Welcome to this next Fireside Chat with Cogent Biosciences. With us today, we have Andrew Robbins, President and CEO. I'm Michael Schmidt, Senior Biotech Analyst with Guggenheim, and it is a great pleasure to talk to you today, Andrew. Welcome, and thanks for joining us. Thanks, Michael. Great to be here. Yeah, why don't you give us a quick overview of the story, and then we'll dive into Q&A. Sure. And just, you know, for the purposes of folks listening in, I'm going to be making some forward-looking statements, so we'd encourage you to refer to some of our recent filings for a full characterization of the risk of the company. But, so again, I'm Andy Robbins. I'm the CEO of Cogent Biosciences. We are a company that's focused on developing small molecule targeted agents for the treatment of patients with rare genetically driven diseases. Our lead asset is a drug called bezuclastinib. It's a potent selective KIT mutant inhibitor. It's currently in three pivotal studies, all set to read out in 2025, starting with a readout of our non-advanced systemic mastocytosis trial, known as the SUMMIT study, in July, in merely a number of months, followed by our APEX study, which is a study of the drug in the advanced population of systemic mastocytosis. That is slated for the second half of the year. And then finally, a readout from our large phase III global study of bezuclastinib in combination with sunitinib in second-line gastrointestinal stromal tumor patients, known as the PEAK trial. That's on the docket for sometime near the end of the year. So we're really excited about the potential of bezuclastinib to become a new standard of care for all three of these patient populations and a very busy year ahead with the three pivotal trial readouts. We also are building what we consider one of the absolute top research teams in small molecules in the industry, a whole pipeline of novel, potentially best-in-class targeted agents. And the first one of those just recently entered the clinic, an FGFR2 selective inhibitor called CGT4859. And so we're now enrolling patients actively in that phase I trial. So I imagine most of the time today will be spent on bezuclastinib, but we're just as excited about the future of the company with all of our growing emerging pipeline. Super. So maybe just one more high-level question. Just remind us how bezuclastinib is differentiated from other KIT inhibitors? Sure. We see bezuclastinib as really the first truly targeted KIT inhibitor. It differs from what I think people see as the benchmark for recent development in the KIT class of a drug known as avapritinib in two very important ways. The first is that selectivity. Our drug is about 10 times selective for mutant over wild type in KIT and really hits no other kinases outside of the KIT gene. Unlike avapritinib, ripretinib, some of the earlier generation KIT inhibitors that not only are potent against KIT, but also hit anti-targets like PDGFR, CSF1R, FLT3, et cetera, et cetera, these are not targets that are important in driving diseases like systemic mastocytosis. Potency against those targets only brings along tolerability challenges of those drugs. Sparing those is very important for bezuclastinib. The other, I think, critically important differentiation for us is we do not have any noticeable penetration into the CNS tissue. That's unlike our competitor avapritinib, which is actually preferential for CNS distribution over systemic distribution, about two to one. So it is one of the most CNS penetrant small molecules ever discovered for any disease and any target. Again, systemic mastocytosis, it is not one of the main challenges to get a drug penetrant into the CNS tissue, and so what that does is it brings along a host of cognitive issues when trying to get to clinically relevant doses, something that bezuclastinib does not have as a liability. Super. And so we'll talk about some of the, just want to revisit some of the data you had at ASH in a second. But before that, just real quick, as we start thinking about the non-advanced systemic mastocytosis market, obviously, Blueprint has a launch ongoing here with success. And just remind us how you think about the commercial opportunity for bezuclastinib in non-advanced SM and, again, sort of opportunity to break into the space. Yeah, it's a great question. So we've spent a lot of time over the past few years getting to know these patients directly as part of our development program. Non-advanced systemic mastocytosis, folks also know it as indolent systemic mastocytosis, is a bit of a misnomer. These patients, especially those with moderate to severe symptoms, are in dire need of new medicines that can help control their symptoms, which are significantly impactful on their quality of life, oftentimes leading to inability to have a job, interact with society, being homebound. And so we acknowledge and congratulate our colleagues at Blueprint for taking a good step forward. Before avapritinib, there was literally nothing from a disease modification that could help these patients. And avapritinib showed, as part of the PIONEER trial, that relative to placebo, it offered some incremental benefit. And so, what you've seen in their first full year of launch (we don't have their Q4 2024 numbers yet. I think that comes next week) is they're going to do about $500 million in first full year sales, give or take. That's pretty impressive for a disease that I think much of the buy side thought as a very, very rare disease, even a year or 18 months ago. So I think what they're showing is that patients that for a long time had no choices are willing to try the first available drug. What we know now in this $500 million (I think Blueprint pegs it at about a $4 billion total available market) is that these patients' symptoms continue to persist, and they are looking for something that offers them even more symptomatic control. And that's where I think in the future you'll see bezuclastinib come into the story. Right. And then maybe just going back to ASH, where you had sort of updated data from your phase I study of Bezu in part one of the SUMMIT trial. And so, yeah, just remind us of the key takeaways from that and then add some follow-ups. Yeah, I think, again, as I said, there is a drug available. There's one drug. There's also nothing else in development other than Blueprint and Cogent. So this is really a two-company story for non-advanced systemic mastocytosis, and what we tried to show at ASH from our phase I or dose escalation from the recommended phase II dose that we've picked to go forward, which is the 100 milligram once-daily dose, is that the symptomatic improvement that patients experience on bezuclastinib is very rapid and noticeably deeper than they can achieve with any other available therapy. We acknowledge it's a small sample size, but what we also showed, and I'll throw out some of these numbers, a nearly 56% improvement at 24 weeks in total symptom score reduction from a mean perspective. Almost 90% of patients within the first year achieving at least a 50% improvement. Quality of life scores going from nearly severe as an average to very mild as an average very rapidly, so across the board, no matter how you measure improvement, what patients on bezuclastinib are showing is that they get rapid, deep improvements in symptoms. We showed these data, and we sort of walked through the story around ASH under confidentiality to the investigators who were enrolling the pivotal study back in September, and what we saw as a reaction to sharing those data under confidentiality is a nearly doubling of the enrollment rate of patients onto the trial, so a recognition from about 70 investigators around the world that the results that were shared at ASH were really game-changing for patients with this disease. And their reaction was, "I need to find a way to get my patients onto this trial before it closes." Just to kind of finish that story, we wrapped the enrollment of SUMMIT Part 2, the pivotal study. We had set out to do 159 patients in about a year and a half. We ended up enrolling 179 patients in 10 months. So 6 months plus ahead of schedule, really based on, I think, the reaction of the investigator and patient community to the early data that we shared. Right. What has been the feedback from physicians on the safety and tolerability profile of bezuclastinib? I know there was some discussion of liver enzyme elevations historically. And yeah, are there any other things that are important? Yeah, it's a great question. So we also acknowledge in this patient population that has a normal life expectancy. This is a disease of morbidity, not typically mortality. You want to have a drug that's very well tolerated. And the profile that we are seeing emerge from bezuclastinib, not just in the phase I that we presented at ASH, but really across all of our clinical programs, all of our patients that are now on even the blinded studies, which we obviously monitor safety from, is one that bezuclastinib will cause patients to experience white hair discoloration. That is an on-target effect of hitting wild-type KIT. And two, patients may, in sort of the minority of cases, in rare cases, experience elevated transaminases, AST and ALT. What we know about these now from a database of over 600 patients on all of our clinical trials is we have no evidence of any true liver toxicity. All of these transaminase elevations are asymptomatic and reversible, most of the time reversible without dose modifications. In some cases, you need to dose reduce, and then the transaminases go back to baseline. And in very rare cases, patients have been discontinued. But in all of those cases, they've returned to baseline within weeks of discontinuation. So what's very important, I think, to the investigator community is we have a very benign safety profile. Patients don't feel that they have elevated AST. And when you reduce or withdraw the drug from the patient, it goes back to normal. So there's no long-term consequences. What's interesting, and I know you didn't exactly ask this, but what's particularly interesting to us is we saw a paper published in Nature Scientific Reports about 10 days ago, because I think there's this debate among the buy side about the relative tolerability profile between avapritinib and bezuclastinib. And to us, it's been a little confusing to hear the narrative of bezuclastinib as the toxic drug. This report showed in an analysis of the FAERS database that between the beginning of 2021 and the end of 2023, when the authors did this statistical analysis, about a third of the adverse events reported on avapritinib are neuropsychiatric events. This is very concerning to patients. We hear both from investigators and patients that one of the main reasons people are timid to sign up for avapritinib is this fear of the cognitive issues as a highly brain-penetrating drug. What's maybe even more interesting, there's a lot of drawbacks to the FAERS database, but what is hard to get away from is during that period, there's evidence of 26 fatalities associated with the use of avapritinib. We actually extended, we took a look after we read the paper, and we brought the FAERS database analysis up until a couple of weeks ago, end of January 2025. And now there's 38 fatalities associated with the use of avapritinib adverse events. What's interesting is eight of those are coded as cerebral hemorrhage. We know from the history of the development of avapritinib that there were 22 cases of intracranial hemorrhage on their clinical studies. But now, the reports from the FDA's adverse event reporting database is that there's actually eight fatalities associated with cerebral hemorrhage. That, to us, and it's hard to tell at what dose and which disease, that's for Blueprint probably to address. But when we are talking about the juxtaposition of elevated or fluctuating transaminase values that in all cases are reversible versus a drug that is causing on an ongoing basis every year multiple fatalities associated with cerebral hemorrhage, that doesn't seem like a very hard case to figure out which drug might be more worrisome to patients for us. Right. Right. Okay, great. And then just one more question. So I know you've changed the formulation of the drug. There has been some discussion around that. Obviously, I think you're saying the 100 milligram QD is about equivalent to the 150 twice a day, if I'm not mistaken. But just remind us, is there any risk in translating some of the phase I data to the pivotal study, which is obviously run on the new formulation? Yeah, it's a good question. We see that there's no risk, and I think I can get you there. We changed the formulation really in order to continue developing the drug in the cancer indication, gastrointestinal stromal tumors, based on the dose there being 600-milligram dose, quite a bit higher on a daily basis, and that was really to handle pill burden. Before, with the original formulation, patients had to take a big handful of pills every day, and we've now reduced that quite a bit. What we did is, before we studied any of the registration-directed trials, any of the pivotal trials, switched all three development programs to the new formulation. We won't need any bridging studies from start to finish, first patient to last, and all the pivotals. They've all taken the V formulation, which is previously known as the optimized formulation. So we're very happy with the bioavailability of the new formulation, the consistency of PK both within a patient and across patients, the predictability of the PK, and in many ways, we've put that in the past. The original formulation won't ever be listed in the Orange Book, and I think if you think long into the future about a successful commercialization of bezuclastinib, this really could also offer some potential IP benefits from extending the protection from generics in the long into the future. Great. Thanks. And then maybe lastly, on the sort of pending data in July of SUMMIT, yeah, can you just talk about perhaps just how much information you may be able to share in the top line announcement just as investors prepare for that, and also just remind us if there have been any differences in enrollment criteria, perhaps relative to the PIONEER study? Yeah, two good questions. So when we think forward to July and what we would be able to share, certainly we would be intending to share the results of the primary endpoint of a pivotal study in some sort of press release, right? We would want to save some amount of information to preserve our right to present it at a scientific conference on behalf of the authors and the investigators and the patients in the study. But we would look to, I think, provide a wholesome characterization of how the study performed, obviously the primary endpoint, obviously safety and tolerability, but probably some of the other key secondary measures as well so that the investor community, as well as patients and their families, can get a sense for how well is the drug working. Your second question. Oh, just patient characteristics relative to PIONEER based on the enrollment criteria. SUMMIT Part 2 is designed in a very analogous way to PIONEER Part 2, which was the blueprint pivotal study that led to avapritinib's approval in this patient population. Probably the most noticeable difference in patient inclusion criteria is we allow for patients to have seen prior avapritinib, where obviously they didn't have the opportunity to allow for patients with prior bezuclastinib based on the time of that study. We think that that patient population, which we've characterized as a minority of patients, it's probably on the order of about 15% of the SUMMIT population that has seen prior avapritinib, can be very impactful. And when we fast forward a little bit further into the future, if the trial is successful to launch, one of the things that we're going to be conversing with investigators and patients about is if I'm on avapritinib and I don't have my symptoms well controlled, am I a good candidate to take bezuclastinib? And I think having a clinical result for a population of those patients will be very helpful in that dialogue about should I switch to a new, potentially better symptomatic control agent. Right. Did you have some of those patients in your phase I or will this be a new experience? We had two of those patients in the phase I. One was a placebo patient originally. So you haven't seen much data because you hadn't seen a lot of the data before they crossed. So I think that data is pretty thin. I think we'll have to wait until SUMMIT Part II to really see is there any difference in effect of a patient who had seen prior Ava or not. We think no, but we'll wait for the results of that trial to see that. Great, then maybe just a couple of questions on Advanced Systemic Mastocytosis. Obviously, a smaller market, but yeah, how do you think about the commercial opportunity there and perhaps the unmet need for bezuclastinib? Yeah, we think that interestingly, and a lot of this is due to how avapritinib was developed with using a clinically relevant dose in ASM and a 90% reduced dose in ISM, that the product profile of bezuclastinib, where the doses and the exposures are very similar between the two indications, is almost the opposite. So in the non-advanced setting that we just went through, I think we acknowledge that 25 milligrams of avapritinib seems to have a reasonably decent profile. We're a little concerned based on the paper I referenced about the commercial strategy of Blueprint to tell physicians to just dose up without knowing where in the dosing up you're going to run into these problems of cognitive issues and cerebral hemorrhage. But in the non-advanced setting, I think we're trying to have a similar safety profile, but a much, much deeper and faster effect on symptoms. In the ASM setting, to your question, it's almost the opposite, where if you can tolerate avapritinib at 200 milligrams, which almost nobody can, the drug is very potent against the target. There's no doubt about it, as is our drug at our 150 milligram RP2D dose from the ASM setting. What is different between the drugs is from a safety profile, we have very low rates of periorbital peripheral edema, unlike avapritinib, with nearly every patient experiencing that. We don't have any evidence of cognitive impairment, unlike the 40% rate they show at their clinically relevant dose. We don't have evidence of cerebral hemorrhage or bleeding. We don't have 30% rates of grade 3, 4 thrombocytopenia, neutropenia, anemia. So from a tolerability perspective, I think it's going to be night and day. That's our expectation when the APEX study reads out. We feel very strongly that these patients, this is a disease of mortality. They want to have their disease controlled. They want to hit the target hard, but they want to enjoy the experience of taking a drug that does that. I expect we'll be very well positioned there based on the safety profile of bezuclastinib. Yeah, and just the size of the opportunity relative to non-advanced. Yeah. Within the world of mastocytosis, the ASM population is about 10% of the opportunity. So if you sign up to Blueprint's numbers for a $4 billion total mastocytosis market, maybe $300-$400 million is the ASM population, with the bulk of it being the non-advanced. Yeah. And yeah, when is that data coming? Remind us. That is in the second half of 2025. Okay, great. And then maybe then the last few minutes just to discuss the GIST opportunity, again, where you're looking at a combination with Sutent, which is the approved standard of care in second-line GIST. And so I know you had another, I guess, encore presentation at ASCO GI recently. But yeah, just remind us again of the clinical profile here and then add some follow-ups. Right. So patients that are diagnosed with GIST are across the board given imatinib or Gleevec, which is a fantastic drug. It's highly active in the first-line setting. Unfortunately, almost all those patients eventually progress due to resistance mutations that imatinib doesn't cover in the ATP and activation loop, so exon 13, 14, and 17, 18. And so what you're looking for in a second-line and later gastrointestinal stromal tumor treatment is a KIT inhibitor that can cover all of those resistance mutations. And so far, nobody has developed a drug that can do that. Sutent is quite good at covering exon 13, 14. And then those early generation KIT inhibitors like ripretinib and avapritinib are very good at covering 17, 18s. I think folks know the history of running a head-to-head study of a 17, 18 versus a 13, 14 has led twice to failed trials, where both arms look to be relatively similar, which is not surprising since cancer is smart, and when you give a patient with GIST an inhibitor that covers half the resistance mutations, you can expect that they will develop resistance through the other pathway relatively rapidly. The difference about our clinical study is that we take bezuclastinib, which is a highly potent 17, 18, and based on its safety profile, because of its selectivity and its inability to hit the CNS, we can combine it with Sutent, a 13, 14, and cover all of the known resistance mutations. Based on the phase I data that was presented long ago and then the lead-in data from the phase III, what that seems to lead to is much longer duration of progression or delaying progression in these patients because of this pan-mutant coverage. And we think that that is going to turn out to be quite different than some of the earlier failures in the second, third-line GIST patient population setting. Right. And so Sutent is obviously not the best tolerated drug out there. Yeah, can you maybe talk about tolerability in combination and what you've seen there so far with Bezu? Yeah, we agree. Sutent is one of these older generation TKIs that hits many targets. The nice part about it is that globally, physicians who treat GIST patients have been using Sutent for 20 years. It is already a generic drug in all major markets. And so they are very adept at managing the tolerability of Sutent. They've had to do it again for 20 years. So they understand it. They have a familiarity with it. And they don't seem to shy away with it. It's still the standard of care in second line across the world. What's nice about bezuclastinib is we don't have any overlapping talks. So when you add that profile of maybe turning patients' hair white, which is an on-target of wild-type KIT, and potentially these asymptomatic, reversible in all cases, fluctuating lab abnormalities, it doesn't add diarrhea. It doesn't add nausea. It doesn't add hypertension. It doesn't add some of the things that are characteristic of Sutent, at least what we've demonstrated in the phase I, II, and so for a while, I think that the bear thesis was cool science idea to cover all the mutations, but when you put two dirty TKIs together, it's not going to be tolerable, which is probably the reason why avapritinib and ripretinib didn't run combo studies. What we've shown now in about 70 patients between a couple of different phase I's is that the combination of bezuclastinib and Sutent is well tolerated. You don't exacerbate the Sutent tolerability. And therefore, it probably will not lead to problems in the large pivotal study that's been enrolled long ago due to dropouts for adverse events, that I think the bear thesis was your trial's not going to work because of dropouts. That's not the experience we're having. And so then I think you revert back to does the science make sense if the patients can tolerate the combo? Yeah, and so we're going to get kicked out soon, but just last question. The study is fully enrolled. I think you said the data is coming by the end of the year. What effect size are you looking for in the PEAK study? Yeah, we're basing the design of the PEAK study on the control arm of the INTRIGUE study. That's the ripretinib failed phase III, where Sutent did 8.3 months of median progression-free survival. And we're looking for a minimum of about a three-month improvement over that for the combo arm in order to get to a statistical win. Okay, great. Well, thank you, Andrew, with that. I think we have to wrap up. Thanks, Michael. Appreciate it. Appreciate your time today.