Okay, I think we're going to go ahead and get started with our next session. My name is Chris Raymond. I'm one of the Biotech Analysts at Piper Sandler. It's my pleasure to introduce the next presentation, which is Cogent Biosciences. Joining us today, we have Cogent's President and CEO, Andy Robbins. And in the audience, we have CFO John Green. So just to go over the format, we have a couple minutes of introduction from Andy, just to set up on the company and the premise behind it, and then we'll launch into a sort of an informal Q&A. When I say informal, I mean this is audience participation, so if anybody has any questions, just raise your hand. I'll make sure it gets asked. If you don't want to do that, just email me and I'll be monitoring that as we go along. But we've got about 25 minutes or so, and maybe Andy kick it off, and then I'll jump in with my questions. Awesome. Thanks, Chris, and thanks for inviting us to participate at the conference this year. So, as you said, my name is Andy Robbins. I'm the CEO of Cogent Biosciences. Just to remind folks, I probably will be making some forward-looking statements today. So, for a better and fuller characterization of risk, I just point you to our recent quarterly filing, which happened a couple of weeks ago. So for those that are not as familiar with the story, Cogent is a biotech company focused on the discovery, development, and hopefully potentially commercialization of targeted therapies for rare patient populations that diseases are caused by genetic mutations. Our lead compound is in late-stage clinical development across three different indications for two different types of systemic mastocytosis. The more advanced form of the disease, we're running a trial called the APEX study. For the more indolent form of the disease, we're running a study called the SUMMIT study. Each of those will have clinical data updates at the annual ASH meeting coming up here in a few weeks. I expect we'll spend a pretty significant portion of our time today discussing those. In addition, the third indication we're running is in gastrointestinal stromal tumors, which is a metastatic cancer population, specifically in the second line, or imatinib resistant refractory population. That trial is a global phase III study of bezuclastinib, our drug, in combination with sunitinib, which is the current standard of care, versus sunitinib as a monotherapy with a progression-free survival endpoint. We reaffirmed guidance, just a few weeks ago, that we're on track to complete enrollment in that nearly 400-patient phase III trial by the end of 2024. So we're literally right around the corner, about a year from now. In addition to bezuclastinib, which obviously is a cornerstone of the company, we're also very excited with the research team we've assembled, some of the best minds in medicinal chemistry in the world, and they're working on a very robust pipeline of new targets. We've talked, I think, extensively about our lead program there and a selective and potent FGFR2 inhibitor. In a few weeks' time, if you read the titles of the abstracts, we'll be detailing two additional programs at the San Antonio Breast Cancer Symposium. First, an update on our selective and potent ERBB2 inhibitor, and then introducing for the first time our selective and potent alpha PI3K inhibitor. So, with a final note, and I'll hand it back over to Chris, we're well-financed with about $312 million on the balance sheet as of the last update, which will support our current development plans into 2026. So maybe with that, I'll pause and turn it over to Chris for some questions. Awesome. Great. Thank you for that, for that setup, Andy. So maybe I want to get into the stuff that you're going to have at ASH. You're going to have, as you mentioned, a lot of data. But maybe just sort of setting the table, you know, you gave a really good overview, but I guess what I want to maybe articulate to folks, you know, you're developing bezuclastinib for GIST and SM, as you mentioned, and in SM, subindications of advanced and in the indolent form and not advanced. There's another player out there, Blueprint, which is a couple of years, you know, ahead with labeling of Ayvakit in both SM settings. Just maybe from a high-level standpoint, you know, we've seen a little bit of data in advanced SM for bezu about a year ago at this time, a year ago. But we're going to get more, obviously, at ASH. Talk about the target product profile in the SM, especially the non-advanced SM setting. And what about what you've seen from the molecule from previous studies and some of your preclinical work that gives you confidence that you'll hit that target? Yeah, it's really interesting. Normally, companies, I think, have a fairly consistent product profile across relatively similar patient populations. In this case, our target product profile is quite different between the advanced setting and the indolent setting, and that's really set up by the development approach that the company Blueprint Medicines has taken historically in these diseases. So, both Blueprint Medicines' avapritinib and bezuclastinib are highly potent against the driver mutation that causes these diseases. It's a mutation in the KIT gene at D816V. The difference in the drugs is, number one, the selectivity. Bezuclastinib is highly selective without potency against other common class III RTKs, whereas Blueprint's drug is equipotent against a kinase called PDGFR and has significant activity against other class III RTKs like FLT3 and CSF1R, which leads to potential off-target toxicity. Another important difference is that avapritinib's drug is among the most brain-penetrant small molecules ever studied in any disease for any target, with a preferential delivery to the brain over systemic delivery of about 200% brain-to-plasma ratio. Whereas Cogent's molecule, bezuclastinib, is not CNS penetrant and does not implicate some of the off-target effects of getting into the CNS for a patient population that doesn't need that. So our target product profile is a long-winded answer. In the advanced setting, is to match the clinical activity and potency that the, that avapritinib has shown in the past at a 200 milligram dose, but without many of the concerning safety and tolerability challenges that that drug is associated with. Conversely, in the indolent systemic mastocytosis patient population, because in order to avoid those safety and toxicity and intolerability challenges, Blueprint moved forward in the development program with a 90% reduced dose intensity. Our target product profile is to preserve that dose intensity and target engagement for the ISM patients and match the tolerability profile of low-dose avapritinib, but with noticeably better efficacy outcomes. So that's, that's the approach that we're using strategically. To Chris's comments, about a year ago at ASH, I think we demonstrated similar levels of efficacy in the ASM population with bezuclastinib, with encouraging safety and tolerability. We look forward to presenting some additional duration on that study in a few weeks' time, and then for the first time, coming with our first clinical look at the ISM trial, the SUMMIT trial, to try to talk about can better target engagement in this patient population lead to better clinical outcomes, which we feel strongly it can. So a couple weeks ago, speaking of the ISM data or opportunity and the data that you're going to present with SUMMIT at ASH, we about killed ourselves trying to do a preview of this data. We published a note a couple weeks ago, trying to sort of ascertain, like, what does success look like? And, you know, comping to the Ayvakit experience at a similar stage of development is incredibly difficult. I think that's one of the issues I think investors are sort of struggling with, is what does success look like? Andy, I know we've kind of gone to the well with you, trying to understand your perspective on this a few times. Maybe for investors... You know, it's difficult because you've got, you know, Blueprint has their own proprietary scoring system. There are a number of shared subdomains from the scoring system that you're using. But, you know, just to kind of give us a sense and a setup, as to, you know, for somebody sort of de novo getting at this, to try to comp it, to what we saw with PIONEER, the Ayvakit study, how would you go about doing that other than reading my notes? Which is a great start. You know, from our perspective, we understand the desire of the investment community and frankly, many people with their eyeballs on this, to crystallize this down to one number, to say, "All you should do on the day of ASH is open our presentation and look at one number, and if it's above X, then it's great, and if it's below X, then it's not." We don't take that perspective. We think the totality of the data is going to be important when we present at ASH. And when I say that, I mean in a patient population like indolent systemic mastocytosis, you absolutely need to have a safety and tolerability profile that would be conducive to long-term chronic dosing. These are people that have a normal life expectancy, but have a significantly impaired quality of life, and they're looking for something that can help them, not just for a few months, but for years and years and years. So that's probably number one. Number two, if you look at our precedent molecule from Blueprint, one of the things they showed is that at high doses of avapritinib, they can reduce a well-known pharmacodynamic marker of disease burden called serum tryptase. It's a circulating protein, by 50% in above 90% of patients. But when you reduce their dose down to that low dose, 25 milligram dose, only half of patients have that same impact on that PD marker. So what we would like to show is, even for ISM patients, reducing that level of serum tryptase, which again, is a marker of overactive mast cell activity and degranulation, is an important PD marker in this disease. And then finally, linking that to a target product profile that demonstrates to patients that the baseline symptoms that they're experiencing in a moderate to severe ISM patient population, are debilitating to these people, can be improved, and they can lead them to living a relatively normal lifestyle. And that is unfortunately, a complicated story, where there are many different measures of how to look at a symptomatic improvement over time. What we've guided to is that we will present data from four different scales at ASH, from first, the mastocytosis activation scale, second MCQOL, third PGIS, and fourth PGIC. We think that looking at the totality of this patient-reported outcomes data, relative to some of the data that Blueprint has shown from their PIONEER, understanding important key differences, like the duration of our trial is unblinded at 12 weeks, whereas PIONEER's Part Two trial was not unblinded until 24 weeks, so only half of the duration of therapy to reach the similar effect size. As long as we're reminded to look at some of these important characteristics and differentiations between the studies, I think there is an opportunity to see how bezuclastinib is performing from a resolution of symptoms that are problematic for these patients. Yeah, you mentioned serum tryptase as a measure. Recently there's been some debate about the relevance of serum tryptase, and some would argue the source of that debate is perhaps your competitor. But you've spent a lot of time talking to KOLs on the topic. What's your sense of how that dialogue is evolving from a clinician standpoint in terms of the relevance of that parameter? It's a good question. When we talk to investigators and physicians who are knowledgeable about treating patients, I think they across the board do agree with us that a goal-directed therapy in indolent systemic mastocytosis is to return patients' serum tryptase to normal. And that's one thing that's very challenging to ascertain from our competitor's data, is how many of those patients in the PIONEER study actually achieve normalization of tryptase. They haven't reported it in that fashion. So something that's important to us is to look and measure the fraction of patients, and in those patients that achieve normalization of serum tryptase, what is their experience as measured on PROs? We know in the world of key opinion leaders who are using avapritinib commercially, that they are willing to increase the dose-... Even with the potential safety risks that come with elevated doses of avapritinib, when their patients at the low dose avapritinib are not normalizing on tryptase. So I think in the minds of the investigators, it is a critical PD marker. I think in their minds, it is expected to correlate to symptomatic improvement. But, you know, really honestly, we're just excited to have a chance to share our own data so we can talk about the facts of bezuclastinib as opposed to the speculation about what does the avapritinib experience mean? Excellent. Okay. And so, you know, we talk about the Blueprint proprietary scoring tool, and you're in the process of developing your own. Maybe sort of give us a sense of where that effort stands. And also maybe for the benefit of folks who don't really understand SM, the mastocytosis sort of SM world, why you have to develop your own scoring tool in the first place? Yeah, the answer to your last question is very easy. Blueprint has decided to keep their patient-reported outcome tool that was used to assess their primary endpoint as a proprietary tool without letting others in the industry utilize it. So we had essentially no choice but to create our own version of that tool. The creation of a PRO is a complicated endeavor, but I'll try my best to crystallize this down into 30 or 40 seconds. Essentially, what you do is you interview a number of patients, a number of physicians, to try to collect the best data you can around the symptoms that are specifically important to that patient population. You create a questionnaire that measures baseline symptomology and utilizes questions to try to track how those symptoms emerge over time. Then what you do is you administer it to a number of patients. In our case, we're administering it to all of the patients in SUMMIT Part One, which we announced completed with 54 patients enrolled in the third quarter of 2023. At the end of it, at the same time, you're concurrently administering other well-known quality of life scales, like I referenced before, MCQOL, PGIS, PGIC. At the end of that process, when you unblind the data, you go through a validation step to look at, are the questions that you selected in your draft questionnaire appropriate? Are they consistent? Do they seem relevant to the patient population? And you often, in almost all cases, make changes. Once you make changes, then you can essentially finalize your questionnaire, your tool, and only then can you apply a scoring methodology to your tool. At that point, you collect all of the steps in your process, and you approach regulators to try to align on the effectiveness and utility of using that questionnaire as the assessment of the primary endpoint for your registration trial. And so what we've said is, during the period between SUMMIT Part One, which is not yet complete, and SUMMIT Part Two, we would expect several months of pause in those studies to complete this validation process and alignment with regulators so that we can embark upon SUMMIT Part Two, which we recently announced will commence in the first half of 2024 with a novel PRO that is designed to measure the primary assessment of efficacy for that trial. What we also have committed to is as soon as we have that scoring system put together for our novel PRO, we can retrospectively score the patients in Part One and report that measure at that appropriate time. Excellent. Okay, so let's maybe pivot to, to the APEX study, the advanced SM data. So you're going to get—you're having longer-term data from APEX, as you mentioned, you know, about a year ago, we got the first glimpse in that setting. I'm biased, obviously, but superior, I thought, you know, ORR versus Ayvakit, again, at that stage development. Give us a sense of what we're going to see now. I know it's longer-term follow-up, with these patients, but just a little bit more flavor for, for how that, that sort of rounds out the, the profile of the product. Yeah. So, as Chris mentioned, we're going to be sharing an update at ASH, also from the Advanced Systemic Mastocytosis study of APEX. If you remember, for those that have followed the company, back in April, we announced that we had selected a dose to take forward into APEX Part Two, which is designed, if successful, to be registration-enabling. At that point, we said we'll come back in the future at a medical meeting and show you the data that we used to pick that dose and go forward. This is that opportunity to share those data. So the ASH data from APEX will include 33 patients that were enrolled in the dose-finding portion of the APEX study. It'll be across a number of the same endpoints that we presented at ASH last year, but with a larger number of patients and longer duration. So even the shortest duration patient we're going to share at ASH is approximately 6 months. Some of the longest duration patients are out more than 18 months. And what we've characterized this data review to be is, I think, a robust and relatively comprehensive look at the safety profile and efficacy or activity as measured in both PD and two different systems for measuring objective response rate in this patient population, as a potential preview to what a registration trial will look like. We're excited to have the opportunity to come back and update the APEX data set again with a target product profile of similar efficacy to avapritinib 200 mg PATHFINDER with a noticeably better safety profile. As if you didn't have enough going on, you're also in the midst of a reformulation program, right? I think you guys have noted that the new optimized bezuclastinib formulation at 150 mg QD provides coverage that you'd expect to be effective in both settings, advanced and non-advanced. I think this dose is being used in both the phase I dose optimization in SUMMIT and then also in the part 2 of APEX, if I'm correct, right? Correct. So maybe just talk about what led to this effort in the first place, and just sort of the benefit of switching to the optimized formula. Yeah, it's a good question. This whole idea of reformulating bezuclastinib was actually born out of the original development program in gastrointestinal stromal tumors, which we haven't really spoke about yet. But that's the program that is in an ongoing global phase III trial for second-line GIST patients in a metastatic cancer indication. In that original Phase I/II program, a predecessor company had done a dose escalation trial using 50 milligram tablets and reached a dose of 1,000 milligrams without seeing dose-limiting toxicities. If you do the math, that would be 20 pills per day, which even in metastatic cancer indication, is a real burden for patient compliance and convenience. So we embarked upon a program to try to reduce that pill burden for the GIST program, and what we found is, in a process of working with several outside CDMOs, we found one who created a novel formulation using the same active pharmaceutical ingredient with a really improved bioavailability, which allowed us to dose at a similar PK at 600 milligrams of the new formulation to 1,000 milligrams of the old formulation, and that data was all presented in a lead-in study to the PEAK trial last summer. What that means is, we can have fewer pills for the metastatic GIST patients. That's great, but it also allows us to harmonize and use a single formulation across all of our clinical trials. If we do that, it probably has significantly positive consequences to our generic patent protection for down the line. Because the formulation patents around the new formulation, we think, are very solid, and it's hard to imagine using other non-proprietary techniques like this to generate bioequivalence to our optimized formulation. So we expect that from SUMMIT-Part I, the two cohorts that are using the original and the optimized formulation, we can use all of those patients from an exposure level to help us select the appropriate dose. We don't expect there to be anything other than exposure differences between those formulations. Excellent. Okay, so let's maybe pivot to, to GIST, since, you mentioned we haven't talked about it, so let's talk about it. Okay, great. So, you earlier this year presented the initial data, Part I of the PEAK study. You know, the premise and the setup is second line. This is a KIT inhibitor that has a safety profile that enables combination with sunitinib, obviously in the second-line setting, that the implications are pretty straightforward if you know the space. Give us a setup on this phase III. Again, the target product profile would seem to be a lot more straightforward than developing a drug in SM, and the timing and what we should expect. Right. So our phase III trial, as you mentioned, is a program that hasn't been run before. It's adding a novel tyrosine kinase inhibitor that has specific activity against some of the resistance mutations to imatinib in second-line GIST to the standard of care. So previous efforts have looked at an individual agent head-to-head against the standard of care. Those have ended in trials that didn't work. We think that our trial will come out with a different outcome because we're actually adding on to the existing standard of care. So the active arm has the benefit of both the control arm, as well as the benefit of adding bezuclastinib on top. The target product profile is essentially to allow patients to live a longer lifespan. So the primary endpoint of the study is median progression-free survival, compared with the doublet of bezuclastinib and Sutent- to- Sutent alone. And, you know, based on some of the data, as you referenced in the lead-in study, where we enrolled about 40 patients, a little more than 40 patients, to look at a couple of things like the PK of the different, optimized formulation to the original formulation. What we're generating is clinical efficacy data that hasn't been seen before in this patient population, with response rates exceeding 30%, depending on if you want to put a couple of different trials together. We've seen 4/10 patients in the second line achieve at least a PR, which is very encouraging in a patient population where you'd expect response rates of less than 10%. What we're seeing from not only just the responders, but from the patients staying on study long, is a duration of treatment now out past 14 months, where you'd expect median progression-free survival of Sutent alone in this population to be approximately eight months. So we're very encouraged by this early, admittedly early, data set, but we think that it provides a very good read-through to the combination of bezuclastinib with Sutent. And again, as you referenced, without bezuclastinib adding really any notable safety or tolerability challenges to Sutent alone. Awesome. So again, assuming success here, it would seem to be obvious the benefit. You can drive better responses and durability in combination with sunitinib in a broader, you know, second-line population. That's self-evident. There's a competitor in the space, another KIT inhibitor, ripretinib, with a label in fourth line, but currently running a study in second line with specific mutations. Just talk a little bit about, you know, sort of your view of how to... You would coexist with that potential competitor. You know, again, it's a subset, but it's also a second-line label, potentially. Yeah. We definitely acknowledge that in Deciphera's failed INTRIGUE study, there was a really interesting subset of patients that who had a genotype of primary exon eleven mutation with a secondary resistance mutation in exon seventeen or eighteen. That represented, in their patient population, about 15% of the patients they enrolled, which we think is probably a good estimate for the second-line population of that genotype. So in a worst-case scenario, if they have an amazing result from their trial and we win the PEAK study, 85% of second-line patients would be eligible to receive the combination. So that's kind of the downside. The upside is that patients with this genotype, which we're also enrolling onto our trial, and we are definitely going to look at that subset at the end of the PEAK study, could perform as good or potentially even better than ripretinib monotherapy, and that we could either compete or take all of that 15% as well. So for us, we, I think, acknowledge that a second-line patient could definitely benefit from ripretinib, but we're not ready to say that they can't also benefit from the combination of bezuclastinib and Sutent. So we'll see how it plays out in a couple of years. Awesome. Okay. Well, with that, we're just about out of time. So Andy, thanks for the great presentation. Awesome. Thanks, Chris. Appreciate it.