Okay, great. Thanks, everyone, for continuing to join us here at the Stifel Healthcare Conference. My name is Brad Canino, biotech analyst here. Happy to share the stage with the good majority of the Syndax team. Right to my left, Michael Metzger, CEO. We've got Neil Gallagher, President of R&D, Anjali Ganguli, Chief Business Officer, Steve Closter, Chief Commercial Officer. Got all that. Thanks so much for being here.
Thank you.
Look, I'll start with the intro to Syndax question, but it's been a busy week, so let's touch on the highlights, too, of what's happened for Syndax.
Yeah, so thank you, Brad, for having us here. We always enjoy spending time with you, and I think this has been such an amazing, it's actually the last two weeks. I'll go back an extra week because it's worth it to mention the fact that we started two weeks ago with a royalty deal, which brought in a fair amount of capital, capitalized us pro forma $750 million on Niktimvo. So now we're fully capitalized through profitability, which set the stage for what came next. We did have quite a bit of ASH data that was released last week as well, which will sort of set us up both in monotherapy and combination data, relapsed/refractory and frontline for ASH this year, which will be really exciting. We had earnings, and then we turned the page this week into NPM1 data.
This is revumenib, now known as Revuforge, which is indicated for KMT2A acute leukemia. We received that approval on Friday. Earlier in the week, we had pivotal data on the second indication, NPM1, relapsed/refractory NPM1, which is the first data of its kind for this molecule as well. That will be ultimately submitted through an sNDA and approved as the second indication for revumenib or Revuforge next year. It will be a really interesting setup for us as we go into the end of the year and launch Revuforge, which I keep having to remind myself to call it Revuforge, which will be the first menin inhibitor, first and only menin inhibitor to be launched in KMT2A acute leukemia with, again, pivotal data behind us, positive pivotal data for NPM1 as well.
So quite a week, quite a two-week period for Syndax as we really set the stage as a commercial opportunity.
Yeah, well, it's a great brand name.
Thank you.
It's great to see that coming early. I guess, can you talk about the label and how you see that positioning you for a strong commercial opportunity in relapsed/refractory AML?
Sure. So I think, again, this is KMT2A, relapsed/refractory, adults, pediatrics, AML, ALL. It covers the broadest segment of patients who have KMT2A. It's roughly 10% of patients who have AML and ALL. So it is a significant segment of patients. And again, this doesn't limit you to more than one prior treatment. So these are patients who have a very poor prognosis and are able to receive Revuforge after the first line, after they fail first line, again, pediatrics included. So we have a very strong label, unprecedented label, if you will, to cover these types of patients. And I think when you look at the strength of the label, it is a very clean, easily administered medicine. Patients do very well, stay on treatment for a long period of time. There's nothing in the label to hinder that in any way.
There's typical monitoring and other things that you would expect in this population of patients, but nothing onerous, and importantly, there are a couple of things in the label which we think are very important, such as an unprecedented ability to take patients to transplant for KMT2A as a goal of treatment, where you have a very young patient population and you're driving them to transplant as quickly as possible, and then the ability to put them back on therapy post-transplant. That is the goal of what physicians want out of a treatment, and we're able to achieve that and deliver on that, and that is reflected in the label, whereas you see about 23%, I think it's 23%, 24% of patients overall going to transplant.
That is, in an unprecedented way, that data is in the label, and it really sets the stage for those conversations commercially that you can have around transplant and then potentially maintenance down the line. So very strong label. We're really thrilled with it.
Yeah, and you touch on the transplant aspect. So maybe a broader question about to talk about just the different efficacy endpoints that you can use in AML, because there are many of them. I guess what I want to know is, what do you think this drug is really doing for the patient in terms of how the benefit is measured in the eyes of physicians and the patients versus perhaps what the FDA picks specifically to get a drug approved?
Right. So physicians are, I mean, the goal of treatment starts off, and for physicians, they're thinking about response. They're thinking about, how do I get my patient to a remission, clear their leukemia? That is reflected in what they refer to as overall response rate. That is not a regulatory endpoint in this trial, but it is a very important physician endpoint. They also think about MRD negativity, the depth of response, the duration of treatment, duration of response. They think about transplant, we just mentioned. They think about how many patients can they take to transplant. With our drug, it was more than five times more than you would expect from this population. And speed of response, how quickly can they get them there? So all of these measures are important for physicians. They're not all measured in the label.
I think the FDA, conservative organization, they're thinking about CR/CRh, which has been a historical endpoint, which has evolved over time. It first started as CR, then it moved to CR/CRh. These are slow-moving changes that happen, as you would expect from the FDA. It is one measure of clinical benefit, but there are a lot of other measures of clinical benefit, as I just described. And so I think those are some of the differences. And it's been an ongoing process. But as we talk to physicians, they think about overall response rate. And for KMT2A, with our drug, about two-thirds of the patients got to an overall response, an ORR, an overall response. And that means they're clearing their tumor. They're getting to a complete response, and their leukemia is gone. And then the rest, of course, is achievable, hopefully, through treatment.
Okay. And now with the high rate of transplants that's reflected on the label and is likely to be seen in the commercial setting, how do you have the ability to help educate the AML physician community about the ability and benefit to put patients back on revumenib as a post-transplant maintenance? And I guess also the second-order question from that is, how much education and training is even needed for maintenance?
Yeah, maybe I'll direct it to Steve with this question.
Yeah, I mean, I think your second question first, Brad. There's not a lot of training that has to happen. I mean, the momentum in the market is, and we've seen this with previous targeted therapies, the drug that gets a patient to transplant, the physician wants to put them back on, right, for obvious reasons. So the physician feels that way, the patient feels that way, and either the family and the caregiver feels that way. So it's probably going to happen on its own. There is data, as Michael suggested, that that's in the public domain. And I think just a general comment on how we communicate with the outside world as a company. We talk often about promotion and what sits in the commercial space, and that's sort of in my space at the company. But physicians are touched by many different touch points.
There's not just the sales team. Under Neil, there's a comprehensive, robust medical affairs team that is able to communicate even more fully than the commercial team does. So when questions come in, whether it's at conferences, one-on-one, we know this is not a huge footprint, right? The 200 academic centers that subsist within the 2,000 that we call on generate about two-thirds of the patient opportunity. So the connectivity to those groups is very, very high. So any details physicians want or need, whether it's how to start patients even outside the label or to continue on past a claim that's not specifically in the label, we'll be able to communicate. So I think the answer is it's going to happen probably on its own, but we'll be there to answer questions as needed.
Okay. And now what proportion of transplanted patients do you expect to restart on a maintenance therapy?
Yeah, I mean, I think I can take that one. The work that we've done with physicians seems to suggest that a very high percentage of patients will be put back on once they go to transplant, put back on maintenance therapy, whether that's 80%, 90%, we don't know. But ultimately, it should be a high percentage. And I think the treatment will be administered more and more second line versus third or fourth line. And I think getting patients to transplant should increase. The rate of transplant should go up. And I think the ability to put patients back on therapy, obviously, in hand with that will go up. So I think just talking to physicians, we feel that they're very much inclined to put them back on the therapy that got the patient to a remission in the first place. So high percentage is the takeaway.
Okay. And then bringing that together, what do you assume for the duration of treatment in the relapsed/refractory KMT2A population? And how is that influenced by the various levels of responses that are obtained in transplants or not?
Yeah. Anjali, do you want to?
Yeah, sure. Thanks, Brad. So with KMT2A, based on the data set that we presented at ASH last year and just got the PI on Friday, we saw three basic groups of patients, those that responded to therapy, which, as Michael pointed out, is about two-thirds of the population, and then those that did not achieve a response, which is the other third. Of the responders, we saw about half of them go to transplant. And those patients, as we said, are very likely to come back on therapy once they engraft. And we are estimating a total treatment duration in that population of about 18 months across pre and post-transplant utilization. In patients that are just treated to progression, they're not eligible to go to transplant. The data suggests an eight-month duration of therapy. And then in the non-responders, about three months.
And so when you do the math on that, you get a median duration of nine months on treatment. That being said, we're looking at a median third-line population in this trial, lots of prior ven, lots of prior transplants. And what we think and what physicians are telling us is that revumenib is going to, or Revuforge, is going to move up to a second-line treatment of choice. There really is nothing that works for these patients. The standard of care in frontline is 7+3. A third of those patients are primary refractory, which means they have no response to intensive chemotherapy. And then the rest of them, a very high percentage relapse. Only a few are actually able to go to transplant even in frontline. So physicians are looking for something that's this effective, and they're going to be using it as soon as they can.
So that will push the number of responders up. It will also likely push the number of patients that are able to tolerate and go through transplant and move some of those estimates.
Okay. Now, Revuforge has a very well-characterized QTc side effect. How would you describe the risk of that? And what is that conversation going to be like in the physician's office with the patient?
Yeah, Neil, take that.
Yeah, sure. So thanks for the question. So, well, first of all, there's no boxed warning, right? So we've been sort of pressure tested on this ever since, certainly ever since I joined the company, I'm sure before, is there going to be a boxed warning for QT? And we said all along that we didn't expect it and it didn't happen. And the reason that we didn't expect it was because we saw an effect that was very well-characterized. It came on early. It was easily managed, and it didn't recur. And patients stayed on therapy. And that profile has remained true all through the development of the drug, including the KMT2A and the recently top-line NPM1 data. So we have a warning and precaution, like we have warnings and precautions for other potential adverse events with the drug.
And therefore, it's going to be discussed in the context of the safety profile of the drug. And the drug is well-tolerated. It's just going to be one thing that happens to be discussed with the patient. But let's put it into context, right? These are patients, particularly for the first indication, the KMT2A patients, who are going to be dead within weeks, right? So historically, these patients were not going to survive. And now we have a drug that has an overall response rate of two-thirds of the. So the physician's going to say, you've got a two-in-three chance of responding to this drug, and maybe we can get you to transplant. So all of those discussions about risk have to be put into the context of benefit.
And when you look at it that way, it's really not top of the agenda to be going into whether or not there's a minor risk of QTc prolongation or what that might mean. It's really all going to be about the benefit-risk. And physicians are used to managing drugs with QTc prolongation. There are other drugs out there with boxed warnings for QTc prolongation because they've resulted in sequelae like Torsades or sudden death. That is not Revuforge. And therefore, I think there will be a reasonable discussion, but in the overall context of benefit-risk.
Great. Maybe to segue to talk about the NPM1 data set, I guess, can we frame how you view those data in relation to the KMT2A-R data, which obviously just led to an approval on Friday?
Yeah. Do you want to take that as well?
Yeah, you can. Sure. So the data are pretty much exactly as we anticipated, right? So the NPM1 data, we have said all along that the activity in NPM1 in the relapsed/refractory setting is similar, that the mechanism of action is similar, and therefore, the activity would be similar. We've seen a consistency of effect across the program from phase one into phase two. For sure, we reported out a slightly higher point estimate in phase one for NPM1 patients. But we've been guiding that the point estimate for CR/CRh would be 20%-30% as recently as the quarterly call. And we said that the median duration of response will be between four and six months. And we landed pretty much in the center of that guidance. The other thing that I think is remarkable is the consistency with how the drug performs in KMT2A.
That consistency, both in terms of the efficacy in the NPM1 population, but also the overall safety that we've observed is highly consistent, makes us feel very, makes us confident, right, very confident about the sNDA, especially on the back of the NDA, that we now have a drug that's approved. We'll have a drug that will be on the market by then. Here we follow it up with a highly consistent data set that we are looking forward to discussing with the agency from the perspective of an sNDA. Overall, we're very happy with the data.
Okay. And now with KMT2A-R, the FDA conducted its own analysis. And the CR/CRh in denominator did change slightly. I think the question that emerges from that is, what is the level of confidence that you have that if the FDA does an analysis on your NPM1 phase 1 and 2 data combined, will it still meet that approvable threshold?
Yeah, we're very confident that it will. Look, I think the way the FDA conducted their analysis, and as you know, it's within their right to do this, right? We had a SAP-defined analysis that we performed and we submitted for the NDA. We also had phase one patients and phase two patients all within the confines of AUGMENT-101. So it was a trial that went on. They took the opportunity to look at the phase one population dosed at the RP2D and used a certain data cutoff. We, of course, didn't do that, but they have the right to do that. So their analysis did differ a little bit from ours. The denominator changed. The CR/CRh went down by one actual patient. And the reason for that was their data cutoff was a week before this patient confirmed their bone marrow.
They didn't count it in their analysis. Subtle little differences can result from these types of the work that they do. If you look at what is going on with our NPM1 trial, we have 64 adult patients, AML patients. We have a phase 1 trial that was performed. We had 14 patients at the RP2D that had a point estimate of 36%. We have a safety database of 84 patients in the phase 2. A good number of those patients, of course, they're all at the RP2D, but a good number of them are mutationally confirmed and will have the proper follow-up. Could the FDA look at those? Could they look at the phase 1? Sure. We already know the point estimate from the phase 1 is higher than what we were at.
And so in terms of whether it's going to be consistent, I think it'll be consistent, certainly no lower than what we've shown today. But I think we feel very confident that there's really going to be no impact, significant impact on the data.
Okay. That's helpful. Now going back to the NPM1 data release, how did the prior therapies that the patients received, particularly venetoclax, impact the efficacy in the relapsed/refractory population, both within the study, but also relative to the proportional treatment percentage at baseline of prior therapies versus the phase one that I think a lot of us were anchored to?
Yeah. I mean, I think the venetoclax utilization in the phase 2, again, remember that the trial was conducted two to three years after the phase 1. The utilization of venetoclax in the phase 1 was roughly 60% prior ven before the patient was dosed on our trial. In the phase 2, it went up to about 75%. I think that has an impact on the patient, right? And we know, physicians know that once you give ven and the patient fails ven, it's very hard to treat that patient. It's basically salvage therapy. And they don't have anything for those patients. So in the context of more venetoclax, to be able to post data the way we did, very strong on all efficacy measures and safety, really gives us a lot of confidence that this is a very strong result that's going to be very difficult to beat.
I think having these later-line older patients. Again, these are patients' average age 65 versus what we saw with KMT2A was mid-30s, so these are heavily pretreated older patients, a little bit more frail, have a lot of comorbidities. So to see 75% of them getting prior ven, you can understand how that could really impact downstream how they do on a drug like revumenib, and yet, again, 50% of them are clearing their tumor and doing very well and getting to response and staying on drugs, so, not to mention some go to transplant, which you wouldn't even expect. So it's, I think, in that context, very important to see kind of how ven impacts.
Yeah. Okay. Now, how do you expect physicians to now build upon this monotherapy profile, potentially with combinations in the relapsed/refractory setting? And what could that do to treatment durations over time in the commercial setting?
Yeah. I don't know. Anjali, do you want to take that?
Yeah, sure. So I mean, we're showing some really strong data in combination with revumenib, both with chemo combos as well as ven-HMA combos in the relapsed/refractory setting. And we'll have additional data in the frontline with ven-HMA. And I think what we're seeing is similar to what was predicted from preclinical work, that there should be significant benefit from the combination, potential even synergy from inhibiting both BCL-2 and menin. And I think that's something that physicians are really eager to do in terms of hitting the disease as hard as possible, trying to affect the largest impact, clearing the tumor as completely as possible. And if they can get, especially in the relapsed/refractory setting, get these patients to transplant, that still is the only opportunity for a cure.
And so I think having the information for physicians to start utilizing these combinations is going to be very impactful in the uptake of revumenib for patients that they feel can tolerate multiple therapies. I think there will be, as Michael mentioned, some of the NPM1 population are older and maybe less amenable to as intensive chemotherapy versus KMT2A. But I think we've shown in relapsed/refractory and in frontline that there's not additive toxicity from revumenib. And so if a patient can tolerate, is deemed to be able to tolerate venetoclax, they should also be able to tolerate the triplet. And that we're showing data.
I think Ghayas Issa is going to have an update of his relapsed/refractory combination trial, which the abstracts came out, and he's showing 88% overall response rate and 58% CR/CRh rate in a fourth-line patient population that's seen more than half have seen prior ven, more than half have seen prior transplant. And they're seeing patients stay on therapy for prolonged periods of time. Multiple patients go to transplant and come back on revumenib post-transplant. And I know he's very excited about the combination. And I think the community will be really excited when it's presented next month.
Great. Now, you mentioned the frontline AML triplet and some of the original learnings from what was conducted in the BEAT AML trial. What's the goal of that study as it continues, and what do you hope for that to provide towards the end of the year?
You want to continue on?
Sure. Yeah. I mean, I think the primary goal for BEAT AML was to establish the recommended dose for taking this into a pivotal trial. We have guided to start that trial by year-end. It's now listed on clinicaltrials.gov. We are doing all the work to get patients enrolled fairly shortly into that study. This will be focused on the unfit patient population, similar to the VIALE-A study. So patients that aren't able to tolerate intensive chemotherapy, which is primarily the NPM1 population, if you think about the KMT2A population. As Michael said, our relapsed/refractory trial enrolled a median age of 34. Most of those patients are young and fit and are getting 7+3 in the frontline, whereas the NPM1 population is more split between intensive chemo and the unfit venetoclax-type population.
So this trial, we're running it in combination with HOVON, who has an extremely strong network of sites throughout Europe with an ability to identify and profile patients very quickly and start up multiple sites all at once. So we think it will help with accrual and enrollment and allow us to get through the trial very quickly. So that's another bonus of working with this cooperative group in particular and gives us access to all the premier institutions across Europe. And we'll also have many sites in the US running this study as well.
Okay. Great. And how much are you saying about powering assumptions for the frontline or things you're thinking about in terms of assumptions of what venetoclax is decided and will do in the control arm and what you need to be in order to show a benefit on top of that?
Sure. Yeah. I'll take that one. So the performance of Venclexta has been pretty consistent from the original phase 3, which is called VIALE-A, which is Venclexta versus Aza. And Venclexta, the overall survival on the Venclexta arm is just between 14.7 months. And there have been other data sets, largest data sets that have replicated that subsequently. So we're fairly sure that that's how the control arm will perform. We haven't discussed in detail the statistical design. However, the primary outcome, the primary endpoint is overall survival. So you can assume that obviously we want to demonstrate a statistical improvement in overall survival, actually a reduction in the hazard for death. And therefore, there's a range of outcomes, right? You can say you want to power the study for a hazard ratio or to demonstrate a 35% risk for death.
But in fact, that gives you a whole range of outcomes, right? Both obviously below, if it's better, then it's going to be positive, but also above that, up to a minimal detectable difference. So what we've tried to do is design a sensible study, an efficient study in terms of the overall powering, which is based on NPM1 for the reasons that Anjali alluded to, will allow in some KMT2A patients. But the primary analysis is based on NPM1. And as I say, we've been a little bit cagey about the statistical design just because we want to be right now. But we have confidence that the study is adequately designed to do what we want it to do.
Okay. Now, maybe a question to either Steve or Michael. There's definitely a cohort of investors that will say to me that this space is really about the frontline opportunity in terms of value generation. Obviously, you're launching in the relapse refractory setting now, but we've got to wait many years before the real value comes on. How would you respond to that?
Maybe I'll start. Look, I think this is a here-and-now opportunity. First mover advantage. We're going to be in the market in relapsed/refractory with the broadest opportunity for KMT2A and NPM1, and we have a significant lead on competition. I think this is an area where standard of care doesn't necessarily interfere with what we're trying to achieve. We're bringing a new medicine with a new mechanism specifically designed for patients, and it's a very broad mandate. I think physicians in this category tend to work towards frontline, right? So they'll try to use the drug earlier and earlier in treatment, whether you're indicated or not, and they will write scripts in combination. We know this is likely to occur. We don't promote that way, but it's likely to occur.
I think we will generate trials, and we will be the first to generate data in earlier line settings in order to make sure that physicians have what they need to safely and effectively prescribe the drug. I think this is not all about frontline. I think the opportunity in relapse refractory disease, we see this as sort of a $2 billion segment, and we will have major advantage in driving that for the foreseeable future. Ultimately, it expands to a $4-$5 billion opportunity as you get closer to frontline, and we will have the opportunity to be there first. At least that's how I see it. I don't know, Steve.
Yeah. I think I'll skew more towards just the markets there. Can we get it? And I know that we can. We've got, I think, a great entry label into the marketplace. You've got an unmet need that is pretty intense. Patients have absolutely nothing, and they are readily identified, and physicians are testing, and treatment centers are testing. And we were deployed and ready to go. We've had our field customer-facing team in place since June. So of the 2,000 treatment centers we've been to most, and I mentioned the top 200 that cover most of the opportunity, we've been there multiple times to understand the patients that are there, how are they identified, we've profiled them, how do they like to get the drug, what does the treatment journey really look like. So I think we'll see some traction right out of the gates.
We often talk about first mover advantage, and it's not something that's a given. You've got to take advantage of it. And that's what this is. I think whether it's KMT2A-R, relapse refractory, frontline, NPM1, being first in market's a big deal. We're going to execute flawlessly and really build a beachhead across the potential use of menin inhibitors in the space that anybody who comes after us is going to have a hard time closing the gap that we've created. Maybe I'll sneak in one last quick one because we didn't touch on axatilimab. The royalty transaction, why is that the right deal for Syndax at this stage?
Yeah, look, I think we have a high conviction around the molecule. I think we have a great partner in Incyte. We have a shared vision for this. This was an asset that the market viewed very differently, valued very differently. And we've been at it for a couple of years working to build value there and have people see the value that we see. We were approached with inbound interest from Royalty Pharma and others to do a transaction of this type, and we were able to drive terms that were highly NPV positive for the company. And it was the right deal at the right time to monetize just a piece of what we have. So, this we have ongoing revenue stream. We'll have ongoing participation. We believe in the product. The deal is actually capped, so we know that there's an end to the royalty potentially.
So we have a lot of upside. So it really was a win-win at the right time and really funds the company through profitability. I don't think there are a lot of companies of our size that can say that, right? So it really takes the need for capital off the table, and we could just drive value and do really well with the products in hand. So that was the setup that we were looking to drive.
Okay. Great. Well, Team Syndax, thank you so much.