Biomea Fusion, Inc. (BMEA) Earnings Call Transcript & Summary

Good afternoon, everyone, and thank you for dialing in. Today, we will be discussing a first clinical update from our Phase I COVALENT-103 study of BMF-500, a covalent FLT3 inhibitor in patients with relapsed or refractory acute leukemia. Some quick introductions. My name is Ramses Erdtmann. I'm the COO, President and Co-Founder of Biomea. With me on the call today from our team and available to answer questions are our CEO, Chairman and Co-Founder of Biomea, Thomas Butler; as well as our Vice President of Clinical Development and Clinical Sciences, Dr. Alex Cacovean, who has spearheaded the clinical development of BMF-500; and also our Chief Development Officer, Dr. Steve Morris. I would like to welcome Dr. Farhad Ravandi, a hematologist/oncologist with extensive experience in clinical practice and research, Professor of Medicine and Chief of Section of Developmental Therapeutics in the Department of Leukemia at the University of Texas MD Anderson Cancer Center. He is one of the principal investigators in our study, COVALENT-103, and will share his experiences with BMF-500 on the call today. Before we start, let me remind you that this nonconfidential presentation contains forward-looking statements about the business prospects of Biomea Fusion, including expectations regarding Biomea Fusion's clinical trial and preclinical study results and potential future product candidates in different areas of therapeutic research and development. Results may differ materially from those expressed or implied in this presentation depending on the progress of Biomea Fusion's preclinical and clinical development activities, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors, and those factors detailed in Biomea Fusion's filings with the SEC, such as 10-Q, 10-K and 8-K reports. All forward-looking statements made during this presentation are based on the beliefs of Biomea Fusion as of this date only, and future events or simply the passage of time may cause these beliefs to change. Please be aware that you should not place undue reliance on the forward-looking statements made today. I will now turn the call over to our CEO, Thomas Butler. Tom?

Thank you, Ramses. Today, we will cover an important clinical update from our oncology program highlighting our FLT3 inhibitor, BMF-500, a novel third-generation and potential best-in-class inhibitor of FMS-like tyrosine kinase 3, otherwise known as FLT3, which is a cell surface receptor enzyme that plays a central role in the survival, proliferation and differentiation of immature blood cells. BMF-500 is an exceptionally potent molecule and the second covalent inhibitor we have developed in-house and advanced to the clinic, showing high target selectivity and inhibition. We are conducting single-agent studies of BMF-500, and based on the early efficacy results, we will proceed with a monotherapy study. We also plan to conduct combination studies with our other product candidate, icovamenib, to explore the potential of this powerful dual mechanistic approach to amplify and sustain patient treatment outcomes. We started our oncology development in AML with icovamenib, addressing primarily patients with mutations in NPM1, but also in MLL1-r. These mutations often co-occur with FLT3 mutations, which are common in AML. These co-mutations can influence the prognosis and treatment response in AML patients and lead to a more aggressive disease and poor outcomes. FLT3 gene mutations are common in patients with acute myeloid leukemia and are associated with a poor prognosis. FLT3 inhibitors such as BMF-500 are being developed to target these mutations and improve treatment outcomes for AML patients. Patients with FLT3 mutations failing gilteritinib are in a dire situation where median overall survival is less than 2 months. These patients are the focus in the escalation portion of COVALENT-103. BMF-500 is also the second investigational clinical compound discovered and developed by Biomea's FUSION System. The Biomea FUSION System is a proprietary platform developed by our team here in our innovation center in San Carlos over the past 5 years. The FUSION System is set up to discover, design and develop next-generation covalent-binding small molecule medicines. These medicines are aimed at maximizing clinical benefits for patients with various cancers and metabolic diseases. The FUSION System leverages the latest technology and novel methodologies, including RNA sequencing, 3D modeling, virtual reality, virtual screening, informatics and expertise in covalent drug design. This comprehensive approach supports a pipeline that enables Biomea Fusion to hypothesize, conceptualize, operationalize and realize what we believe are the most optimized drug candidates to evaluate in the clinic as efficiently as possible. Our first patient was dosed with BMF-500 about a year ago in our clinical trial, COVALENT-103. Our lead investigator, Dr. Farhad Ravandi, will provide a first clinical update during this call on this program and walk us through the early results. Dr. Ravandi is one of the most published experts in AML. He has contributed to over 750 publications and participated in over 350 clinical trials. I would now like to turn the call over to our VP of Clinical Development and Clinical Science, Dr. Alex Cacovean, who is leading the COVALENT-103 study. Alex?

Thank you, Tom. AML is a type of blood cancer, which originates in the bone marrow where blood cells are being produced. It interferes with the development of red blood cells, white blood cells and platelets, leading to severe health complications. AML is a genetically and clinically heterogeneous disease with a diverse array of subtypes determined by genetic mutations and other factors. In the United States, over 70,000 people live with AML and more than 20,000 new cases are expected each year. Mutations in FLT3 gene play a crucial role in the progression and treatment resistance of AML. Discovered in early 1990s, FLT3 mutations are among the most common genetic aberrations in AML, making up approximately 30%, 35% of newly diagnosed cases, which represent more than 7,000 newly diagnosed patients in U.S. each year. These mutations worsen the prognosis, increase relapse risk and reduce overall survival of AML patients. Targeted FLT3 mutations has become a key focus in AML with therapies designed to inhibit the abnormal FLT3 protein. However, despite advancements, FLT3-mutated AML remains challenging to treat due to drug resistance and relapse. To date, FLT3 inhibitors have added a new dimension to AML treatment but have produced relatively low rates of durable responses, and overall survival remains a highly unmet need. Three key drugs are now approved for FLT3, including midostaurin, which has been approved in 2017 for newly diagnosed FLT3-mutated AML and is used more broadly with chemotherapy, common side effects include gastrointestinal issues and febrile neutropenia; gilteritinib approved in 2018 for relapsed/refractory FLT3-mutated AML is associated with side effects like fatigue and elevated liver enzymes; lastly, quizartinib was approved in 2023 for a subtype of newly diagnosed FLT3-ITD-positive AML, having a QT interval prolongation as a notable side effect. These 3 therapies face significant challenges such as resistant mechanism, adverse effects and limited duration of efficacy. Most importantly, in the relapsed setting, the CR rates are only in the low teens, similar to chemo agents with just marginal benefits for the overall FLT3 patients demonstrated by a median time on drug of just about 3.5 months. As Tom mentioned, FLT3 mutation patients post-gilteritinib treatment failure have a median overall survival of less than 2 months, a truly dire prognosis. This was the patient population enrolled in the escalation portion of COVALENT-103. AML patients with FLT3 mutations, especially those who relapsed or are refractory to their prior treatment, have an urgent need for therapies that offer durable responses, overcome resistant mechanism. We believe that BMF-500 has potential to help address this need, and the data we will share with you today will shed light on our progress toward this goal. Let me now provide a bit of background on BMF-500. This molecule was discovered and developed in-house at Biomea using the company's proprietary FUSION System and has shown potential based on extensive preclinical studies that supported our clinical trial. We also designed BMF-500 with a therapeutic profile to allow for combinations with standard of care and/or novel targeted agents like BMF-219, Biomea's investigational covalent inhibitor currently in clinical development across solid and liquid tumors. BMF-500 is an investigational novel, orally bioavailable, highly potent and selective covalent small molecule inhibitor of FLT3. The kinase profile of BMF-500 showed high target selectivity, suggesting the potential for minimal off-target liabilities. In preclinical studies, BMF-500 has demonstrated approximately twentyfold greater potency compared to gilteritinib in acute myeloid leukemia cells, MV4-11 and MOLM-13. We also demonstrated that BMF-500 retains potency against FLT3 inhibitor resistant mutations such as the F691 gatekeeper and D835 mutations. In addition, we observed that BMF-500 had a high affinity for FLT3 with the lack of cKIT inhibition and sustained cell-killing capacity that persisted even after prolonged drug washout. Previous data we presented at the American Society of Hematology Annual Meeting in 2022 showed BMF-500's picomolar affinity to activating FLT3 mutations, including FLT3-ITD and various tyrosine kinase domain, TKD, mutations. There, we presented data showing complete tumor regression in mouse models of FLT3-ITD AML and maintenance of effect without continuous exposure. In both subcutaneous and disseminated xenograft models of mutant FLT3-driven AML, BMF-500 has shown sustained tumor regression and improved survival. I'd like now to turn over the call to Dr. Farhad Ravandi from MD Anderson, who will discuss our ongoing COVALENT-103 clinical trial of BMF-500, where we're examining BMF-500 safety and efficacy in patients with relapsed or refractory acute leukemia with FLT3 wild-type and FLT3 mutations. Farhad?

Thank you. I'm Dr. Farhad Ravandi, Chief of the Section of Acute Myeloid Leukemia at the University of Texas MD Anderson Cancer Center. It's a privilege to be here with you to discuss the exciting progress of BMF-500 and the COVALENT-103 study. As many of you know, relapsed and refractory acute leukemia remains a significant challenge, particularly in patients with FLT3 mutations. In this study, we are exploring BMF-500, a novel oral covalent FLT3 inhibitor that has shown promise for patients with both FLT3 mutant and wild-type disease. Today, I will go over the preliminary Phase I data from the COVALENT-103, where we are evaluating the safety, efficacy and pharmacodynamics of BMF-500 in these patients. We hope that our findings will provide critical insights into how we can better target FLT3 mutations, including resistant mutations, and ultimately improve outcomes for these difficult-to-treat patient groups. Starting on Slide 2, FLT3 mutations are present in about 37% of patients with AML and approximately 5% of patients with ALL, both of which have poor outcomes. For patients who have failed gilteritinib, an FDA-approved drug for FLT3 mutated patients in relapse, the median overall survival is only about 2 months, highlighting the urgent need for more effective treatments. Furthermore, many FLT3 inhibitors that are currently in use only target FLT3-ITD mutations and leaving gaps on treatment for patients with other, particularly TKD, mutations. BMF-500 is a promising oral selective FLT3 inhibitor that has shown activity not only against FLT3-ITD mutations, but also wild-type FLT3 as well as TKD mutations, including D835 as well as gatekeeper mutations such as F691. Key attributes of BMF-500 include its high selectivity and strong affinity for FLT3. Importantly, BMF-500 does not inhibit other kinases such as cKIT, which avoids disruption of normal hematopoiesis, which is a critical advantage, minimizing side effects such as myelosuppression. As a covalent inhibitor, BMF-500 also retains its ability to kill leukemia cells even after drug washout, offering potential for sustained therapeutic effect. Preclinical studies of BMF-500 have shown encouraging results, including tumor regression and improved survival in FLT3-driven AML models. Currently, BMF-500 is available in 5-milligram, 25-milligram, 100-milligram oral tablet formulations for clinical trials, providing flexible dosing options for patients. Moving to Slide 3. Here is an overview of COVALENT-103 study. This is an open-label Phase I trial evaluating the safety, tolerability and clinical activity of BMF-500, which is taken orally twice daily. The study focuses on patients with relapsed and refractory acute leukemia, both with and without FLT3 mutations. As of November 2024, the trial is being conducted exclusively in the U.S. at 21 sites shown here on the map. It began in late 2023, and so far, over 20 patients have been dosed, with enrollment continuing. Moving to Slide 4. This slide provides an overview of COVALENT-103 study design, objective and eligibility criteria. The dose escalation phase comprises 2 parallel arms. Arm A is for patients not receiving CYP3A4 inhibitors and is currently enrolling participants at the 150-milligram dose level. Arm B is for patients concurrently receiving CYP3A4 inhibitors and is enrolling participants at the 50-milligram dose level. Importantly, no dose-limiting toxicities have been observed to date. Following this dose escalation phase, the study will transition to a dose expansion phase where at least 2 dose levels will be evaluated across distinct patient groups. The study objectives include determining the optimal biological dose as well as recommended Phase II dose for BMF-500. Additionally, the trial seeks to characterize the pharmacodynamic effect of the FLT3 inhibitor and evaluate molecular profiling changes in leukemic cells. Regarding eligibility, the study includes patients with both FLT3 mutant and wild-type relapsed or refractory acute leukemia. During the dose escalation phase, up to 1/3 of participants in each arm may be FLT3 wild-type. Furthermore, all FLT3 mutant patients must have previously failed treatment with one or more approved FLT3 inhibitors. Moving on to Slide 5. This slide highlights the baseline characteristics of the 20 patients enrolled to the study as of November 2024. You can see there is an overall balanced patient population between arms A and B. Key points to note are the median of 4 prior lines of therapy with a range of 1 to 10, approximately 2/3 of patients who received prior intensive therapy, nearly half of the patients had a history of hematopoietic stem cell transplantation, and 90% of participants have been treated with venetoclax-containing regimens. These data underscore the heavily pretreated and high-risk nature of the patient population. On Slide 6, this slide provides information on the FLT3 mutational status of patients at study entry, determined by a central laboratory analysis. Among the 20 patients, 13 or 65% were FLT3 mutated, including 10 who had FLT3-ITD and 3 who had TKD mutations. All FLT3-mutated patients experienced disease progression on or after gilteritinib-containing treatment regimens. Additionally, 5 of the 13 FLT3-mutated patients had been treated with at least 2 prior FLT3 inhibitors prior to the study entry. 5 of the 20 patients had FLT3 wild-type relapsed and refractory leukemia and 2 had undetermined FLT3 status as the central lab FLT3 mutational status was not available. This data again underscores the inclusion of a heavily pretreated and genetically diverse patient population. On Slide 7, this slide presents data on treatment-emergent adverse events, which include any adverse events occurring from the first dose of BMF-500 through 28 days post treatment discontinuation. It is important to note that treatment-emergent adverse events denote a temporal association with the study drug and do not indicate causation. BMF-500 showed a generally well-tolerated safety profile across all dose levels with no dose-limiting toxicities consistent with its mechanism. No treatment-related cytopenias were observed, and there were no reported QT prolongation. The table on this slide highlights the most common treatment-emergent adverse events reported on both study arms. On Slide 8, we observed that despite extremely poor prognostic population included in the study, there are early signs of clinical activity in the significant majority of the efficacy evaluable patients. These are defined as patients who received at least 1 dose of the treatment and had at least 1 disease assessment. It is critical to note that for patients who failed gilteritinib treatment, the median overall survival, again, is less than 2 months. However, approximately 2/3 of the efficacy evaluable population achieved the best overall response of stable disease or better. A particularly encouraging sign is that most patients experienced a reduction in bone marrow blast as early as the first disease assessment. On Slide 9, we see a swimmers plot representing treatment durations for the 20 enrolled patients at the cutoff date of November 20, 2024. Patients in Arm A are shown in blue and those in Arm B are in red. The left side of the plot indicates dose levels and FLT3 mutational status at the start of the study. At the time of reporting, 7 patients or 58% of patients remain on treatment, which is noteworthy given the poor prognosis of this population. Although not displayed here, efficacy data showed that approximately half of the evaluable patients in each arm achieved a stable disease or better, with approximately 90% experiencing reduction in bone marrow blast as early as the first assessment. On Slide 10, we feature a waterfall plot illustrating the best relative change in bone marrow blast. Count from baseline in 6 of 13 FLT3 mutant patients is deemed efficacy evaluable. The remaining 2 of 13 FLT3 mutant patients were still undergoing treatment, with their initial on-treatment disease assessments pending at the time of this analysis. This data suggests a potential dose response relationship, which warrants further investigation. Slide 11 describes a case study of a patient with FLT3 mutant relapsed and refractory AML, who achieved a confirmed complete response with incomplete hematological recovery, or CRi, while on BMF-500 at 100-milligram BID dose. The patient's leukemia was FLT3-ITD mutant and other mutations detected in the study entry are shown in the upper left-hand side of the slide. This patient had undergone 4 prior treatment regimens, including venetoclax and gilteritinib and had received an allogeneic stem cell transplant. Clinical objective response as assessed by the PI per ELN2017 was observed as early as the first disease assessment at the end of cycle 1, and the best response at CRi was achieved by the end of cycle 2. The CRi was reconfirmed at the beginning of CR4. The patient has completed 4 28-day cycles and continued study treatment at the originally assigned dose. Multiparameter flow cytometry MRD assessment revealed detectable disease at cycle 4 day 1. Although cycle 5 day 1 does not require a marrow assessment, peripheral blood assessment revealed MRD-negative status. Although the patient continued to require peripheral blood and platelet transfusion, the total normal white cell count and both the neutrophils and monocytes progressively improved during the course of treatment. The values over time reported by the central lab are displayed on the right-hand side of the slide. Finally, Slide 12 summarizes the preliminary Phase I findings for the BMF-500 study in relapsed and refractory acute leukemias. These data suggest a generally favorable safety profile with no dose-limiting toxicities or concerning adverse events observed at the date of the cutoff table. Secondly, I believe the clinical activity is encouraging with evidence of response, including 1 reported CRi and reduction in bone marrow blast in most evaluable patients. Finally, the PK/PD data confirmed on-target FLT3 inhibition, showing dose proportional activity and good compartmental penetration. Together, I believe these data strongly support the continued development of BMF-500 as a unique covalent FLT3 inhibitor. Thank you very much.

Operator?

[Operator Instructions] I show our first question in the queue comes from Yigal Nochomovitz from Citigroup.

I'm just curious, for the expert, if you could comment on the potential for this drug to be used in earlier lines of therapy for FLT3-positive AML given the very good safety so far and high potency as was described in the preclinical work.

Yigal, great question. Farhad Ravandi is not available for Q&A, but let me pass that question on to Steve Morris.

Can you hear me?

Yes, we can hear you, Mr. Morris.

Yes. This is Steve Morris. Thank you for the question. I think the favorable safety profile bodes very well for the ability to combine BMF-500 with conventional chemotherapy, with hypomethylating agents with venetoclax. The one issue with these combinations with other agents, for example, gilteritinib, although gilteritinib is, in general, well tolerated, it does have safety issues. And those safety issues can limit the ability to dose with durability in patients in a combo setting. But again, we have to prove it, but the safety profile to date with BMF-500 suggests that we would not encounter such issues.

Yes. Thanks, Steve. And I would just add, this is Tom again, what we heard from our KOLs while at ASH was that, as Steve mentioned, given the safety profile of the molecule, adding it to a ven/aza combination or ven as a combo would be very attractive, likely limiting the myelosuppression.

And then the other question, obviously, we saw a lot this weekend at ASH from all the menin inhibitors. Just curious, what's the overlap in terms of the people that have co-occurrence of the FLT3s and the KMT2A or the NPM1.

It's about 40%, Yigal.

And then remind us on your plans. Aren't you going to do some combo work with 500 and 219? Where does that stand?

Yes, absolutely. So as we get to our recommended Phase II dose for 500 and also for icovamenib, which should be happening very soon here in the coming months, we'll be well positioned to start that novel-novel combination in 2025.

And I show our next question in the queue comes from the line of Peter Lawson from Barclays.

I guess the first question is just like where are you in that dose escalation, and then secondly, if you're kind of seeing dose response, whether it's in the side effect profile, lower doses having a better side effect profile? And kind of how are you thinking about efficacy in differentiation syndrome and if you could see it at higher doses?

Sorry, Peter, could you repeat the initial part of your question? It broke up.

I guess on the dose response, are you kind of seeing that, are you seeing the dose response? And are you seeing a dose response in the safety profile as well?

Yes, we have seen a dose response from an "efficacy perspective" and what I can say from an efficacy perspective is we are conducting a plasma inhibitory assay in the background so that we can confirm to what extent our patients are getting suppression of phospho-FLT3. So we knew that dose level 1 wasn't quite there. Dose level 2, we were getting coverage in some patients, but not all. And we feel like dose level 3 is now at a point where we're starting to get proper inhibition of phospho-FLT3 in the majority of patients. And then as you can see in the safety table, the safety of BMF-500 looks quite strong and we don't see differentiation and it has not been an issue to date. I don't know if you want to add anything, Alex?

Yes. Thanks, Tom. You're absolutely right. I think in terms of dose response, maybe to add, even if you look at the waterfall plot that shows the best relative change in bone marrow, we displayed the doses there, and they do align from 25 milligram all the way to 100. And you can look at the bar charts there. In terms of differentiation, certainly, we keep a watchful eye. It's not as common necessarily in FLT3. We haven't necessarily seen it, but we're just keeping a watchful eye for any of this as we learn more about the drug and the mechanism of action.

Great. And then just a question for Tom, just on the timing of the diabetes data, when should we expect it?

Yes, diabetes, we should expect it this month, so it's coming soon. And we expect before Christmas.

And I show our next question in the queue comes from the line of Eric Joseph from JPMorgan.

This is Billy on for Eric. First one for us is, do you have a sense of sort of the prevalence of co-mutation of D835 with the FLT3-ITD? And then any sort of differences in responses with the co-mutation patients?

Would you like to take that, Steve?

Certainly, happy to do so. The 835 mutations are the major type of hardwired resistance mutations to the reversible inhibitors. So they are a significant problem. They comprise at least 1/3 of resistance mutations. So they are a significant clinical challenge.

And I would just add that what we have seen today, at least preclinically, it's hard to talk about clinical experience just because of the so few patients today, but we've seen preclinically that we expect very potent activity in those kinase domain mutations as well as the gatekeeper. And I can point you to Slide 8, at the 100 BID dose level, you can see one of the FLT3-mutated patients had a TKD, and that patient experienced clearance of the peripheral blasts as well as a reduction of their bone marrow of greater than 50%.

And then just one other quick question about the case of hypertension. Do you mind just commenting a little bit more on that case, how it resolved and whether that's something that might be expected a little bit more frequently as you dose escalate?

Happy to. Alex?

Sure. So this was, I'll say, an N of 1. The highest grade was 2. It resolved. The patient continued on treatment. I guess, for whatever reason, the PI made an assessment of potentially related to the drug. We displayed the data as we get. And that's all I can tell you. It's not been an issue necessarily, and it resolved and was not an obstacle by any means.

And I show our next question in the queue comes from the line of George Farmer from Scotiabank.

This is Chloe on for George. A couple from us. Do you expect cytopenia to become more of a problem as you escalate to higher doses? That's one. The second question is, in the context of the combo with BMF-219, can you maybe speak to the expected safety profile there and any sort of evidence you should be looking for? And the third question, maybe I missed it, but what happened to the CRi? Did they remain on treatment? Did they go to transplant again, if you could clarify?

Chloe, this is Tom. I'll try to address a couple of your questions and then pass it on to Alex. For the combination of icovamenib and BMF-500, we think it's quite an exciting combination. We published last year at ASH, some of the effects we were seeing preclinically from that combination. And I think because of the drug-like properties of BMF-500 and 219, capturing this first in the dose escalation and then into a single-tablet regimen is something that gets us developers really excited. So we think, because of the potency we're seeing now with BMF-500, this could really be a strong combination for AML patients. Alex, do you want to address the first two questions of cytopenia?

Sure. So in terms of cytopenia, one item to say is that there's like a cKIT inhibition based on the preclinical data. So we do not necessarily expect that to be something that we'll see. With the drug necessarily, we haven't seen it reported. So far, so that's not an item of any issue at all. Actually, in terms of ability to combine probably with the BCL-2 and others, I think that gives us confidence that that's an opportunity. So far, we do not have that. Whether or not that's something that's going to come up as you escalate doses, again, not necessarily expected, but we'll have to see. Your other part of the question, about the patient that achieved CRi, the patient as of now continues on treatment. It's in the midst of cycle 5 of therapy. The most recent bone marrow blasts were 5%, kind of staying in the same range as we've seen in the prior cycles. And the patient does require still blood product support in the sense that the platelets haven't recovered and there's still anemia. The patient is prior transplanted, prior venetoclax treated, prior gil treated but as of now, as I said, continues on treatment. And whether or not there is opportunity for further transplant down the road, the physician will make that decision.

And I show our next question comes from the line of Matthew Biegler from Oppenheimer.

I wanted to ask Dr. Farhad, but maybe Steve can chime in on the unmet need for patients that co-present with NPM1 and FLT3 because it seems like there's some conflicting evidence out about whether that co-presentation confers a higher risk or a lower risk. Can you just comment on that?

Yes, happy to take that. So the issue with the co-mutated patients is that you're essentially playing whack-a-mole. The clinician is confronted with a decision as to whether to treat the FLT3 mutation or NPM1 or KMT2A or NUP98, which are all menin inhibitor-sensitive mutations. So it's a quandary as to the better approach. You can treat one or the other, but not both. And as Tom mentioned, the attractiveness of a menin inhibitor-FLT3 inhibitor combo would be that you can treat both from the get-go. And that, again, we have to prove it, but you would anticipate that treating both simultaneously should be associated with a better outcome ultimately. So it is a problem now. It's a challenge. It's an unmet need. It's a quandary for the clinician.

And I show our next question comes from the line of Joe Catanzaro from Piper Sandler.

This is Michael on for Joe. Just one from us. We noticed that there were 7 patients in the 25 mg dose cohort of Arm B, and we were wondering if there was something that triggered expansion of that cohort.

Yes. A great question, Michael. So it was interesting with that dose level of 25 milligrams, the first patient really had strong suppression of phospho-FLT3 from our PIA assay. And so we decided to transition to 3 plus 3. Unfortunately, as we enrolled the additional 3 patients, we saw suboptimal suppression. We think it's because this patient just had better exposure to the 25 milligram than the other 3. So that encouraged us to dose-escalate. And Alex, I don't know if you want to add anything further?

Yes, that's absolutely right. One thing I would add just to confirm, that was a decision to pivot to 3 plus 3 solely based on PK data and PIA data. And there was no safety issue of any kind. Therefore, we continue to up-dose after more data came in. And probably that first patient was a bit of an outlier, but as we continue to dose more patients, we decided to proceed further. But just to highlight, there was no safety-based decision there.

And I show our next question comes from the line of Kripa Devarakonda from Truist Securities.

This is Alex on for Kripa. I wanted to know, is there any correlation between time to response and durability of response that you could see with the patients so far? And then could you remind us of the significance of the hydroxyurea reduction among the clinical activity that you observed?

Alex, it's a great question. Alex, do you want to take that?

Yes. I think in terms of durability of response and time to response, it's probably premature to make that assessment. The idea is that majority of these patients where we see clinical benefit or any benefit in terms of parameters improving bone marrow blast reduction, we see it as early as the first assessment. As we demonstrated here with one particular patient, that particular patient first achieved MLFS and the counts and the parameters continue to improve and achieve CRi at the subsequent assessment. So I'd say it's too early to answer that question. It's certainly something we'll look for, but we have limited data on hand. In terms of Hydrea use, so we had a couple of instances. Hydrea is allowed and cytoreductive measures are allowed for these patients as they are in screening and enter the study and are allowed in the early part of the study in terms of cycle 1 while getting the disease under control. And we did have a few patients where they require less Hydrea and were able to decrease the use of it. I don't have the details in front of me, but I know they were able to taper it down for a couple of them.

And I show our next question in the queue comes from the line of Tony Butler from Rodman & Renshaw.

There are two. One is, I think, Alex, you made a comment about, at least in the CRi patient whose blasts were below 5%, some recovery of platelets but they still require exogenous or hydroxyurea therapy. Question is, did you say, or did I hear you say, that those platelets continue to improve? And I guess the question is, how long do you think that would take? Is that common? And the same could be said for neutrophils. I mean, if I look at the ADMIRAL study for gilteritinib, I think ideally, you'd like to get to 1x10^9. Am I correct with that, at least as it relates to platelets and neutrophils, assuming the blasts stay low?

Thanks, Tony. Great question. Alex, do you want to clarify about the hydroxyurea for the patient?

So this particular patient, I don't think this patient is using any. Not using any hydroxyurea, just to clarify that. Certainly, we've seen a nice recovery in terms of neutrophil, and that's quite an important factor, as you know, for these patients and keeping them off any infections. In terms of platelets, the platelets actually have not recovered or any recovery was relatively low. I just want to clarify that. We haven't displayed the platelets in here because we displayed just the monocyte neutrophils in the chart. But the platelets continue to be -- whatever improvement was, was relatively minimal, as I recall.

How long do you think it would take the neutrophils? If the platelets were to move up, how long do you think that would take to get to an appropriate level where you could really call the patient, I guess, a CR, a true CR?

Well, in order to be CR, as you know, platelets needs to be over 1,000 at least per the criteria. I would say that's the ULN criteria. The platelets within the normal range, that's what we're looking for. And that's what we were able to see with this patient. Not sure if I fully understand the question otherwise, or Steve, feel free to chime in.

Sure. Happy to comment. Typically, platelets, when they recover, do so within the first couple of cycles, sometimes 3 cycles. Occasionally, however, you can see a delayed platelet recovery, but the more frequent scenario is within the first 2 to 3 cycles. One final comment regarding this. The platelet recovery sometimes is not necessarily a factor that is attributable to the therapy. And what I mean by that, keep in mind, these are patients who are post-multiple prior lines of therapy, which are myelotoxic, compromise normal marrow function. And simply because of that, even if you have a highly effective therapy, the marrow may be so beat up that it compromises the ability to have that platelet recovery. So I just wanted to emphasize that point as well.

I'm showing no further questions in the queue. At this time, I'd like to turn the call back over to Thomas Butler, the company's CEO, for closing remarks.

Great. Thank you very much all for dialing in this afternoon. Very much appreciate it. And we look forward to providing our diabetes update in the coming weeks. Take care.

Thank you. This concludes today's conference call. Thank you for attending. You may now disconnect.