Good morning, and welcome to the Cogent Biosciences conference call. Currently, all participants are in a listen only mode. There will be a question and answer session at the end of this call. I would now like to turn the call over to Christi Waarich, Senior Director of Investor Relations at Cogent. Please proceed.
Thank you, operator, and welcome to the Cogent Biosciences conference call and webcast. Please be reminded that remarks made during this call may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about our future expectations and plans, clinical development timelines, including future presentations of clinical data and financial projections. While these forward-looking statements represent our views today, they should not be relied upon as representing our views in the future. We may update these statements in the future, but we are not taking on an obligation to do so. Please refer to our most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with our business.
With that, it's my pleasure to turn the call over to Andrew Robbins, President and Chief Executive Officer. Andy?
Thanks, Christi. Good morning, everyone, and welcome to our call today. We're pleased to have you and are looking forward to sharing with you an exciting clinical update from our APEX trial of bezuclastinib in advanced systemic mastocytosis patients. With me today on the call, I have Dr. Jessica Sachs, who's the Chief Medical Officer at Cogent, and we're very pleased to welcome a special guest, Dr. Dan DeAngelo, who's the Chair of the Division of Leukemia at the Dana-Farber Cancer Institute and is a well-known recognized global opinion leader in the field of novel drug development for systemic mastocytosis. I'm gonna make a few comments about the background, both about Cogent and bezuclastinib, and then we're gonna hand the call over to Dr. DeAngelo to walk us through the initial clinical data update out of the APEX study.
I'll come back on to do a quick summary at the end, and then we'll open up the call for some Q&A. Christy, let's go to the next slide. Just as a reminder, we here at Cogent Biosciences are an emerging leader in the field of precision medicine for genetically defined diseases. Our lead asset and our current focus is on bezuclastinib, which we believe is a potential best-in-class potent selective KIT inhibitor. Today we're excited to share the first clinical data, which we believe helps support that belief. We're also excited, very excited about the potentially best-in-class medicinal chemistry-focused small molecule research team that we're building at Cogent Biosciences.
Recently we announced our first two lead programs are a selective FGFR2 and a selective ERBB2 mutant inhibitor. Today we won't have time to cover the entire pipeline, but we definitely will look forward in the coming months to an opportunity to tell you more about all the exciting things that are going on with our amazing research team. Just to finish off the slide, to remind folks listening in, we do feel we're in a very strong position with a cash balance of $191 million at the end of Q1. That would help us execute our goals both on bezuclastinib and overall as a company, including the research programs into 2024. We can go to the next slide.
Before we get to the clinical data today, let me just talk for a few slides about the background of the disease and bezuclastinib. For those who are not familiar, advanced systemic mastocytosis is a life-threatening form of SM that's primarily driven by mutations in the KIT D816V and leads to uncontrolled proliferation of mast cells. The disease is divided into three subtypes, each of which is associated with a median overall survival for patients of less than four years. It is a very severe, life-shortening disease. You can see here on the right a series of symptoms that comes along with the disease, for patients.
What's clear, based on the current available treatment landscape, is that while there are drugs that have activity, there is a significant unmet need for patients to find new drugs that have activity against the disease that can help prolong life but are also well-tolerated and don't come along with some of the associated dose-limiting toxicities that we've seen in the past few years. We can go to the next slide. While systemic mastocytosis is a rare disease, there are an estimated 20,000-30,000 patients living with SM in the U.S. today. About 10% of these patients have the advanced form of the disease, and that's the population in which we're studying bezuclastinib on the APEX trial, and we will be sharing initial clinical results today. We can go to the next slide.
Today we're gonna provide an update on the progress of bezuclastinib.
As I mentioned before, we've spent the past year characterizing bezuclastinib's non-clinical profile. Bezuclastinib is an oral selective and potent kinase inhibitor with activity against KIT D816V, which is the driver mutation of this disease. Preclinically, we've shown that it's highly specific for mutations in the KIT gene, specifically exons nine, 11, 17, and 18. Importantly, we've shown that bezuclastinib spares related kinases, so it has very good selectivity, which you see in the chart below. It has very minimal brain penetration, which is an important differentiation from some of the available therapies. You can see in the chart the cellular inhibition profile, where bezuclastinib, as well as some other well-known drugs being developed in this patient population, have very low nanomolar potency against D816V.
Interestingly, bezuclastinib does not inhibit many of the well-known anti-targets for this patient population, including PDGFR, which is, we believe, important as we build a profile of bezuclastinib as a very well-tolerated selective KIT inhibitor. We can go to the next slide. Finally, before I turn the call over to Dr. DeAngelo, who will take us through the initial clinical data, I'd just like to set the stage because the advanced systemic mastocytosis in the assessment of response in patients is not nearly as well understood by the general investment community as it is, for instance, with solid tumor oncology indications. We've tried to put together this graphic, which is a summary of the response criteria.
You'll see later, we are not at a position in this trial where we're presenting confirmed objective response data, and that's driven solely by the duration of therapy so far in the trial. We will get there soon, but today we'll be presenting clinical activity across several measures, including serum tryptase improvements, as well as improvements in mast cell burden. What we'd like to share with you is that there are specific clinically relevant thresholds that investigators think about when assessing patient improvement on available therapies. For instance, in these first two columns you see on this graphic, serum tryptase and mast cell improvement, you can see that in order to be eligible for achieving PR status, a patient would need to demonstrate a 50% reduction in correspondingly either serum tryptase and/or mast cell improvement.
If you move up to the eligibility criteria threshold for a patient achieving a complete remission or complete response, you would need to, on these metrics, achieve less than 20 nanomolar nanogram per milliliter absolute value on serum tryptase or elimination of all mast cell aggregates on mast cell improvement. In addition to those, in order to achieve PR and CR, you would need to achieve the criteria under C findings and under peripheral blood counts. Today we're gonna focus on looking at the early data on serum tryptase improvement and mast cell improvement in these patients, again, primarily driven by the early stage of the available clinical data. Just keep that in the back of your mind as Dr. DeAngelo goes through his presentation. With that, I'd like to turn the call over to Dr.
DeAngelo to walk us through the very exciting initial clinical data from APEX.
Great. Thank you very much. My name is Dan DeAngelo. I'm from the Dana-Farber in Boston, and I'm gonna present some high-level data of the APEX trial, which is a phase II study of bezuclastinib in adult patients with advanced systemic mastocytosis. If you could forward this slide, I'm on slide 10 now. The APEX trial, just to remind you, is a 2-part study. The eligibility criteria are patients with advanced systemic mastocytosis, and there's 3 histologic subtypes. There's ASM, which is aggressive systemic mastocytosis. Although there may be a little bit of a thinking that's a semantic change from advanced to aggressive, it really means that it is or these patients have just pure systemic mastocytosis.
The most common entity or subtype is systemic mastocytosis with an associated hematologic neoplasm, really two separate or but related disorders in the bone marrow. Mast cell leukemia. Patients have to have one of these three advanced forms of systemic mastocytosis as diagnosed by the WHO. They have to have measurable disease findings by the modified IWG that was just presented to you on the slide prior. No restrictions to prior therapy. We're currently in the early part of the part one. In the part one, patients are stratified in four different treatment groups based on dosing of bezuclastinib, either 50 milligrams twice a day, 100 milligrams twice a day, 200 milligrams twice a day, or 400 milligrams once a day.
Once an optimum dose has been decided, we'll proceed on to part two, the expansion, with two cohorts, one with the IWG evaluable, that is measurable findings, and one with C findings that are not IWG evaluable. We can talk about that later. If I can move on to the next slide. These are the groups of patients. So far we've enrolled 11 patients. I find this to be rather exciting. We're ahead of expectations slightly. You can see the patients are equally stratified into all four of the cohorts.
If you look at the column on the right, which is a total 11 patients, you'll see that these are predominantly male patients with a good performance status. As I alluded to, 70% of the patients have the SM-AHN phenotype, which is what we reported in both the midostaurin and the avapritinib studies. More than 90% have a KIT D816V mutation, which was again reported in both prior studies. Most of the patients on this particular study are treatment naive. The bone marrow burden is actually relatively high, around 30% with a range of 70%-80%. The tryptase, which is a surrogate marker for total mast cell burden, the median was 180 with a range of about 70 to as high as 1,500.
If you could forward to the next slide number 12. I found so far, again, it's all early, that the bezuclastinib has been extremely well tolerated. The majority of treatment emergent adverse events were low grade, with one serious adverse event and no grade 4 events, which I think is very important. If you can look at the table, there's just really some mild cytopenias that are grade 3, and these very well may be disease-related. There was one diarrhea that was assessed by the investigator as not related to therapy. Remember, diarrhea is very common in patients with systemic mastocytosis, and there was one hypersensitivity, which again is likely related to the underlying mastocytosis. No treatment discontinuations due to adverse events, which is very important.
There were two patients who've had a dose reduction. One was re-escalated to the randomized dose. Reasonably well tolerated to date. Next slide. Slide number thirteen. Bezuclastinib has demonstrated, you know, really substantial serum tryptase reductions early on. 100%, all 11 patients enrolled so far have had a marked response, and that's defined as a greater than 50% reduction in the serum tryptase level. You can see in these bar graphs, you know, some of the patients have normalized their tryptase. 90% reduction in serum tryptase levels. Six out of the 11 patients have achieved a serum tryptase level of less than 20.
Even patients with prior therapy, specifically avapritinib, have also had a very similar reduction in their serum tryptase level, and that's highlighted by the A and the M for midostaurin in those two patients with previous therapy. Forward to the next slide, please. The time to response is actually rather quick. You can see here in the diamond, these are the swimmer plots, looking at the beginning the time of initiation of bezuclastinib and then, you know, how long they've been treated. The farthest patient is in the fourth cycle of therapy. Each cycle is 28 days. You can see in the diamond that patients are having a 50% reduction relatively early on within the first cycle of therapy.
The circle represents when the patients achieve that magic less than 20 and that's happening sometimes in the first or second cycle. 10 of 11 patients achieved a greater than 50% serum tryptase reduction within the first week of treatment. 4 patients achieved a less than 20 during the first month of treatment. That's the first cycle. The tryptase reduction seemed to cross all three patient subtypes, although, of course, the majority of patients are in the SM-AHN. If we can move to the next slide. This is slide 15. Looking at another disease assessment is bone marrow reduction in the bone marrow mast cell burden. You know, there's different ways of determining this. It's really looking at aggregates, mast cells.
We all have mast cells, and they should be scattered throughout, but these are looking at aggregates, mast cell aggregates. Eight of the patients that are evaluable for response, the second bone marrow, there's one at the initiation of therapy. The second bone marrow for disease assessment is on day 1 of cycle 3, so after 2 months of bezuclastinib. All 8 patients have had a reduction of 50% or more in their bone marrow mast cells. Six of the 8 patients, remarkably, have had clearance of all mast cell aggregates. These are done by central review. This is not local review. This is done by central review and adjudication. Really an astounding early response. If we could forward to the next slide, please. This will be number 16.
Looking at allele burden, which is important in many disease subsets, and it's being reported by Dr. Reiter and colleagues as a very, very important correlative in terms of response and survival. Again, early data, but all 8 patients that are evaluable at cycle 3, day 1, have demonstrated a decrease in their KIT D816V variant allele fraction. This is by Droplet Digital PCR. You can see here in the bar graphs the magnitude of some of that reduction in the allele burden. Early data, but really substantial. All patients have had a reduction. As I alluded to with other agents such as midostaurin, avapritinib, this has really been an important surrogate marker for disease-free survival and overall survival.
If I can move to the next slide. This is slide 17. We thought we would highlight two cases. You know, I usually view this as anecdotes, but I think they're important. This is a patient with advanced disease, SM-AHN, prior treatment with midostaurin, progressed on midostaurin, and then had a toxicity to avapritinib with thrombocytopenia, which is not uncommon with that agent. I had a very high disease burden with the serum tryptase, which was the highest on the study so far of about 1,600, 1,578 to be specific, and a mast cell burden of 80%. His C finding by both WHO and the modified IWG with a platelet count of less than 75. His platelets had to be greater than 50 to enter on study.
He's tolerated the drug well. He was randomized to 100 BID cohort. He had some grade 3 anemia. Again, he does have anemia at baseline. As you can see in the background, that was due to his disease as well as the prior therapy. He remains on study now more than 2 months with treatment, and he's had a reduction in his serum tryptase level by more than 90%, and a more than 60% reduction in the bone marrow mast cell burden. You can see this based on the plots. I think most importantly, the patient also had a marked reduction in the KIT D816V variant allele fraction.
This is just an example of a patient who was previously treated with both available agents, at least in the United States, and is having a remarkable response, with no significant toxicity other than the expected anemia that's seen in all of these patients. If we can forward to the next slide. Again, not to torture everybody with lots of anecdotal cases, but this is yet another case showing a rapid and durable clinical activity. This is a patient with aggressive systemic mastocytosis. This is a subtype of advanced disease where the entire marrow or the entire disease burden is just mast cells. There's not this other associated hematologic neoplasm, so it's just pure mast cells.
This is a treatment-naive patient with a baseline tryptase level of 370, but a really substantial amount of mast cell. 80% of the marrow is filled with mast cells, and his WHO C finding was a spleen that was large, and not just palpable, but large and greater than 5 cm. This individual was randomized to the high-dose cohort, the 400 mg cohort. The patient has tolerated the drug well. He did have a mediator flare due to his underlying mastocytosis on the second day of therapy. The drug was reduced to 200 mg, and the patient has tolerated without interruption further. All of his symptoms resolved within 24 hours, remains on study now 4 months.
It's hard to maybe from a non-clinical perspective to show or to understand some of the pictures, but if you look at the second picture, the brown stains, that is the tryptase stain that's the CD117, the KIT stain actually. That represents the mast cell burden within the bone marrow. You can see, as I mentioned, more than 80% of the bone marrow is filled, or of the cells in the bone marrow are mast cells. If you go to the last slide on the right, that's a repeat staining of a bone marrow now after, on cycle 3, day 1, after 2 months of therapy.
You can see that the CD117 or the brown stain is only highlighting a small fraction of the total number of cells, showing that there's been a remarkable decrease in the total mast cell burden after only 2 cycles of therapy. If we can forward to the next slide. In conclusion, bezuclastinib has a potential to provide, in my opinion, a significant, meaningful clinical benefit. I've tried to demonstrate early data showing its high potency. It is a selective tyrosine kinase inhibitor that's been previously discussed that targets the KIT D816V mutation, which is the primary driver of systemic mastocytosis and mutated in more than 90% of all cases. Bezuclastinib has been well-tolerated across all 4 dose levels. The majority of the adverse events were grade 1 and 2.
I would argue, probably attributable to a disease baseline. Only 1 SAE has been reported. There's been no grade 4 events. There's been no reported periorbital or peripheral edema. There's been no reported cognitive effects or intracranial bleeding. We think this is an important differentiator from other agents. The hematologic events, which I've tried to allude and state repetitively, are expected in this patient population, specifically as this patient population includes only individuals with advanced disease. Patients present at baseline. This is how they get onto the study. If you have advanced disease, the vast majority have to have cytopenias related to the underlying disease in order to be eligible. It shouldn't surprise one that we're gonna see some adverse events in the hematologic venue.
I think these are encouraging early signs of clinical activity. A meaningful reduction in the serum tryptase, which is a surrogate marker for total mast cell burden. I've also shown you early data, after two months of therapy and reductions of the mast cell bone marrow burden, as well as very impressive reductions in the KIT variant allele frequency, across all dose levels. Patients treated with prior KIT inhibitors, including avapritinib and midostaurin, also demonstrated similar magnitudes of reduction in this particular presentation. With that, I'd like to close, and I thank you for your attention.
Thank you so much, Dr. DeAngelo. I really appreciate you walking us through the initial clinical data and appreciate you staying on with us for some questions in a few minutes. I'm just gonna take a minute or two to sort of summarize things. On that point, to summarize our thoughts on the initial APEX results, we're just incredibly impressed with the early safety, tolerability, and activity data that we've shown in these slides.
We feel that bezuclastinib represents the first truly selective KIT inhibitor studied in this population, and we're excited to see these data mature as we enroll additional patients to the study. In addition, we believe the emerging broad therapeutic index and safety profile suggest that bezuclastinib has significant potential for the ISM patient population and look forward to enrolling part one of the SUMMIT study, which is ongoing, and sharing those results as well. On that point, you can see on slide 21 at the bottom, we're updating our guidance today to commit to another presentation of the APEX clinical data by the end of 2022, and to sharing initial SUMMIT data from part one of that study in the first half of 2023.
We haven't spoken about bezuclastinib's future in gastrointestinal stromal tumors, but to round out the guidance, we also are planning to share clinical data from the lead-in to that phase III study during the first half of 2023. A lot of exciting clinical updates to come in the near term for bezuclastinib. Before I open up the call for questions, I would like to extend our sincere thanks to all of the patients, investigators, and Cogent employees who have spent the past year helping develop bezuclastinib and get us to this point. We're truly excited with the data and truly excited to accelerate the development of bezuclastinib. With that, I'll open it up for questions.
As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from the line of Chris Raymond from Piper Sandler. Your line is now open.
Hey, thanks for taking the question and congrats on the data. Maybe a question for Dr. DeAngelo or a couple of questions for Dr. DeAngelo. Maybe first, I'd love to get your perspective, you know, when thinking about your clinical practice, you know, especially with all your experience that you've had with avapritinib. If these data hold up, when you think about your advanced SM patients, how do you think about choosing between the two drugs, you know, between ava and bezu? Again, that's assuming that the data holds up.
Maybe also just on the ISM opportunity, I think I remember that your practice is predominantly focused on advanced patients, but would love to understand how you think, you know, with this data, you know, especially, you know, with the treatment effects seen even at the lower doses, you know, how it might translate into utility in the indolent setting.
Yeah. Thank you very much. Those are two outstanding questions, so I'll take them sequentially. The first question is on the advanced SM group and how does this compare to you had said avapritinib, but I'll include midostaurin as well. I mean, midostaurin and avapritinib has really been a paradigm shift in the treatment of advanced SM, and both represent huge leaps forward. Midostaurin is difficult to get in because of some of the GI toxicity. It doesn't have the issue, though, of thrombocytopenia being an exclusion for the label, and avapritinib does, so it's only included for patients 50 and higher. I remind you the APEX study only includes patients with platelets of 50 or higher.
My hope is we may be able to readdress that. So I think that's one of my issues in terms of treating my patients, is for those patients who present with thrombocytopenia. The other issue is some of the toxicity, as you know from the EXPLORE and PATHFINDER studies that we've presented many times, you know, although we have outstanding responses to ava, we are seeing and requiring some dose reductions due to some cytopenias and/or, you know, cognitive issues. You know, we'll have to see, you know, is the magnitude of the efficacy and the durability, which is gonna be very important, does the durability hold up in comparison?
I mean, this is not a randomized trial, so I always hate to compare apples and oranges in a way because different drugs, different studies. If the toxicity profile holds up, that we're able to get the doses in without requiring a lot of dose reduction, not seeing the cytopenias, not seeing the peripheral edemas, and more importantly, not seeing the cognitive defects, I think this may open up the window for preferential use of bezuclastinib in these patients. You know, that's you know, we're talking about this is 11 patients and early on. The science hat on me says we need to wait for that. That's a great question, and of course, that's the enthusiasm that we're addressing.
The second question that you asked is on the ISM. As you rightly alluded, I see mostly advanced patients, although I do have an emerging clinic with indolent. I think I have three consults next week, in fact, as I was just reviewing this morning, with indolent disease. We're seeing more and more of that. I think the reason is, although I'm not sure, pathologists are more accurately diagnosing SM. You know, when you have drugs, you're able to make diagnosis, and so people are alerting that, "Oh, there's a mast cell population there." Then very few people really know much about mastocytosis that are getting referred into the academic centers.
These patients really have a lot of symptoms that was alluded and discussed early on, and they are on polypharmacy to have it. To have a safe and effective drug without any of the toxicities that have been associated with the other agents would be a wonderful advance. We look forward to participating on the non-advanced trial as well. I hope that addresses both your questions.
Yeah, it does. Thank you very much.
Thank you.
Thank you. Our next question comes from the line of Yun Zhong from Jefferies. Your line is now open.
Hi, this is Nancy on for Yun. Thanks so much for taking our questions. I'm curious for the N=2 with prior avapritinib, they seem to be intolerant patients, but do we know if these patients responded to avapritinib or if they continued treatment too fast to see a response? I'm also curious if in which order they took midostaurin or avapritinib, if they took midostaurin first. My second question is how's the pill burden? I'm curious how many pills are required for the 50, 100, 200 or 400 mg doses, and if each pill is 50 mg. If you plan to use the reformulated product in the expansion phase. Thanks so much.
Thanks, Nancy. This is Andy. Maybe I'll take the second question and then I can either ask Jessica or Dan if they're familiar with the.
Yeah.
Specifically, the two patients.
Yeah, I can answer the first question.
Okay.
I'll wait for you.
Okay, great. With regards to pill burden, you're right. We are using the original formulation of bezuclastinib that was used in both the phase I to solid tumor study and now again in the APEX study that is 50-milligram tablets. So if you know, just with math, it's somewhere between 2 and 8 pills per day for these patients. We have already announced as part of our development program in the gastrointestinal stromal tumors side of bezuclastinib that we've created an updated formulation which we're in the process of clinically testing as the lead into that phase III trial. I don't think there's any reason to believe we would want to launch with two different formulations.
At some point, I think it's likely that we will be able to take advantage of a noticeably improved patient experience on the updated formulation for GIST on the SM trials as well. I'll let Dan maybe speak to your first question.
Yeah. I mean, again, an outstanding question and an astute one as well. Both patients that were previously treated had progressed on midostaurin. It's not uncommon. You know, we didn't see a huge number of complete remissions in the midostaurin studies. We did see a lot of PRs, so that shouldn't surprise you. The patients had toxicity issues that warranted discontinuation of the avapritinib. What I don't know is what was the response to avapritinib. I have to tease that out. I don't have that information for you. What was their response to their last agent? I don't know the answer.
Thank you.
I can speak to that if.
Okay, sure.
That'd be helpful.
Thanks, Jessica.
Yeah, sure. One of the two patients, the one who discontinued due to an intracranial hemorrhage, did have a partial response prior to having the toxicity. The other patient, who had thrombocytopenia, had I think a decrease in serum tryptase, but not sufficient to reach a measurable response, and ultimately progressed.
Thank you.
Thank you.
Thank you.
Our next question comes from the line of Sam Slutsky from LifeSci Capital. Your line is now open.
Hey, good morning, everyone. Thanks for the questions and great to see the data. A couple from me. I guess first, from a therapeutic window standpoint, every dose tested looks great on the metrics that you presented on. Could you just comment on the potential benefit of this wide therapeutic window as well as what you want to see to help you select the go-forward dose in advance of that?
Yeah. Good morning, Sam. Thanks for the question. I'll just say a couple things and then maybe I'll ask Dr. D'Angelo to share his thoughts. The trial has a pre-specified interim analysis that is planned for when 28 patients or somewhere in that ballpark have been enrolled and treated for at least a couple cycles. At that point, we would plan to sit down with Dan and his colleagues on our steering committee to take a look and review all the available data across safety activity, PD/PK, to try to determine if at that point we would be in a position to choose a go-forward dose and move into an expansion phase.
I do share your reflection that the drug looks in the early data to be active across doses, and I'll share with you that the tolerability or the relatively low level of adverse events reported don't seem to be clustering at necessarily the high doses. You know, it's an opportunity for us, I think, to share a drug that looks like it has strong activity across a wide range of doses, which is important not just in the ASM population, but also potentially for the ISM population, where you are probably looking at an even better or a higher bar for tolerability in a chronic setting. We're excited by the fact that the therapeutic window looks to be fairly broad in the early going.
We're not ready at this point to say we think we know what the dose is. We wanna accrue some more patients and see how the data emerges. Maybe I'll ask Dr. DeAngelo if he has any additional thoughts on that.
Yeah, no, I think you accurately described it. I mean, it's the luxury of riches, right? To have the ability to choose among four what seems to be equally efficacious dose levels, but and well-tolerated, having patients on all four. You know, and also the thing in addition to toxicity concerns and efficacy would be time to response. That's gonna be a player, a factor in terms of our decision in terms of moving forward. You know, it's nice to be able to choose as opposed to be forced into this is the best. We'll have to see how things go. Right now it's very promising.
Got it. Okay. Next question is just for the reduction in bone marrow mast cell numbers. I know historically that data with, let's say avapritinib on this metric has been presented as best change from baseline. Since you've only done one bone marrow biopsy for patients so far, is it safe to say that this should only improve from here for this particular group of patients as we think about best change? And then also, could you just comment on the relationship between time and response to bezuclastinib?
Maybe I'll just have Dan D'Angelo to come up.
You know, if you look at the serum tryptase levels in patients who have gone beyond cycle 3, day 1, they've continued to improve. We expect and anticipate that the next bone marrow exam will not only confirm the initial responses and therefore allow us to assess a complete remission or something like that, but that the responses will continue to deepen. This is what we saw with the other agents, and this is typically what you see with tyrosine kinase inhibitors in general, even in other diseases, is that you initiate a response and then the responses continue. Your second question, I'm sorry?
I think you answered both.
Okay.
Other than that, just talk about the relationship between time on study and response.
Yeah. It's just one of those things that just, you know, you just keep chipping away at it. The nice thing about this particular observation here is that the drop off in terms of response seems to be very rapid. You're seeing, you know, just plummeting disease burden, so, you know, rapid drops in serum tryptase and as you saw from my presentation, which is correlated very, very nicely with the bone marrow mast cell and the variant allele fraction from the KIT mutation. I think all three are good correlates of response, and I think that's just gonna continue. Sam, just to-
Last. Yep.
Just to build and just to clarify one thing, and it's a logistics thing. The way that the trial is designed from a protocol perspective is that patients get bone marrow biopsies on cycle 3, day 1, and then not again until cycle 6, day 1. You're right, based on the duration we've shown the bone marrow mast cell burden from bone marrow is based on all patients' single assessment, just to clarify that.
All right. Just, one more from me. Just, going back to the read-through from these data to non-advanced SM, could you just talk about the responsiveness to KIT D816V inhibition in non-advanced SM versus SM or advanced SM being should we expect, you know, deeper responses per dose level in a non-advanced SM population?
Deeper responses in terms of the marrow?
Well, just in terms of non-advanced SM patients being more responsive to KIT D816V inhibition.
Yeah. It's an interesting question and, you know, the disease is the same, right? The difference between indolent systemic mastocytosis, smoldering systemic mastocytosis, and advanced systemic mastocytosis really has to do with whether or not the mast cells have caused organ dysfunction, either hepatic, liver, spleen, or bone marrow, low blood counts or the resulting effusions in the lung or abdomen. It really has to do. It's not necessarily associated with bulk of disease, but it often is. We don't anticipate that there would be any difference in terms of the magnitude of the response. The response in terms, it's gonna be based on the histology, the marrow response and the tryptase level.
We think that would be very similar, if not more, because the disease burden is less. In the IWG, you also have to have those C findings resolve. Those get a little bit tricky in terms of assessing response. That's where Andrew's trying to show you in that chart that it gets very, very cumbersome very quickly with the IWG versus ISM. It's really just disease burden 'cause there are no C findings by definition. I anticipate the responses to be identical, if not more.
Got it. Thanks, everyone.
Thank you. Our next question comes from the line of David Nierengarten from Wedbush Securities. Your line is now open.
Hey, thanks for taking my questions. First off, maybe one for Dr. D'Angelo. In your experience, since you've had experience with avapritinib and bezuclastinib, did the thrombocytopenias associated with avapritinib, maybe you could remind us, start immediately? Did they take a few cycles of treatment to occur? Then as a follow-up, or this is for the company too, were there any changes in platelet counts that, you know, I know it's tricky 'cause they vary, but, you know, was there any trend or anything that could be detected towards, you know, or to that end?
Next question for the company, you know, since there is an approved agent on the market in a rare disease, how do you anticipate the regulatory requirements unfolding, you know, for a pivotal study over time? Thanks.
I'll answer the first question is a lot of it depended upon where the patient started. If the patient started with a low platelet count to begin with, then obviously you saw a marked reduction in that platelet count. I mean, the bottom line is that many of the hematologic adverse events with ava were seen early, and that represented some of the two patients that were previously treated, as alluded to. There were some patients who had cytopenias that were later in the course, but most of them were occurred earlier within the first few cycles of therapy, as would be expected in patients with high marrow disease burden.
I'll leave the other two questions for Cogent.
David, I'll take the question about the clinical development plan. APEX is designed, and we're in part one of APEX now, to essentially enroll somewhere between, I think, at the minimum 28 patients, because we want to get to that interim analysis and up to 60 patients is what the design of part one allows in order to convince ourselves and folks like Dr. DeAngelo that we have selected an appropriate dose to expand. Then part two is to enroll approximately 80 patients at that expansion dose. We feel if the trial is successful and demonstrates strong clinical efficacy and a drug with a tolerability profile that looks differentiated, that the APEX trial itself could serve as the basis for a conversation with regulatory agencies.
We don't at this point think we need to run a subsequent study in order to to demonstrate that effect. Of course, it'll be dependent on the magnitude of effect and the overall clinical data that emerges. I know Dr. DeAngelo answered your question about onset of thrombocytopenia, and then I think I handled the one about the regulatory path. Was there another question?
Oh, yeah. Were there any, you know, any changes in platelets? I mean, I know they're variable, but I was just curious if there was any, you know, excursions, you know, if you wanna call it that were close to a thrombocytopenia event but didn't quite qualify.
I think overall we're very encouraged by the you know relative platelet counts across the 11 patients with only a couple of very low-grade lab value instances of grade you know low-grade thrombocytopenia. Just supporting what Dan said before we think of bezuclastinib and its emerging profile as a product that has the potential not just to have lower rates of thrombocytopenia but I think as Dan said potentially working over time to use clinical data to relax the criteria for not allowing patients under 50,000 platelets to enroll. If we could do that and the drug demonstrates the potential to do that that would be an important opportunity for us to demonstrate a broader population that would be eligible for bezuclastinib.
Great. Thanks.
Thank you. Our next question comes from the line of Matt Kaplan from Ladenburg Thalmann. Your line is now open.
Hi. Hi, good morning, and thanks for taking the question. I guess, you know, in the context of these early results, maybe could you give us a little bit more detail on the side effect profile, specifically with respect to the different doses? Are you seeing increased rates of side effects or treatment-emergent adverse events as you increase the dose, or is it pretty flat across the dose range that you're testing so far?
Yeah. I'll take it. I mean, the nice part is we don't actually have probably enough adverse events that bezuclastinib has generated to make a definitive statement about that. What we can tell you is that it doesn't look like there's an obvious clustering of the low rate of low-grade AEs at the higher doses. I think what we're seeing and what Dr. D'Angelo said is that there are these sick patients that have a serious disease of the bone marrow, and that's associated with just underlying complications without even the presence of any systemic therapy. We're gonna need to enroll more patients. We're gonna need to see more time on therapy before we can make a determination if there's a relationship between dose and frequency of AEs.
At this point, I think it's fair to say we don't see that. And I'll ask, you know, Jessica or Dan if they have anything to add there.
No, I don't have anything to add. I mean, it's just early on, so it's hard when you only have two or three patients in each dose. There does not seem to be a dose response, as was alluded to, in terms of increasing AEs with increasing dose.
Okay, great. Thanks for that detail. Then, I guess, Andy, you mentioned that there's going to be additional data from the APEX by the end of the year. Can you give us a sense in terms of what we should expect in terms of number of patients, or is this just a completion of the part one of the study? Or what should we be looking for by the end of the year?
Yes, you know, it's hard to forecast the future. I'll say a couple things. You know, we're obviously very, very interested to see how these 11 patients do as we continue their swimmer plots out to the right and they, you know, hopefully stay on therapy for longer to see if these early signs of clinical activity turn into more objective assessments of response. That would be interesting to us. Then, of course, to accrue more patients to see if we can, you know, keep the activity and tolerability profile that's emerging in place as you grow it into a larger population. That would be the goal for a subsequent presentation.
Again, I can't pin the specific number in the future, but I can say that, in past lives, when you demonstrate that you have an agent that is showing a significant level of clinical activity with a well-tolerated safety profile at a major scientific meeting with very well-known opinion leaders supporting the development of the drug, it often translates into improved accrual on your trial. We're hopeful that will also happen in this situation.
Great. Thanks a lot, and congrats on the initial results here.
Thank you.
Thank you. As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. We have time for one more additional question. Our next question comes from the line of Christopher Liu from SVB Securities. Your line is now open.
Hey, guys. Congrats on the data. Just a couple of questions, if you don't mind. In terms of the cognitive AEs, I was just wondering how you guys define that and if that included headaches. For my next question, just wondering what the dose reductions were caused by in terms of the AEs. Just lastly, a quick question. Do you have any patients enrolled that were less than 50K per microliter platelets?
Thanks for the questions, Chris. I can. The last one's easy. No, we have that as an exclusion criteria, and that's per conversations with the FDA, as I think the agency still is, you know, being conservative and appropriately so, that damage to platelets could potentially be a class effect. We're hoping to demonstrate to them with these data, and as the APEX trial continues, that it isn't a class effect and that bezuclastinib may have differentiation there. Maybe I'll ask Jessica or Dan. Jessica, I don't know if you have this information handy on the specific dose reductions. I know that Dr.
D'Angelo pre-presented a case of the patient with ASM who experienced an early onset transient allergic reaction who was reduced from 400 to 200 and now is doing quite well 4 months later. That represents one of the reductions. Jessica, I don't know if you have at your fingertips the other one.
I'm sorry, Andy. The two dose reductions on bezuclastinib?
Yeah. One is the patient that we did the case study on. I don't have handy the other one. I don't know if Dr. DeAngelo, if you
The other one was the patient who was subsequently able to re-escalate, and the de-escalation was a little unusual because it happened in conjunction with an unrelated adverse event of diarrhea.
That's right. Chris, remind me of your first question. Sorry, I was working backwards.
Sure. Yeah, no problem. I was just wondering in terms of cognitive effects that you guys have mentioned here, you guys didn't show any, but I was just wondering how you guys define that, and then if that included headaches, and if not, if you guys have seen any headaches.
Right. We instructed our pharmacovigilance and safety team to include anything from a defined term that could possibly be associated with cognitive effects because we wanted to look specifically at that adverse event as a group, which we did formally include headache in the search, and we recorded zero cognitive effects, including headache.
Got it. Thank you, and congrats on the data once again.
Thank you.
Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.