Syndax Pharmaceuticals, Inc. (SNDX) Earnings Call Transcript & Summary

Perfect. Thank you so much. Good morning, my name is Peter Lawson. I'm one of the biotech analyst at Barclays. Welcome to Barclays Global Healthcare Conference in Miami. I'm really pleased to have up on stage with me, management from Syndax. [Operator Instructions]. So up on stage with me, I've got Michael Metzger, CEO; Keith Goldan, CFO; and Anjali Ganguli, Chief Business Operator.

And first question, as always, we're kind of thinking about what's coming up. And I'm sure I have to provide some context around the question, but just as we think about the approval for KMT2A, kind of what's the time line there? And then in particular, that NPM1 and how important -- how much delay is there between KMT2A and NPM1 and AML. Sorry, big question.

Well, first of all, thank you for having us. It's great to be here at Barclays and to see everybody. So maybe a little context around the program first before we start. So Syndax is focused on 2 programs as of now. We have finished their pivotal -- first pivotal trials. And 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. So these are AML and ALL patients first treated with menin inhibitor and 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. So the timing is such that we submitted -- last year, we've actually under artery, a 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. And 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, be our second indication for revumenib, and that will be submitted through an sNDA process and expect to have approval in '25. So just to kind of give a little bit of context, this is first and best-in-class menin compound 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 that diagnosed 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 the -- in this year, sometime in the third -- hopefully in the third quarter of this year, followed by a second indication next year.

Got you. And then as we think about that launch, kind of what should we model it against? What are those initial dynamics look like? And what are the best drugs to compare it to?

Do you want to maybe lean on that?

Yes. No, thanks for that question, Peter. I think it's super important. And 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 is 34 years old versus 68 to 72 for the other targeted therapies, and that changes the dynamics of what physicians are looking to do and how aggressively they treat. And I think the other major point of difference is that nothing out there as standard of care today works in the KMT2A population. So the unmet need is quite significant. The IDH inhibitors, the FLT3 inhibitors do respond to venetoclax, 7 + 3 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 2-step launch. We'll have the KMT2A out there. Then we'll have data that is in potentially actionable because they have the drug available to them and then a launch. And so there will be a 2-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 '24. And so there's just a bigger data set building here for MET inhibitors than there was the other AML agents prior to launch.

Got you.

Maybe one more add to that. I think it's 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, initially 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 in terms of -- 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.

Got you. So should we look at like the FLT3s, IDH1s as kind of a floor for revenue as opposed to like 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 can see 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 sort of second line immediately. This is -- 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 TAM's perspective, it changes because you have the ability to treat them early, get them to a transplant and then keep them on. So it could be quite different. We'd say significantly higher in terms of overall performance for revumenib and met inhibitor than perhaps these others. So 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 in NPM1 to start getting used?

That's a possibility. Yes. I mean we're generating data and we've put out data this year at ASH. The combination data that we had includes NPM1 patients, includes KMT2A, but we'll also obviously have our pivotal data, which will 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 this like first quarters of launch, are there any kind of puts and takes that we should be thinking about patients that are essentially waiting for therapy or patients that it would be on an existing trial that whether you just can't put one therapy immediately?

Sure, do you want to?

Yes. I mean I think there are -- 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 in 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. And so we don't expect there to be a large pool of patients that will come on in day 1. We do anticipate that as physicians identify patients, they will be going on to revumenib very quickly. We've heard a very strong support for this drug and the need that this drug addresses and physicians, despite the fact that our trial enrolled the 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're going to embrace revumenib uptake. But I don't think there's a bolus that we can anticipate because it's such an acute disease.

Got you. The NPM1, you kind of talked about it, it was in maybe a third line option. And that's -- you're kind of viewing that because there's other options that they can have, but what moves it earlier line into secondly, is there an option there?

Yes. I think there are second-line patients that could be available for NPM1. It really depends on the way the patient presents to the physicians. So in AML, generally, there are 2 buckets of patients at initial diagnosis. Those are that are deemed fit for intensive 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 co-mutation, you can also get FLT3 inhibitor at that time. And so those patients are -- will be treated that way in frontline. 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 frontline, 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 them frontline. 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 the patient has not seen a menin inhibitor, has an NPM1 or 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, like 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.

Got you. I'd love to jump to the CRC update, just because label expansions are always kind of exciting. I know there is plenty 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 is referring to -- this is our first foray into solid tumor. 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 is 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 yield something about 15% disease control rate, meaning either they're stable disease or partial response. And so we're looking for something hopefully in that realm relative to revumenib. So looking at patients over an extended period of time to see if we see disease control in that range. And so we should have some data in the second quarter, somewhere in the 10 to 20 patient range without being too specific. And 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. And that would obviously be a large patient population, about 50,000 patients in colorectal disease at that stage. And so there's obviously a need and 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 Ib to accumulate more data. Ultimately, this is a combination approach for colorectal.

Got you. And then safety, what's the bar there? What do you want to see and maybe durability?

Hard to say with -- you don't want to worsen safety, obviously, for these patients. There -- 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 good health -- 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 4 to 6 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 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 Stivarga, yes, they're very hard to take. The physicians prescribe it because there really is nothing else. And as Michael said, they only expect a very short increments in efficacy despite...

Is there anything special about your menin inhibitor to like 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 met inhibitor in colorectal cancer. And so the profile will bear out over time and what the differentiation is relative to other MET inhibitors will have to just see if they -- first, if we continue on in this indication and then if others go into it as well. So I think it's very early days to draw conclusions about where we are with or where others could be with colorectal cancer.

Got you. And we kind of touched upon this is thinking about moving the drug at 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 -- to what BEAT and also the SAVE?

Yes. So there are 2 trials that are ongoing now. One is BEAT-AML, which is the Leukemia Lymphoma Society trial. It's an umbrella trial, where they're testing different regimens. This is a frontline trial, so newly diagnosed patients, combination ven/aza plus revumenib. We did put some data or they presented some data at ASH this year, which were quite compelling, 100% response rate, very good tolerability. The patients were -- we need to follow these patients longer, right? So we're looking to follow up, not only to roll additional patients and hopefully have that presented in the second half of this year. Additional patients with longer follow-up. So we hope to see a continuation of very high response rates, no worsening of side effects. This is what we saw in the initial presentation last year. And that was 13 patients. I don't know have a 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 is -- this would be very exciting because this builds for us the frontline indication and 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 will take into the pivotal trial. And 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 relapsed/refractory patients. So I mentioned BEAT-AML was in frontline patients. This is relapsed/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 of patients being on drug at 6 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 will be presented, but you could expect one of the major medical meetings where that will come out.

Got you. And the BEAT trial, just for like a 7 + 3 -- sorry, ven/aza combination. I would imagine that's enrolling very well.

It is.

Yes. So it could be kind of a meaningful update in the second half of the [indiscernible].

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 the additional patients and following that up is a high priority for us.

Got you. And so just really kind of dispose many of the problems of like is there any issues with QT prolongation, et cetera, but it's any combination issues that?

No. Look, I think we've done a lot of work in relapsed/refractory patients. Again, I'll remind you, these are patients who have seen in relapsed/refractory patients prior than -- 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 it is in combination. And I think you'd expect to see a 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 seems 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.

Got you. And then maybe in the final minute, just kind of what we should expect to see in that BEAT data set? What -- 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 100% response rate in MRD rate of 90% or so. We would like to see duration 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 then 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.