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

[Audio Gap] the Barclays Healthcare Conference in Miami. Do e-mail us or messages on Bloomberg, if you have any questions. My name is Peter Lawson. I'm one of the SMID cap biotech analyst at Barclays. I'm really delighted to have up on stage with this pretty broad representation of management from Syndax. So we've got Michael Metzger, CEO and Director; Anjali Ganguli, Chief Business Officer; and Keith Goldan, CFO.

So I guess first question is just around Menin inhibitor and the Phase II kind of how enrollment's going? And I'd love to know about this kind of the pace of enrollment -- so augment 101 kind of between the 2 different classes of the MPN1 versus rearranged or [ KPM2 ]?

Maybe if you don't mind. First of all, thank you for having us. It's always a pleasure to be at the Barclays conference and to be in [ my handy ] with you, Peter. But maybe I'll take a 2-second introduction to Syndax on people understand kind of where we are before we jump right into the questions. So very exciting time for the company. We've -- many of you know, we have 2 programs in pivotal trials, key malignancies. First one is revumenib, which is the first-in-class best-in-class Menin inhibitor directed KMT2A, leukemia as well as NPM1 leukemia, both in AML and ALL adults and pediatric patients. That program will have its first of its 2 pivotal readouts this year. The first one, KMT2A rearranged leukemia and AML and ALL. We recently announced that we'll have a pooled analysis. I know we'll get into this a little bit on the 2 cohorts that will be available in the third quarter with our first filing by the end of the year, so that's for revumenib. We'll have additional data next year for NPM1 as well as, we believe, our next filing for that in 2024. Also very exciting is our second agent for chronic graft versus host disease, which is axatilimab, partnered with Incyte. We have a pivotal trial, which we've enrolled and are now waiting on data and we'll have that top line data in the middle of the year and a filing -- BLA filing by the end of 2023. So what that leads to is potentially lots of data this year, 2 filings as well as potential approvals and launch next year for both drugs. And so we're very excited about the opportunity we have for both of these as well as expansion opportunities, which I'm sure we'll get into. But it's a good -- a very good time for the company. We've raised money recently. So we're financially capable to carry out all the work that we have ongoing and then some. I just wanted to start there. Now maybe…

No, thank you. Maybe pivoting off that introduction, just kind of cash runway, how far it takes you.

Sure. We ended the year with $480 million on the balance sheet, no debt. It's a very clean balance sheet. We gave guidance that, that was enough cash to get us into the second half of 2025. So Michael will review a lot of the catalyst value creation events that we have between now and then, there are many, but we expect that to be circa 1 year after launch of both of our drugs.

Got you. And I guess the obligatory question at the moment kind of exposure to SVB and kind of regional banks and I guess, nonbank lenders, anything we should be kind of thoughtful of, particularly with this kind of disruption.

Sure. So I'll start by saying we're in a very good position. So luckily or thankfully, we had 98% of our cash and equivalents at another institution as custodian. Like I said, we ended the year with almost $0.5 billion on the balance sheet. So we have a cash manager to kind of maximize the return of that and a very under the of a very conservative investment policy. One of the largest banks in the U.S. is the custodian for that money, the 2% that we did have with SVB, we do use them for some of our operating accounts. We reached out to all of our analysts, all of our top 20 shareholders right away to let them know that we had minimal exposure in material. That being said, since the moves that the Fed made Sunday evening, we do now have full access to all of that 2% of cash. And we've been able to transact and make payroll everything this week.

Got you. And would that be transferred out and...

Yes. So we're evaluating what we're going to do for the operating accounts that we use. Again, we keep most of our cash, 98% being managed by a third party. And we're very comfortable with the custodian of that cash. Like I said, it's one of the largest U.S. banks. We're evaluating what relation what do we do with that operating account relationship going forward.

Perfect. Thank you so much I have been anticipate to be asking this question.

Underappreciated finance departments of every company in our space, and now the people know a lot more about operating accounts and how it all works.

Not exactly goes through in the round in these cycles, right? So back to the data, so kind of enrollment pace between the 2 different classes in kind of AML and I guess, ALL, but the NPM1 versus the rearranged patients how is that tracking? Why is there a difference?

Well, I think they're both tracking well. And I think the enthusiasm that we've seen from physicians, patients since the data was updated at last year's ASH, I think it's been very, very high. So the enrollment continues to pace well. We gave guidance that we have the first cohort fully enrolled. We weren't necessarily indicating which one was to be the first of the 3 to be enrolled in the first quarter turns out of his KMT2A and that has something to do with the fact that we do have BTD, and we've been able to pool data sets from AML and ALL together. So it's a little -- the KMT2A I think, is a little bit advantaged, if you will, by the pooling that we're going to be doing relative to what you -- what their visibility around enrollment. NPM1, we had given guidance that we'll have enrolled in the second half of the year, and we're quite happy with that pace.

Got you. And so is that kind of the data that you've shown so far and also the kind of the accelerated approach from the FDA has kind of allowed that increased pace.

I think it's -- what I was trying to indicate is that it's more about the fact that we have the ability to pull the data and bring it together. ALL was going to lag AML. We've always said that. But now we have the ability because we don't have to enroll for this analysis. We don't need to enroll 64 patients times 2. In other words, both don't have to be fully enrolled in all in order to have the pooled analysis that we need. So it has the effect of pulling in ALL on a more accelerated time line into one filing. So that's part of the what we're dealing with here. I think the other side of it is KMT2A has -- the patient populations are different, right? KMT2A the patients really have nothing else after they fail first-line therapy, which most of them do, they have nothing else for their disease. And so physicians have been waiting for years for a an agent like this to come along to treat these patients. And so we've had receptivity very early on in our Phase I and our first patients were KMT2A patients. The body of evidence for NPM1 has taken a little bit longer. I think it's been very strong. The biology was a little less clear how NPM1 the same target that drives the tumors. And so I think the idea being that the body of knowledge has taken a while to accumulate. I think physicians now can appreciate based on the data that they're seeing most recently that this is a driver, not only a driver mutation, but this agent can really impact that mutation as well for NPM1. There are other agents -- targeted agents that are used for patients. Patients do -- NPM1 patients do better in the front line than KMT2A patients do take a little bit longer to relapse. And in those cases, there are targeted therapies to address the co-mutations for many of these patients, which continues on into the relapsed/refractory setting. So there's a little bit of competition, if you will, for approved agents to treat these patients. When they get to the relapsed/refractory setting, I think there is -- they look the same. We believe that they are similar to KMT2A in terms of prognosis. And so that's when we're seeing them. So the opportunity to get patients is impacted by the current treatment of patients by other agents. And that, I think, has something to do with overall how we're enrolling patients.

Got you. And the decision to pull AML and ALL what drove that? And is there a difference between the disease? Or are they sufficiently close to.

Yes. I think it's a good question. I think the agency when we first started this program, we separated out AML from ALL in adult pediatrics and then slowly started to see things converge. I think the BTD that we received in the fall of last year was very important because the agency had asked us to look at all the data, they cut the data and they wanted to understand whether the disease was with the mutation or the rearrangement was really the same in AML and ALL and after looking at all the data, I think they concluded it was. And so they gave us the broadest designation, which led to further conversations about, well, if you see the disease the same and all of these -- in the different -- in AML and ALL adults and pediatrics, can we do a pooled analysis in order to have one filing rather than wait for ALL. And that led to this approach.

Got you. And how homogenous is that group? I mean it's a rearrangement at the end of the day, and there's different rearrangement partners can -- does your Menin inhibitor bind the same way or act the same way with those different rearrangements? And maybe kind of what's the percentage of those rearrangements that's kind of one part of this is multiple.

Yes, do you want to...

Yes. Thanks, Peter. So the rearrangement occurs at the C-terminal end of MLL1, the binding of MLL1 home is at the end terminus. So it really doesn't matter what the rearrangement partner is. It's still binding with the same 5 amino acids to Menin, and that's what you're inhibiting with a Menin inhibitor.

Got you. And there's no kind of steric changes or anything going on that's -- like you've seen this in different patients take.

Yes. And I think in our ASH presentation, we break out the top 10 different rearrangements that are included in the trial, which patients. And as you saw, we're seeing a 50-plus percent response rate across all patients with a KMT2A rearrangement. Really deep durable responses. So we haven't -- we -- I don't think we have enough patients to say, is there a statistical difference between rearrangement A and rearrangement [ B ]. But in general, the effect of Menin inhibition seems to be very impactful across all of the range.

And I think we -- just to follow on to that. We know this to be true based on preclinical data as well, which we profiled lots of different partners in terms of the rearrangements and now we see the same impact on the model. So it has been consistent preclinically as well as the [indiscernible].

Got you. Your comments around kind of the NPM1 patients and how it kind of coalesce in the relapsed refractory setting. How -- does that mean in any way that first-line setting because there are other medications they can be on or be combining with. Does that just make it more complex? Should we be thinking of that as a smaller opportunity, thinking about drugs in that space?

Yes. I mean it's -- for MPM 1, it's a little bit more complex. I mean [ ven/aza ] used in the front-line setting, as you know, for unfit patients. And so the ability to impact these patients early, I think, will be important. But I think you'll have to combine with those other regimens in order to have access to those patients, whether it's with ven/aza 7+3, high-dose chemotherapy in the [ FIT patient ] population, and we'll look at all of those combinations and potentially to have a follow-on or maintenance-type treatment for patients who have gotten to a response, but you want to keep them in response. And if they have either NPM1 or KMT2A rearrangement. You want to keep them in the CR state for as long as possible in an MRD-negative state, if you will. And so we're looking at all of that in some of our subsequent trials in order to impact the front line. And to your question about market size, I think relapsed/refractory setting, I think it's between KMT2A and NPM1. I think there's -- and we have often said that it's up to 40% of the patients overall in AML and ALL. I think that's true, I think, from the frontline setting. I think in the relapsed/refractory setting, it's perhaps a little bit more equal, maybe overrepresented on KMT2A, a little less than 30% on the NPM1. So there are more approximate for each other than necessarily what you see in the front line, which is probably more of that 30% and 10% breakdown.

Perfect. Just as we think about safety, kind of, I guess, the QT comes up often, how -- is it to manage? Does it get better or worse if you move to frontline?

Yes, it should certainly not get worse. I think the -- it's been a very easily managed phenomenon for us. I think the -- our drug, as many of you know, has a reasonably short half-life does not accumulate QT prolongation is something that relates to interaction with the HER channel, which we knew about from the time the drug was in the preclinical stage. We monitor for this. We pick it up very early on in treatment. And so patients who have a Grade 3 QT, which is 10% or less in our trials. We dose adjust those patients. They don't need to go on a drug holiday or stop dosing. We dropped their dose, 1 dose down. Many of those patients, if they had a grade 3 well, have gone on and done very, very well with CRs, transplant, stayed on drug for months. But this is not something that patients have even know that's happening. Physicians are not concerned about what you get concerned about is this if they have an ongoing QT and it gets more serious over time, we're seeing resolution within one dose very often. And so -- and that's because it's a [ Cmax-related ] effect once you drop the dose, it kind of goes away. And so patients are not walking around with a prolonged QT that could be problematic. We haven't seen any [ casas ] or any arrhythmias or anything that would signal to physicians that they should be concerned. And essentially, it's very easily managed. So for us, it hasn't been something of concern. We don't expect it to get worse in the front line. In fact, by the time patients actually get to the relapsed/refractory setting and they take a chemo and things that could have a long-term effect on their heart. And so that could prolong the -- or lead to a QT potentially in the relapsed/refractory setting. Earlier on, they don't have as much interaction with those therapies, of course. So the chances are that it could be even less of an impact. As I said, if we don't think it's something to be worried about physicians. And I know you've talked to many physicians are not particularly concerned at all with the side effect and with our drugs, in particular, not so -- and they're used to seeing it, right, with lots of other drugs in AML.

Got you. I guess just going back to the pooled analysis included in ALL. Would you break that out when we see that data set? And what's the expectations around response rate you'd see or CRA you see for the ALL patients?

Yes. I think the expectations are the same. I think when we say break out the data, I assume you mean that when we present the pivotal data, we'll have, as I mentioned, in the third quarter, we'll have top line data and then we'll follow on perhaps at a medical meeting with a more fulsome data set. We haven't really said what the cadence of that data will be. We tend to like to reserve something so we can present it at a medical meeting. So we expect that we will be breaking that out at some point, but you'll certainly see it as time goes on. I'm not going to speculate exactly when that will occur. But yes, I think up until now, and I think reinforced by the BTD that we received for AML and ALL patients, response rates have been pretty similar.

Got you. What are the puts and takes between kind of, I guess, the Phase I data and kind of where that CR rate is and there's -- I guess there was some debate around what the CR rate was between the rearranged and the NPM1 patients, kind of how that's kind of flushing out? And then how we kind of crosswalk between the Phase I and Phase II data or pivotal data?

Right. I guess the population should be generally the same between Phase I and Phase II. I mean there's always a chance that we can be treating slightly earlier stage patients than we got in the Phase I when you first start a trial and the mechanism is unproven. Physicians tend to use it as a very last resort. There's always a chance. And for us, fifth-line for us to move up on potentially one line of therapy and interact with these patients earlier could benefit the data set, but that's to be determined. But sorry, what was your...

There was a couple of questions buried in there, but one of them was just around the kind of the underlying CR rate kind of patients included excluded...

Sure. So right. So I think we had presented data at the most recent update of breaking out NPM1 versus KMT2A and at the RP2D, which is, I think, what was one of your questions, and we presented that data in the same way that the FDA asked for it, which was at the RP2D and what will show in the Phase II, and they were both 27%. Fewer patients NPM1, of course. We only had 11 overall, 3 of those patients at the RP2D were CR/CRH, and so I think we showed a 27% for both. And I think that's something in terms of the bar and what we would expect to see in the Phase II, we'd say we would expect similar data for that data set as well.

Got you. And maybe I guess the final question just around DS kind of what's the acceptable rate you're kind of hearing from physicians? I know you're kind of scoring better in that [ certific ] profile?

Right. Well, we don't get those questions really because I think we -- for DS, we've seen 16% grade 2. So it hasn't been an issue. We have a drug profile that is very well -- it seems to be very well accepted by physicians at this point. So DS questions we don't really get. I think some of our competitors have seen Grade 5 DS and even heavy rates of grade 3, I think it's -- that's a potential problem for those agents that have to deal with severe DS. Physicians aren't that excited about it because it's something that is hard to predict, right? And it comes on and it sometimes comes on quickly. And so you have to treat aggressively with steroids in Hydria to get it under control, and there's always the chance for some drugs that's not possible for us. Whatever we've been able -- when we see it, we treat it aggressively with the physicians treated aggressively up front. And we've been able to get it under control. It has not been a prompt. So physicians aren't really kind of thinking about it in those terms for us, but maybe for others.

Yes. If you increase risk because of safety, then you should -- the only reason you're going to choose that drug is if they give you something in terms of efficacy, there has to be a trade-off.

No, exactly. So do you think it gets even better as you move into frontline with combination regimens or I guess it depends on which kind of chemo is...

I mean we've heard that hypothesis. I don't know that anybody knows if that's true or not. It seems rational. But again, if we're not seeing anything as a monotherapy, we wouldn't expect it to get worse in combination.

Okay. Perfect. I guess GVHD, kind of the data set in the middle of the year, kind of what should we expect temper patients durability? What should we be honing in on?

Yes. We're very excited for our GVHD data just like we are for Revumenib. We published the Phase I/II data set at the end of last year, showing a 68% response rate overall. Efficacy across any organ manifestation, really high levels of response on the lease symptom score. We think it's a very competitive profile for axatilimab. And I think there's some key points of differentiation that will help it distinguish itself in the market. So axatilimab is the only agent going directly at the macrophages and targeting reducing that population, which is responsible for the fibrotic process in this disease, which is ultimately what leads to end organ damage in these patients. And so we've seen significant benefits across the skin manifestations, which are the most common as well as the lung manifestations which are the most hard to manage and ultimately one of the most fatal conditions that patients develop. And so as that plays out, we anticipate that perhaps it's not necessarily even a treatment algorithm basin line of therapy, but perhaps based on manifestation of what does this disease present as in a given patient and which is the best drug to address that. And I think Incyte got really excited about the opportunity with axatilimab and bringing it even earlier in treatment so that you could address the fibrotic process early on and maybe change the course of the disease and improve survival in these patients. And so that's something we're really excited to get started later this year.

Do you think the label would kind of narrow it around that or just reflect the idea of...

No, I think you probably try to showcase where you've shown an efficacy benefit, but I think the label would be similar to what REZUROCK.

Do you -- have you started to get that feedback from physicians as well, just like [indiscernible] or loan, this is when I'd use it? And do you think it will be used differently in the real world versus the clinical trial setting?

I think we're hearing really significant excitement from physicians at Tandem and the TCT meeting. They're really excited to talk about axatilimab and get access to axatilimab. We over-enrolled our trial because they wanted to put a lot of patients on the drug. I think it's an evolving treatment landscape. There is no established paradigm today. There's only a couple of drugs that have been approved. And before that, it was all generic off-label agents that don't have large data sets of how does this -- how to treat the disease. And so I think as we start to have more data and thanks to our partnership with Incyte, who's out there already talking to physicians with Jakafi. And I think they can keep this top of mind and it helps them think about how will they incorporate it in the future. But I think it's a little bit to TBD.

Do you think the main use is going to be in combination versus single agent just your ideas of how it would be used from physicians.

I mean today, the first indication will be as a monotherapy. And I think in general, most of these agents are used as monotherapy with the exception of adding on steroids or calcineurin inhibitors. But yes, the goal would be to move it into earlier lines of therapy and maybe like in oncology, it's best to treat more aggressively?

I think the promise of moving steroids out is a big idea. And I think that's what's really on the table here. Can you change the treatment paradigm for physicians, patients and really get steroids, eliminate steroids as an absolute necessity in the front line. And that's what we really want to get to. That's the big -- even bigger idea than just monotherapy.

Perfect. Thank you for allowing me to [ take ] extra time. So thanks so much.

Thank you.

Thank you.

Thank you.

See you.