really strong MRD negative rates, there is a compelling interest to add on. And they're not seeing additional toxicity, so there's no reason not to. So I think that is another way we could get to second line.
Gotcha. I'd love to jump to the CRC update just because label expansion is always kind of exciting. I know there's plenty of runway in the AML and ALL side of things. But what should we expect to see in 2Q for the CRC patients?
Right. So Peter's referring to this is our first foray into solid tumors. So we had initiated a signal-seeking trial in colorectal disease. This is third-line plus metastatic stable patients who have failed other therapies, notably EGFR inhibitors, chemotherapy, to name a few. And so these are patients who are in dire need of additional therapy, and we're looking to see if there's a signal for a menin inhibitor, revumenib, in colorectal disease. First testing it as a safety trial, but looking at seeing if there's activity, tracking really stable disease or something potentially better than stable disease. But this is about disease control, hopefully having some measure of disease control within the third-line, fourth-line patient as a monotherapy, which is very difficult to do. So today, I believe standard of care yields something about 15% disease control rate, meaning either they're stable disease or partial response.
We're looking for something, hopefully, in that realm relative to revumenib. Looking at patients over an extended period of time to see if we see disease control in that range. We should have some data in the second quarter, somewhere in the 10-20 patient range without being too specific. We haven't picked a venue yet as to when we would have that data available. But essentially, looking at these patients over an extended period of time to see if there's activity there. That would obviously be a large patient population, about 50,000 patients in colorectal disease at that stage. There's obviously a need. If we could impact the disease, that would be great.
Obviously, the next step would be to expand the number of patients if, in fact, we see sufficient activity to move into a phase 1B to accumulate more data. Ultimately, this is a combination approach for colorectal cancer.
Gotcha. And then safety. What's the bar there? What do you want to see? And maybe durability?
Hard to say what you don't want to worsen safety, obviously, for these patients. They've had a lot of therapy, and they are at a pretty advanced stage of their disease. So you want to keep them in reasonably good health and tolerating therapy. And so I don't think we have a specific bar. But again, we're trying to track patients over a reasonably extended period of time. If you could see stable disease for four to six months, I think that's pretty impactful for these patients. Again, overall response rate here is less than 5%, right? 15% disease control. So you don't want to worsen their symptoms. I don't have a specific bar for it, but they need to be able to stay on therapy for a reasonably extended period of time. And that goes for the safety as well as the efficacy.
And actually, the drugs that are approved right now in third line are not very well tolerated, Lonsurf and.
Stravaga.
Stivarga, yeah. They're very hard to take, but physicians prescribe it because there really is nothing else. And as Michael said, they only expect a very short increment in efficacy despite.
Is there anything special about your menin inhibitor to preclude others from entering CRC, or will kind of good results drive imitators?
We're going to have to see. Look, I think it's the first look at a menin inhibitor in colorectal cancer. So the profile will bear out over time. What the differentiation is relative to other menin inhibitors, we'll have to just see if they first, if we continue on in this indication, and then if others go into it as well. I think it's very early days to draw conclusions about where we are with or where others could be with colorectal cancer.
Gotcha. Thank you. And we kind of touched upon this as thinking about moving the drug in earlier lines, but the combination data has been really interesting. Kind of what should we expect to see in the second half for your updates around let me get this right. So what.
Beat AML.
Beat and also the SAVE?
SAVE, yeah. So there are two trials that are ongoing now. One is Beat AML. This is the Leukemia & Lymphoma Society trial. It's an umbrella trial where they're testing different regimens. This is a front-line trial, so newly diagnosed patients, combination Ven/Aza plus revumenib. We did put some data out, or they presented some data at ASH this year, which were quite compelling, 100% response rate, very good tolerability. Patients were that we need to follow these patients longer, right? So we're looking to follow up, not only enroll additional patients and hopefully have that presented in the second half of this year, additional patients and longer follow-up. So we hope to see continuation of very high response rates, no worsening of side effects. This is what we saw at the initial presentation last year. And that was 13 patients.
I don't know the specific number of patients, but there will be more to add to that group of patients and hope to see continued high rates of MRD negativity, high rates of response, and hopefully duration as well, which would be what you'd hope to accomplish with those patients. So this would be very exciting because this builds for us the front-line indication. We'll be starting a pivotal trial before the end of this year to follow up on that. This is the first part of the Beat AML trial is to really get to a recommended phase II dose, which we'll take into the pivotal trial. Then there's the other regimen you mentioned, which is the SAVE trial, which this is Dr. Issa's trial at MD Anderson. It's a combination with ven plus INQOVI, which is an oral hypomethylating agent.
These are in relapse refractory patients. So I mentioned Beat AML was in front-line patients. This is relapse refractory patients. And we saw data at ASH this year, which was very compelling. Again, 100% response rate, patients getting to MRD negative responses, staying on drug, doing very well. We did have initial duration there. It was ongoing, but majority patients being on drug at six months. So I think we're looking to follow that up. And Dr. Issa will have some more patients enrolled in his trial. And then obviously, looking at an extended period of time and how well these patients do. They were able to go to transplant and do all the things that we've been able to demonstrate in our pivotal trial.
So it's another regimen for relapsed/refractory patients, very important that physicians have an understanding of how this drug can be used in a variety of settings. So very important data as well. Again, I don't have a specific venue where that'll be presented, but you could expect one of the major medical meetings where that will come out.
Gotcha. And the BEAT trial, just with a 7+3 oh, sorry, Ven/Aza combination, I would imagine that's enrolling very well.
It is. Yes.
It could be kind of a meaningful update in the second half, not to put words.
We hope so. We expect so. I think this is really anticipated data by the medical community. They were, I think, really encouraged by what they saw at ASH this year. You're adding to a regimen that's well established with Ven/Aza. Physicians like that regimen. It's not always the most easily added to. And having efficacy already in the 60% range for Ven/Aza and seeing a 100% response rate with very high rates of MRD, that's noteworthy to them. So additional patients and following that up is of high priority for us.
Gotcha. And so this really kind of dispels many of the problems of is there any issues with QT prolongation, etc.? But any combination issues that have happened?
No. Look, I think we've done a lot of work in relapse refractory patients. Again, I'll remind you, these are patients who have seen in relapse refractory patients prior ven, prior transplant. They've had multiple lines of therapy. And our side effect profile is now pretty well understood, right? And so you go to earlier line therapies, earlier line setting, rather, and test Ven/Aza in combination or chemotherapy, 7+3, for instance, in combination. And I think you'd expect to see very mild side effect profile. Physicians are used to seeing QTc prolongation with other drugs in AML. And our drug has some as well. I think there hasn't been any issue with combining with any of these other regimens. And it's been very consistent with what we've seen prior.
The earlier you treat patients, it seems that the side effects, obviously, seem to be even better, right, in terms of the profile of adding our drug to other regimens. So we've been encouraged. Physicians are excited about the data. So we don't think there's any barrier to combination whatsoever.
Gotcha. Thank you. And then maybe in the final minute, just kind of what we should expect to see in that Beat dataset. Is there a particular things we should be thinking about, durability or safety, or?
Right. So I touched on it a little bit before. I think the efficacy that we saw in 13 patients was very encouraging. I don't think you can improve much upon a 100% response rate and an MRD rate of 90% or so. We would like to see duration and patients staying on therapy and doing well over an extended period of time. We didn't have enough time to demonstrate that yet. I think we'll follow that up.
So I think we're going to be looking for continuations. I don't know if it's always be 100%, but high rates of adding on to ven in all the categories I just mentioned, that's what we would hope to continue. So more of what we've already shown. I don't think we need to demonstrate anything necessarily new, but just the ability to tolerate the treatment and stay on drug for a period of time.
Perfect. Thank you so much. It's been a pleasure speaking. We haven't touched upon the GVHD, but hopefully, that gets flushed out in your meetings today.
Yes. Thank you so much. Thanks, Peter. Thank you.