Thanks everyone for joining us at the Goldman Sachs Global Healthcare Conference. I'm glad you're all here, even though the sun finally started shining, which is, which is good news. We'll start out with: We are required to make certain disclosures and public appearances about Goldman Sachs' relationship with the companies that we discuss. The disclosures relate to investment banking relationships, compensation received, or 1% or more ownership. We are prepared to read aloud disclosures for any issuer during the sessions upon your request. However, these disclosures are available in our most recent reports available to you as clients on our firm's portal. In addition, updates to those disclosures are available by ticker on the firm's public website. Goldman Sachs agrees to host this conference on the basis that no third-party speaker will provide confidential or material non-public information.
In addition, by attending this conference, you provide Goldman Sachs the right to record and redistribute the conference information. The views of third-party speakers do not necessarily reflect those of Goldman Sachs. Really excited to be joined by the team from Syndax Pharmaceuticals today, ahead of several events coming, not, like, in months or years, but in weeks. It's a pretty exciting time to be in front of the Syndax team. Maybe let's start at a high level. Why don't you give us an overview of where things are and where things are headed?
Thanks, Madhu. Thanks for having us. It's a pleasure to be here at Goldman. I hadn't heard that full disclosure statement, so that's always.
Okay
... a good thing to start off with. thanks for joining us. As Madhu said, it's a really exciting time for Syndax. We've been in business for a number of years, but now we find ourselves with two pivotal programs, which we will probably discuss today in great depth. revumenib and axatilimab. We'll plan to have pivotal data for axatilimab in middle of this year, so in a very short period of time. We'll have 240 patient trial reading out, and then we'll have, with our partner, filing a BLA by the end of the year. That'll be exciting.
Obviously, a lot of work ongoing beyond our first initial registration program for chronic graft-versus-host disease with axatilimab in the frontline setting, and we're also starting an IPF trial before the end of the year. A lot of work ongoing beyond what you know, our first indication for axatilimab, and it's exciting. We have revumenib, which is our menin inhibitor, first-in-best-in-class as well. New mechanism, and now an exciting area for leukemic patients, having either KMT2A rearranged leukemia or NPM1 leukemia as well. This is the first agent that will be indicated, we hope, for KMT2A and NPM1 broadest potential opportunity, up to 40% of patients in acute leukemia. Again, very exciting.
We'll have our first pivotal study reading out in the third quarter of this year, and then an NDA filing before the end of the year. Again, lots going on, and the opportunity to be sort of first-in-best-in-class doesn't come too often for a company our size, so excited.
Maybe before we get into kind of those two readouts and those two programs, can we get a little bit of a hot take from the weekend? Obviously, you all had data at the European Hematology meeting. Do you want to walk through that data and also how we should think about those results?
Sure. Maybe, Neil, you want to-
Yeah, sure.
Okay.
We presented the data from Compassionate Use program. One of the things that it's important to bear in mind is that these were extremely sick patients who couldn't be included, for instance, couldn't be included in the pivotal program because they had CNS involvement, or graft-versus-host disease, or comorbidities, including other other malignancies. Also included... I won't go through all of the data, 'cause it was quite a complex presentation, but maybe just to draw your attention to in particular, six patients who had undergone response to revumenib, got transplanted, also incredibly heavily pretreated, including, you know, several of them had failed more than one prior transplant. Those six patients then went on to revumenib maintenance within the Compassionate Use program .
Four of them, I think, stayed on treatment for over five months, and at the time of the cutoff for the data that we presented in the poster, three of them were still ongoing. One patient was still ongoing at almost a year, like, 330-something days, and two other patients also for extended periods of time. We thought it was important to get those data out there because we believe, I mean, in the pivotal study, of course, patients can respond, become MRD negative, be transplanted, and then on protocol, go back onto revumenib maintenance therapy. We thought that it was important to share the information that we shared over the weekend in that context, because we believe that that's gonna be, you know, the standard of...
That will be the practice of medicine once revumenib is approved for those patients.
Okay, with that connecting line, we'll come back to revumenib. Let's start with the more proximal readout with your CSF-1 receptor drug, axatilimab. I guess kind of as you think about the catalyst path of this program, how should we start thinking about, like, the data through mid-2023 on forward to 2024?
Yeah, I think I mentioned briefly when we'll have. Again, this is third-line. The indication will be for third-line chronic graft-versus-host disease patients who had failed at least one prior therapy. Again, the data will be in 240 patients. It's a randomized trial, so you'll see, you know, patients at different doses. Three different doses. One is a convenient dose, three milligrams every four weeks, and then two other doses at two weeks. The data should be available in the middle of this year.
We can't necessarily be more specific than that as of now. Data will come. We'll present that with our, hopefully at a medical meeting, before the end of the year as well. We'll have a BLA filing before the end.
... Okay, maybe starting with that program, the mid-2023 AGAVE readout, just at a high level, can you walk us through the rationale for CSF1 pathway inhibition in chronic graft-versus-host disease?
Sure. Neil, do you want to take that?
Yeah, sure. CSF1R signaling is important for the for monocytes basically becoming macrophages. Once the macrophages are localized in the tissue, in this case, it could be any, you know, multiple different tissues throughout the body because graft versus host disease affects, you know, many different organ systems. The macrophages can adopt a couple of different phenotypes, actually two different phenotypes. They can be pro-fibrotic or pro-inflammatory. There are, and all of that goes back to CSF1R signaling. The hypothesis, which is now proven from our initial clinical data, is that if you block CSF1 signaling, that you will block these pathogenic mechanisms mediated through macrophages in the tissues.
Because it's the same or similar in all of the affected tissues, we've seen activity throughout, you know, different system organ classes. That's the hypothesis for the MOA, which is now, of course, proven clinically.
Right. maybe coming into brass tacks here, as you think about the mid-2023 readout, what do you think is the bar for both, like, in a primary endpoint of objective response rate and duration of response in this third-line GVHD population?
Yeah. Angela, you want to take this?
Sure. Yeah, thanks, Neil. you know, what we've seen in the last couple of years, two different drugs get approved in chronic graft-versus-host disease, Jakafi in the second-line setting, with a response rate around 70%, Rezurock, similar level of response. In the third-line setting, we feel that anything above 60% would be competitive in that population, definitely approvable. In terms of duration of response, the primary endpoint is response at cycle 7, day 1, so after 6 months or by 6 months of treatment. I think physicians are looking for optionality for these patients. As Neil said, this mechanism treats both anti-fibrosis and anti-inflammation seen in GVHD, which isn't something that's addressed by the current standards of care or the current therapies approved. It gives both physicians and patients some optionality.
We've seen efficacy across all organ systems tested, and we believe there's some potential benefits from that axatilimab could bear on the extent of fibrosis on these organs that we aren't seeing with other agents.
Maybe following up on that, I mean, something that comes up a lot in discussions is the fact that axatilimab in its current form is an IV formulation versus many of the novel therapies in GVHD are oral. How do you think about how that influences, not just the kind of in a post-approval setting, the kind of utilization of axatilimab relative to these other novel agents?
Yeah, why don't you continue?
I mean, I think it all comes down to efficacy and what these patients need. A lot of times when the disease is out of control, they are going to see their physician on a regular basis to maintain control of their disease. axatilimab is IV, but it's a 30-minute push infusion. It's not a difficult process, they can do it in the office. It actually, in some cases, physicians like the fact that they know their patients are compliant. We have, in the AGAVE trial, allowed patients, after 6 months of treatment, the physicians, the choice to translate to a once-monthly dose. That will be data that we'll have and may enable real-world use.
I think also that we're, you know, we're working on a sub-Q formulation that could also enhance the benefit of axatilimab. I think it's really about the efficacy, and if you're able to control the disease, I think it will be a compelling opportunity. A lot of the agents that are used today, you know, besides these oral ones that were recently approved, are even more onerous than what we're talking about for axatilimab. It's not, it's not a new paradigm for this class of disease.
I'd also say that just to follow what Angela said, I mean, the enthusiasm by investigators has been high, and I think the trial was intended to enroll 210 patients or so, and we enrolled 240 patients. There's just been a lot of interest in what we're doing, and the unmet need is there. I think, as Angela said, it's about efficacy, it's about controlling patients, it's about making sure that you're not making their quality of life worse than it was before, of course. They want to see these patients and interact with them, and I think a treatment like this fits in very well with their paradigm.
I guess kind of more and more focusing in on kind of, are there certain manifestations of graft versus host disease where you think there's a specific utility, specific benefit to axatilimab relative to other, agents? I think we think particularly the lung, which is the recent data you guys put out at ATS.
Mm-hmm.
How do you think about kind of like specific organ involvement that could kind of more meaningfully drive uptake for axatilimab relative to other agents?
Yeah. Do you want to talk a little bit about the lung?
Yeah, sure. I'll get to the lung, but just to reiterate the point that several of us I think we've all made, is that the drug is active across all affected organ classes, right? That's important. With respect specifically to the lung data that we presented at ATS, it was in a subgroup of patients with bronchiolitis obliterans, an extremely severe manifestation or consequence of chronic graft-versus-host disease, amongst some others, where, you know, the lungs are severely affected. It's a subgroup of patients from the study because.
... it was a subgroup of, like, nine patients who had at least one post-baseline pulmonary function assessment. Baseline and at least one post-baseline. What we showed in the poster is that five of those nine patients actually had improvements in their FEV1, which is pretty remarkable, right? The other four had stabilization of pulmonary function. You know, that in particular, you know, is highly encouraging.
A couple weeks from now, we'll all be sitting in front of our computers, press release, top-line data from axatilimab and graft-versus-host disease. What should we expect to see from the top line in a few weeks' time versus a kind of later, more fulsome data presentation?
Yeah, it's always a tricky question, right? Look, I think the objective here in presenting top-line data is always to give people, stakeholders, an understanding of what the drug can do and the profile differences relative to competition. I think you want to get as much out there into the hands of physicians, as well as investors, to understand kind of the profile you're dealing with. Having said that, I think we're gonna obviously try to present this data at a medical meeting, so we would want to hold back some elements of what's available to us, and we'll continue to do analyses that will make that a robust presentation at a medical meeting. I think we'll have enough in the top line.
Without giving you specifics, I think there'll be enough in the top line to, you know, fully assess the, and characterize the activity.
Let's shift gears over to revumenib in KMT2A rearranged and NPM1 mutant leukemias. Why don't we start before we kind of get into the more mechanistic data, remind us what the kind of treatment unmet need is in these two types of leukemia, the KMT2A rearrangements and NPM1 mutant disease?
Yeah. Do you want to take that?
Yeah. For the KMT2A population, the patients in particular that we've been treating on the study have been, you know, median of four prior lines of therapy. For these patients, there really is no treatment alternative, right? They are end-stage patients, and therefore, the kinds of responses that we've alluded to a little bit earlier on that we're observing, it's been pretty special, right? Patients who are actually, you know, close to end of life, suddenly actually responding and having extension to their lives or even going on to transplant. For those patients, it's a, you know, particularly severe form of the disease, and there's really very little that works, right?
They're a very poor prognosis group in general. For NPM1, it's a little bit different. NPM1 represents a sort of, you know, intermediate risk factor in when they're newly diagnosed. I think we also have to put that. You have to put that into context, right? AML overall is not a great disease, right, in terms of overall prognosis. The fact that there's a large subgroup of patients fall into an intermediate risk population, at least at initial diagnosis, and we shouldn't, you know, we should be careful how we interpret that. However, once patients relapse, that good or that intermediate or better prognostic association is lost, right? Once an NPM1 patient relapses, they begin to assume a much more high risk profile, right?
How they're currently managed is somewhat different because they still may respond to existing therapies, to chemotherapy, if they've got co-mutations such as FLT3 or IDH mutations. Particularly for FLT3, they may be, even if they've been previously, treated with FLT3, they may be reexposed to FLT3, where an alternative FLT3 therapy is available. As they fail, subsequent lines of therapy, so second line, third line, then they become higher and higher and higher risk. Yeah, go ahead.
That's okay. We're gonna come back to that later on.
Yeah.
With all of that in mind, can you walk us through again the rationale for targeting the menin-MLL interaction in these two genetically defined subsets of leukemia?
Yeah, sure. Let's start with menin KMT2A rearrangements. The KMT2A rearrangement in association with menin has been shown to drive HOX gene expression , okay? The genes that are driven by those particular transcription factors are associated with maintenance of the leukemic state, right? In other words, it's beneficial to have that complex, the KMT2A menin complex, KMT2A/R menin complex, driving these pro-survival genes, right? They maintain the cells in a primitive state, closely called blasts, and the cells continue to replicate, right? They're like parasites on the human body. What happens when you switch that off by basically giving revumenib and breaking apart that complex, is that the genes stop being transcribed, and the cells start to differentiate into something that approximates normality.
Once that happens, then various complex, various processes within the cells, apoptosis and associated. Apoptosis is programmed cell death, kick in, right? The genes have been preventing that, and once those processes kick in, then the cells realize, the internal machinery of the cells realize that actually there's something wrong here, and the cells die, okay? The mechanism is quite similar with NPM1, where NPM1 is also associated in conjunction with menin KMT2A in driving HOX gene expressio n. The same, so pro-survival signals for the cells, pro-leukemic signaling for the cells. Again, once the once that signaling is broken up, same thing happens, which is the cells begin to differentiate.
Their internal machinery kicks in and realizes that actually they're not, you know, they shouldn't be alive, and they undergo programmed cell death.
Okay, great. With that rationale in mind, can you walk us through briefly the existing clinical results for revumenib in the phase 1 portion of the AUGMENT-101 trial?
In brief, I think many of you know, the results most recently presented at ASH was it's our phase 1 results in 60 patients who either had the KMT2A or NPM1 mutation. Response rates of what we track for the primary endpoint is CR/CRh, and that was 30% between the two populations, 27% at the recommended phase 2 dose. The median duration of response was 9.1 months. We had up to, I think it was about 40% of patients going on to transplant who responded, which is a very high number, MRD rate of close to 80% in these patients.
These are patients who have achieved minimal residual disease by a very sensitive measure, which is what is generally required to go to transplant for physicians, that's what's led to a very high transplant rate. What we've seen is patients have stayed on, as I said, for 9.1 months. Many patients had asked to go back on, or physicians had asked to put their patients back on transplant, or rather back on drug post-transplant, that was not allowable in this trial, but we've been able to do that in our pivotal trial. Time to response, very quick, less than a cycle.
Patients are actually getting drug, going to response, and getting to response very quickly, which is important, especially in a disease like leukemia, where patients are at, you know, sort of the end of their journey and need something to intervene quickly. That's the general reprise of the data.
Okay, great. kind of with those results in hand, can you walk us through the phase two portion of AUGMENT-101? more kind of practically, what the cadence of data updates could be from the cohorts and that study?
Right. I think we've mostly covered this, but I'll kind of tease it out again. We have three cohorts in the pivotal trial. There's an AML KMT2A cohort, an ALL KMT2A cohort, and an AML NPM1 cohort. Each of the cohorts are 64 patients, adult patients, up to 20 pediatric patients can be enrolled as well. The statistics drive off of the 64 adult patients. We had said that we're pooling the KMT2A cohorts together, so that'll be the first analysis that comes out, that'll lead to our first filing. The NPM1 will be available. We'll have that fully enrolled this year and then data next year.
Okay. Maybe let's come back to, like, the very early of coming back to KMT2A. As we think about this data coming, potential approval and gonna use case, where do you think this drug fits in relative to the kind of regimens of care that exist in KMT2A-rearranged leukemia?
Yeah, I mean, I think simply stated, that these patients don't have anything specifically for their mutation, for their rearrangement. These patients, typically in the frontline setting, get chemotherapy, and then they relapse rather quickly, and so they're sort of out of options. Again, the idea being, you would love to be able to get them to a transplant as quickly as possible, you have to get them into an MRD negative CR, and that's where our drug comes in. It could be as early as first relapse, even with this first indication, where they're going to get our, get revumenib and hopefully get them to a CR and get them to transplant.
As Neil mentioned earlier, the emerging paradigm in relapse refractory disease is to be able to put them back on, these patients back on treatment once they've got engrafted, you know, post-transplant. That's the idea being you can get them to a complete cure, a durable remission, and keep them on for hopefully many, many months.
Yeah, that actually gets to the kind of eternal optimist versus the eternal pessimist conundrum, that this drug works so well at getting you the minimal residual disease, you get to transplant, then you don't have to take the drug anymore. How do you think about the kind of path effectively? In the trial, you're running the option of maintenance therapy post-transplant.
Right.
how do you like the kind of regulatory path to getting on-label use of post-transplant maintenance on revumenib?
Right.
in the KMT2A population?
Right. I'll maybe handle the first part of it, which is, you're right. This is a trial we're running that is not intended to have a label for maintenance. I think that's an important distinction here. We will have experience in the maintenance setting in relapse refractory disease, and that experience, I think, will influence physicians. That is, in fact, an important piece of how they should practice medicine. The idea being that these patients are extremely fragile, right? They're at risk of relapse and anything that can keep them in relapse, and in fact, our drug actually helped them get to a CR, an MRD negative CR. You would like to keep them in that state. A transplant is important, but actually keeping the cancer at bay is equally as important.
That's why you'd want to put them on a drug that actually doesn't have a heavy side effect burden. In fact, the drug is extremely well-tolerated, so that opportunity is not lost on physicians. While we won't have a frank label for maintenance coming out of this first registration trial, I think the experience will speak volumes to physicians, and that will probably influence them quite a bit. I think maybe Neil could handle the, what are we going to do about maintenance maybe in the frontline setting, which is important.
Yeah. Michael's right, and just maybe to add on to that, it's important to remember as well that the physicians asked us, right? The investigators were very keen for us to have the option to include patients, to be able to retreat patients post-transplant on study. Whilst we won't have an indication, we will have language in the label describing how the study was conducted, right? That was part of the experience. We can expect, you know, I mean, we're not going to get into the detail of the labeling, but I would anticipate that will be the case.
In the earlier study, in the fit patients, we're currently about to start dose ranging with 7+3, which is a standard chemotherapy for fit patients that could go on to fit, meaning that they could be eligible for not just for intensive chemotherapy, but also subsequently for transplant. Our anticipation is that we will start dose ranging soon. We haven't really discussed publicly what the, you know, a pivotal study design could look like in that space, but we're certainly getting ready to position ourselves to be able to do a study potentially in that space.
Okay, great. maybe coming back to a different flavor of the question we asked earlier for axatilimab, third quarter data from AUGMENT-101, saying I'm going to France second half of August, hopefully it's not then, but let's say blue email, top line data for revumenib and KMT2A rearrangement leukemias. What should we expect to hear then versus potentially in a more fulsome data presentation later in the year?
No, thanks, Madhu. I think it's. Again, it's an equally challenging question to give you much detail, I think people have seen how we've presented data and what's important for revumenib in terms of endpoints. We had talked about CR/CRh, we had talked about duration. I think, we are challenged with we want to make sure that everybody has a fulsome understanding of the data set, and that can make a judgment on that, at the same time, obviously, maintain our optionality around presenting the data in more detail at a medical meeting.
I think we've been, in our disclosures, we've been very detailed, to kind of break out the key measures that would influence whether a drug can get approved, and I think that this will be the first opportunity to do that. I think it will be consistent with what we've shown in the past.
Okay. Maybe one last question, specifically around the monotherapy studies. How have you think about risk-benefit on some of the kind of tolerability considerations seen within the class? Obviously, for y'all, there's QT prolongation as an observed AE. For other drugs, there's differentiation syndrome as a kind of, like, AE of focus. How do you think about that kind of tolerability profile for your drug and kind of the future use of it in treatment of various leukemias?
Look, I think the data suggests with our drug, I mean, again, every drug has its own AE profile, I think, for us, the drug has been extremely well-tolerated. Low rates, I think, our dose-limiting talks, people know, is QT prolongation. We've seen some grade 3 at a low level, about 10% or less of grade 3 QT, which is easily identified, managed, through dose adjustment. You don't have to stop dosing patients. Patients don't actually even know that they have a QT event, asymptomatic, so it's a lab abnormality, and it goes away within the next dose. It's a very easily managed side effect, which a lot of other AML drugs have. We're...
You know, we've sort of been through that, and physicians are very comfortable in how to manage that. We've seen differentiation syndrome at lower levels, no grade 3, so this is part of, as you said, these are differentiation agents, so you'd expect to see some, and we expected to see some. Easily managed again, and others in the class have seen differentiation syndrome of more severe variety, and they have to go to more heroic measures to manage that with their physicians do to manage it with their patients. Again, there's some differences in the profile, and more will emerge over time.
I think this, as a class, as seems to be, you know, a very efficacious and, I would say, more benign side effect profile relative AEs than perhaps other targeted agents that have come down the pike. I mean, we're excited. I think there's, I don't know if there's anything else to add on the AE side of the equation.
No, I think you hit it. I think, you know, very manageable safety profile.
Maybe one last one on the kind of recent data y'all have put out, and then we'll kind of get into more big-picture discussions. The thing that's come up in a lot of investor discussions has been your publication about resistance mutations and how resistance mutations read to other drugs versus not. Where do you kind of sit in thinking about kind of MEN1 resistance mutations for revumenib versus other drugs and where you kind of see that leading for the class?
Yeah. Paisley, you want to take that?
Sure. Yeah, thanks, Madhu. I think one place to start is just the publication that was put out in Nature, based on the work Scott Armstrong has done, to really profile how do menin inhibitors work and what are ways that the tumor can get around a menin inhibition. To do that, they looked very carefully in very sensitive methodology to try to understand what are the realm of possibilities, and that's what they published in the science paper.
They've identified 3 mutation sites within the, within the binding site, where the inhibitors across the class 1 set of you know, all of the agents that are currently in the clinic are susceptible to, where you can push out the ability of those agents to bind but maintain binding of MLL1 to menin. That was what then was published also at AACR in April. You can see that different inhibitors, because of their different chemical structure, have different levels of sensitivity to these mutations in the active site. I think, most prominently, all of them are susceptible to 1 or more of these mutations, and the protein will find a way to get around it.
I think that was the basis of these resistance publications. I think it's not surprising for a targeted therapy. It's what we've seen across all of these ALK inhibitors, EGFR inhibitors. That's what happens with cancer biology. I think what we've shown in our Phase 1 data is, despite the presence of these mutations, we've got very robust response rates, very durable results, you know, 9 months of durability. We're getting a very transformational effect for these patients. Again, just to reiterate, these are patients who are fifth-line patients, very unstable, in a very unstable disease. As we move into frontline therapy in combination with chemo, if we can get patients to an MRD negative disease, perhaps these resistance pathways won't be an issue anymore.
Coming to that, we briefly walked through the AUGMENT-102, Beat AML, and INTERCEPT trials. Kind of briefly describe them and kind of walk through when we might see some initial data from those studies and how you actually think about the initial data from those combination studies?
Sure. Yeah. As part of that process, we're looking at combinations with standard of care agents. Venetoclax and azacitidine is a frontline treatment for the unfit patient population. We're looking at that combination. We should have safety data and a recommended phase 2 dose at the end of this year, the goal would be to then start a pivotal trial with that triplet to understand and to get approval in combination for the unfit population for AML. We also are looking at combinations with chemotherapy in the relapsed refractory population. This is to address, you know, how physicians like to treat with standard of care if patients can tolerate it, especially in the pediatric population.
Again, we hope to have some safety data and recommended phase 2 dose by the end of the year. In collaboration with the Australasian Leukaemia and Lymphoma Group, we're doing a maintenance trial, monotherapy revumenib after CR, to see if we can get patients from MRD positive to MRD negative state and keep them in response for longer. That has started, and we haven't guided on when we'll see data on that one.
Just one last thing. We'll have 7+3 trial will start before the end of the year. That's in the unfit, I'm sorry, the.
Fit
fit patient population, yeah.
Okay, great. Well, as ever, with the question, we're asking every company at the conference.
Yeah
It's kind of a silly one, given the context of this whole conversation: What is the reason to own Syndax stock in the next 12 months?
Look, I think, as I think we said, we have very unique situation here at Syndax, where we have two drugs that'll have pivotal data in the coming weeks, for, you know, being first and best, the potential best-in-class agents with really high unmet medical need areas with big expansion opportunities. You know, where we're valued today, I think, you could potentially get there on axatilimab alone, let alone, what revumenib will bring in terms of value. It's a tremendous setup for the rest of the year. We'll also have filings that will solidify that before the end of the year. Exciting times for Syndax.
All right, great! thanks so much, team from Syndax, for joining us this afternoon.
Great. Thank you.