Cogent Biosciences, Inc. (COGT) Earnings Call Transcript

Good morning. Thank you for coming to the 2025 Citi Biopharma Conference in Boston. I guess let's get started here. Next up, we have Cogent. Cogent has had some news recently. If you could just kind of introduce yourselves, perhaps talk about the company, the mission and your overall path to this point.

Yes. Great. So David, thanks so much for inviting us to your conference. My name is Andy Robbins. I'm the CEO of Cogent Biosciences. Cogent is a company that's focused on the discovery, development and hopefully very soon commercialization of targeted therapies for patients with rare genetically driven diseases. Our lead asset is a drug called bezuclastinib, which we believe is the best-in-class selective potent KIT inhibitor for patients whose diseases are driven by mutations in the KIT gene. Those groups are typically divided into patients with mastocytosis. That disease is further divided into several subgroups grouped mainly into the advanced form of the disease and the non-advanced form of the disease as well as a completely different disease driven by KIT mutations known as gastrointestinal stromal tumors, which is a malignancy or rare sarcoma. We've, several years ago, kicked off pivotal studies across all 3 of those patient populations. As you mentioned very recently in just this summer in July, we read out the first of those 3 pivotal trials known as the SUMMIT study in the non-advanced systemic mastocytosis population with what we believe are very positive data, speaking to the potency, the favorable safety profile of our drug, and we believe will lead us to our first FDA submission and ultimately approval in 2026. In addition, the other 2 pivotal trials known as the PEAK study in gastrointestinal stromal tumor patients and the APEX study in the advanced form of mastocytosis are slated to read out later this year. So certainly a very busy 2025, looking at those products. In addition to bezuclastinib, which I believe we will spend most of the time talking about today, Cogent is also building a portfolio of early-stage early clinical and predominantly nonclinical at this point, best-in-class programs for other targets, including FGFR, ErbB2 and PI3K as well as KRAS or pan KRAS. And while we won't talk about those programs today, we're certainly very excited about the future of the company, building what we believe to be a broad portfolio of many, many best-in-class therapies for these patients with high unmet medical need.

I guess to start, could we just talk about the mechanism itself of targeting mutant KIT has a long history, a lot of trials through multiple indications. And what about the mechanism itself is attractive for each of these diseases? What have been the challenges that the various competitors have had? And use that to kind of move into bezuclastinib and how that molecule is designed and how it might be different to actually achieve something that some of these other molecules have not been able to achieve.

Yes. I think as with many other targets and many other genetic mutations, one of the keys to finding a best-in-class drug for these patients is really focused on potency, how well your drug can engage the target and the cells that have the mutation as well as selectivity, how well your drug does at avoiding off-target effects with these patients that have very specific genetically driven diseases. I think we can all get behind the science of trying to find a program, a molecule, a drug that can hit that target and not do a lot of other things. There's other sort of drug properties that think prospectively around either designing in or out depending on the specific disease. And in the case of mastocytosis, this is all of the immune system where mast cells have a specific mutation in the KIT gene known as D816V. Mast cells typically don't aggregate in the CNS tissue. And so when you're designing a therapeutic, you want to design out the penetration into the CNS tissue. And so some of the elements of differentiation for bezuclastinib in mastocytosis are not being CNS penetrant unlike a very well-known predecessor compound that's already approved known as avapritinib, which is significantly CNS penetrant as a liability of that compound and then also being very selective. So if you look at the track record of KIT inhibitors past and present, almost every other KIT inhibitor that has been characterized clinically is essentially a pan- Class III receptor tyrosine kinase inhibitor. So in addition to hitting the KIT gene, they also all hit PDGFR as well as many other kinases such as CSF1R, FLT3, VEGF, KDR. And in diseases like mastocytosis and then GIST, bringing along inhibition of those other kinases simply brings along off-target side effects. It doesn't bring any benefit to those patients. So having a drug like bezuclastinib, which is very specific and selective for only KIT and spares all of those other Class III receptor tyrosine kinases is exactly the type of profile you want in these patient populations.

Got it. So let's start diving into systemic mastocytosis. I know that it's really broken down into multiple segments. I know the Street tends to look at it as to advanced and nonadvanced or ISM indolent. Could you tell us about the disease as a whole, the spectrum, frankly, in more detail than we usually get into the Street of what is the mild side of the disease and what is the severe side of the disease? What are the differences?

Right. So I think you got it right. Typically, folks think about mastocytosis in 2 large buckets. And then within those buckets, there's definitely subgroupings of patients depending on severity of disease and prognosis. But in the advanced form of the disease, that really is a disease of mortality. So again, both of the -- all patients in mastocytosis are fundamentally driven by the same point mutation in D816V. But in the advanced patients that arises sort of a more serious mortality disease where in addition to mast cells having mutations circulating in the body, they tend to aggregate in large numbers in places like the bone marrow, in the spleen and the liver and cause significant challenges for patients ultimately left untreated, shortening significantly. In the nonadvanced form of the disease, the mutant mast cells continue to proliferate probably don't aggregate nearly as much in places like the bone marrow, the spleen and the liver, but cause significant symptomology. So the non-advanced form of the disease, you can think about it as a disease of morbidity, where the patients that have this disease tend to live a normal lifespan, but their life is compromised significantly on a spectrum of symptomatic severity with a host of different symptoms, probably most commonly symptoms of skin in the GI tract, but also leading to issues with pain, with fatigue, with CNS issues like anxiety and somnolence, depression, cognitive symptoms, et cetera, et cetera, et cetera. So while the sort of manifestation of the diseases is quite different, advanced form of the disease mortality, nonadvanced all these patients are driven by the same mutation. And so when you look across mastocytosis, there's a very good scientific basis for having a potent selective KIT inhibitor that can turn off cells that express this mutation in the body.

When we drill into the non-advanced side of themselves, there's a whole host of symptoms you start talking about relative to the disease. which are the most problematic -- clearly, skin is the most prevalent, which are the most problematic, which are the symptoms patients to go see doctors and actually begin them within the kind of diagnostic process to be identified as systemic mastocytosis?

Yes, it's an excellent question. And over the past few years, we've gotten to know many of -- many patients with the non-advanced form of the disease and of course, interacted with many investigators. And one of the biggest issues and challenges right now is that there are thousands of patients with this disease, but only a handful or a fraction of patients have affirmative diagnosis of the disease. It is a challenging disease to diagnose. And many of these symptoms when a patient presents to a primary care physician or a community gastroenterologist or immunologist or allergist are not well known among tens of thousands of physicians. And really, it's a patient struggle over probably years and multiple physician referrals before they finally find themselves in a physician's office like a hematologist or what we call a sophisticated allergist who really understands how to see those signs and how to affirmatively diagnose a patient with this disease. When you look at the patient populations that we've enrolled, and I think it's consistent across some of the other clinical trials that have looked at non-advanced mastocytosis, probably the most severe symptoms tend to aggregate either in the skin. So things like skin redness, itching, wheels, rash, it's about 30% to 40% of patients suggest that those are the most significant or bothersome most severe symptoms. And another 30%, 40% probably in fatigue. So just debilitating tiredness as a result of their disease, inability to sort of interact with society, hold a job, interact with people outside of their world. And then there's a whole host of others that make up the last 20% to 30% of most severe symptoms at baseline, including some of those CNS symptoms, some of the pain associated with this disease. And really, that's the symptom side of the disease. There's also -- I think it's important to point out for these patients, this constant fear and the potential of a severe anaphylactic reaction as a result of overactive and proliferating mast cells, which can be brought on by a host of different environmental triggers. And so you can sort of see how this constellation of symptoms, along with that sort of underlying fear on a constant basis of severe anaphylactic reaction leads to significant morbidity for these patients. And they are really looking for options to address how do I keep all of these things under control and not just stick Band-Aids onto the symptoms, but really searching for a therapeutic option that can get to the heart or the root of what their disease is caused by that can lead them more towards really broad resolution of the symptoms. And I think for the first time after we presented data this summer, there's starting to be talk of what does true disease remission look like from an agent like bezuclastinib that can potentially bring hope to this patient population.

So if we look historically before avapritinib came out of the market, these patients basically had to run through the antihistamines, some got up to Xolair, which would have been off-label. And of course, avapritinib came along. To this point now, how do you think the market has changed with Ayvakit there versus these other medications, which are almost certainly because they're cheap, probably still easily used. And what is avapritinib done to change it?

Yes. So we acknowledge that avapritinib represented a very important step forward for the first time patients had an approved KIT inhibitor, albeit at a dose that's significantly below the target exposure that you would look to in a mutant-driven disease for resolution of symptoms and clearance of the objective measures of disease. But as a step forward, what avapritinib can offer at the 25 or even a 50-milligram off-label dose is some symptomatic improvement in an oral pill, right? And so that's a great option for patients to take, but we know that patients very rarely on lower dose avapritinib can achieve full resolution of their symptoms. So they can get some improvement, which we, again, acknowledge is an important step for this patient population, but it leaves these patients still searching for something that can bring them all the way to resolution of their symptoms. The challenge with avapritinib, as I think folks know, is as you increase its exposure, you bring in some of the liabilities of that molecule, namely that it hits many other kinases in addition to KIT as well as its potency in crossing the blood-brain barrier. So patients have a trade-off with that molecule of as they want to dose up to get the benefits of removing mutant mast cells, D816V KIT mutant mast cells, you have to take the trade-off of nearly ubiquitous periorbital and peripheral edema, frequent cognitive symptoms and then the risk of things like intracranial hemorrhage due to the off-target effects of avapritinib.

So SUMMIT Part 2, you announced top line data earlier this year. Could you talk about what you saw in that data versus what we know about avapritinib? And how much closer are we to full symptomatic resolution?

Yes. I mean we're very excited to demonstrate a clear statistical win in the SUMMIT Part 2 data, bezuclastinib compared to placebo. We acknowledge that for basically a blueprint-driven reason of wanting to trademark their patient-reported outcome scale, we at Cogent created a new patient-reported outcome scale in concert with the FDA and working with investigators. When you look across trials and what we do to make it easy for folks is we score our data using the speed improvement is noticeably higher, deeper, better, faster with bezuclastinib compared to what you're used to seeing in the PIONEER study at low-dose avapritinib. And that is really backed up in the data by what we showed with the objective measure of disease response, namely circulating serum tryptase, which is a protein marker of mast cell activity, where we showed close to 90% of patients getting what was considered a response, a greater than 50% reduction in serum tryptase at 24 weeks compared to low-dose avapritinib, which is closer to about half of patients getting to that measure. So backing up sort of the potency, the exposure, the target engagement of a stronger KIT inhibitor and then translating that into faster, deeper, more pronounced symptom resolution, sort of all those things are tracking in the same direction to make sense for what we believe will become the standard of care in the non-advanced mastocytosis patient population.

Got it. So if you look back at the PIONEER data, they eventually got to start releasing the more details of the data, getting into the actual specific symptoms within the TSS itself, the total symptom score. What were the areas of strength that you saw? I mean, it was hard because you start spreading it out into symptoms, the powering goes way down naturally because of patient numbers. What did you see in there? And where could we see differences once you ultimately get to the more detailed updates?

Yes. So we're speaking at the PIONEER data, and this has been presented and published across many conferences in journal papers. If you look at individual items, which are things like fatigue or redness in the skin or any of the individual symptoms themselves or you looked at the aggregated sort of sets, which are domains on no individual symptom aggregate of all the symptoms together did avapritinib sort of squeak out a win statistically over placebo. To be fair to avapritinib and just based on lots of conversations with investigators, with patients, low-dose avapritinib does seem to have some benefit in the skin symptomology. So patients that have rash or redness or wheels or itchiness, when they take low-dose avapritinib, some relief is gained with 25 mg of ava. But really, people don't have a lot of anecdotal evidence that -- or stories about patients whose fatigue or CNS symptoms or GI symptoms or pain is resolved with low-dose avapritinib. And so I think the standard practice that we've seen emerge is to try to titrate avapritinib up to higher doses and try to find that balance between driving to exposure in a mutant-driven disease against the target, where at 25 milligrams, they're below IC20 on target engagement. And so I think science would tell you, you want to push that dose up until you can engage those mast cells, the mutant cells and get rid of them, but balancing that on the titration with bringing in the PDGFR inhibition, bringing in the CNS penetration, trying to avoid replacing symptoms with side effects. So that is where Cogent and bezuclastinib come in. If you look at the profile that we've delivered and you think about the symptoms -- the side effects that are symptomology for patients, patients feel, we have very infrequent, especially compared to placebo, side effects that patients experience as replacement to symptoms. And so that allows us to dose bezuclastinib in the SUMMIT trial up to 100 milligrams, which is just around IC90 target inhibition of the KIT gene and really show that through the objective measures of disease like the serum tryptase where 100 milligrams of bezuclastinib is dramatically different than 25 milligrams of avapritinib at removing the bad actor mutant mast cells from the patient.

Got it. So I guess, fast forward, specifically with respect to the safety profile, what types of tolerability issues have been observed with bezuclastinib? I know that certainly the Street had concerns about it after the first update, which was, I guess, 1.5 years ago now. What were the expectations originally? What are they now? And how have they evolved?

Yes. If you look at the safety profile that we presented in July, we're certainly very pleased as I think are the investigator in the broad systemic mastocytosis community. So if we rewind back to when we had our Phase I results, we can sort of with hindsight, understand from the investment community why there may have been concern with reporting a handful of patients with higher than grade 2 elevations in liver function tests because the concern in a small Phase I study is that when you see those and you show up 2 years later into a larger pivotal trial, will those manifest into true liver toxicity. And so again, putting ourselves a couple of years ago, maybe that's a rational concern, but now that we've read out the pivotal data and that did not occur, there are no patients that had any liver side effects other than lab abnormalities reported in the trial, treatment emergent completely across the board, nor are there any patients that have true liver consequences, no hospitalizations, no DILI reported as adverse events, no liver transplant, no liver toxicity. This is really truly confined to lab abnormalities in LFT numbers moving up and down, all of the patients, whether without dose mods, with dose mods and in rare cases with discontinuation have had their liver enzymes return to baseline very rapidly. And we've even extended that a little bit further by saying across all of our clinical trials, including the PEAK study, which is dosed at 6x the dose in patients that have fundamentally compromised livers, which is one of the main sites of metastasis of second-line GIST patients, we, again, have no significant liver toxicity findings, albeit in a blinded basis at this point. So look, where we are now, I think it's pretty clear that the profile of the drug, we will with bezuclastinib have patients with fluctuating liver enzymes. We have no evidence that, that will lead to true liver toxicity or consequence. Beyond that, the safety profile looks very close to placebo. Probably the only other thing that you can point to is that patients, which is an on-target effective kit have their hair grow in sometimes with white color. That is an easy to fix side effect. If you care about white hair, there are cosmetic ways to fix that. And so we think the profile of bezuclastinib at the appropriate target engagement in this mutant-driven disease, reaching that ICEC90 type drug concentration is exactly what these patients are searching for. As a consequence of removing the bad actor mast cells from the body, we see a direct correlation to symptomatic improvement. And while our predecessors, now Sanofi, but before Blueprint had told a story of really no relationship between the objective measures of the disease and the symptoms of the patients, Cogent is going to tell a different story, and I think a story that makes more sense scientifically.

So one more question on non-advanced, and that's regarding the actual process of treatment. Avapritinib, when they go in patients essentially for the first few doses, they have to be -- they're monitored for a period of time. I would expect that you assume that practice would continue at least at the beginning of any prescription and then eventually, that would kind of dissipate once patients are beyond the initial few months.

Yes. So the question is about monitoring. So in the practice of treating mastocytosis patients with KIT inhibitors, let's start with avapritinib today. Number one, you want to monitor patients for signs of disease improvement, not dissimilar than in a cancer treatment setting, the idea of never providing patients with a solid tumor, a scan again after initiating treatment to see if their tumor is changing size or shrinking, that seems sort of strange as it would be for us to never take blood from a mastocytosis patient to see if their tryptase or their variant allele fraction is changing. So there's a positive reason why you want to monitor patients to see if the treatment you've chosen and that the patient has accepted is doing something beneficial to the patient. So on a regular basis, physicians are going to monitor for things like tryptase and variant allele fraction. From a safety perspective, starting at 25 and definitely in an off-label higher dose avapritinib setting, it's a responsible thing to monitor those patients for their platelet counts because we know the history of avapritinib when the patients' platelets drop they puts them in significant risk for bleeding events, including intracranial hemorrhage. So on an ongoing and I think indefinite basis, patients with avapritinib are going to be monitored for platelet counts. We have shown that on bezuclastinib with regards to liver function tests, it's probably a good idea to measure patients' LFTs for the first several cycles of treatment. There are going to be a small number of patients based on the SUMMIT data, it's probably a small single-digit percent number of patients for whom bezuclastinib might not be the long-term chronic treatment. For the other 95% plus of patients, they will not have issues. They will not have to dose M. They will be able to get through the first several cycles without any LFT issues. and continue on benefiting from the drug. So we don't see any practice changing for bezuclastinib's hopeful approval next year to the frequency or sort of underlying reasons for monitoring patients receiving KIT inhibitors for non-advanced mastocytosis.