This is Eun Yang, a biotech analyst with Jefferies, based in New York City. Our next presenting company is Cogent Biosciences. We are going to have a fireside chat with Andy. So presenting from Cogent is Andy Robbins, CEO of the company. So Andy, thanks for joining us today. Before we begin Q&A, can you give us a brief overview of what Cogent does? Sure. Thanks, Eun, and thanks for inviting us to the conference. I'll just remind folks that I'll likely be making forward-looking statements, so I'd direct you to our recent Q3 filings for a more full disclosure of risks to the company. With that said, again, we're happy to be here today at the Jefferies London Conference. My name is Andy Robbins. I'm the Chief Executive Officer of Cogent Biosciences. We are a publicly traded biotech company that's focused on the invention, development, and hopefully future commercialization of what we think to be best-in-class targeted therapies, focused for rare disease populations of patients with mutationally driven diseases. Certainly focused in the world of oncology, but also in other rare diseases like our lead indication in systemic mastocytosis. We're excited about our lead drug called bezuclastinib. As I just referenced, it's in active development across three different indications. Number one, for patients with the advanced form of systemic mastocytosis. Number two, for patients with the more indolent form of the disease, and then number three, for a relatively rare form of cancer called gastrointestinal stromal tumors, in the second-line setting for patients who are resistant to imatinib in combination with sunitinib. So we're excited to be here today to talk about our clinical development plans for bezuclastinib, as well as potentially for some of our pipeline plans for some of our other assets as well. Thank you, Andy. So bezuclastinib is in three different indications in clinical development, and two—for the two out of three indications, it is already in pivotal stage. So maybe we can start with advanced systemic mastocytosis that the product, the bezuclastinib Part 1. So you guided that the patient enrollment in that pivotal study is gonna be completed by end of next year. So when do you think we would be able to see the data? Yeah, it's a good question. You're referring to our trial called the Apex study for bezuclastinib in patients with the advanced form of systemic mastocytosis. We have disclosed data from the dose-finding portion of the study previously at originally EHA in the summer of 2022 and then ASH last year. We also announced recently that we'll be presenting what we sort of consider to be the completion of the dose-finding phase of the trial, Part 1 of Apex, upcoming here in a few weeks at ASH. At that point, we'll be able to show an update from all of the patients enrolled in Part 1, so it's more than 30 patients, I think 33, to be precise. All those patients will have pretty significant duration on therapy, at least six months for on the low side, and potentially even up to 18 months or longer for some of the earlier patients enrolled. As we've shown before, and I think we'll probably be consistent, our drug at the levels we're testing is highly active in these patients, has shown really dramatic drops in the PD markers that are associated with a response, including serum tryptase and mast cell aggregates in the bone marrow, leading to high rates of response in these patients at a very well-tolerated profile, which is important, given that the current standard of care is a drug that's quite active but has some significant safety and tolerability issues. We think that demonstrating we have a drug that hits the target, similar, with similar potency, but does spare some of that off-target toxicity that's associated with commercially available options, could be differentiating for us. So we're looking forward to sharing that data at ASH. With regards to the second part of the trial, as you mentioned, we announced back in the spring of 2023, we had already selected a dose and moved into the enrollment phase of the pivotal study. That trial, again, as you referenced, should be done enrolling by the end of 2024. So while we continue to provide data updates on the dose escalation phase of the study, we're rapidly enrolling that study, and it shouldn't be long after the completion of that enrollment where we'll be able to say, "How did the drug perform in its registration trial? Okay. So basically, ASH update, in the Part 1, dose escalation, phase, we are going to see continued efficacy and durability and safety of the product? That's right. At ASH, you'll see across the board, safety, tolerability, PK, PD, and efficacy as measured in response rate. Again, just as a reminder, in the advanced setting, we do acknowledge that the competitive, the main competitor, a drug called avapritinib, marketed by Blueprint Medicines, is quite active. It's just that given its off-target kinase activity, it comes along with some liabilities in the form of safety and tolerability issues, namely very high rates of edema, both periorbital and peripheral edema, high rates of hematologic toxicity across platelets, white blood cells, and red blood cells, significant cognitive issues, cognitive disorders associated with the treatment of the drug at those levels, and then finally, a low but important risk of intracranial hemorrhage. We feel that there's many ways that our drug has the potential to differentiate from a safety and tolerability perspective, and that's, I think, the important part of the profile in the ASM setting. Okay. So the fact that the competitor drug is on the market and for advanced ASM, can you comment on how your enrollment is going in Part 1? Yeah, the enrollment is, I think, going to plan. Again, we expect to enroll a trial of about 75 patients by the end of 2024. We don't seem to be having trouble to finding naive patients to other TKIs to enroll into the study, and I think that is a testament to some of the early data we've presented and the potential for this differentiation to deliver patients the target engagement they need for this specific driver mutation without the off-target liabilities of the other available therapies. Okay, and the second indication, I mean, it's not a order of importance, but for the discussion, because we started with the SM. Sure. So the second indication is indolent SM, that's milder than ASM and much larger market opportunity, and that study is a Summit trial, and it's in the dose escalation phase, and we are gonna be seeing data at ASH. So can you give us a kind of a, you know, brief overview of what we should be expecting at ASH? Right. So we're excited that in just a few weeks' time, it'll be the first opportunity for us to share any clinical data from patients with the indolent form of the disease receiving bezuclastinib. So the Summit study is designed, at this point, Summit Part 1, to explore the appropriate dose of bezuclastinib in indolent systemic mastocytosis patients. We're exploring four different doses across two different formulations. At ASH, just based on the time and the number of patients that we have the opportunity to unblind, given this is a randomized, blinded, placebo-controlled Part 1 study, we'll have data from the first 20 patients, and we'll be able to report on safety and tolerability, which is critically important in a disease state, in a patient population where you are looking to have a drug that supports chronic, year-long, multiple year-long therapy. So safety and tolerability, as well as pharmacokinetics, pharmacodynamics across those same markers that are relevant in this disease as well. The goal-directed therapies here in ISM, you also wanna reduce patients' tryptase back to normal, remove any, bad actor mast cells from the bone marrow aggregates, and remove circulating mutated, mast cells from the blood, so we'll present data on that. And then importantly, it'll be the first opportunity for us to share how bezuclastinib performs on what are called patient-reported outcomes, essentially asking patients that have a wide variety of different symptoms that are impacting their quality of life, "How did those symptoms that are affecting you as an individual patient improve or change over time on therapy?" So we're certainly looking forward to the opportunity to present that data upcoming here in a few weeks at an oral presentation at ASH. So, could you comment on what the tryptase levels in patient are? Look, I'm sure that it's, like, a high variability and wide range, but in indolent SM patients, so what are their kind of a baseline tryptase levels, and what's the normal that you would like to get to? So patients that are diagnosed with indolent systemic mastocytosis in sort of rare cases can have normal levels of tryptase, but the majority of patients have elevated tryptase, which is a marker of overactive or proliferating mast cells and degranulating mast cells in the body. And the biology suggests that those in cases of patients that are diagnosed with this disease, those are the cells that have a D816V mutation. So the idea is to attack or target those cells and remove them from the body, so you bring those pharmacodynamic markers of proliferation and activity back down to normal. The numbers that we're looking for in the advanced setting, reducing a patient's tryptase by 50% would be characteristic or criteria for achieving a partial response. I think folks are familiar with objective response rate. If you bring a patient's tryptase down under 20 ng/mL as an absolute value, that would be criteria in the advanced setting for a complete response. Other things have to happen, but just on tryptase. In the indolent setting, we feel very strongly that the goal, again, of interventional-directed disease-modifying therapy is to return patients' tryptase to normal. Normal tryptase or the upper limit of normal for patients without diagnosed mastocytosis is 11.4 ng/mL. So one thing that we're gonna be looking at is, what proportions of patients with ISM treated with bezuclastinib can be reduced by 50%, can be reduced under 20 ng/mL, and reduced under 11.4 ng/mL? It is a metric that we're particularly interested in as a marker of target engagement, exposure, and noticeable activity of a drug in a patient. I see. So, what do you expect the baseline range of tryptase levels in ISM patients? Without remembering exactly what numbers we've discussed, I think mean or median, tryptase levels for a population of ISM patients are probably in the neighborhood of 50-100 ng/mL. There are, of course, patients that have tryptase even higher than that, and as I referenced before, patients that enter with symptomology even at levels close to normal. But I would, you know, from memory, I think that that's probably- Okay ... the range of what the studies have shown. All right. So the data we are going to see at ASH, 20 patients' data, but that's the patients in the old formulation cohort. Is that the place of order for the study, or when we actually, when you actually present the data at ASH, are we going to see new formulation patient data as well? It's simply an order of time. So in order of time in the study, we were enrolling patients originally on the formulation, but then we created a novel higher bioavailability formulation, essentially for the gastrointestinal stromal tumor program, which we haven't talked about yet, given the doses we need to get to in order to achieve target exposure for that disease. But what we noticed is that the new optimized formulation behaved, again, with higher bioavailability, allowing for lower number of milligrams of finished product to be delivered and achieve the same target engagement. So we modified the Summit protocol to allow for patients to receive this optimized formulation, and it was at approximately that point where we decided to switch from old to optimized formulation. So the optimized formulation or the complete set of the dose finding, the 54 patients we've already enrolled in Part 1, we've guided that we'll have that data at a medical meeting in the first quarter of 2024. So it's not long in the future that we'll be able to see the complete set of our Part 1 patients. Okay, but ASH, we are going to see 20- That's correct ... patient data. So, new formulation, older formulation in GIST, we actually saw the translation. Do you think there is a difference in bioavailability of a new formulation and new formulation in different diseases, for instance, like a GIST versus systemic mastocytosis? It's possible, but really the difference between the two formulations is mostly the excipients. The active pharmaceutical ingredient is identical between the formulations, so it's really about what amount of drug is systemically delivered, depending on which pill you take. And so we like the fact that we have an optimized formulation where patients have to take fewer pills or less total milligrams of finished product to achieve the same amount of active ingredient being delivered systemically. So in ISM, the older formulation is 100 mg QD and 200 mg QD. So, can you talk about how that would translate into dosage in new formulation? Right. So we're studying doses, as you mentioned, of 100 and 200 mg once a day of old formulation, and then in the second part of Summit Part 1, we're studying 100 mg and 150 mg once a day of the new formulation. We believe that those four doses, sort of in order of exposure, goes 100 old, 100 new, 200 old, 150 new, and maps approximately IC50-IC90 target engagement for D816V. And so that is the window that we're looking to explore, is how does the exposure. It's not about the dose, it's about how does the exposure of bezuclastinib translate to things like safety and efficacy in PD markers across that window? I see. So when we see the whole set of data in the first quarter of next year, I'm assuming it's at a medical conference, probably EHA, could be wrong, but I'll just guess that. There would be no surprise in terms of new formulation versus older formulation data we are going to see at ASH this year. It's just like a different exposure PK profile. Is that correct? That's right. Okay. For us, we can map all of the new and old formulation patients on the same exposure chart. There should be no other differences other than what exposure patients are receiving. The most important thing for us is to pick the exposure to take forward into Summit Part 2, the registration part of the trial that we announced is gonna start in the first half of 2024, at the appropriate dose that delivers optimal efficacy and tolerability to support chronic dosing in these patients. Okay. And there are another piece of important aspects of a Summit trial is a patient-reported outcome tool, because that's gonna be the primary endpoint in Part 2 study. So can you talk about your PRO validation process? Right. So in order to, based on a decision that a competitor made, who created a PRO to measure the performance of their drug in the population, but chose to keep it as a proprietary tool, in order to move forward with the developing our drug, we had to go through a similar process of creating a novel patient-reported outcome tool. That part of the process, at the end, is going to be alignment with regulators, that it is an appropriate tool to use as the assessment of the primary endpoint of efficacy in the registration phase. So in the dose finding phase, Part 1 of Summit, what we're doing is we first interviewed a number of patients, interviewed a number of physicians, to collect data upon what are the relevant symptoms that patients face with this disease. Then we used that draft questionnaire in Part 1, administered it to patients along the way, along with many other, well-known, I think folks call these off-the-shelf quality-of-life scales, but those, those are not validated for regulatory approval. At the end of the trial, after we've collected the Part 1 data, we'll go through a process of validating the tool. How appropriate was our tool? How closely correlated was it to some of the other more well-known scales of quality of life? At that point, we'll be able to create a scoring system for it. We'll be able to have a conversation with regulatory agencies about the process that we've used and, and align on, a tool that we can use for Part 2, and subsequently, and eventually score the patients in Part 1 on our own novel tool. But until all of that takes place, we don't have the, the capability to score the tool. So what we're gonna do at ASH is present data from four other well-known quality-of-life scales in order to characterize the symptomology impact of bezuclastinib in this patient population. Great. So in advanced ASM, your the bezuclastinib advantage compared to competitor on the market is similar efficacy, but much better tolerability. Now, in ISM, what you are aiming for is, you know, because the competitor is using a lower dose, the safety is quite good. So what you are aiming for is with the safety, you can push the dosage higher, so you can have a better efficacy than the competitor. So do you think we would be able to see that, okay, bezuclastinib is differentiated, in ISM compared to, avapritinib currently on the market at ASH? ... I think you, you pegged it exactly right. The target product profile that we're aiming for in ISM, because Blueprint's avapritinib had to reduce their dose by 90% in order to achieve a safety profile that was acceptable in this patient population, that's driven primarily by morbidity and not mortality. We believe that if you can preserve target engagement, at or near the doses that you would want, to effectively treat patients with the advanced form of the disease, that the outcome should be better for these patients. We would like to present data at ASH that starts that conversation about whether there's the potential for a drug like bezuclastinib, where we believe the target engagement will be quite a bit higher than commercially approved avapritinib 25 mg to translate into better outcomes for patients. We're certainly excited and looking forward to the opportunity to share that data in a few weeks. Okay, thank you. And then third indication, which is in phase III, it's in a GIST cancer setting. And again, here, you are guided the patient enrollment is gonna be completed end of next year, but this still is event-driven study because of progression-free survival. So, can you talk about the study design, and then based on the PFS of a competitor drug in the background therapy, when might we expect to see the data? Yeah. So I think you got the timelines right. We are in the midst of running a global phase III trial, the design of which is sunitinib as the current standard of care in the second line versus sunitinib plus our drug, bezuclastinib, as a combination active arm. It'll be measured as a primary endpoint against median progression-free survival, and it'll enroll approximately 400 patients, probably just underneath that number. We think we'll complete enrollment. We're about halfway through the enrollment phase, and we're on track to complete enrollment by the end of 2024. And as you said, in a progression-free survival trial, you're at the mercy of when the events accrue. We're currently projecting that to be by the end of 2025, so that would put us in a timeline for when we would have the top-line results from that trial. The nice part about our study is, as a lead-in to the phase III, we enrolled just over 40 patients in two different cohorts, and we have the opportunity to continue reading out data, safety, tolerability, and efficacy data from that. Recently, at the CTOS conference a couple weeks back, we showed that in the population of patients who are truly second-line GIST patients, they've only seen imatinib, the ongoing duration, median duration of therapy for the combination of bezuclastinib and sunitinib is now at 14 months and counting. If you look at a very recent phase III trial in second-line GIST, the expectation for the control arm of sunitinib alone is about eight months. So if we could replicate the activity we're seeing in this lead-in portion of the phase III trial, we would be well-positioned to win a progression-free survival endpoint compared to sunitinib alone. Okay, thank you. And then we have just a couple of minutes left. So, can you talk about the pipeline that you are building behind the bezuclastinib, and then whether it's gonna be more focused on oncology or maybe it could also include the inflammatory disease or allergy indications? Yeah, we're very excited by the research team we've assembled. I personally think they're best in the world at creating small molecule tyrosine kinase inhibitors. We have, for 18 months now, said our lead agent is a selective FGFR2. We recently presented data on our lead clinical candidate at the Triple Meeting, the ENA meeting, back in October. That product is designed as a reversible inhibitor that covers all the relevant molecular break and gatekeeper resistance mutations that available and in development FGFR2 inhibitors are unable to cover. So we're really excited about what that product has the potential to do for patients with FGFR2 fusions and mutations. After that, we have announced that we are gonna present data at an upcoming meeting, on both ERBB2 selective, that is, designed to be highly CNS penetrant for cancer patients, as well as for the first time, on an alpha selective PI3K inhibitor. So that is our growing portfolio of, targeted therapies in the oncology space. To your question about therapeutic area, I think going forward, we'll be biased towards creating products for oncology patients, but not exclusively. We also are looking at opportunities to develop novel drugs for other rare diseases that are driven by mutations. Okay, so our time-