Dan, we can still hear you, so you might want to go on mute. Good day. Welcome to the Cogent Biosciences conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. Instructions will be given at that time. As a reminder, this call may be recorded. I would like to turn the call over to Andrew Robbins, President and CEO. You may begin. Thank you and good morning, everyone. Welcome to a special Cogent Biosciences webcast, in which we are going to provide additional details on the progress of bezuclastinib in Advanced Systemic Mastocytosis patients. Before we get started, I'd like to remind everyone that along with the other presenters today, I will likely be making forward-looking statements this morning. We encourage you to review our recent SEC filings, including our Q3 10-Q for a comprehensive discussion about risk factors associated with the company. With that said, I'd like to introduce myself, Andy Robbins. I'm the CEO of Cogent Biosciences, Dr. Daniel DeAngelo, who's the Chief of the Division of Leukemia at the Dana-Farber Cancer Institute, and Dr. Jessica Sachs, who's Cogent's Chief Medical Officer. On today's call, after a brief intro, Dr. D'Angelo will provide a detailed review of the slides he presented at the annual American Society of Hematology meeting yesterday afternoon. Once he's finished, we would be happy to field questions about this clinical trial update. As a reminder, Cogent Biosciences is focused on discovering, developing, and commercializing targeted therapies for patients fighting rare, genetically driven diseases. Our lead program, bezuclastinib, is enrolling patients in 3 late-stage clinical trials. APEX for patients with advanced systemic mastocytosis, SUMMIT for non-advanced systemic mastocytosis patients, and PEAK for gastrointestinal stromal tumor patients. In addition to bezuclastinib, we have assembled a very experienced internal research team who has already built an impressive preclinical product portfolio, including selective and potent FGFR2 and ERBB2 inhibitors as our first 2 in-house programs. With nearly $290 million as of the end of Q3, we are well positioned to invest across these programs into 2025. Turning now to advanced systemic mastocytosis. This is a rare, aggressive, and life-threatening disease which is primarily driven by a specific mutation known as D816V in the KIT gene. ASM patients with this mutation have an estimated median overall survival of about 3 years, and although in recent years important advances have been made, these patients are still desperately searching for effective and well-tolerated treatment options to help them extend and enjoy their lives. As you can see here on slide 6, it is estimated that there are approximately 2,500 ASM patients in the U.S. What I'd like to point out in addition is that the much larger non-advanced systemic mastocytosis patient population also remains hopeful that additional therapeutic options will be developed that can demonstrate clinically meaningful improvements for the devastating symptoms they suffer from. Finally, before I hand it over to Dr. D'Angelo, I'd like to describe why we are so excited to develop bezuclastinib for systemic mastocytosis patients. As you can see on slide 7, bezuclastinib is a potent inhibitor of the specific mutation which drives this disease. Among the very small group of known products which share this characteristic, bezuclastinib is uniquely selective against key anti-targets such as PDGFR, FLT3, and CSF1R. It has minimal CNS penetration. We believe that based on this profile, bezuclastinib holds real potential to emerge as the best-in-class treatment option for patients fighting systemic mastocytosis. Now it is my pleasure to introduce Dr. Daniel DeAngelo to review the latest clinical update from APEX. Dan. Thank you very much. Good morning, everybody. I'm gonna move on to slide number nine. The APEX trial, which is a phase II open-label, multi-center clinical trial, has been enrolling, and I presented this data yesterday at the American Society of Hematology. Patients are eligible for this study if they have a WHO 2016 classification of advanced systemic mastocytosis, and this did require central adjudication. We had central path review for every patient. There was also central review based on an eligibility committee for measurable C findings in terms of eligibility as well. There were no restrictions on prior therapy, but all patients had to have a platelet count of greater than 50,000. As you can see on slide nine, there are two parts. Right now, we're enrolling into part one or the dose optimization. These patients would be randomized in a 1-to-1-to-1 ratio, depending on the dose level of 50 milligrams twice daily, 100 milligrams twice daily, 200 milligrams twice daily, or 400 milligrams once daily. Once an optimized dose is selected, then Part two will initiate, which will include 60 patients with a measurable IWG finding and another 20 patients who have advanced SM but no measurable IWG C finding. The primary endpoint for Part 1 or the dose optimization is safety and tolerability with pharmacokinetic and biomarkers. The primary endpoint for Part two is the classic overall response rate and durability of response. If I could have the next slide. On slide 10, we can see that the patients so far 16 patients have been enrolled with a median age of 69. These patients are predominantly male and have a preserved ECOG performance status. Not surprising, the most common histologic subtype is the systemic mastocytosis with an associated hematologic neoplasm, which accounts for 75% of the patients or 12 out of the 16. This is the exact and typical allocation that we've seen in the other studies. Most of the patients were treatment naive, but three patients had been previously exposed to avapritinib and another three patients previously exposed to midostaurin. 14 out of the 16 patients had a KIT D816V mutation. The bone marrow mast cell burden was median was 30%, and the median serum tryptase level was 178. There was no discernible differences between the demographics between the 4 dose levels that were enrolled. If I could move on to the next slide 11. The safety and tolerability of bezuclastinib is detailed on this slide. Most of the treatment emergent adverse events were low grade. There were several grade 3 neutropenia, thrombocytopenia, and one case of anemia that were transient and did not require dose reduction in order for these to be mitigated. There was one hypersensitivity reaction that occurred after the first dose, required dose reduction, but the patient's been able to tolerate bezuclastinib thus far. There was but importantly no cognitive impairment, and we have seen no bleeding events reported thus far on this trial. The majority of the hematologic treatment emergent adverse events, as I mentioned, were low-grade, reversible, and did not require dose modification. There were no dose continuations due to adverse events, and three patients had dose reductions due to an adverse event. One patient was able to be re-escalated. If you look at the safety and tolerability between patients who have been treated as a de novo or patients treated with prior exposure to tyrosine kinases, there seems to be no added or differential toxicity. If you look at the 4 dose levels, again, there seems to be no different in terms of the safety and tolerability amongst the 4 dose levels tested. Moving on to the next slide 12. We see that there's a limited effect of bezuclastinib on the platelet count. A preclinical study, data is presented at the left part of the slide, and this is comparing bezuclastinib to avapritinib and ruxolitinib in terms of the dose-dependent reduction of the colony-forming unit megakaryocyte on the top, colony-forming unit, granulocyte macrophage in the middle, and then on the erythroid cells. On the right, importantly, is spider plots looking at the effect of bezuclastinib on the platelet count. Each individual patient is represented as a line from the starting platelet count throughout the therapy. And the bottom line you can see there was a small dip for a very transient period. That was that grade three thrombocytopenia that without dose reduction improved. These patients so far to date have not had any significant clinically relevant reduction in their platelet count, as you can see in the spider plot. This is slide number 13. Probably the most important slide that I presented, which is the demonstration of the reduction of the mast cell burden in the patients treated thus far. These are waterfall plots. The first waterfall plot shows reduction of the serum tryptase level. 88% of patients achieved a greater than 50% reduction in the serum tryptase, and importantly, half the patients achieved a level of less than 20. The next waterfall plot shows the reduction in the mast cell burden in the 13 evaluable patients and all of the 13 patients that had at least 2 cycles of therapy achieved a greater than 50% reduction in their mast cell burden. In fact, three-quarters of the patients treated thus far had complete clearance of their mast cell aggregates, and this was confirmed by central review. The waterfall plot at the bottom looks at the KIT D816V variant allele fraction. 92% of patients with at least 2 cycles of therapy achieved a greater than 50% reduction in their variant allele frequency. Rather dramatic reductions in mast cell burden. Moving on to the next slide number 14. We see where the patients ended up in a consort-like diagram. There were 16 patients started. Two patients were invaluable. One patient was enrolled who on adjudication had no measurable C findings, and another patient is receiving concurrent medications and was deemed invaluable. That left 14 patients, of which three were excluded to our study, and one is too short of a follow-up to undergo central adjudication of response. This leaves 11 patients with centrally assessed mIWG-MRT-ECNM assessment and adjudication. Moving on to the next slide number 15. What I've done here is just show the differences between the mIWG-MRT-ECNM response criteria in the middle column versus the pure pathologic response, which is an exploratory response in the right column. The mIWG-MRT-ECNM requires both histologic reduction of the mast cell, so the absence of these neoplastic aggregates, is termed a marrow remission, reduction of the serum tryptase below 20 and remission of the peripheral blood counts. In addition, mIWG-MRT-ECNM requires complete resolution of all C findings that have been adjudicated. Whereas the pure pathologic response, which again is an exploratory endpoint, only requires histologic reduction of the mast cell burden. The mIWG-MRT-ECNM does require 12 weeks in order to have a confirmed response and obviously given the brevity of the patients that have been on the trial so far, we're reporting both confirmed and unconfirmed responses. Moving on to the next slide. This is slide number 16. These are the early responses that have been observed thus far. The top table is the mIWG-MRT-ECNM and the bottom, the pure pathologic response, which, again, is an exploratory endpoint. In the mIWG-MRT-ECNM on the top, we see an overall response rate of 73%. One looks at histologic improvement, that is CR, CRH, and PR. It's 55%. It's important to know that the median duration of treatment is about 20 weeks, and the first confirmed CRH by mIWG-MRT-ECNM was as early as 8 weeks, and the first confirmed CR was 20 weeks. We are seeing, you know, rapid responses as demonstrated both by the waterfall plots as well as on this table. Longer follow-up will probably mature these responses. Moving on to the swimmers plot on slide 17. We can see that for the vast majority of the patients, they remain on therapy. You can see with the open figures, the earliest unconfirmed centrally adjudicated response, and then these responses deepen with time as we've had the opportunity to re-adjudicate. So, you know, again, very impressive early responses with a lot of patients still ongoing, and we expect that these responses will deepen with time. The next slide is slide number 18, which shows the dose-dependent increase in steady-state levels of bezuclastinib. What you can see here are four levels that have been tested. The bottom dotted or dashed line is the 50 milligrams twice daily, followed by the 100 milligrams twice daily. The two top lines are the 200 milligrams twice daily, and the 400 milligram once daily that have virtually identical PK properties. This is really establishing a dose-dependent increase in the bezuclastinib as measured on cycle 2, day 1. Moving on to the next slide. This is my final slide on slide 19. This is the clinical summary of bezuclastinib. I think I've tried to demonstrate here that bezuclastinib is a highly potent and selective tyrosine kinase inhibitor against the D816V KIT mutation. It was extremely well-tolerated across all 4 dose levels tested and continues to demonstrate a differentiated safety profile. Importantly, there's been no related cognitive effects, and also importantly, there's been no bleeding events reported thus far in the trial. The limited effect of bezuclastinib on platelet count is supported by the preclinical data that I showed you earlier. Bezuclastinib has resulted in encouraging early signs of clinical activity. Obviously, these will deepen with time. The overall mIWG-MRT-ECNM response rate, both confirmed and unconfirmed, was 89% that I showed you. If one looks at the reduction in the mast cell burden, 88% of patients had a 50% or greater reduction in serum tryptase, 92% of patients had a reduction in their KIT D816V allele burden, and all patients that had received 2 cycles of therapy had a reduction in their mast cell burden, and 75% of those patients had actual clearance of mast cell aggregates. Enrollment to Part 1 is ongoing. Of course, once a dose optimized, dose and schedule can be obtained, part two will start enrolling. With that, I'll thank you for your attention, and I'll turn it back to Andy. Great. Thanks, thanks, Dan, for reading the presentation this morning and certainly for all of your leadership and guidance on the APEX trial to date. Before we open up the call for questions, I'd just like to reinforce a few points if I could. First, we're very excited with the clinical activity that bezuclastinib is demonstrating in ASM patients this early in the trial. With a modified IWG ORR of 89% in tyrosine kinase inhibitor, naive ASM patients, we are encouraged with bezuclastinib's rapid and deep clinical responses. Second, with an overall safety profile that is tracking, as we expected, with no related cognitive effects, no reported intracranial bleeding, low levels of peripheral edema, and very encouraging results on overall platelet health, our belief that bezuclastinib has the potential to become the best-in-class KIT mutant inhibitor is growing. Third, I'd like to remind folks who are listening that the APEX trial is only 3 of the patient populations where we think bezuclastinib can become a best-in-class offering. As a well-tolerated KIT inhibitor at clinical exposure levels that have demonstrated robust clinical activity, we are excited to see part 1 results from the non-advanced systemic mastocytosis We were excited to announce last month that patient enrollment in the phase 3 portion of our GIST patient PEAK trial is underway. Based on its kinase selectivity and corresponding tolerability seen in an earlier phase 1/2 solid tumor patient clinical study, we believe the combination of bezuclastinib and sunitinib has the potential to become the standard of care in second-line GIST patients. Finally, I'd like to extend our sincere gratitude to the Cogent team working hard every day to advance bezuclastinib along its clinical development path. Most importantly, to the patients and their families who are participating in the APEX, SUMMIT, and PEAK clinical trials. If I could ask the operator, we'd like to open up the call for questions. If you'd like to ask a question, please press star, one, one. Our first question comes from Chris Raymond with Piper Sandler. Your line is open. Hey, good morning, guys, and congrats on the update. This is Nicole Gabreski on for Chris. Thanks for taking the questions. Maybe just first can you talk a little bit about the choice to disclose treatment-related AEs versus treatment emergent AEs, like you guys presented before at the EHA update? Maybe just help us understand the rationale behind that change. Secondly, just around serum tryptase, I guess for the patients that had prior midostaurin and ava, those patients saw nice serum tryptase reductions, but at this point it doesn't seem like it's translated to a response. Can you maybe help us or I guess, can you generally comment on what you're learning about the correlation of the biomarker to response and maybe how you're thinking about that translating to the into the one setting? Thanks. Sure. Thanks for the questions. I, maybe I'll try to take a stab at them and then I'd, you know, be interested to hear Dan's perspective on the second question. With regards to TR AEs and TE AEs, I think what we try to do is do our best to characterize what's going on in the trial at this point. Instead of reporting a long list of individual low-grade AEs that single patients experienced, we wanted to try to say, what is the emerging profile look like for patients and what patients might expect going forward. There's nothing untoward that we're trying to hide. TR AEs we think very well characterizes the safety and tolerability profile. With regards to the difference between naive and prior TKI-treated patients, I think it's pretty early to make any conclusions at all, given that we're talking about I think three patients on study so far that have seen prior avapritinib. Just a couple points. I think it's encouraging that investigators continue to be willing to enroll patients who haven't seen ava onto the APEX study. That's important for the trial. We also believe that patients that have demonstrated an intolerance to other medicines like midostaurin and avapritinib absolutely deserve to be treated with a new potential therapy. We're gonna continue allowing those patients on the study to see how they perform. Maybe I'll see if Dan wants to add anything to that one. No, I don't. Okay. I think you answered the question accurately. I think, you know, with only three patients, all of which have been exposed to prior both ava and mido, it's really hard to draw significant conclusions, especially on an early phase part one dose escalation of this of this trial. We'll really have to wait to see more patients and probably confirm that on the part two of the trial before we can really assess the differences between newly diagnosed or untreated patients and those that have been previously treated. Okay. Thanks. That's helpful. Thanks for taking the question. Our next question comes from Samuel Slutsky with LifeSci Capital. Your line is open. Hey, good morning, everyone, and thanks for the great update today. A couple from me. I guess, just to confirm, for the thrombocytopenia and anemia cases, so no dose reductions occurred in those patients and the decrease in blood counts was transient? Hey, Sam. Thanks for the question. Yeah, I can confirm just quickly that no patients on study had dose reductions for any heme tox. None of the cytopenias led to any dose reductions. I can also confirm that all of the grade 3 cytopenia patients had their blood counts go back to baseline, at least, without dose reduction. Got it. I guess just to follow up on Nicole's prior question on treatment related versus treatment emerging, I mean, I guess is it fair to say you're being a bit conservative here? You know, again, without saying we're not trying to stack the deck. We're trying to, at this point, disclose and communicate to the investigator and patient community what the profile of the drug looks like, to the best of our knowledge. I'll defer to Dan maybe to give his perspective, but I think from a safety perspective, we're trying to do our best to describe what bezuclastinib looks like when given to patients. Yeah, no, I would agree. I'm really not a big fan of attribution when you see adverse events. You just report what you see, and let the dust settle later. I think it's a much more conservative approach to just see what happens, you know, because patients will have variability in their counts. It could be due to disease, it could be due to just, you know, laboratory subtleties and just reporting it and then seeing what happens later. That would be my preference, and that was the preference that we chose. Got it. I guess just based on the profile of bezuclastinib there's a couple interesting aspects of it. I know Dr. D'Angelo yesterday, you had mentioned that there's potential for it in patients with platelets less than 50,000, given its tolerability profile, also makes the treatment pretty amendable to combination approaches for the AHN population. Could you just kind of walk through potential strategies there to kind of expand these into these markets? Sure. Maybe I'll let Dr. D'Angelo start and I'll see if I have anything to add. Sure. Yeah, I mean, these are, you know, conjecture, right? I mean, you know, the avapritinib label requires patients to have a platelet count of greater than 50,000. You know, that was done, you know, primarily because of the intracranial bleeds that were seen on the EXPLORER trial and none that really that have been seen since the modification of those of the PATHFINDER trial that limited the platelet count, and that's obviously on the label. When I see a patient with a platelet count of less than 50,000, which is not a huge population, it's about 15%-20% of my advanced SM, you know, I'm really left with midostaurin, number one. Number two is, you know, although most patients with SM-AHN will have their AHN component will be of low grade. What we've demonstrated in the midostaurin studies and we've demonstrated again in both the EXPLORER and PATHFINDER studies is SM-directed therapy is able to abrogate many of those symptoms, number one. Number two is patients get bona fide responses. There are patients who progress on the AHN, and there are patients who present with advanced AHN that would require dual therapy or focus on the AHN. Right now, with the current in-class molecules, midostaurin, avapritinib, they're very difficult to combine them so far with HMA therapy. My hypothesis is, you know, again, limited number of patients, we haven't seen significant myelosuppression, as Andy had already mentioned. You know, does the platelet count really have to be 50,000? I'll leave that to him in terms of a regulatory issue. That's the way the study is right now. Obviously, as a clinician, putting on a different hat, I like to be able to treat, you know, more or all of my patients. Of course, you know, as patients' AHN starts progressing or for those patients who present with advanced disease, I like to have the opportunity to treat both aspects of their disease. Right now my hands are somewhat tied. You know, those are just forward-looking thoughts in terms of trying to treat all the patients that I see. Yeah, that's great. Just to kind of build on that a little bit, I think if we can, and again, as a forward-looking thought, if we can demonstrate in maybe a slightly larger set of patients. As a reminder, we do have a plan in part 1 of APEX once we have about 25-30 patients enrolled, which, by the way, we're forecasting we should have those patients enrolled in Q1 of 2023, so not that far in the distant future. Our plan is to sit down with folks like Dr. D'Angelo and his colleagues to discuss, number 1, do we feel confident about a dose in moving into part 2? Many other things, including do we feel like we should go back and approach the regulators and have a discussion about, you know, potentially allowing us to treat patients below $50,000. That's certainly on the docket. We'd like to have that discussion both with the experts in the field and with regulators to see if that's possible. The other thing I'll say, and this is to the investors listening in, one of the reasons in the GIST development program we think we can be successful is based on the tolerability profile of bezuclastinib, which enables it to be combined with a drug like sunitinib for GIST patients, which is unique, relative to some of the other KIT mutant inhibitors that have tried to go in a head-to-head fashion. We think some of those same properties and concepts can apply here in the SM-AHN world because of what looks like to be an emerging differentiation on tolerability, where we believe that bezuclastinib holds the potential to also combine in the heme side of this development program with other AHN-directed therapies. We're working together with folks like Dan and his colleagues to figure out exactly the right way and the right time to do some of those concomitant use trials. Super helpful. Thanks. Our next question comes from Charles Zhu with Guggenheim Securities. Your line is open. Hi. Good morning, everyone. Congrats on the data, thanks for taking the questions. For my first one, if you could perhaps humor just one more on some of the treatment-emergent adverse or treatment-related adverse events, particularly the cytopenias. I mean, we could probably glean a lot of that from the spider plots, just given the, you know, the patient-level data that you provided. I guess, you know, from that perspective, given that cytopenias seem to be characteristic of the disease, and maybe, could you provide some color around how our investigators perhaps, you know, distinguishing a lower platelet count as something that's attributable to the disease as opposed to something that's attributable to the drug? Thanks. I think that sounds like a great question for Dan, if you're willing to talk about that. Yeah. Yeah. I mean, obviously that could be a struggle. you know, it's, you know, as you're seeing a patient and caring for a patient, it's always hard to know. you know, if you, if you really blow up the spider plots that I showed you, I mean, you know, this patient that had a grade three thrombocytopenia, his baseline platelet count was just above 50, and then it was transiently just below 50, so that was an AE, and then it went back up above 50. you know, you know, the variability of the lab in terms of measuring platelets is, you know, is within the error bar of about 5,000-10,000. this very well may have just been, you know, one of those, you know, clinically irrelevant issues. Of course, it gets reported in a regulatory fashion because it just dips below this line in the sand. In general, to address your question, irrespective of that particular case, because I think that case is just a nuance, is when you're treating patients in general, it can be very difficult to know whether it's drug or disease or some other problem. You know, I think that, you know, this particular agent, at least so far, most of the investigators have been very comfortable, you know, continuing to treat with these minor perturbations in the cytopenias. They've been very trivial and clinically irrelevant. You know, a platelet count of 47 is not any different than a platelet count of 58. Yet it's gonna be a different AE if you understand what I'm saying. We've been, you know, very comfortable, you know, continuing to treat those patients. As time goes on, we'll get more confidence and more data to support that, especially given the fact that we're not seeing any bleeding events or any cognitive issues. I hope that helps. Got it. Great. Yeah. Thanks for that color. Maybe as a follow-up to one of the comments that the company had put out regarding the go-forward plans. In terms of potentially selecting a recommended phase 2 dose off of that interim analysis, I guess, given that your dosing was effectively 100, 200 and 400 mg daily, is there perhaps a scenario where I guess, are you locked into potentially selecting one of those doses, or is there a scenario where you could potentially go forward with an intermediate dose, let's say, for the sake of argument, 300, based on the current design of APEX? Would that, you know, necessitate additional patients? Thank you. Yeah. Charles, it's a great question. I'll kind of remind folks that one of the other things we're going to do during the transition from Part 1 into Part 2 of the study is change to the new optimized formulation, which was really designed to enable a much friendlier patient convenience and compliance dosing regimen for the GIST phase III trial. Now that we have an optimized formulation that looks like it has benefits beyond simply pill burden, we certainly want to get the optimized formulation into the hands of the mastocytosis patients as well. It's very possible that the go-forward dose is not the identical number of milligrams that we're exploring in Part 1. The most important thing about choosing a dose in our mind, as Dan mentioned before, the primary endpoint is obviously safety and tolerability of picking a dose, but it's also to really understand your level of exposure. We're going to likely pick a dose based on what we know, looks like is an emerging exposure response trend. Although of course, we want to enroll up to that 25-30 patient level so we can see a more full picture of what that looks like. The exposure is really what's going to drive what numerical number of milligrams we'll pick for the go-forward dose. Nothing's off the table, to answer your question directly, but that gives you a little, I think, insight into how we and the experts that we'll work with to figure out what to do after the 25-30 patients are enrolled, what we'll be talking about at that meeting. Got it. Great. Thanks for taking the questions and congrats again on the data. Our next question comes from Eun Yang with Jefferies. Your line is open. Thank you. A few questions. 1, in SM-AHN patients, in general, what% of those patients are under active treatment for the underlying cancer? Hey, Eun. Okay, we can do these one at a time. I don't know that there's a good source that will tell you a point estimate for that number. I'm happy to let Dan speak to it. I think, Dan, the question is how many SM-AHN patients off of clinical trial protocols are receiving therapies directed for AHN. Yeah. I mean, that's a great question and one that, for whatever reason, a lot of folks have been asking me, at the various, poster boards. It's interesting, you know, because we've tried to demonstrate now with, three prospective studies, first with midostaurin, then the next two with the EXPLORER and PATHFINDER studies, that for patients with low risk AHN, if you target their mast cell component, that you get bona fide responses that are durable. I mean, I think in the community that are uncomfortable with, the SM, a lot of these patients are receiving therapy that are directed towards the AHN. That percentage is really hard to quantify outside of a clinical trial. What we've demonstrated in this study as well, is that for these SM-AHN patients, for which about, as I mentioned, about 80% of them are low grade, these patients can be, you know, their therapy can be initiated actually that with SM-directed therapy. Dipti got that question as well yesterday when she presented the updated PATHFINDER data and tried to answer it in the same fashion. You know, there are patients where their AHN component, because the SM is in remission, will progress at some point, and those patients may be deemed eligible to receive AHN-directed therapy or even stem cell transplant. The vast majority of patients can be treated safely with their SM. In the community, it's a little bit unclear as to what their pathologists are providing them and what their understanding is of the dualness of the disease. They often will treat what they know, which is if the, if the pathologist says, "Oh, you have a MPN or an MDS or a CMML," they'll treat that without knowing about the SM. I think we've tried, maybe unsuccessfully, but we've tried with a lot of prospective trials with other agents, and now with this agent, it's really to document bona fide responses and durability of responses when SM is targeted. Yeah. Just to quickly add to Dan's comments. We've heard very similar commentary from not places like Dana-Farber, where obviously Dr. D'Angelo deeply understands this disease, but from the community physicians who are treating this, often the primary diagnosis is for the AHN, and the SM is discovered subsequently. After initiating directed therapy for the AHN, those physicians in the community struggle with whether to add SM-directed therapies which may have overlapping toxicity. Again, in the future, if you could deliver a profile of a drug that potentially doesn't have overlapping toxicities, then you could either solve the problem with concomitant use, or you could solve it long-term with education, as Dr. D'Angelo is speaking to. I see. Thank you very much. I'll just ask you a couple of questions in a row. With the emerging data from ASM, in non-advanced ASM studies, SUMMIT study, I mean, obviously you are incorporating the optimized formulation, although the doses may not be exactly the same as 100, 200, or 400 QD. Are you considering actually modifying the dose through the optimized formulation? Second question is, with a similar bezuclastinib exposure between QD and BID, I mean, it may be a stupid question, but in ASM, do you feel that you need to use BID in Part Two? Thank you. Sure. I'll take a stab at both of those. Thanks again for the question. In SUMMIT, while we haven't disclosed the numbers yet, we absolutely have said we're in the process of amending that protocol to allow for within Part One, switching to the optimized formulation to ensure we're exploring the optimized formulation in those patients. The long-term doses of bezuclastinib in the non-advanced setting and in the advanced setting may or may not be equivalent. We do believe from an exposure perspective, we will study exposures which are similar and overlapping, and then we will allow the data from each of the trials respectively to help us drive to decision on appropriate dose in each patient population. As far as your question about QD versus BID in the APEX study, we certainly had a perspective going into the trial that there may be a benefit of exploring BID dosing. As Dan presented yesterday and this morning, the PK chart doesn't seem to show a significant difference between the various schedules, especially if you look at the 400 QD versus the 200 mg BID at cycle 2, day 1 from an accumulation perspective. We don't think that there's a big difference after a couple days of dosing. What I'd say is you probably Given we're at QD dosing in both the PEAK GIST protocol and QD dosing in the SUMMIT protocol, I would say don't be surprised if we move to a QD dosing regimen in the APEX trial as well. Thank you. Our next question comes from David Nierengarten with Wedbush. Your line is open. Hey, thanks for taking the question. Most of them have been asked, but I was curious if you have the breakdown on prior treatment by subtypes, you know, AHN or, you know, mast cell leukemia. Thanks. David, thanks for the question. We did not disclose that. I'm just trying to remember off the top of my head. As both Dan and I mentioned, there's only 3 patients that had prior AVA. From memory, I don't think all 3 are in one subtype. But given that the majority of the patients in the trial are SM-AHN, I wouldn't be surprised if at least 2 of the patients are... Oh, no. 2 of the patients are SM-AHN, I think. That's right. Okay. Yeah, that's correct. Okay. That's correct. Two were AHN and one was ASM. Okay. Thank you. As a reminder, to ask a question, please press star one one. Our final question comes from Christopher Liu with SVB Securities. Your line is open. Hey, thanks for the question. Just have 2 questions. For the first one, in terms of the heme AEs, you know, we heard that for the Grade 3 thrombocytopenia, kind of dipped below and that was the Grade 3 and then it recovered to baseline. Just wondering if something similar happened with the other Grade 3 AEs, heme AEs with neutropenia and anemia. For the second question, just following up with a previous comment about kind of picking the dose with the optimized formulation going forward for the APEX study. I think previously you said you'll be adding patients to a previous question. How many patients do you think you'll need to have with the new formulation in order to figure out that right dose? Thanks for the questions. Again, I'll maybe take a stab at the second one, and then I'll say a couple words on the first one about the heme AEs and then ask Dan to weigh in on that as well. From the optimized formulation in APEX, specifically what we've said is we think we know a lot of information about the performance of the optimized formulation relative to the current or the older formulation. We acknowledge that we ran a fairly robust, healthy, normal volunteer study in the first half of 2021, which led into the lead-in trial on the PEAK protocol, which includes 19 patients dosed with the optimized formulation of bezuclastinib in combination with sunitinib. We have a lot of understanding about the behavior of the optimized formulation relative to the existing formulation. I don't believe in APEX that we will need to add incremental patients for the purpose of seeing the performance and exposure of the optimized formulation. As an example, we still feel confident in our guidance that after 25 to 30 patients are enrolled in part one, which, given where we are in part one enrollment, those patients will be on the existing formulation that we'll be in a position to talk with folks like Dr. D'Angelo and colleagues about the appropriate dose to take forward into part two. With regard to your question about heme AEs, I'll just reinforce the point I made earlier in the call that all of the incidences of grade three cytopenias, there were, I think, five of them. Each of those patients resolved their blood counts to baseline or above without any dose reductions. And across the board, even for the low grade cytopenias, there were no instances of any dose reductions for those patients. I don't know, Dan, if you wanna add anything additionally to the comments you've already made about the heme tox associated with bezuclastinib. No, no. The Andy, you summarized it accurately. The nobody required a dose reduction. None of these were really clinically significant or relevant, and they all resolved on their own, so. Got it. Thank you. If I, if I could just add another question. you know, no dose discontinuations or reductions, any dose interruptions? We didn't report interruptions. I'm sure that there are cases where a patient didn't take a drug for a day, but there were no significant dose interruptions that certainly resulted in any additional adjustment of doses like reductions or discontinuations. Got it. Thank you very much. Thanks. Thanks for the questions. We have a follow-up question from Eun Yang with Jefferies. Your line is open. Thank you for taking the follow-up question. Andy, you mentioned that about 25-30 patients should be enrolled by Q1. After looking at the data, you will decide, you will talk about how whether you're gonna be moving into part two and all the details. From the timeline perspective, when should we expect an update from you regarding the decision on APEX trial? That's a good question, Eun. As I sort of, I think you got it right. As I suggested before, we think we're on track to finish enrolling about 25 to 30 patients in Q1 2023. Certainly in order to sit down with our team of outside experts to help us make decisions, you would want at least a few cycles of treatment for those last patients in order to, you know, see their performance on trial as well. I think it's probably fair to say mid-year 2023 would be a good time and a good forecast for when we would be able to make an update based on that pre-specified analysis of the part one patient population. Thank you. Thanks, Eun. There are no further questions. Thank you for participating in today's program. You may now disconnect. Everyone, have a great day. Thank you.