The Barclays Healthcare Conference in Miami. Do email us or message us on Bloomberg if you have any questions. My name is Peter Lawson. I'm one of the SMID-cap biotech analysts at Barclays. I'm really delighted to have up on stage with us the pretty broad representation of management from Syndax. We've got Michael Metzger, CEO and Director, Anjali Ganguli, Chief Business Officer, and Keith Goldan, CFO. I guess first question is just around menin inhibitor and the phase II, kind of how enrollment's going. I'd love to know about this kind of the pace of enrollment for AUGMENT-101, kind of between the two different classes. The NPM1 versus the rearranged KMT2A.
Maybe if you don't mind.
Yeah.
First of all, thank you for having us. It's always a pleasure to be at the Barclays conference and to be in Miami with you, Peter. Maybe I'll take a two-second introduction to Syndax so people understand.
Perfect.
Where we are before we jump right into the questions.
Okay.
A very exciting time for the company. We've, many of you know, we have two programs in pivotal trials, key malignancies. First one is revumenib, which is the first in class, best in class, menin inhibitor directed at KMT2A leukemia, as well as NPM1 leukemia, both in AML and ALL adults and pediatric patients. That program will have its first of its two pivotal readouts this year. The first one, KMT2A rearranged leukemia in 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 two cohorts. That'll be available in the third quarter with our first filing by the end of the year. 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. What that leads to is potentially lots of data this year. Two filings as well as potential approvals and launch next year for both drugs. 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.
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.
Perfect.
I just wanted to start there. Now.
No, thank you. Maybe pivoting 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. Michael will review a lot of the catalyst value creation events that we have between now and then. There are many. We expect that to be, you know, circa one year after launch, of both of our drugs.
Gotcha. I guess the obligatory question at the moment, kind of exposure to SVB and kind of.
Sure.
regional banks and I guess non-bank lenders. Anything we should be kind of thoughtful of, particularly with this kind of disruption scaling?
Sure. I'll start by saying we're in a very good position. you know, luckily or thankfully, we had 98% of our cash in equivalents at another institution as custodian. You know, like I said, we ended the year with almost half a billion on the balance sheet. We have a cash manager to kind of maximize the return of that in a very under the auspices 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 and 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. We've been able to transact, make payroll, everything this week.
Gotcha. Would that be transferred out or?
We're evaluating what we're gonna do for the operating accounts that we use. Again, we keep most of our cash, 98%, being managed by a third party. 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, you know, what do we do with that operating account relationship going forward.
Perfect. Thank you so much. I didn't anticipate to be asking these questions.
Yeah, of course.
Underappreciated finance departments of every company in our space. Now they're, people know a lot more about operating accounts and how it all works.
No, exactly. It goes through round in these cycles, right? Back to the data.
Yes.
kind of enrollment pace, between the two different classes in kind of AML and I guess ALL, but the NPM1 versus the, rearranged patients.
Sure.
Kind of how's that tracking?
Yeah.
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. The enrollment continues to pace well. We gave guidance that, and we'd have the first cohort fully enrolled. We weren't necessarily indicating which one was to be the first, of the three to be enrolled in the first quarter. Turns out it was 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 .
The KMT2A, I think, is a little bit advantaged, if you will, by the pooling that we're gonna be doing, relative to what you know, 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.
Gotcha. It's like, kind of the data you've shown so far and also the kind of the accelerated approach from the FDA has kind of allowed that.
Yeah, I think that's.
Increased pace.
I think it's what I was trying to indicate is it's more about the fact that we have the ability to pool the data and bring it together.
Yeah.
You know, ALL was going to lag AML. We've always said that. Now we have the ability, 'cause we don't have to enroll for this analysis, we don't need to enroll 64 patients times two. In other words, both don't have to be fully enrolled in all this in order to have the pooled analysis that we need. It has the effect of pulling in ALL on a more accelerated timeline into one filing. That's part of the, what we're, what we're dealing with here. I think the other side of it is KMT2A has, you know, the patient populations are different, right? KMT2A, the patients really have nothing else after they fail first-line therapy, which they, most of them do, they have nothing else for their disease.
Physicians have been waiting for years for an agent like this to come along to treat these patients. 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, you know, taken a little bit longer. I think it's been very strong. The biology was a little less clear how NPM1. It's the same target that drives the tumors. I think the idea being that the body of knowledge has taken a while to, you know, 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. NPM1 patients do better in the front line than KMT2A patients do, take a little bit longer to relapse. In those cases, there are targeted therapies to address the co-mutations for many of these patients, which continues on into the relapse refractory setting. There's a little bit of competition, if you will, for approved agents to treat these patients. When they get to the relapse refractory setting, I think there is, you know, they look the same. We believe that they are similar to KMT2A in terms of prognosis, that's when we're seeing them.
The opportunity to get patients is impacted by the current treatment of patients by other agents, and that's, I think, has something to do with overall how we're enrolling patients.
Gotcha. The decision to pull AML and ALL, what drove that? Is there a difference between the disease or are they sufficiently close to?
It's a good question. I think the agency, when we first started this program, we separated out AML from ALL in adults and 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 to look at all the data. They cut the data, and they wanted to understand whether the disease was, whether the mutation or the rearrangement was really the same in AML and ALL. After looking at all the data, I think they concluded it was. So they gave us the broadest designation, which led to further conversation about, well, if you see the disease the same in all of these, you know, in the different...
In AML and ALL in adults and pediatrics, can we do a pooled analysis in order to have one filing rather than wait for ALL? Then that led to this approach.
Gotcha. How homogenous is that group? I mean, it's a rearrangement at the end of the day, and there's different rearrangement partners. Does your menin inhibitor bind the same way or act the same way with those different rearrangements? Maybe kind of what's the % of those rearrangements that's kind of one partner versus multiple?
Yeah. Do you wanna?
Yeah.
Yeah.
Thanks, Peter . The rearrangement occurs at the C-terminus end of MLL1. The binding of MLL1 to menin is at the N-terminus. It really doesn't matter what the rearrangement partner is. It's still binding with the same five amino acids to menin, and that's what you, what you're inhibiting with a menin inhibitor.
Gotcha. There's no kind of steric changes or anything going on. It's like you've seen this in different patients.
Yeah. I think in our ASH presentation, we break out, you know, the top 10 different rearrangements that are included in the trial, which patients. You know, as you saw, we're seeing a 50+% response rate across all patients with a KMT2A rearrangement, really deep durable responses. I don't think we have enough patients to say, is there a statistical difference between rearrangement A and rearrangement B. In general, the.
Effect of menin inhibition seems to be very impactful across all of these rearrangements.
Gotcha. I think we, just to follow into that, I think we know this to be true based on preclinical data as well, in which we profiled lots of, you know, different partners in terms of the rearrangements, then we see the same impact on the model. It has been consistent pre-clinically as well as clinically.
Yeah.
Gotcha. Your comments around kind of the NPM1 patients and how it kind of, they kind of coalesce in the relapse refractory setting, 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 other drugs in that space? Yeah, I mean, for NPM1, it's a little bit more complex. VenAza is used in the frontline setting, as you know, for unfit patients. The ability to impact these patients early, I think, will be important.
I think you'll have to combine with those other regimens in order to have access to those patients, whether it's with VenAza or 7+3, high-dose chemotherapy in the fit patient population. We'll look at all of those combinations and potentially to have a follow-on or a maintenance type treatment for patients who have gotten to a response, but you want to keep them in response. If we, if they have either NPM1 or KMT2A rearrangement, you want to keep them in a CR state for as long as possible and in an MRD negative state, if you will. We're looking at all of that in some of our subsequent trials, in order to impact the front line.
To your question about market size, I think relapse refractory setting, I think it's between KMT2A and NPM1, 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 relapse refractory setting, it's perhaps a little bit more equal, maybe over-represented on KMT2A, a little less than 30% on the NPM1. They're more approximate for each other, you know, for each other than necessarily what you see in the front line, which is probably more that 30% and 10% breakdown.
Perfect. Just as we think about safety, kind of, I guess the QT comes up often. How easy is it to manage? Does it get better or worse as you move to front line?
It should certainly not get worse. It's been a very easily managed phenomenon for us. 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 hERG 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. 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 drop their dose one dose down.
Many of those patients, if they had a grade 3, well, have gone on and done very well with CRs, transplant, stayed on drug for months. 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 relate, you know, gets more serious over time, we're seeing resolution within one dose very often. That's because it's a Cmax related effect. Once you drop the dose, it kinda goes away. Patients are not walking around with a QT, a prolonged QT that could be problematic. We haven't seen any Torsades or any arrhythmias or anything that would signal to physicians that they should be concerned. Essentially, it's very easily managed. 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 relapse refractory setting, they've taken chemo and things that have, you know, could have a long-term effect on their heart. That could prolong the a QT or lead to a QT potentially in the relapse refractory setting. Earlier on, they don't have as much interaction with those therapies, of course. The chances are that it could be even less of an impact. As I said, we don't think it's something to be worried about physicians. I know you've talked to many physicians are not particularly concerned at all with this side effect and with our drug in particular, not so, and they're used to seeing it, right? With lots of other drugs in AML.
Gotcha. Thank you. I guess just going back to the pooled analysis of including the ALL, would you break that out when we see that data set? What's the expectations around the response rate you'd see or CR rate you'd see for the ALL patients?
Yeah, I think the expectations are the same. I think when we say break out the data, I assume you mean 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. We expect that we will be breaking that out at some point. You'll certainly see it as time goes on. I'm not gonna speculate exactly when that will occur.
Yes, I think up till now, and I think reinforced by the BTD that we received, for AML and ALL patients, response rates have been pretty similar.
Gotcha. What are the puts and takes between kinda, I guess, the phase 1 data and kind of where that CR rate is? 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 1 and phase 2 data or pivotal data?
Right. I guess, the population should be generally the same between phase one and phase two. I mean, there's always the chance that we could be treating slightly earlier stage patients than we got in the phase one when you first start a trial and the mechanism is unproven, physicians tend to use it as a very last resort. There's always the chance and for us, fifth line, for us to move up potentially one line of therapy, and interact with these patients earlier could benefit the dataset, but that's to be determined. Sorry, what was your?
Sorry. There was a couple of questions buried in there, yeah, one of them was just around the kind of the underlying CR rate.
Under the CR rate.
I know there were kind of patients included, excluded.
Sure Right. I think we had presented data at the most recent update of breaking out NPM1 versus KMT2A at the RP2D, which is I think what was one of your questions? We presented that data in the same way that the FDA asked for it, which was at the RP2D and what we'll show in the phase two, and they were both 27%. Fewer patients, NPM1, of course. We only had 11 overall. Three of those patients at the RP2D were CR/CRh. I think we showed a 27% for both. I think that's, you know, something in terms of the bar and what we would expect to see in the phase two, we'd say, you know, we expect similar data for that data set as well.
Gotcha. Maybe just 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 side effect profile.
Right. Well, we don't get those questions, really, because I think we've for DS, we've seen 16% grade 2, so it hasn't been an issue. We have a drug profile that, you know, it seems to be very well accepted by physicians at this point. DS questions we don't really get. I think some of our competitors have seen grade 5 DS and even, you know, 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, you know, hard to predict, right?
It comes on, and it sometimes comes on quickly. You have to treat aggressively with steroids and Hydrea to get it under control. There's always the chance for some drugs that that's not possible. For us, when we see it, we treat it aggressively or the physicians treat it aggressively up front, and we've been able to get it under control. It has not been a problem. Physicians aren't really kind of thinking about it in those terms for us, but maybe for others.
Yeah. If you increase risk because of a safety, then you should. The only reason you're gonna choose that drug is if they give you something in terms of efficacy. There has to be a trade-off.
Yeah. No, exactly. Do you think it gets even better as you move into frontline with combination regimens? I guess it depends on which kind of chemo it is.
I mean, we've heard that hypothesis. I don't know that anybody knows if that's true or not. It seems rational. You know, again, if we're not seeing anything as a monotherapy, we wouldn't expect it to get worse in combination.
Yeah. Okay, perfect. I guess GVHD, kind of the data set in the middle of the year, kind of what should we expect in terms of patient's durability? What should we be honing in on?
Sure.
Please. Yeah. 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 Lee Symptom Scale. 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. You know, 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.
You know, 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, you know, ultimately one of the most fatal conditions that patients develop. You know, as that plays out, we anticipate that perhaps it's not necessarily even a treatment algorithm based on 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. I think, you know, Incyte got really excited about the opportunity with axatilimab in 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.
That's something we're really excited to get started later this year.
Gotcha. Do you think the label would kind of narrow it around that or just reflect that?
No, I think. You would probably try to showcase where you've shown an efficacy benefit, but I think the label would be similar to what Rezurock has.
Gotcha. Do you are you starting to get that feedback from physicians as well of just like, 'Yeah, for fibrotic or lung, this is when I'd use it' and do you think it would be used differently in the real world versus the clinical trial setup?
I think we're hearing really significant excitement from physicians at Tandem in the TCT meetings. 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 a evolving treatment landscape. There is no established paradigm today. There's only a couple drugs that have been approved, and before that, it was all generic off-label agents that don't have, you know, large data sets of how to treat the disease.
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, you know, I think they can keep this top of mind, and it helps them think about how will they incorporate it in the future. I think it's a little bit TBD.
Got you. Do you think that the main use is gonna be in combination versus single agent? Just your ideas of how it would be used from physicians.
Yeah. I mean, today, the first indication will be as a monotherapy, I think in general, most of these agents are used as monotherapy, with the exception of adding on steroids or calcineurin inhibitors. Yeah, 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. I think that's what's, you know, really on the table here. Can you change the treatment paradigm for physicians, patients, and really get steroids, eliminate steroids as a absolute necessity in the front line? That's what we really wanna get to. That's the big even bigger idea than just monotherapy.
Perfect. Thank you for allowing me to run into extra time. Thanks so much.
Thank you.
Thank you.
See you.