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

Good day, everyone, and welcome to the Syndax ASH Annual Meeting Data Update Call. Today's call is being recorded. At this time, I would like to turn the call over to Michael Metzger, Chief Executive Officer of Syndax Pharmaceuticals.

Thank you, operator, and thanks to everyone joining us this morning to review our revumenib data presented yesterday in 2 oral presentations at the 64th ASH Annual Meeting. I want to begin by pointing out our forward-looking statements on Slide 2. Before we review the Phase I data for revumenib, our highly selective menin inhibitor and hear from 2 of our principal investigators, I would like to take a moment to outline Syndax goals for this year's ASH meeting on Slide 3. Our team is first and foremost focused on physician engagement and our disease awareness campaign at ASH. As leaders in the menin inhibitor field, we continue to build the awareness of the benefits of using a menin inhibitor to treat mutant NPM1 and KMT2A acute leukemia in preparation for the potential commercial launch of revumenib in 2024 and Medical Affairs is at the forefront of these efforts. We continue to gather positive feedback on revumenib's clinical profile and potential. As a reminder, we expect to share pivotal data from the Phase II portion of our AUGMENT-101 trial beginning in the third quarter of 2023 and filed by the end of next year. And as Briggs will cover later in the presentation, we will also have several other trials ongoing to expand the market opportunity for revumenib. Our second focus during this year's ASH meeting was to share the exciting updated revumenib data on the Phase I portion of the AUGMENT-101 trial. These data continue to showcase revumenib's potential as not only a first-in-class but also a best-in-class treatment option for patients with NPM1 or KMT2A acute leukemia. Importantly, the robust data set presented yesterday show CR/CRh rates improving over-time as we've treated at our recommended Phase II dose with safety remaining manageable and consistent. As announced earlier this week, we received Breakthrough Therapy Designation, or BTD for revumenib for the treatment of adult and pediatric patients with relapsed or refractory KMT2A rearranged acute leukemia based on the breadth of patients treated at the RP2D in the Phase I portion of the AUGMENT-101 trial. This further underscores revumenib's potential as a first and best-in-class therapy to meaningfully change the treatment paradigm for these patients. Based on the data shown to-date, revumenib has the potential, if approved, to be the first drug to address the significant unmet need in KMT2A leukemia believed to occur in up to 10% of all acute leukemias, including approximately 80% of infant acute leukemias. And based on the data, which we will review shortly, we also believe the same broad opportunity is available for revumenib to address the unmet medical need in NPM1 patients, which comprise approximately 30% of the addressable AML market. With that, let's turn to a review of our ASH data on Slide 4. We're honored to be joined this morning by 2 key opinion leaders, Dr. Ghayas Issa, Assistant Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center; and Dr. Eytan Stein, Chief of the Leukemia Service, Director of the program for Drug Development in Leukemia and Associate Attending Physician at Memorial Sloan Kettering Cancer Center, who will recap the data presented and put it into context with the current treatment landscape. Dr. Issa and Dr. Stein as well as our management team will be available for a Q&A session at the end of today's call. Dr. Issa, floor is yours.

Thank you. Hi, everyone. I'm having issues with my WiFi. I will be using audio only. I hope you can sense my excitement towards revumenib from my voice alone. Today, I'm going to talk to you about the data from the Phase I study of revumenib in patients with KMT2A-Rearranged or NPM1-mutant acute myeloid leukemia. And this data was presented yesterday at ASH. Next slide. So the interaction of menin and KMT2A is a critical dependency in acute leukemias with rearrangement of the KMT2A gene previously known as MLL or mutations in NPM1, which leads to an aberrant gene expression that causes leukemia. KMT2A rearrangements are associated with an adverse prognosis, they lead to myeloid lymphoid or mixed phenotype acute leukemia and affect infants, children and adults with this disease, whereas NPM1 mutations form the most common genetic alteration in acute myeloid leukemia. And despite an increasing knowledge of leukemia underpinnings caused by these alterations, there are no specifically approved targeted therapies for these subsets to-date. Revumenib previously known as SNDX-5613 is a potent and selective small molecule inhibitor of the menin and KMT2A interaction. Revumenib binds a discrete, well-defined pocket within menin, where both KMT2A-wild-type and fusion proteins bind leading to disruption of this aberrant gene expression and an anti-leukemic effect. Next slide. So in this Phase I, first-in-human dose escalation study, revumenib was given orally every 12 hours with continuous dosing. Escalation was performed using a rolling 6 design and an early amendment of the protocol restricted enrollment to only leukemia with KMT2A rearrangement or NPM1 mutation. Dose escalation was divided into 2 separate cohorts, Arm A, for those not taking strong CYP3A inhibitors and Arm B for those who are taking strong CYP3A inhibitors. There were 2 dose-limiting toxicities of prolonged QTc and Arm A at the 339 milligram dose level and Arm B at 226 milligram dose level. And because of this, intermediate dosing cohorts were added for further exploration. We defined 2 separate analysis cohorts, a safety population of 68 patients who received at least one dose of revumenib, including 8 without KMT2A or NPM1 mutations and an efficacy analysis cohort of 60 patients with either KMT2A rearrangement or NPM1 mutation and the pre-specified criteria to declare the recommended Phase II dose are listed on the right-hand side. Doses that met the RP2D are shown in purple boxes. Next slide. These are the baseline characteristics. Infants as young as 10 months of age were enrolled on this study, children and adults with any leukemia phenotype. These patients were heavily pretreated, had received a median of 4 prior lines of therapies. Half have had a stem cell transplant. Patients with KMT2A rearrangements had a variety of translocations that represent the wide possibilities of KMT2A fusion partner genes across age and leukemia phenotype. Next slide. The disposition of all patients treated on study are listed on this slide. Two patients remain on study and 66 have discontinued treatment. 39 patients are off study because of progressive disease or no response. 12 patients discontinued treatment because they proceeded to an allogeneic stem cell transplant. And further data from this group was also presented at ASH, and I will talk about it a little more today. Next slide. Revumenib was well tolerated. The treatment-related adverse events as attributed by the investigators are listed on this slide. 53% of patients had a prolonged QTc, but the rate of grade 3 or higher QT prolongation was 13%. Of note, at the doses meeting the criteria for RP2D, the rate of grade 3 or higher, QT prolongation was 10%. There were no treatment discontinuations for QTc prolongations or associated ventricular arrythmias. Differentiation syndrome was observed in 16% of patients. All were grade 2 and were successfully managed with corticosteroids requiring no dose interruption or modification. Next slide. In this cohort of patients with highly refractory acute leukemia with KMT2A rearrangements or NPM1 mutation, revumenib demonstrates a highly promising clinical activity. No patient with either of these genotypes was excluded from the efficacy analysis. The overall response rate was 53% with a rate of complete remission or complete remission with partial hematologic recovery or CR/CRh of 30%. Notably, the rate of MRD negative remissions and those who achieved a CR/CRh or CRp, was 78%. This is the highest MRD-negative response we're aware of with any therapy for these leukemia subsets. With the limitation of smaller sample size, the rate of CR/CRh was 33% in patients with KMT2A arrangements and 21% in patients with NPM1 mutation. Next slide. In patients that received doses meeting the criteria for RP2D, the overall response rate was 52%, with a CR/CRh rate of 27% and an MRD negative rate in those that achieved CR/CRh or CRp of 78%. In this population, the overall response rate for KMT2A arrangement and NPM1 mutations were 54% and 46%, respectively, with MRD negative rates of 70% and 100%. Next slide. Revumenib led to rapid and durable responses. The swimmers plot depicts patients from the efficacy population treated to-date and their outcomes. The blue bars are those with KMT2A rearrangements and the purple bars represent those with NPM1 mutations. The median time to achieving CR or CRh was 1.9 months. Next slide. This Kaplan-Meier curve shows the duration of response and those who achieved CR or CRh and it was 9.1 months. Next slide. Importantly, this translated into the promising improvement in overall survival compared to what is expected for this population, with previously available salvage regimens. The expected median overall survival would have been about 3 months. The median overall survival with revumenib monotherapy on this study was 7 months. Next slide. This is the data from the 12 patients from this cohort that underwent a stem cell transplant. I will take you through some of these patients and show that a good number are still in remission. So this swimmer plot depicts patients who achieved remission with revumenib. 11 of the 12 had attained MRD-negative remission prior to transplant. The blue bars are KMT2A and purple bars are NPM1. The blue diamonds indicate time of transplant. So 4 patients had remissions lasting longer than one year without additional maintenance therapy with revumenib. One patient has been in remission for 11 months at the last data cutoff and had received post-transplant maintenance with revumenib. Only 2 patients depicted in red squares have relapsed. This encouraging duration of remission following transplant in these patients with highly refractory leukemias resistant to prior therapies likely reflects the depth of response attained prior to transplant using revumenib monotherapy. Next slide. In the next 2 slides, I will take you through the cases where patients have received maintenance therapy. These patients have received revumenib under single-patient compassionate use protocols prior to the current amendment, which allows resuming revumenib post transplant for maintenance. In this first case, a 40-year-old female with KMT2A rearranged acute myeloid leukemia and a FLT3 co-mutation was enrolled on the Phase I study of revumenib after progression following 3 lines of therapy and an allogeneic stem cell transplant. She attained a complete remission with partial hematologic recovery and MRD clearance. She successfully underwent a second allogeneic stem cell transplant, received 2 cycles of azacitidine as maintenance therapy, while waiting for approval of single patient protocol for revumenib and subsequently started revumenib at 163 milligrams q12 with a strong CYP3A inhibitor, the same dose she had when she was enrolled prior to transplant. Revumenib was held because of thrombocytopenia twice and was subsequently reduced to 113 with recovery of platelet counts to above 100,000 and no further recurrence of thrombocytopenia. She continues to have MRD-negative remission one year post transplant. Next slide. So this is the preclinical data that supports combinations of revumenib specifically here with the BCL-2 inhibitor venetoclax. And this model of mice with NPM1 mutations, mice were treated with either venetoclax or the revumenib in this case at various doses or the combination of both. And you can see that venetoclax and revumenib have different target populations. The venetoclax targets earlier populations, whereas revumenib targets later populations, so specifically where NPM1 originates. That's the common myeloid progenitor. But the combination is able to eradicate both populations, which probably would translate into an improved MRD-negative response and durable remission when combining these both making high synergy of revumenib and venetoclax. Next slide. In this analysis, we looked at what is the impact of FLT3 co-mutation on responses with revumenib. In the patients that were enrolled on study, 14 had mutations in FLT3 and 13 out of these 14 have been treated with a FLT3 inhibitor prior to enrolling on revumenib study. So the overall response rate for patients who had KMT2A rearrangements and of the FLT3 co-mutation was 66%. So 2 out of 3 responded. And in those that have NPM1 and FLT3, the overall response rate was 27%. So in other words, FLT3 in this case did not affect chances of response to revumenib, which is consistent with the hypothesis that NPM1 as a [indiscernible] in leukemia will take care of later events such as FLT3. Additionally, we looked at changes in gene expression on this analysis using bulk RNA sequencing. And you could see that the revumenib affects the target genes that we intended. So MACE-1 and HOXA9 are reduced significantly following treatment. It's also associated with signs of differentiation. So these leukemia cells are turning into normal cells. And interestingly, the FLT3 levels go down with treatment, which could be an effect of revumenib targeting transcription of the FLT3 because the target of revumenib MACE-1 controls expression of FLT3. Next slide. So as I have mentioned, NPM1 is considered a founding event in leukemia. The normal sequence of events in acute myeloid leukemia is having clonal hematopoiesis, that's DNMT3A followed by a mutation in NPM1 that causes leukemia and later events such as FLT3 that offer [indiscernible] advantage. So by targeting a founding event in acute myeloid leukemia, we hope to take care of any later events that may arise such as FLT3 or [Brass]. That's why we think that revumenib would be an important therapy in acute myeloid leukemia. And the graph that you see to the left, bottom left, this is the presentation of all the preclinical studies that show that using menin inhibition will target expression of FLT3. And then interestingly, the combination of menin inhibitor and a FLT3 inhibitor is highly synergistic. And this mouse model that you see to the right also presented this ASH, you could see that the green line is gilteritinib monotherapy, the purple lines or orange lines are revumenib monotherapy. So in this FLT3 model, although this is one model and more data has done, revumenib performed better than gilteritinib than single-agent FLT3 inhibitor in an NPM1 FLT3 mutation and then the combination led to substantial improvement in overall survival of these mice. Next slide. So the AUGMENT-101 Phase II study continues to enroll in 3 distinct patient populations. And these are planned pivotal cohorts with the plan for FDA approval. Next slide. And revumenib recently received the BTD designation. So this highlights the importance of revumenib for this patient population, the robustness of the data and the fact that we've included patients from peds to adults and most importantly, the unmet need where revumenib is a promising therapy to solve what would be a devastating disease for many patients. Next slide. In conclusion, revumenib resulted in deep and durable responses in heavily pre-treated pre-relapsed and refractory KMT2A rearranged and NPM1 mutant acute leukemia and demonstrated a clinically manageable safety profile. 30% of patients attained CR/CRh with a median duration of response of 9.1 months. 78% of patients with CR/CRh attained MRD negativity. 38% of responders proceeded to a stem-cell transplant. Maintenance after transplant appears feasible and is a loud and pivotal portion of the AUGMENT-101 study. The median overall survival was 7 months in the relapsed refractory population, an improvement compared to what is expected for these patients with a bad prognosis. The safety profile is clinically manageable. Only DLT was asymptomatic Grade 3 QT prolongation observed in 10% of patients treated at doses meeting criteria for RP2D and 13% in patients treated at all doses tested. Differentiation syndrome occurred in 16% of patients and all cases were Grade 2 and responded to management with steroids with and without hydroxyurea and revumenib offers a promising potential for future combination therapies. Next slide. Thank you. I will turn it over to Dr. Stein.

Okay. Thanks so much, Gus. What I wanted to do is take a step back and think about really what are the treatment goals for patients with relapsed and refractory acute leukemia. And of course, the first treatment goal is to eliminate that leukemia. You eliminate that leukemia by giving a therapy that traditionally we've measured as successful if a patient achieves a morphologic CR that is less than 5% blasts. And that category includes all of these different manifestations of CR. So what we call CR/CRh/ CRp/CRi and MLFS. All of these mean that less than 5% blasts are present in the bone marrow. And even if you haven't had count recovery, that is usually sufficient to take the patient to an allogeneic stem cell transplant. But of course, we want to get remissions that are as deep as possible. So we now talk a lot about achieving an MRD-negative complete remission, meaning by the most sensitive methods that may be available, whether it's flow cytometry or next-generation sequencing, whether we can eliminate all detectable leukemia cells. So after we eliminate the leukemia next build, what you'll see is that we make a decision, is this patient eligible for an allogeneic stem cell transplant, in which case, we move them on to an allo transplant. And if they're not eligible for an allogeneic stem cell transplant, certainly, what you want to do is you want to improve the patient's quality of life by maintaining that remission, which helps the patient avoid infections, not need to come into the hospital for transfusions and generally lead a normal and healthy life, especially if they're taking a therapy that is oral and can be administered by themselves at home. Next slide, please. The importance of MRD negativity has been explored in a number of large retrospective series. This is a study that was published by Nick Short in JAMA, just making the point that for patients who are MRD negative, which is in the orange line, their overall and disease-free survival really vastly exceeds the group of patients who are MRD positive after they receive their therapy. So the importance, I think, of making a patient or giving a therapy that can make a patient MRD negative, really, I don't think can be overstated. And when you have an agent, as Gus showed with revumenib that leads to an MRD negative rate of remission in 78% of those patients who achieve a complete remission or CRh that is really, really quite dramatic. And as Gus mentioned yesterday, I am not aware of any other therapy, oral therapy for sure, but maybe any other therapy in general that leads to levels of MRD negativity like we've seen in AUGMENT-101. Next slide, please. I want to talk just for a second about this patient of mine who is kind of seared in my brain because of her story. So she is a 24-year-old woman who 3 months prior to me meeting her had her first child. And after she had her kid, he had this general signs and symptoms of a patient with newly diagnosed acute myeloid leukemia, bleeding and infections. And she came in, she had a bone marrow biopsy and was found to have a KMT2A rearrangement with a 6;11 translocation. These patients are notoriously difficult to treat and don't respond really to any conventional chemotherapy. And that was the case with her. She was refractory to [indiscernible] Vyxeos, she was refractory to [indiscernible] and then we tried venetoclax/decitabine, she was refractory to that as well. And during the course of her being neutropenic for 3 or 4 months, she developed a very, very unusual disseminated fungal infection called scedosporium, and that infection was really widespread throughout her body. And I strongly advised her to go on the menin inhibitor on revumenib study. I have to tell you that many of the people I work with, the nursing staff and some other doctors thought that I was doing something unethical by trying to enroll her on this clinical trial because they thought I should just let her pass peacefully. And I said, no. And we enrolled her on AUGMENT-101 at 226 milligrams twice a day. And you can see at the very top that fairly rapidly, she achieved a MRD-positive CRp. And because it's a differentiation agent, that subsequently turned into an MRD-negative complete remission. Now someone like this, I normally would have taken to transplant right away, but she had some psycho-social issues that were barriers to transplant. So she remained on revumenib for 2 years, while we're working out the psycho-social issues in an MRD-negative complete remission back to a normal quality of life, until at around cycle 22, we were able to finally get her to an allogeneic stem cell transplant, which she received and she's currently doing well now. Next slide. Like Gus showed you, revumenib is important in turning off leukemia transcriptional programs both in the MLL setting and the MLL rearranged setting, or KMT2A rearranged setting in the NPM1 mutant setting. In the KMT2A rearranged setting, what happens is that menin binds to the KMT2A complex with its fusion partner, and that's what causes the turning off of the HOX, MEIS genes. And on the next slide, you'll see how this works with NPM1 is similar, although in the NPM1 mutant context, menin binds to the wild-type KMT2A complex and NPM1 is important in that binding and that interaction going on. There are a couple of papers recently published in Cancer Discovery, one by Scott Armstrong's group, they really elegantly describe how this works. And I would encourage you to have a look at those if you haven't already. Next slide. And finally, I just want to highlight what Gus showed before, which is these rates of complete remission, both in KMT2A and the mutant subsets. And again, really highlighting the rate of MRD negativity amongst the patients who achieved a CR or CRh. It's really dramatic. Just for some comparison, it's like you -- when we did the IDH inhibitor studies, the rate of IDH1 or IDH2 clearance, so that's not even complete MRD negativity, but just IDH1 or IDH2 clearance is in the range of 30%. And here you're getting essentially the absence of measurable residual disease in a much, much higher percentage of the patients. Next slide. And with that, I'll turn it over to Briggs, who will be talking about broadening the use of revumenib in acute leukemia.

Thanks so much, Eytan. Before I move on to the Q&A, I just want to take a minute to again highlight the unmet need in both KMT2A and NPM1 acute leukemias. On this slide, we see that approximately 10% of all AML or ALL, or KMT2A acute leukemias. It is particularly common mutation in infants where 80% of those have with acute leukemia have a KMT2A rearrangement. The 5-year overall survival for adult MLL-rearranged leukemia, is less than 25%. And as patients progress through lines of therapy, the relapse rate increases with over 80% of patients relapsing after second-line treatment. The median overall survival for patients decreases as they progress. And as Gus pointed out earlier, the median overall survival in the third-line patients is less than 3 months. NPM1 mutant AML is more common. It presents an approximately 30% of AML patients, it is the most frequent genetic alteration in AML. The 5-year overall survival for adult and NPM1 mutant AML is approximately 50%. And while the prognosis is more favorable than KMT2A, it worsens with age and when commutations are prevalent. So against this backdrop, I just want to remind everyone that the patients in the Phase I portion of our AUGMENT-101 trial were very heavily pre-treated, receiving a median of 4 prior lines of therapy and over 30% of patients had co-mutations, including FLT3, RAS and TP53. Patients who were treated on the study as Gus nicely summarized had a median overall survival of about 7 months with a duration of CR/CRh response of about 9 months, 20% of our patients in the trial went on to transplant. So we feel really quite excited about the data and the overall clinical profile and that excitement really stems from the excitement we hear from Gus and Eytan and all the other investigators who participated in the trial. On the next slide, you can see our ongoing and planned trials fit across the full treatment landscape. We believe that revumenib's excellent safety and efficacy profile lends well to expanding its use in earlier settings and in combination with approved therapies. And I'll expand on these designs in the next trial. So starting with the Phase Ib AML umbrella trial as part of our collaboration with the Leukemia and Lymphoma Society, revumenib is being combined with venetoclax and azacitidine to treat newly diagnosed AML patients with either NPM1 or KMT2A rearrangement who are unfit for induction chemo and azacitidine is the first menin inhibitor to be included in the trial, which will assess safety as well as the initial efficacy. Enrollment is ongoing. We expect initial data from this trial to be available next year. Long-term, we expect that the Beat AML trial results will lead to a Phase II/III trial, which would serve as the basis for our future regulatory filing. We're also enrolling patients in the AUGMENT-102 trial designed to assess revumenib in combination with standard salvage chemotherapies for patients with relapsed or refractory NPM1 or KMT2A rearranged acute leukemias. And again, we expect to have some initial data from this trial again next year. And finally, moving on to the INTERCEPT trial. This trial is focused on investigating novel therapies to target early relapse and clonal evolution as preemptive therapy in AML and is being conducted as part of the INTERCEPT Master clinical trial led by the Australian Leukemia and Lymphoma Group. The trial is designed to explore the activity of revumenib as monotherapy in patients with AML who have MRD-positive disease following initial treatment, a group of patients who are, of course, a very high risk of relapse. Of note, revumenib is the first menin inhibitor to be included in INTERCEPT AML master clinical trial, and we continue to expect the Australia and Leukemia Lymphoma Group to initiate dosing by the end of this year. So look, we believe that revumenib could be one of the most important new medicines in the leukemia setting. You can see on the next slide, expanding into the front line and maintenance settings continues to grow the number of patients that can be treated, the so-called addressable patient population. And as discussed, we have ongoing in planned trials to address all of these populations. And further, the clinical opportunity could expand into solid tumors as a reminder, we're exploring revumenib as treatment for solid tumors, and that study is on track to initiate quite soon, a Phase I signal seeking trial in 20 to 30 patients with refractory colorectal cancer. With that, I think I'll turn it back to Michael, and we'll open up to Q&A.

Great. Thank you, Briggs. As Briggs said, let's maybe take questions, please.

[Operator Instructions] Our first question will come from Phil Nadeau with Cowen and Company.

A couple of clarifying questions and then a couple of broader ones. In terms of clarifying, Briggs, did you just say that the AML trial could itself be pivotal and supported frontline label?

BD AML trial is set up as a -- initially, of course, a Phase I dose-finding trial to figure out the right dose. Once we have that dose, there is the opportunity that, that could be expanded into a Phase II/III trial that could be registrational.

And then second, in terms of the data presented over the weekend, would you be able to break up the CR versus CRh rates for the 2 different mutations for NPM1 and KMT2A specifically?

Maybe I'll turn it over to Dr. Issa, and he can describe that data.

Sure. So we had 46 patients with KMT2A rearrangements and 14 patients with NPM1. The overall response rate was 59% KMT2A arrangements, 36% in NPM1. But if you look at the RP2D at the recommended Phase II dose that we have identified in the study, the overall response rate is 54% KMT2A, 46% in NPM1. The CR/CRh is similar, 27%. But we didn't include this in this slide, but I would highlight that the confidence interval is wide and that my inclination as a physician treating these patients, likely the response rate is similar between these 2 populations, and it's just a matter of sample size. Does that answer your question?

Yes. And maybe follow-up on the QTc prolongation, that continues to be controversial among investors. Can you describe the nature of the QTc prolongation and how problematic or not problematic it is for patients?

Yes. I don't think I've met a clinician or a patient who would describe QTc prolongation as problematic, especially those that have KMT2-rearranged leukemias. So for us on the study and on many previous drugs that have been approved for acute leukemia, it's something we can do easily. We just monitor the EKG and make sure that there are no prolongations. And like we did in this study, the actual rate of Grade 3 was 10% and none of them led to dangerous complications. So in clinical practice, I do not foresee this being an issue in any way.

And then last question from us. In terms of the pivotal cohorts, any update on the enrollment, specifically the AML cohorts, the NPM1 and KMT2A. I know you're saying that first data could be available in Q3, but specifically on those 2 cohorts, any update on how the enrollment is going.

So certainly, I think the trials are enrolling nicely. And I think our guidance remains as it's been that we'll have the first of the 3 enrolled in the first quarter, and that will have top line data in the third quarter and the filing by the end of the year. We haven't yet talked really much about which of the 3 is going to be first, second or third. We have guided that AML is likely to accrue faster than ALL just based on patient numbers. But our guidance remains the same. We'll have more to say about probably enrollment and where we stand in the beginning of next year.

Our next question will come from Madhu Kumar with Goldman Sachs.

So I guess first one for Dr. Stein and Issa is, how to think about the use of these drugs in NPM1 mutant disease relative to co-mutations like FLT3, like IDH, where would you position this drug relative to other agents for other trailing mutation and these co-mutant patients?

So all these targeted therapies are exciting, FLT3 inhibitors, IDH inhibitors and menin inhibitors. But there's a rationale to use menin inhibitors more likely in some of these co-mutations because NPM1 is a founding clone. In other words, if you think about AML development, NPM1 is most often the cause, the route of AML, whereas FLT3 is more often to be a later event. And by targeting FLT3, even though FLT3 therapy is very successful, almost the majority of the time, we may take care of the FLT3 clone with leukemia may come back with a RAS mutation or another form of mutation. So we think by targeting NPM1, we can take care of the early event and the later events. So we need to learn more from the data. We need to enroll more patients, but I think of it as a very promising strategy. And for IDH inhibitors, it would be the same, maybe complementary mechanisms of action. There are some posters presented this ASH showing that adding to an IDH inhibitor or comparing to an IDH inhibitor that menin inhibition would be very promising.

I would echo what Gus said. And I think that down the road, we'll likely be doing is combining different inhibitors together to target different therapeutic vulnerabilities of the patient's leukemia, but certainly menin inhibitors will always be part of that combination.

So one for the company. So you guys got breakthrough therapy designation earlier this week in MLL rearrange leukemia. How should we think about how that influences the kind of development path for AML versus ALL? [indiscernible] forward path for those distinct diseases versus staying within an umbrella of MLL rearranged leukemia.

Maybe I'll ask Briggs to address your question, please.

Yes. So as you saw or as you know, the pivotal program right now is set up with 3 independent cohorts, MLLr AML, MLLr ALL and NPM1c AML. And so we intentionally did that to try to characterize the efficacy in the different types of MLLr disease, whether it presents as AML or ALL. As we pull the data together, both the preclinical data and the clinical data, we got breakthrough therapy designation that is really agnostic to either age or how the patient presents. So adults or kids, AML or ALL. As Michael pointed out earlier, we had thought that the ALL group would enroll a little bit more slowly than the AML group. So there is the option. I'll phrase it as that there's an option that at the time that we complete the AML cohort, we could look across both AML and ALL and see if that data set could be useful for our initial MLLr filing that would cover both AML and ALL adults and peds.

Our next question will come from Kalpit Patel with B. Riley Securities.

Maybe a couple of questions for the KOLs joining us today. One on differentiation syndrome. Based on your historical experience as well as what data are available for approved AML targeted agents, does it get easier or more difficult to manage differentiation syndrome when you're combining these targeted therapies with other agents?

I can take that one. It's Eytan. So typically, it actually gets easier when you're combining it with standard of care chemotherapy because there's just not as much because you're getting a cytotoxic effect from the standard of care chemotherapy. And therefore, there aren't as many leukemia cells around to differentiate. We've seen that the historical proof of that is when you combine ATRA with chemotherapy, an acute promyelocytic leukemia, you get lower rates, differentiation syndrome and then with IDH inhibitors, when we combine them in a Phase I study with chemotherapy, the rate of differentiation syndrome was about, I think, 10 points lower than with IDH inhibitor monotherapy alone. So I would expect that as these agents get combined with the standard of care therapies and the trials that Briggs mentioned, you're going to see lower rates of differentiation therapy. And I also want to point out again, like Gus did the differentiation therapy that we're seeing with this agent has been relatively low and quite manageable. So I have no concerns there.

And talk to us now that we have a bigger subset of patients treated for both revumenib and ziftomenib. Talk to us about your overall view on the toxicity profile of both indications.

Let me speak specifically about revumenib because that's the drug that I've used and that I know. And I would say that revumenib seems like an extraordinarily well tolerated compound. I mean in all of my patients that I've treated on the study, none of them have really had anything that would approach a significant toxicity and even the ones who've developed some minor differentiation syndrome, it's been managed appropriately and not been an issue. I can only speak to what I've seen of the data from ziftomenib. And of course, there was a patient who had severe differentiation syndrome on that study. But I want to highlight that with revumenib, I think that it's a great compound with a very, very good toxicity profile.

And then one last question on the patients that receive stem cell transplant after. It looks like you have durable responses in these patients with or without revumenib maintenance therapy. So based on the data that you've collected to-date, how should we be thinking about the impact of revumenib maintenance therapy on overall patient outcomes?

I'll take that. We still need to learn more about this. But the biggest take point of that abstract and that data is that no other therapy would have allowed this to happen. There's no chance that some patients that have had 2 prior transplants get into a third transplant and remain in remission for a year without a therapy that's capable of taking care of the leukemia. It's a good question, whether maintenance will add to transplant. I personally think it will because I believe in the mechanism of action of this drug and I've seen what it does, but we just need more data. We don't have enough patients to answer that question.

I do think, though, that there will be. I think though there will be, I think, a bias -- not a bias, but a desire among clinicians to use this as maintenance therapy fairly liberally given how refractory these KMT2A rearranged patients end up being and how commonly they relapse post-transplant. So I can tell you on the study, I think we were all clamoring to get our patients on post-transplant maintenance therapy because we are also worried that they have a very high risk of relapse and standard of care agents really are not very effective in getting rid of the disease once the patient does relapse.

And maybe I can squeeze in one last question. The CR/CRh rates with revumenib and ziftomenib were 27% and 30% in the relevant doses. I guess, was there anything in the baseline demographics in the 2 trials that would suggest that one group was a little more difficult to treat than the other?

Maybe I can answer that. I don't think there's anything in this cohort that would tell us that one is more difficult than the other. And our group at MD Anderson recently published on the outcomes of NPM1 and relapsed refractory disease. And in fact, it's as bad as any other acute leukemia without NPM1. KMT2A may be more severe, but it doesn't retain the same prognostic factor that NPM1 has in frontline. And these patients had 4 prior lines of therapy as a median with a range to up to 12. So these are impressive responses. I don't think other therapies would have given us these responses.

And just to build on what Gus is saying, I think there's a mistake that people make that they think that when you have a relapsed patient, you look at the [ELN] breakdown of favorable intermediate and unfavorable and it applies, but that's not true. Once a patient has relapsed there by whatever their genetics are, by definition, they have unfavorable risk disease because relapsed leukemia is a disease that is very, very difficult to treat with across all initial diagnostic risk groups that has a very, very poor overall survival.

Our next question will come from Bert Hazlett with BTIG.

Just a couple, maybe one for the company initially. With regard to the post-transplant consideration of revumenib, is that an additional registrational effort or can that somehow be tucked into the pathway that you're developing the molecule for now?

I'll make a comment, Briggs can follow. I think the post-transplant experience, as you know, patients are allowed to go back on therapy as I think both Gus and Dr. Stein talked about. We'll have that experience as part of the Phase IIs that we're enrolling in. Ultimately, that experience will, of course, be available and be part of the package. And so perhaps part of the label, getting an actual label for post-transplant maintenance is not really part of the trial design. And so therefore, you have to do a -- in order to get a discrete label for that, you probably have to do another trial to establish that. But of course, the patient experience and the follow-up and all of that will be part of the data package. And so I think that's something that physicians will look to understand a little bit better. We could, of course, follow on in the frontline setting, which we have plans to do relative to maintenance. And so we'll have additional work ongoing relative to that. And ultimately, we do think we'll get a label at some point for post-transplant maintenance, which is a big opportunity for this franchise. But in terms of the trial that we're running today, I think I've sort of answered that that's part of the experience, but not necessarily part of the label. And Briggs, is there anything to add to that?

No, you got it.

Just is there any difference then in the safety and tolerability. Again, it doesn't sound like, but I want to ask the specific question, in the safety of the tolerability of revumenib in the post-transplant setting as opposed to in your earlier use of the molecule?

Maybe I'll ask Gus or Eytan to comment on that, please.

In the small numbers that we've had, I don't think we've seen a major safety concern different than any other maintenance therapy that we use in transplant.

And then just with regards to co-occurring mutations, you've spoken a little bit about FLT3 and how it might play a role. Are there any co-occurring mutations that either you think are leading to a favorable response or perhaps more challenging response in these patients?

It's small numbers when we divide more on co-mutations. We haven't found any particular mutation that is associated with better response or worse response. One example I can think of is p53, which is something notoriously leading to resistance. On the study, it did not affect responses. So in small samples, sample size 2 of the patients with commutation of p53 responded and 2 with p53 did not respond. So I take it as an encouraging sign.

And just one more for me then. With regard to combination use for revumenib as you move forward with studies with venetoclax and other molecules, are there any particular concerns with regards to combination regarding the safety or efficacy of the molecule as you look forward to -- again, to use with other agents.

I think Dr. Stein commented on this a little earlier, so maybe I'll ask him to follow on to your question.

Yes. I don't have any concerns at all. I mean, because revumenib is extremely well tolerated, I can't think of any overlapping toxicity that would be of any significant concern. I mean, of course, the trials need to be done to get some clinical data. But before the trial start, I have no concerns at all.

Our next question will come from Yigal Nochomovitz with Citigroup.

I just had a few for the physicians. With respect to the transplantations, I was just curious of the 18 that had the CR/CRh. Was there a specific reason that 6 of those were not transplanted. And is there potential in the future that, in fact, some or all of them may be transplanted. And then could you say what the -- if you've reached the median OS yet in the 12 that were transplanted.

Maybe Dr. Eytan?

Yes, I can take that one. So transplant is complicated. It depends on availability of a donor on the possibility to time that transplant. So if given the option, anyone who's eligible at that time, we thought that he should go to transplant. So I don't have a clear or a good reason to answer you why, but I would suspect that this is just dependent on transplant eligibility. And that's why these patients, the 12 of 18, which is, by the way, a very high number. Again, without this therapy, we wouldn't have any eligible transplants for patients -- any patients eligible for transplant. I'm sorry, what was your second question?

Just if you've reached the median OS in the 12 that were transplanted.

I don't recall that data. I don't know Briggs team members -- I don't think we've done that analysis.

No, we haven't.

And then, Dr. Stein, that was interesting perspectives on the 24-year-old patient. Just curious, once they started reviewing revumenib, how long did it take for that fungal infection to clear?

Now, that's a good question. So as soon as the patient had neutrophils, they stopped -- so the patients started differentiating the blasts differentiated into neutrophils. As soon as the patient started having circulating neutrophils over one, her fevers went away. She still had some radiologic evidence of perhaps fungal infiltration into her bone, which over-time, it became clear that, that was probably scar tissue. So it took probably another 3 months that she had a normally functioning immune system in addition to sort of broad spectrum anti-fungal for her infection to clear.

Our next question will come from Peter Lawson with Barclays.

I guess a question for both Dr. Stein and also the company, whether you're seeing different response dynamics with revumenib in the NPM1 versus the rearranged patients?

I mean I can answer that. So far, we have not seen any consistent difference in response dynamics. I think that, that's going to require a much larger data set to tease out. But to-date, we have not seen anything significantly different.

And then on QT, what was the highest grade of QTc and did you see Grade 4, Grade 5? And was that QTc pronounced or skewed between the NPM1 versus the KMT2A.

Yes. I think we heard from Dr. Issa earlier about this, I guess, maybe he'll share the floor with Dr. Stein on the same questions, the experience.

Yes. So all the QT prolongations were asymptomatic. There was no Grade 5 QT Prolongation, is that the patient doesn't make it. So they have a fatal arrhythmia. So that certainly did not happen. And I would echo what Gus said earlier, which is that from a clinical perspective, the QTc prolongation is of no concern to any clinician that I am in contact with or aware of. These are some things that we see on an EKG that mean absolutely really don't mean anything to the patient or to us. And the QT, the rate of QT prolongation seen at the recommended Phase II dose is in line with other standard of care drugs that are currently approved for acute myeloid leukemia, like the IDH1 inhibitor, ivosidenib and the FLT3 inhibitor, gilteritinib and then quizartinib is likely going to get approved, and that's a compound that has sort of had a history of prolonging the QT. So I really don't think it's an issue at all.

And then a question for the company. The 3 NPM1 patients that are excluded from the recommended Phase II dose versus the overall set that we saw in the abstract. Sort of I guess that 14 to 11 patient question. I wonder if you could talk through that if there are higher doses if those patients ended up for the recommended Phase II dose. Just curious about it.

So yes, so we ran the same analysis for NPM1 that we ran, obviously, for the BTD application for KMT2A. And we obviously have to exclude patients that are not at the RP2D because that's the analysis. And so 3 patients were excluded for MTM1 and that yielded the 27% as we discussed. So the 3 patients, I believe, were at a higher dose than the RP2D.

Were these 3 patients did they dose deescalate, did they get down to the recommended Phase II dose eventually or stay at the higher dose?

Yes. I mean by protocol, if you have a DLT or you're above, I should say, at a dose that's not deemed to be the RP2D, you go to a lower dose if you continue on therapy. But I don't -- let me ask Briggs, if he has more detail on those patients.

I don't.

Our next question will come from Joel Beatty with Baird.

First question is, is achieving MRD negativity mainly meaningful for patients who are healthy enough that they might go on to transplant or is it also meaningful for patients who might not be going under transplant due to their current baseline status in age?

I can take that one. I think it's meaningful for both groups of patients. Certainly, it's meaningful for patients going on to transplant because there's robust data that going into a transplant MRD negative, the overall survival was better than if you go into transplant MRD positive. But there's similar data that if you become MRD negative, you do better than if you're MRD positive, which kind of makes sense, right, because if you're eliminating every reservoir of leukemia that can be detected, you getting that depth of response is much higher, even if you ultimately relapse, it is likely that your relapse will come later than someone who has some detectable leukemia cells floating around. So an MRD-negative CR is what we always aim for whether a patient is going to transplant or not because we feel based on the data that the absence of MRD portends a prolonged overall survival.

And then a follow-up question. When comparing efficacy across trials with other agents, would you tend to focus on just kind of CR/CRh rate and looking at which one is higher than the other or would you also tease into the kind of percent CR versus the percent CRh kind of looking for more of a CR over CRh?

I usually group it all together. I don't look at one or the other. I think the FDA views it that way also that there's a recognition that the blood count recovery criteria for CR probably don't mean as much as people thought it meant, and it's just having blood count recovery over a certain threshold, whatever that threshold is, but that threshold seems to be lower than 100,000 platelets and 1,000 neutrophils, and that's why they have grouped CR and CRh together.

Thank you. At this time, there are no further questions. So I would like to turn the call back over to Michael Metzger for any additional or closing remarks.

Thank you, operator, and thank you, everyone, for joining us this morning, continued support. While we only focused on revumenib today and the ASH data, I look forward to providing a corporate overview and a detailed review of our other pipeline program in clinical trials, axatilimab in future investor conferences, including at the JPMorgan conference where we'll be presenting in January. I'd like to say thank you, and goodbye, and I wish everybody who's still attending ASH a good rest of the meeting. Thank you, operator.

Thank you, ladies and gentlemen. This does conclude today's call, and we appreciate your participation. You may disconnect at any time.