All right, well, welcome everybody, and thank you for joining us once again for the 44th annual Citi Global Healthcare conference. I'm Yaron Werber from the biotech team, and it's a great pleasure, along with my colleagues, to moderate the next session on leukemia. So we're with us really with a terrific lineup. There's a lot to cover, and so it's going to be a tour de force in covering a lot of new things in leukemia. From Foghorn Therapeutics, we have Alfonso Quintás-Cardama, who's the Chief Medical Officer. From GlycoMimetics, we have Harout Semerjian, who's President and CEO. From Kura Oncology, we have Troy Wilson, President and CEO. From Syndax Pharmaceuticals, we have Neil Gallagher, President and Head of R&D. And from Terns Pharmaceuticals, we have Erin Quirk , President and Head of R&D. And also from our own team, we have Eva and Nick as well.
We have one more colleague, Nicole, who's finishing the panel and joining. Thanks so much. Let's start by talking about, there's a lot going on in AML. Between targeted therapeutics, there's obviously some cell therapies that are being developed to a certain degree still. A lot going on. There's a lot that's molecularly based as well in leukemia broadly, not just AML. Maybe, Troy, we'll start with you. When you're looking at AML specifically, there are, as I mentioned, multiple therapies in development. Is it hard to recruit patients and open new sites? Kind of give us a sense how are things shifting.
It's hard to recruit new sites only because the sites are still recovering after COVID, and they've just been picked over and broken over by the industry and CROs. We've not seen any challenges recruiting patients. For those of you unfamiliar, we at Kura Oncology have a menin inhibitor in development, in a registration-enabling trial in NPM1-mutant AML, in the relapsed/refractory setting. But we have a large combination study underway, and it's enrolling like gangbusters. I think there's, in our view, really, and my fellow panelists can comment, but we're seeing a real optimism among physicians that we may really be at an interesting tipping point for leukemia. And that's, I think, driving a lot of the excitement, the enrollment, the engagement.
Yeah. Neil, do you want to maybe comment on that too?
Yeah, actually, I agree with Troy's comments. Maybe seeing a little bit less challenge around finding sites. There's been an extremely high level of enthusiasm, I think, for so just for those of you who don't know, I'm from Syndax. We also have a menin inhibitor called revumenib. So I think there's a very high level of enthusiasm. We're very pleased with, of course, we've completed our KMT2A accrual, and that's currently under review. And we're extremely pleased with the progress that we're making with NPM1 accrual. So these are different molecular subtypes of AML, for those of you who don't know. And I think that enthusiasm drives physicians wanting to put patients on drug, and we're seeing exceedingly high levels of enthusiasm. So I agree with Troy that there has been some effort. There was some pandemic hangover, but it seems to be on the way.
Erin, maybe what do you see in your side? On the CML side, what?
Yeah. So Terns is not working on AML. We are working on chronic myeloid leukemia, which is a completely different disease state. Really one of the greatest success stories in medicine, I'd say, because it's turning a deadly disease into a chronic disease, and these patients generally have normal lifespans if they can attain and maintain a molecular response. For that reason, it's been a little bit underappreciated and overlooked in drug development lately. Novartis has been doing a fair amount of work, but biotechs have not been in the space much. So I completely echo what you said, Neil. We're finding with our investigators, we're just getting underway with our first phase one study. Nonetheless, they're incredibly excited that there could be a second allosteric BCR-ABL inhibitor in the clinic.
There's only currently one option for patients who have many options throughout their generations of living or decades of living with their disease. So yeah, I would agree that COVID has taken a toll, particularly on academic centers, we're finding. And that's mainly just a backlog and a workload issue, I think, and getting things up and running. But once up and running, now these investigators are excited, and patients are excited for another option.
Yeah. What about you, Alfonso? You have a novel mechanism of action.
I'm sorry, is there?
You have a novel mechanism of action.
Right. So we have Fulcrum. What we do is we're dealing with or trying to drug chromatin remodelers. And I concur with my co-panelists. There's plenty of patients out there, and the sites will always be interested in innovative therapeutics. So we haven't encountered any problems finding patients or recruiting sites.
Yeah. For us to see them as well, in the U.S., there are more than 21,000 patients in AML that are, unfortunately, diagnosed every year. 60% of them advance to a relapsed refractory. So if the unmet medical need is as high as it's ever been, the excitement about new possibilities, new modalities, is definitely over there. As you know, we have E-selectin antagonists, and our challenge has not been enrolling in patients because we have enrolled two major trials with 650 patients in between back in November 2021 and December 2021. So we haven't really seen that challenge. Even during the pandemic, there were a few months that we had a bit of a softness, but then things picked up. And our ongoing ISTs as well are enrolling, but these would be single sites where you had a motivated investigator who was really interested in this.
We see there is a good momentum in AML, which is good for patients.
Yeah. Maybe just to stay with you, so complete response rates are always important to measure, and it's always a question of when you do an induction, going into a CR, and then how do you measure the CR sort of afterwards and the relationship between the interplay and the relapse to the frontline setting. Can you talk about that? And is the FDA shifting at all? What the endpoints look like?
Yeah. It's an interesting one. I mean, of course, complete responses are important. What we aspire to do in GlycoMimetics with AML is really bend the curve, bend that survival curve. That's what we're really trying to do, is get more patients into cures, into long-term remissions. And as you know, our program is based on that with overall survival. So the whole idea is, can you get to deeper responses as measured by MRD negativity, complete responses? So we think complete responses are important, but durability is also important. Depth of response in terms of MRD negativity, that's an emerging topic over the last few years that has come to also start playing a role in AML like we've seen in other areas. So hopefully, at one point, from the regulatory pathway as well, that would make it.
Ultimately, as we know, the gold standard in this area is overall survival, which is something we're pursuing.
Yeah. Alfonso, do you want to talk about that same point?
I don't think the endpoints have changed. Certainly, have not changed for me in my mind. I don't think that they've changed for the FDA. To your point, I think overall survival is going to be the best endpoint. I think, in general, there tends to be a good correlation between complete responses and that prolongation of survival. Anything less than a complete response in AML, as we know, is not really worth much. One, because it doesn't prolong survival. Two, because it doesn't allow patients to be bridged to transplantation. So the endpoints have continued to be the same as they've been for the last 20, 30 years.
Complete response is complete response on all counts, or do you need full hematologic recovery, or that's not as important?
Correct. Well, so, right. So there are nuances around the quality of the complete response, but certainly, the elimination of the bulk of the majority of the blasts that are experienced is important. That typically goes hand in hand with hematologic recovery, but not always. And it depends quite a bit on the therapeutic that you employ. Some of them are more prone to induce more complete responses, per se, as opposed to complete responses without hematologic recovery. But as we've shown when I was at MD Anderson, and many others have shown similarly, the recovery of the counts is important, especially for patients going to transplantation. Those are the patients that tend to do better during transplantation, less infectious complications, less peritransplantation mortality. So if you get to pick, obviously, the complete recovery of the counts is desirable.
So Erin, in CML, it's a little different.
Yeah, it's quite different. So chronic myeloid leukemia, there is an established surrogate endpoint. We don't do outcome studies anymore on chronic myeloid leukemia because patients live normal lifespans. So instead, what you're looking for is decreases in the transcript of the BCR-ABL fusion protein, which is the nidus of the disease, in the blood. And it's patients who get to a less than 1% transcript level in the blood or have a major molecular response. And that is the approval endpoint with FDA and has been for years now. So that's another nice feature of developing drugs for CML is that you have this endpoint that is validated, easily measurable, non-subjective, and that, for example, in a third-line setting, major molecular response at six months is the accelerated approval endpoint for CML, and maintenance of response at two years is the full approval endpoint.
Back to AML?
Yes, back to AML. So I agree with the comments that were made a little earlier. I see the fit/non-fit populations as being potentially somewhat different. I think in so-called unfit populations, these are older patients who aren't fit for transplant, tend to be older and unfit for transplant. The current standard of care is Venclexta. And if you look at from the pivotal trial, the median overall survival was, I think, 14 point something under 15 months, 14 point something months. And it's likely, therefore, in the real world, in fact, median overall survival is probably a little shorter than that. So there's a significant unmet need in the unfit adult AML well, adult and children AML population, but in non-unfit population.
Given the duration of median overall survival, the standard of care, it's highly likely, I agree, that anybody who's running a pivotal trial in that setting, right, in combination with Venclexta, would be expected to run an overall survival trial. I think that with respect to the fit populations, these are patients who are treated with curative intent, with intensive chemotherapy, with the potential to go on to transplant. Not all of them do, right? So a lot of them receive induction consolidation chemotherapy and then some form of potentially some form of maintenance. I think there's a conversation that needs to be had around the potential acceptability of MRD negative CR in that setting.
I don't think a drug has been approved on that basis, but I would imagine that some of my colleagues are probably anticipating having that kind of conversation with regulatory authorities in due course. But the current standard is for overall survival. I agree.
I'm not sure I can add much to what's been already said being fifth. So yeah.
We're putting you first, then you're fifth. You take a break.
Time to think.
Eva, over to you.
Yeah. So to you, Troy, so it's a common strategy in oncology to develop and relapse refractory and then move to earlier lines. Is this a reasonable expectation in leukemias, particularly in light of the large number of therapies in development?
I think it is. Leukemia is unusual among oncology indications. I don't know that it's unique, but it's certainly unusual in that a single-arm study can serve as the basis for an application for full approval. That's not the case in most of the solid tumors. That's the path that we're pursuing with our KOMET-001 study. I think, again, interestingly, menin inhibitors are highly active, as are a number of these agents. The FDA will still put safety first, so it makes sense to start there. And there is a very high unmet need, but we're seeing a tremendous pull to combinations, earlier lines of therapy, maintenance. If the drug is active as monotherapy, and I think all of the menin inhibitors thus far are very active, that's supportive of that broader development strategy. But that's still kind of the gold standard.
Yeah.
Well, I agree. Again, in fact, that is our development plan, right? So we have our first application under review, and that's for KMT2A-rearranged acute leukemias. I agree with Troy. Our anticipation is that we would gain full approval in the relapse refractory setting for that subgroup. And then we've also guided that we will have data by year-end for the NPM1 cohort from the same pivotal trial called AUGMENT-101 with an anticipated filing, therefore, in 2025. And again, that's in the relapse refractory NPM1. In addition, we've talked a lot about our combination data, particularly from the BEAT AML platform trial, combination with venetoclax. So that sets us up to initiate a pivotal trial in the unfit, newly diagnosed population. And we're pushing hard to get that done by year-end. The combination looks to be highly feasible.
And likewise, we've initiated a 7+3 in combination with standard chemotherapy for the fit population. We anticipate that that will set us up for initiating a pivotal trial in 2025. So to answer it, just in summary, we will have the first approvals in relapse refractory NPM1 and KMT2A, and then move quickly to the frontline.
Erin?
So again, the dev plan's a little bit different in clinical leukemia. We're underway with our CARDINAL study, which is a phase one dose escalation, dose expansion study, open-label single-arm, multiple different doses of TRN-701 administered once daily to patients with either second-line or third-line chronic myeloid leukemia. That's a real first because development to date in CML, since Gleevec actually has really been in third-line treatment as a phase one opportunity. We think that's really important because the allosteric inhibitors have been shown via preclinical head-to-head studies to be superior to second-generation active site TKIs in efficacy and also better tolerated. For patients who are living lifelong with the disease, having a better tolerated, superior option is clearly going to move into earlier lines of treatment.
The very fact that FDA recognized that and allowed us to recruit second-line patients into our study is important. Patients need only a failed 1 prior line of active site TKIs. Following our dose escalation and expansion study, we anticipate that we would then go into a pivotal phase III study. Whether that needs to be an active control study or single-arm, I think, remains to be seen at this point. We think there's a huge opportunity in second line for TRN-701 for CML. We could talk a little bit about that later, but that's the thinking about the development plan.
Yeah, along the same lines. So absolutely, I think all of these agents, as soon as they demonstrate some degree of efficacy in the relapse refractory setting, they should be moved into the frontline setting. I mean, these patients should get, given the aggressiveness of the disease, they should get their best shot up front. And so if you have a drug that is active in the relapse refractory setting, that should be moved as fast as possible to the frontline setting. I mean, case in point, if you look at the development of midostaurin up until not that long ago, the only FLT3 inhibitor approved for these patients, that agent had intriguing, but somehow underwhelming activity in the relapse refractory setting. And it was only when it was moved to the frontline setting that proved to render a benefit in terms of prolongation of survival.
That's the philosophy as well as Foghorn. If we demonstrate efficacy in that setting and the relapsed/refractory setting, we'll be moving the FHD-286 compound in the frontline setting as well.
Moving on to the next question because I'm not sure how much more we can really add anymore. Within the AML setting, there are several mutations, and there's targeted therapies for some of these mutations. How should we think about the sequence of these therapies? How should we think about what types of potential drivers there are for these mutations, and if this is something that will continue on within the future as these targeted therapies, or will we move more towards a broader approach or reverse?
It's kind of hard to predict that. But I mean, the unmet medical need is so high that you almost hope all of these work, right? You want targeted therapies to work. You want broad utility agents to work. You want combinations. You want these assets to work well together as well because the world is going towards doublets and triplets. So not only each has to have their efficacy, but they got to play well in the sandbox together. So hopefully, aspirationally, we're able to get there. To Alfonso's point, there are differences in patient characteristics. Obviously, if you're fit for intensive therapy, transplantation is still the gold standard. You want to get as many patients to a transplantation. Hopefully, you put them on a long-term survival curve.
If you're not able to get there to the point Neil was making, is how do we go through some of these lines of therapies? Because as you address certain mutations, other new mutations are coming up, and it's just kind of a cycle. So you want multiple lines of therapies. And at the end, we're measuring survival in months. That's something that's really important to keep in mind, is we would want to be able to address the polyclonal nature of AML in many cases. And we want to address it in some sort of combination. So hopefully, we're able to deliver all these therapies so that treating physicians are able to customize it according to the patient type.
Alfonso?
Yeah, no, I agree. I think the good thing is that, particularly for patients, that now we have the tools to address those driver mutations. As to how to sequence them, I mean, that's a nice problem to have, right? But I think that's going to be dictated mostly by the clinical presentation of these patients. Take, for instance, the FLT3 mutated AMLs, typically considered historically high-risk AMLs. They are no longer high-risk AMLs because of FLT3 inhibitors, right? And so if you have a FLT3 mutated AML because of the highly proliferative nature of that disease, I'd probably go in with a FLT3 inhibitor first and then address other potential drivers of the disease. But again, it's going to be clinically driven, and it's a nice problem to have.
Erin, obviously, we're not going to talk about AML, but what would you say about the sequence of therapies for CML?
Probably the most important thing to recognize in CML is there's a lot of switching that happens in patients who have been chronically managed. Sequencing made sense when you were talking about first-generation and imatinib, where 25% of patients fail within the first six months, two years of treatment. So going to a more potent but less well-tolerated second-generation active site TKI made sense. Now, we see within the second-generation class that patients switch a lot. Again, they have the disease for decades, and they could be switching because of failure as a sequencing sort of thing, or they could be switching because of tolerability. Dasatinib, for example, is associated with pleural effusions, right? And so if a patient comes in, they're pleural effusion, they're going to switch them to something else within that class. They could switch because of a new drug-drug interaction.
They could switch because of a new comorbidity, for example, that they no longer can take the long-term cardiovascular risk of nilotinib if they've been newly diagnosed with type II diabetes, for example. So it's less about sequencing and more about providing options. And because there is so much switching that goes on, these three completely undifferentiated second-generation active site TKIs altogether generated more than $5 billion in revenue last year just because it was a different option, and they had slightly different profiles. So I think what we're going to see CML heading is instead of sequencing with Project FRONTWIRE, more patients are going to be moved to better tolerated, more efficacious meds upfront.
Those who are still on these less well-tolerated drugs will have an opportunity to switch to the allosteric inhibitors, maybe because they're sequencing, because of failure, oftentimes because of new tolerability, or quite frankly, because of just the preferred profile, not having to take it in a fasted state forever, not having a drug-drug interaction, this ease of prescribing, ease of taking medicine.
Neil, anything to add on AML?
On AML, well, I think the availability of new medicines represent new opportunities, right? And I think that certainly all the feedback that we've been getting is that, to echo a point that Troy made a little bit earlier about the enthusiasm around the class, is that particularly for KMT2A, that if once approved, revumenib will become a standard of care in relapse refractory KMT2A because currently, the outcome for these patients is extremely poor, right? The median overall survival is under three months. So with the level of activity that we're seeing, that's in the relapse refractory setting. The objective is to move it in combination upfront and then a similar study, as I mentioned before. But I think the broader question is, do we see room for improvement or room for additional therapies within the broader group of AML diseases?
Because they are slightly different diseases based on the molecular subtype. The answer is yes, right? This is a disease that still has a very poor outcome. Therefore, there's significant opportunity for improving those outcomes.
Anything to add on AML?
Yeah, I appreciate you asking. I thought we were going to change again, but I actually do have something to add here. So just for the audience's benefit, the menin and KMT2A interaction is unusual for the following respect. It's functionally equivalent to the BCR-ABL example in CML. It is so foundational that, in fact, if you just double the expression of two of the downstream genes, MEIS1 and HOXA9, patients can be born with full-blown leukemia. It's why KMT2A rearrangements predominate in infant and childhood leukemias. That being said, it also sits upstream of most of the other sort of murderer's row of mutations. So FLT3, IDH1 and 2, it interacts with BCL-2. It interacts with MCL-1. It's unusual. And the final thing I'll add is it's powerful in the following setting. The FLT3 inhibitors effectively put leukemic cells to sleep.
Yes, they reduce leukemic blasts, but if you take your foot off of them, they will come roaring back. Menin inhibitors are unique in the following respect. When you disrupt that protein-protein interaction, you induce differentiation of the cell. You actually do the Holy Grail. You transform small T. You convert a leukemic cell, a leukemic blast, into a mature cell. That's a one-way trip. That doesn't come back. So if you can do that and you can do that systemically, that is remarkable. So the activity, the breadth, the combinability with other agents, and the unique mechanism of action, I mean, we really have it. A lot of investors are pattern recognition animals. They say, "Well, I want to see an analog." And you say, "Great, look at CML." "No, no, I want to see another analog." "Okay, great, look at myeloma," right?
That's, I think, the promise of some of these new agents in acute leukemia and AML in particular.
I think we'll start moving and talk about each specific program, each specific company. Maybe, Alfonso, I'll start with you. When you're looking at you're working on the BAF complex, which is transcription factor regulation sort of complex, which is fairly novel. It's novel to Foghorn. It's not necessarily an AML. Initially, there was a question, is it going to be mutationally based or not, or is it going to have a more pleiotropic kind of broader activity? Can you talk about what does BAF really do? Maybe a little bit, how do you target it in AML, and why it's relevant?
Yes, thanks for the very easy question.
We have about 43 minutes, by the way, to cover that.
Okay. So BAF is a chromatin remodeler, probably the most important chromatin remodeler. There are others, but this is one of the big ones. What it does is essentially opens and closes chromatin so that it allows transcription factors to come in and regulate transcription that way, grossly speaking. It's a huge multi-subunit complex, the composition of which varies from complex to complex. There's a number of subunits, and there's multiple iterations of these combinations that you can find in these complexes. What actually doesn't change is that there is a catalytic subunit within the complex, which is typically either BRM or BRG1. It's one or the other. They're mutually exclusive. These are mutated very high prevalence in human cancers. Around 20%-30% of human cancers will contain a mutation or more than one mutation within the BAF complex.
So probably after p53, this is the tumor suppressor that is most frequently mutated in cancer. That speaks to the importance of these complexes in the pathogenesis of cancers. What we do at Foghorn is we have developed a dual inhibitor of BRM and BRG1. We can inhibit both of these catalytic subunits, which is what powers the BAF complex. So the complex effectively collapses, cannot do what it's supposed to do. So that's very important in the context of setting up synthetic lethal interactions because there's only one of the subunits in the complex. When the other subunit is mutated, if you inhibit the paralog, you essentially kill the cell because the cells depend on these ATPases. But also, it's important because, as we and others have found, the BAF complex is highly activated in instances of TKI resistance, resistance to targeted agents. Why?
Because they regulate the pathways that come up in response to the inhibition via TKIs of those driver mutations. And so they set in place these signaling pathways to keep cancer cells going. So shutting down BAF in that context, independent of the presence of mutations, has also a role in cancer because you can suppress cancer growth and restore sensitivity to targeted agents by suppressing the activity of BAF. So those are the two areas that we are exploring within the company, the reversal of resistance to targeted agents as well as the targeting of cancers that depend on BAF, such as AML, which is highly dependent on BAF, particularly BRG1 for the pathogenesis of the disease.
If you look at the literature, you will see a large number of papers showing that if you inhibit the BAF complex, the vast majority of the cell lines will either differentiate, which is actually we're actually proving in vivo in patients, or they will induce apoptosis. So that speaks to the central role of BAF in AML.
In serial passaging, have you seen any resistance yet to 286 in cells?
So it is expected to see resistance to inhibitors of BAF. I would feel offended if I didn't see any resistance to our agent. That means that nature doesn't care about what we do. And that resistance can come in different flavors. So one of them is, and it's been reported recently. There is this other complex, this other chromatin remodeler called EP400, that comes up when you suppress BAF and opens the chromatin at places where BAF used to do it. So if BAF goes on vacation, EP400 comes on and opens up chromatin for transcription factors to come in. So that's a potential way of bypassing the inhibition of the BAF complex. Obviously, with enzymatic inhibitors, the other potential mechanism for resistance is the accumulation of mutations within the target itself.
I'll address my questions to Troy. So Kura has menin inhibitor ziftomenib as a pivotal development that is progressing in NPM1 mutant relapse refractory acute leukemias. Can you talk about the design of the pivotal trial and give us an update on how enrollment is progressing and when it's expected to complete?
Sure. So as you said, this initial registration-enabling trial is in patients with relapse refractory NPM1-mutant AML. The COMET001 study, the registration-enabling portion is a single-arm phase II with registrational intent, 85 patients. The benchmarks are sort of 20%-30% CR/CRh, median duration of response, four, six months. That's what the FDA has sort of consistently guided that it's looking for. We started enrollment in February of last year. We've guided that the trial should be fully enrolled no later than the middle of this year. Enrollment has been robust, and we're making good progress and should be fully enrolled, as I said, no later than the middle of the year.
When could data be released? Is a six months expectation reasonable after completion of enrollment?
Yeah, I mean, you typically want to go six months. These patients can take time for the counts to recover. So as I think was discussed by one of my co-panelists, you want to clear the leukemia and then give the counts an opportunity to recover. Sometimes that happens more quickly, sometimes a little less quickly in this setting. You're typically going to wait six months until the last patient. Then you realistically need a couple of months for data cleaning just to really make sure you don't put something out there that you're not going to stand behind. So that hopefully gives you. We haven't formally guided to when to expect top-line data, but that kind of gives you a flavor.
Yeah, I know ziftomenib has produced pretty compelling data, but what do you think are some of the risks to the success of the trial?
I don't think there are any risks. I mean, I said in the fireside chat this morning, I can't rule out an asteroid hitting the Earth, kind of a but I think if you look at what we've done, we have a phase Ib study, 20 patients at the recommended phase II dose, a 35% CR rate with full-count recovery. The trial's 85 patients with a reasonable null hypothesis. I mean, you all can do the statistical powering. I think we're feeling very good. Barring, again, some extraordinary safety event, which I don't foresee happening given the experience we have, I think at this point, it's execution.
Thank you.
Harout Semerjian, GlycoMimetics, it's probably the more important question is the phase III trial for uproleselan, it's ongoing right now. It's fully enrolled for about two years. So can you update us on or just remind us what the design is of that trial and when we should expect to see data and what has taken so long for some data to actually happen? Does it have to do with discontinuation rate, or is there anything else? Yeah.
Yeah, no, thank you for that. Yes, for the benefit of everyone, what we're studying is uproleselan, which is an E-selectin antagonist. It's in combination with two different forms of chemotherapy-based therapies, which are typically standard of care and fit for intensive therapy, relapse and refractory patient populations. So our trial is a phase III randomized controlled trial across nine countries around the world, half enrolled in the U.S., half globally, ex-U.S., so Europe, Canada, and Australia. This trial has enrolled 388 patients. Last patient in was in November 2021 with an overall survival endpoint as the primary. So to your point, Nick, we've been waiting until then, which is a long time for any company. And if you're a tiny biotech, that's even more important. Obviously, we're very happy that patients are living longer. That's why we are not getting to the event count that was needed.
We continue to monitor this trial. Last year, in the summer, we announced that we have gotten FDA alignment that we will introduce an alternate path to trigger the full events analysis, which is a time-based in addition to the events-based, given the slowness of the number of events. The whole mechanism that we're targeting is getting patients who are fit for intensive therapy into deeper remissions, as many of them into transplant and through transplantation, and hopefully, we're able to put them on a long-term survival curve. So that's kind of what we're trying to do. What's driving that? It's difficult to say. The only reason I can say is with definitively, the number of events are less than what we thought it will be.
There are multiple trials out there in the randomized controlled setting that have established what a median overall survival would look like with standard backbone therapy, which is around that six to eight months period. So basically, what we announced on Friday, last Friday, is that we're going to be triggering the full events based on a data cutoff of end March, and our data will be in Q2. So to the point that Troy made, we need some time for all the data cleanup. This trial has been going on for six years or so. So it's a long time across multiple different countries. So we're very excited about what this potential can be for patients, for relapsed refractory patients who are fit for intensive therapy.
We're happy that this journey, we're going to get to a point where, hopefully, we're able to report positive overall survival outcomes. Once we report that, it's pretty straightforward. It's OS as a primary endpoint. Stay tuned. We're going to find a lot of information in terms of what's happening, what's going on because, as you know, our mechanism of action is agnostic to mutational type, agnostic to cytogenetics, agnostic to backbone therapy. We're probably going to have all types of patients that we can further analyze and study for years to come.
Just one follow-up on that. What led to the FDA approving that change? Obviously, the trial's going on long, but what specific arguments led to that?
Well, I would say three things. One is we aligned on Q2 2024, which would be around three years of follow-up. So median follow-up would be beyond three years. So it's going to be around 37 months, which is quite compelling by itself. Patients who've gone to transplantation, remember, this trial is not censored to transplant. So if we're able to get more patients through transplantation, we capture that benefit. So we're going to have data on the vast majority of those patients.
You're not censoring for transplantation?
We're not censoring for transplantation.
You don't want to do that, or you were not allowed to do that?
No, we aligned with the FDA that that's not appropriate. We want to get more patients to transplant.
No, no, it's a good strategy.
Yeah, yeah. Thank you for that. It would have been difficult to change it at this point. But the point is, all the patients who've gone to transplant, we're going to have data two years plus post-transplant, which if you look at the CIBMTR databases, if you're able to survive two years plus post-transplant, you're typically on a longer-term survival benefit. So those would be the two things. And then most importantly is the number of events just slowed down dramatically. Many of my colleagues mentioned midostaurin. When Neil and I, we were there. I launched midostaurin as part of the U.S. hematology at the time at Novartis. And that was where it was an NCI-led trial.
How confident were you the study was going to be positive?
Well, I mean, at that point, to be honest, I mean, as a big company, we were launching assets every two, three months. So at one point, they're like, "Oh, the NCI went and talked with the agency, and they said, 'Okay, we're going to be triggering this at that point.'" So it came to us after that. Obviously, it's a different but the point is there is a regulatory precedent in AML for doing that. So these are the three things, I would say. And of course, we share with them some of the pool-blinded data that we're seeing.
Actually, that's the right way to run a study like that.
Yeah. No, I appreciate that. I mean, that's kind of, to be honest, a lot of us have joined also in the last few years where, I mean, kudos to the folks who were before us in GlycoMimetics, where it's not very typical to start these long trials. It just takes a long time, and it can potentially kill you as well as a company. But as one of my colleagues said, hopefully, good things come to those who wait. So we're waiting.
Our next question goes to Neil. So Syndax's menin inhibitor revumenib has succeeded in its pivotal trial. Can you summarize the efficacy data that were most recently presented at ASH?
Yeah. So the data that we presented at ASH, so just to step back, the pivotal trial is called KOMET-001. There were, in fact, three cohorts originally, three single-arm cohorts: KMT2A-rearranged ALL, KMT2A-rearranged AML, and the ongoing NPM1-mutated AML cohort. And all three contained adults and up to 20 pediatric patients. So the data that we reported out, the pivotal data that we reported out, it's from a pooled analysis of the first two, ALL and AML. And what we reported overall was that the response rate was 63% with a 23% CR/CRh rate. And so from an approvability perspective, the trial was statistically significantly positive based on the 23% point estimate. And it's currently under review, and I'll come back to that in a moment. We also saw significant, so historically, these patients, these are third-line-plus patients.
Historically, very few of these patients will get to transplant. The transplant rate overall is around 5%. The median overall survival for these patients is under three months. These patients are really prior to the availability of revumenib and other menin inhibitors, these patients have really not had any real treatment options. So with respect to transplant, we saw overall a 25% transplant rate on the trial. And within the line of the trial, patients were allowed to recommence maintenance therapy after transplant. And what we saw was that 70% of patients went back onto maintenance, either went back onto maintenance at the time of the data cutoff, most of them, or a small number were still within the treatment window.
So two-thirds of patients responding, lots of patients going to transplant, going to transplant before actually achieving full-count recovery because that's what the physicians, obviously, decided to do in the best interests of their patients with exposure, then re-exposure for most patients in the most responders in the or most transplanted patients, rather, in the post-transplant maintenance setting. Median duration of response is six, four months. The median overall caveat here, it's a single-arm trial, but the median overall survival is eight months in the most recent data release at ASH compared to, like I said, that historically, these patients tend to die very, very quickly. Overall status, it's under review. Submission is in. We were invited to take part in RTOR. Obviously, we've been under BTD with the agency for this since the end of 2022.
Our anticipation is, as we sort of mentioned a little bit earlier, our anticipation is we'll get potentially full approval based on these data for acute leukemia, quite a broad indication in adults and kids.
Can you talk a little bit about our trial and what are some of the benefits of that program, and when do you expect to receive a PDUFA date?
Yeah, sure. So PDUFA date first, we anticipate during the first quarter. RTOR is real-time oncology review. It was implemented initially, I think the first program went under review in 2018. And what it means is that there's no validation period. So quite often, the agency is familiar with the program already under BTD, and they understand what's coming, which is exactly the case for us. So they understand there's a lot of interaction with the agency prior to that. Then they decide whether or not to invite you in. And it means they start reviewing your submission from the start. So you start submitting the modules. We started last October. We completed all plan modules, submission of all plan modules by year-end. And they've been actively reviewing those as we go along. So in terms of benefits, a couple of things. There's no formal validation period.
So there's no risk of a refusal to file, for instance. And generally speaking, they tend to do this with drugs that have a high likelihood of approval that fall within a space with high unmet medical need. Certainly, high unmet medical need is the case in this particular instance, so. And I would say that the collaboration tends to at least my experience of gone through this before, it tends to be a very active process, right? So once they decide that they're going to do this, they get on with it. And quite often, they don't wait till the PDUFA date necessarily for approval, so.
Okay, Erin. So for Terns, in October, you guys announced that you had your IND clearance for the CARDINAL One design for your STAMP inhibitor TRN-701. So can you remind us a little bit about just the overall design of the clinical trial and then just provide an update on how trial startup activities are going, as well as when we can expect some interim data?
Sure. Trial startup activities are underway. We're in the phase I study now, which is pretty exciting for us. Cardinal, I mentioned earlier, is a dose expansion, dose escalation, two-part phase I study, recruiting previously treated CNL patients, either second- or third-line patients. We can include a patient previously treated with asciminib who have been intolerant to asciminib, although not have kind of failed asciminib. We're planning on looking at several different dose levels in part one of dose escalation. It's a BOIN design, so at least three patients per dose group and then the ability to backfill. Importantly, we were able to start at what we think could be a potentially efficacious dose. We're starting at 160 milligrams as our starting dose in our trial. Recall that China rights to TRN-701 were outlicensed to our partner, Hansoh, a few years back.
So they've had a phase I study enrolling in China for a while. We were able to leverage the accumulated data from that study, present that to FDA, and successfully positioned TRN-701 as not a first-in-human study, right? The Cardinal study is not first-in-human. We're starting at a dose four times higher than our partner started with. 160 milligrams compared to 40 milligrams. As we stated in that press release, based on emerging data from our partner, we think that 160 milligram dose could be a clinically efficacious dose. That's really important for a number of reasons, not the least of which is that's where a lot of the exuberance that I talked about earlier from investigators is coming from, that they could be starting their patients on a potentially efficacious dose.
That relieves the slowness of the earlier pace of enrollment, where patients and providers are reluctant to participate at lower doses that may not be effective. The study is underway. We are planning to have interim data from part one of the dose escalation phase of the study in the second half of this year. We're on track for that.
Fantastic. Just a quick follow-up, do you guys ever plan on releasing the data that you guys have gained from your partners out in China, or is that up to them, or how will that be?
Yeah, they're developing the drug independently in China. So that would be Hansoh's decision whether to release the data. They did have a trial-in-progress poster at ASCO last year giving an update on the study and where the recruitment was to that date.
Thank you. Alfonso back to you. So going back to the BAF complex, you said differentiation is what happens on mechanism. That's exactly what you saw early on. And it's a good sign in many ways because you're actually on target, and you're actually causing the cell to differentiate. The challenge was trying to find the right therapeutic window. So you decided to continue with either low-dose cytarabine or low-dose cytarabine, and that study is now ongoing in phase I. Can you talk maybe a little bit about the trial design or how you're thinking about dosing or the combo and why even do that combination specifically vis-à-vis differentiation syndrome?
Yeah. So just to recap a little bit, we run a monotherapy trial, dose escalation study with 286, a single agent in 40 patients with AML. The major lesson coming out of that trial is that we can induce differentiation across the board. So typically, differentiation agents are very effective, as we heard from our esteemed colleagues, in specific genetic backgrounds. We have the ability with 286 to induce differentiation across a broad range of genetic backgrounds. That's something we learned during the conduction of that monotherapy study, a very important one because that may serve as a backbone going forward for therapy beyond specific genetic abnormalities. The second thing we learned is, obviously, with differentiation, that comes at a price. The price to pay is differentiation syndrome, which in that monotherapy study happened to 6 patients.
We applied those lessons learned in the monotherapy trial to the study that we're running right now, which is in combination with either cytarabine or low-dose Ara-C. We decided to shelve the low-dose Ara-C for the moment. We focus on the cytarabine combination. And what we're doing right now is we're running two cohorts in parallel where the backbone is cytarabine at the standard dose of 20 mg/m² for five days and increasing doses of 286. And we do that in the presence or the absence of azoles. Why? Because there is a drug-drug interaction with azoles, which is typically what happens in many of these agents being developed in AML. In the presence of azoles, we see higher exposures to 286, and that may have implications both for safety as well as for efficacy.
So the dosing ranges are slightly different for the with or without azoles. So without azoles, we started treating patients at 2.5 milligrams, which is exactly the same initial dose we used in the monotherapy study. In the presence of azoles, because that's expected to increase the exposure to 286, we started at a slightly lower dose, which is 1.5. And we're going to dose escalate both cohorts up to 7.5. And so that's where we are right now. Why the cytarabine? Well, the cytarabine, obviously, being an agent that is active in AML, a couple of reasons. We think that the combination may actually increase the activity of 286, number one. But number two, because of the differentiation syndrome we observed in phase I, may act as a way dampening a little bit that differentiation syndrome we observed with the monotherapy component.
It could be helpful in terms of safety, but also in terms of efficacy with synergism between both agents.
To move into an expansion or into the next dose, is it based on responders, CR rates, or durability?
Well, it's going to be, obviously, a combination of safety and efficacy, but mostly efficacy because we're in a relapse refractory setting, and those patients have a very short survival. The response rates are very, very low, 10%-15% at best. Anything that goes beyond that would be a good signal to then launch an expansion cohort.
Troy Wilson recently released initial combo data for ziftomenib. Can you summarize that data?
Sure. Yeah. So the data, Ava, that you're referring to is from our COMET 007 study. That's a dose escalation study of ziftomenib with two standards of care, 7+3 and venetoclax-azacitidine. We started in the venetoclax population in the relapse refractory patients. We started in the 7+3 area with patients with adverse risk characteristics. We are enrolling KMT2A rearranged and NPM1 mutant AML cohorts separately, at least 6 patients per dose starting at 200 milligrams per dose. That's a lot of information. They give it as four parallel cohorts, three potential doses, 6 patients each. If everybody enrolls, it's at least 72 patients. The data that we showed as of our update in January was a cut on the first 20 patients. And to the comments that were made, we saw a very high rate of differentiation syndrome, particularly among the KMT2A patients, as a monotherapy.
It actually limited our ability to develop ziftomenib. It's actually too potent in the KMT2A population. When we coupled it up with the standards of care, the DS rate among the first 20 patients went to zero, zero at all grades. So too, the idea, I think it very well supports the idea of going in combination. The activity, it's early days. Again, this is the 200 milligram dose. If you go back to the monotherapy, which is instructive, we were one of the first companies to go through Project Optimus with FDA. We evaluated 200 milligrams and 600 milligrams, non-overlapping doses. The safety and tolerability in the monotherapy were identical. The activity, you could drive a truck between them. Really, the vast majority of the activity was at the 600 milligram dose.
That being said, we saw meaningful clinical activity at a 200 milligram dose in both cohorts, 100% CR rate in the front line and 7+3, among menin-naïve patients in the relapse refractory setting at 56% CR/CRH rate and a 70% ORR rate, to the point that I think Neil made the goal of many of these physicians is to get patients to transplant. Even with the high rates of activity that we've seen with menin inhibitors as monotherapy and I think we're cheering for our colleagues at Syndax in the KMT2A setting, the combinations promise even more. So we're now at 400 milligrams in those cohorts, Ava, except for the third, the fourth cohort, the KMT2A 7+3. We've said that when we get to 600, we'll likely disclose that publicly because that's going to be very informative of what people can expect.
That doesn't mean we'll disclose the data. We'll disclose that we're at that dose, whether it's PK, safety and tolerability, clinical activity. I think the fact that we continue to dose escalate is very encouraging, and we'll provide an update in the course.
When can we expect to see any additional data from COMET 007?
Yeah. So we're sort of keeping options open here. Really, as I said, the near-term question people should ask is, "At what dose are you expanding?" The longer-term question is, "You want to see safety, tolerability, signs of activity." Given that we're not yet dosing patients at 600, it's a little hard to project that. We may give an update here on just the ongoing study, or we may wait a little longer and give it once we're at whatever the RP2D is. I think there's optimism that it'll be 600. We'll just have to wait and see. We haven't guided to a specific time, but that's the next meaningful update.
To the point that was made about combos, we're similarly looking to start a first combination study in the venetoclax population frontline around the end of the year, probably dose the first patients early next year. But that trial is just enrolling like gangbusters. So I think we're on a good path.
Similar question to Neil. Can you also summarize the combo data that revumenib has produced?
Sure. Just before I summarize the combination data, although I described the KMT2A monotherapy data, I'd just like to remind everyone that we also have monotherapy NPM1 data with the 36% CR/CRH rate. So we see very similar activity in both the NPM1 and KMT2A populations. So we reported three combination datasets, either ADASH or a combination event around ADASH. And they were from so the three trials were BEAT-AML, so a combination of revumenib with venetoclax azacitidine, which is a standard of care for unfit newly diagnosed patients. And that's in the newly diagnosed setting. So we were able to proceed to dose ranging straight away in the newly diagnosed setting, which also positions as well. And I'll come back to that in a moment. The other trial was SAVE, which is an investigator-initiated trial, which is a combination of revumenib with venetoclax and oral decitabine.
The third was a company-sponsored trial called AUGMENT-102, which is a combination of revumenib with fludarabine and cytarabine in the relapse refractory setting. The SAVE trial is in the relapse refractory setting. The BEAT-AML trial was in the newly diagnosed AML setting. There were two doses of revumenib tested in all three, only two, 113 and 163. 163 is the presumptive monotherapy dose in combination with at approval in combination with the strong CYP3A4. We're also anticipating a dose for approval without CYP3A4 inhibitors of 270 at the time of approval. So the two doses were 113 and 163. And for all three trials, the dose-limiting toxicity windows had been passed. So the combinations were feasible across different lines of setting, different backbones, including two different VEN combination regimen and chemotherapy. Overall, we saw extremely high levels of response.
So we saw 100% response rates in both BEAT-AML and SAVE. We saw very high levels of CR/CRH. So for instance, in BEAT-AML, we saw an 85% CR/CRH rate and an MRD negative rate of 100% among evaluable patients. No, but one patient was evaluable. So that compares pretty favorably to the historical controls from VIALE-A. And that puts us in a very good position to be able to initiate the phase III as quickly as possible. Also, SAVE-AML, very high response rates, 100%, very high MRD negativity rates. And then in AUGMENT102, the combination with chemotherapy, again, response rates that were three times higher than one would be expected in a very refractory population. So overall, we're feeling pretty well positioned.
On to GlycoMimetics again. Specifically, the NCI is running a phase II/3 trial in the frontline AML setting of uproleselan. Can you walk us through the design of that trial? Specifically, what are the benchmarks for success, and what are the potential outcomes for this trial when they do end up reading out?
Sure. So basically, after we ran a phase III trial, after the recommended phase II dose, we had two cohorts of patients, frontline, fit for intensive therapy, elderly population, and relapse and refractory, fit for intensive population as well. So based on those two cohorts, our phase III, we took the cohort that was the relapse and refractory, and that's where our phase III, we've expanded it, and that's our registration program. The NCI was very interested in the frontline, fit patient population. So they started a trial, which is an adaptive phase II, III trial in frontline, fit patients, elderly than 60 years old. That trial has fully enrolled the phase II portion with 267 patients. So we have 388 in our phase III, and then we have 267 patients with the NCI. That trial is an EFS endpoint, and it's phase II.
Last patient in was in December 2021, literally two weeks apart from our own relapse and refractory trial, both trials fully enrolled at that time. With an EFS endpoint, it's expected that within a year, we should get that EFS trigger. That would have been December 2022. Here we are in March 2024, and we still don't have the number of events needed in that trial as well. Obviously, it's an NCI-led trial, so it's not our trial. The beauty is they do it. They pay for it. The downside of that is we're blinded as well. We are in continuous conversations with them to ensure that everybody's looking at the right things and that we're informed as soon as they can. So that can read anytime. We're way in overtime already.
What we do know is what we can control is the phase III, that we're going to be triggering it. That data is coming in Q2, and the NCI, it can come before that, it can come during that, or it can come after that.
Great. So Erin, your 701 candidate is a BCR-ABL STAMP inhibitor. Can you maybe talk about the key differences that it has with Novartis's asciminib?
Sure. To back up from there, let's just talk a little bit about what allosteric inhibitors are versus the historic class of active site TKIs. So the active site TKIs just do exactly that. They bind the same pocket that ATP does on the kinase portion of the BCR-ABL fusion protein. That pocket is conserved across multiple different kinases, however. So that means that those drugs can also inhibit other off-target kinases, and that probably leads to their safety profile. The tighter you bind that pocket, the more off-target activity there is. The allosteric inhibitors are completely different. So Novartis's asciminib and TRN-701 bind the myristoyl pocket on the ABL moiety. That's important for a couple of reasons. First of all, in native ABL, one terminus of the protein flips into the myristoyl pocket to turn off ABL. So this mimics the way that the ABL kinases naturally inhibited.
The other key reason that's important is the myristoyl pocket is very specific to ABL. So there's not even ABL2 activity. In fact, TRN-701 is so specific, it doesn't even inhibit native ABL. It only inhibits BCR-ABL. So these drugs have much more targeted activity towards BCR-ABL and therefore less off-target and potential safety effects. And we've seen that with asciminib, which is better tolerated than a second-generation active site TKI. When you look at the label, there's very little in there in terms of adverse effects or safety findings. So our goal with TRN-701 was to discover and develop an allosteric inhibitor that would be at least as active as asciminib, which in both in vitro preclinical experiments has been shown. And actually, in vivo, in mouse models, TRN-701 can outperform asciminib in some models. So that's exciting.
We think that there's a huge potential opportunity for TRN-701 even with minimal differentiation from asciminib, simply because there is nobody else that's working on this mechanism, save one small biotech in China. And so we very likely could be second in class for a class that's going to really dominate, we think, the treatment of CML in years to come. Having said that, we do think there are some important opportunities for differentiation. I've talked about second line. We know that Novartis is not pursuing a second line, at least label-enabling study at this point in time. In addition, we think there's an opportunity to dose-optimize TRN-701. There was a lot of headroom in terms of safety where asciminib could have been developed. They went with a lower dose.
We think that as long as the safety margin is maintained, we can probably go with a better dose-optimized drug that would be less subject to things like food effects or drug-drug interactions, which kick the trough down of the drug at 24 hours, which is important to maintain. We know that revumenib has some labeling precautions for drug-drug interactions with CYP3A4 substrates. That's a bit of a problem in the older patient population that's taking a lot of medicines. It also has to be taken in the middle of a 3-hour fasting window. We think there's room for improvement there to make it easier for patients to adhere to their treatment.
Great. And just as a quick follow-up, so Novartis is pursuing first-line treatment now. Is that a strategy that Kura plans on pursuing, or how do you see the first-line opportunity?
Yeah. Potentially, what Nicole is referring to is just some recently top-line data from Novartis that asciminib has now shown potentially improved activity head-to-head against the choice of active-site tyrosine kinase inhibitor in a first-line setting. We think that's exciting and actually creates all that much more opportunity for 701. So yes, while we're really interested in the second-line population, it completely opens up the possibility that we could do a parallel phase sorry, first-line study as well.
Thank you so much. I know we have about 2.5 minutes left, but I know there's panels right afterwards. So I'm going to take the liberty to thank everybody for coming. This was really instrumental and very informative. Thank you. And we'll continue to monitor closely.
Thank you.
Thank you.