Welcome to this next session of the Guggenheim Healthcare Conference. My name is P aul Jeng. I'm a member of the biotech research team at Guggenheim. And we're very pleased to welcome Cogent Biosciences as our next presenting company. And with us today is Andrew Robbins, President and CEO of Cogent. Andy, welcome.
Thank you, Paul. Thanks for having us. Certainly excited to be here.
Great. W e can start with a brief introduction to the company overall and maybe some background on your lead asset, which is the selective mutant KIT inhibitor, Bezuclastinib .
Sure. Again, thanks for having us here, and I'll start just by reminding folks that I'll probably be making forward-looking statements today, so just point you to our recent filings, I think even as of this morning for our Q to have a more wholesome discussion of risks associated with the company, but we're happy to be here. Cogent Biosciences, for those that don't know, is a company that's focused on the development of selective small molecule medicines for patients with rare genetically driven diseases. Our lead asset, as you alluded to, is a selective and potent KIT inhibitor known as Bezuclastinib. It's currently being advanced in three clinical trials, each of which has the ability to serve as a basis for approval if successful. Each of those three trials, known as APEX, SUMMIT, and PEAK, are on track to have top-line results in the second half of 2025.
W e're coming up towards the end of the year and then beginning the year 2025, which will be a very exciting time for Cogent. There's not a lot of small-cap biotech companies that have three pivotal studies all reading out around the same time. So that'll be a busy and exciting year for us. Just at a high level, the reason that we're so confident and excited in bezuclastinib is that, A, there aren't a lot of KIT inhibitors being developed for mastocytosis and gastrointestinal stromal tumors. And we believe we're the only one that is truly potent enough to help patients and selective enough to avoid some of the pitfalls of the other products that are out there.
And so in mastocytosis, we're developing a drug as a single agent, but at clinical exposures across both the advanced and non-advanced diseases that we believe are sufficient to hit the target, the underlying mutant driver of the diseases. And in gastrointestinal stromal tumors, we're developing our drug in a novel way in combination with another drug known as Sunitinib that, put together, our two drugs can fully cover all of the known resistance mutations in that patient population. So certainly excited to talk a little bit more about bezuclastinib. In addition, you alluded to, we have a whole series of other pipeline candidates. We have an exceptional medicinal chemistry and research team that is very productive and very efficient at making these potential best-in-class candidates.
We now have four programs publicly announced, including the news this morning that we initiated our first phase I study with our FGFR2 inhibitor, which is the first clinical trial that we're running of a Cogent-invented drug. Certainly very proud on behalf of the research team to put our first drug into the clinic as of a few weeks ago.
Great. So thanks for that. Look forward to diving a little bit more into the early pipeline towards the latter half of the conversation. But starting perhaps with Bezu, one of the indications that you're evaluating is in non-advanced systemic mastocytosis. Could you remind us of what the market opportunity is there? What's the main sort of treatment objective and what differentiates Bezu in this space?
Right. This is a critical and very important question. So I think there's a little bit of a misperception that patients with Non-advanced Systemic Mastocytosis, this is not a primary care indication. These are patients whose disease impacts their life to the point where they're often forced to stay in their homes. They can't hold a normal job, and they have a whole host of symptoms driven by the underlying mutation in their mast cells that cause them to lead a debilitating life. And while it's not a disease typically of mortality, living this sort of significantly impacted quality of life for decades and decades is a situation where these patients are seeking out something that can help them return to a life of normalcy. We acknowledge that there's another company that recently got a drug approved. They're doing quite well from a commercialization perspective.
We think that that's positive news. It shows that this is a commercially attractive market to the biotech investment community. I think folks now are putting this at about a $2 billion total available market in the U.S. alone, and then even larger than that when you think about expanding globally or internationally. And what patients are looking for right now is a drug that actually has the ability to help their symptoms and their quality of life. So we've taken a small step forward with a recently approved drug. And what we're trying to do now with our SUMMIT program is take a much larger leap forward to show that there is a drug that has the potency and the exposure that can change patients' quality of life dramatically.
Great. B efore maybe diving into the details on SUMMIT, so as you alluded to, the market has recently seen the launch of the first approved drug last year, been building ever since. Can you just comment on how that commercial progress and any updates on that have driven your views on the market? And how has that reinforced your view on the opportunity for Bezu?
Yeah, I t's a good news story. Certainly, Blueprint has done a good job of identifying patients and getting patients on drug. Not surprising for a community of patients, again, that have a chronic debilitating disease, and prior to that, drug had had no disease-modifying agents approved to help them. They were on a cacophony of medicines to try to help individual symptoms, stacking polypharmacy on top of each other, and so the hope of some drug that could help them certainly has driven a lot of patients to try Avapritinib, and what we know from talking to physicians and patient groups in the community is that the dose at which Avapritinib was approved is probably not sufficient to address the underlying symptoms.
That even when patients try to escalate the dose off-label, they often run into some of the struggles and symptomatic adverse events that are associated with Avapritinib at higher doses. What we know today, now I think 16-18 months into that launch, is that patients are taking Avapritinib because there's nothing else available, but there is still a pretty significant unmet need for a drug that actually helps across the board with all the various symptoms that these patients are experiencing.
Gotcha. Okay. So you're now currently enrolling the phase II SUMMIT trial. Can you remind us what has been presented so far from the study and what the clinical learnings have been to date?
Right. W e've presented data from the dose escalation portion of the SUMMIT trial known as SUMMIT part one several times, originally at ASH in 2023, then subsequently at QuadAI in February of 2024, and then sort of an encore presentation most recently at EHA in the summertime. Across all those presentations, what we've shown is that the drug is well tolerated and highly active, maybe surprisingly highly active. So maybe we can start with the pharmacodynamic effect. We've shown that essentially every patient in this disease, you want to look at the ability of a disease-modifying drug to reduce serum tryptase and some of the associated markers like mast cells and variant allele fraction. Essentially, every patient has a rapid reduction and return to normalcy on these PD markers when taking Bezuclastinib .
What we also demonstrated is that when you look at the recommended phase II dose that we've chosen, which is 100 milligrams of bezuclastinib going forward, we demonstrated that 70% of patients had within 12 weeks 50% improvement in symptomology, which is a level that I think is quite surprising for the investigators in the patient community that are used to maybe numbers that are much lower and take much longer to get to for other therapies. That's balanced by an adverse event profile with essentially no symptomatic adverse events, which we think is what these patients are really looking for in a new drug, something that can push the efficacy much further than what is currently available while still having a very positive safety profile.
Okay. So you'll be presenting updated data from the open label extension portion of SUMMIT at ASH. There was perhaps some initial confusion when the abstract data came out on the old versus new data. Can you just clarify what was in the abstract and what you do plan to present at ASH?
Right. So again, we were also confused by this when the abstracts came out. The SUMMIT, we're talking about the non-advanced, there was literally not a single letter or number that was any different than data that was presented a year ago at ASH and QuadAI. So we are confused that many sell-side analysts, not our friends here at Guggenheim, but other sell-side analysts wrote stories and notes about the new data that came out in the abstract, which is just factually inaccurate. All of the data in the SUMMIT abstract had been presented publicly at conferences long, long ago. What we're looking forward to at ASH, as you mentioned, is that looking at longer follow-up from patients.
The design of the trial in part one is that patients were randomized to either get bezuclastinib or placebo for a 12-week period for us to help pick the right dose to take forward into the pivotal study known as SUMMIT part two. But all patients after that 12-week period, whether they were randomized to active or placebo, would be given the opportunity to take bezuclastinib from that point forward for as long as they benefit. And what we plan to present at ASH coming up in a few weeks is the results of patients, predominantly patients at our recommended phase II dose. That's what we're most interested in and how they did for a longer period of time taking bezuclastinib. In this specific disease, the primary endpoint of both Blueprint's PIONEER study and our SUMMIT part two study will be mean improvement at 24 weeks.
And so 24 weeks of active therapy is a particularly interesting time point for us to look forward to. We will present all of the endpoints that I think folks are interested in seeing from safety and tolerability to pharmacodynamics, and then items like total symptom score at 24 weeks, mean improvement, threshold analyses, individual items as part of symptomatic domains, as well as quality of life measures so that we will do our best to create a wholesome presentation so people can really understand the effect size that bezuclastinib is conferring to this population.
Great. So for this data, as well as potentially the part two of the trial, which you've guided to data next year, how should we think about benchmarking to the PIONEER study for Avapritinib? And what data will we get from the registrational study next year?
Right. So in the upcoming ASH presentation, what we're looking to demonstrate, again, our profile in non-advanced mastocytosis for bezuclastinib is really about pushing the efficacy and symptomatic resolution forward. So the benchmarks from the pivotal study on which Avapritinib was approved is they generated about a 30% mean improvement at 24 weeks, and about a quarter of their patients had at least a 50% improvement. Those are important numbers to think about as we get to presenting our data. For us to have a competitive profile, we are going to need to deliver significantly higher numbers on symptomatic improvement. With regards to what's going to happen next year, SUMMIT part two is a randomized placebo-controlled blinded pivotal study comparing bezuclastinib to placebo.
Again, we plan to enroll just under 160 patients to demonstrate that bezuclastinib has an advantage over placebo on the primary endpoint of mean 24-week improvement on total symptom score, and so that's the headline primary endpoint, but many of what we've talked about before, many of the endpoints we've talked about in this conversation will be important, like what is the percentage of patients who achieve certain clinically relevant thresholds like 30% improvement, 50% improvement? What about the impact on quality of life? How much better do patients actually feel? And how does that translate into living a better quality of life? And then, of course, other measures like the pharmacodynamic effect of the drug, as well as the safety and tolerability of the profile, so we look forward. Again, that primary endpoint is a time function of the end of enrollment.
Six months after the last patient's first visit would be your ability to cut that data. And so as we get closer and closer to the end of the enrollment of SUMMIT part two, which I can tell you is going fantastically well, much better than we had even originally hoped. And I think that's a credit to the profile of the drug and how excited the investigator and patient community are about getting onto a clinical trial even before trying the commercially available drug in this patient population. But as soon as we get to that last patient first visit, we'll be able to pinpoint exactly when we would plan to have those data.
Super. So we can't forget about the other indications that Bezu is also being evaluated in. The first one that comes to mind being the advanced SM segment. You're currently enrolling in the phase II APEX study. So can you talk about the data we've seen so far and clinical learnings about what differentiates Bezu?
Right. In the advanced setting, it's interestingly a different profile. And some of this is based on how our competitor developed their drug with dramatically different doses across those two indications, whereas we are choosing very similar doses and very similar exposures based on the profile of our drug. So in the advanced setting, this is a disease of mortality. Prior to the advent of KIT inhibitor therapy for advanced SM patients, they had an overall survival from diagnosis of a mean of about three and a half years. So this disease is much more like a hematological malignancy than it is a more indolent disease.
In this patient population, what we're shooting for is activity similar to what Avapritinib has shown at their very high dose or their active dose, which is somewhere in the 50%-60% objective response rate with very durable patient performance, but notably with much, much improved safety and tolerability. At those high levels of the approved drug, there are many issues that patients face, including a large number of intracranial hemorrhages, 25% or greater rates of grade three to four heme tox across thrombocytopenia and neutropenia and anemia, nearly ubiquitous periorbital and peripheral edema, as well as nearly a 40% rate of cognitive issues. Our drug doesn't seem to have any of those liabilities at the dose and the efficacy level that we can generate to match Avapritinib.
In the ASM setting, what we're looking for is to once again recapitulate very high levels of activity for a potent KIT inhibitor, but without all of the potential safety and toxicity issues of the incumbent.
Great. So then maybe shifting gears to the GIST setting. This is a setting where perhaps there's been some baggage from prior clinical failures. So can you just walk us through the market opportunity in second line and why you chose to proceed with this particular study and combination?
Sure. It's a great question. As most folks know, in first-line GIST when patients are diagnosed, they are essentially all given an amazing drug, Imatinib or Gleevec, which is highly effective for first-line GIST patients, and so really the future of GIST drug development starts in the second line. It's going to be very challenging to design a trial that shows advantages over Gleevec in the first line, so we are developing our drug in second-line GIST patients, those that have developed resistance or intolerance to Imatinib in the first line. That patient population in the U.S. is estimated to be about 2,500 to 3,000 patients per year, and really the commercial opportunity is going to be a function of the durability and the PFS associated with a new active treatment.
Currently, the standard of care around the world is single agent Sunitinib and has been for about the last 20 years, and Sunitinib generates approximately an 8-month median progression-free survival in this patient population. Sunitinib is quite a good exon 13 and 14 KIT inhibitor, which makes up about 50% of the mutations in the second line, but it is not very good at controlling resistance mutations that occur in exon 17 or 18, and that is where a lot of the field has gone. If you look at other drugs like Avapritinib or Ripretinib, which was owned by Deciphera and now Ono Pharmaceutical, as well as bezuclastinib, all of our drugs are quite good at hitting exon 17, 18 mutations.
The key difference in what we're doing to some of those historical failed large phase III trials is we're combining bezuclastinib with sunitinib in an attempt in the active arm to cover all of exon 13, 14, 17, 18 resistance mutations, and the reason we can do that is because of the selectivity of bezuclastinib. We are a KIT inhibitor, and that is what we do. We don't hit other kinases, unlike Avapritinib and Ripretinib and some of these other new all-in-one KIT inhibitors that hit PDGFR and FLT3 and CSF1R and KDR and have potential off-target liabilities of dosing up to the levels that they would need to get to.
So by joining forces in our phase III trial, which we announced the enrollment had been completed in August of this year with over 400 patients around the world, we think that covering all of the resistance mutations will actually deliver a better and different outcome and a win. And what we're looking forward to is from our phase I/2 trials, where we showed a median PFS in this patient population of just over 19 months, can we do in a large phase III trial something anywhere even close to that number, which would be a PFS statistical win and probably a rapid adoption of a new standard of care in this patient population?
From just getting back to the commercial potential, with even a 12-month median progression-free survival, we see this as north of a $1 billion market opportunity in the U.S. with essentially no competition, only a generic drug as the standard of care.
Sunitinib has a couple of known tolerability issues, hypertension, stomatitis, fatigue. How confident are you that adding an additional TKI will not sort of stack on top of that?
It's a great question, and the data we've presented, which now includes north of 60 patients across two different phase I two studies at full dose combination of bezuclastinib and Sunitinib, has shown no numerical increases in any of the SUTENT adverse events that you've shown, so hypertension, stomatitis, fatigue. That is the profile we're shooting for, is we can't get rid of the things that are associated with SUTENT, but as long as we don't add to them, SUTENT has been used for so long around the world as the standard of care that physicians and patients have learned how to manage the SUTENT-related side effects, and if we don't add anything to it, then we feel very confident that that will be adopted very rapidly as the new standard of care.
Great. So the phase III PEAK study has completed enrollment and you've got it to top line data next year. Have you provided any color on the powering of the study and what would be considered a win in the trial?
Yeah, we've said publicly that with 90% power, we can show a statistical advantage at about three and a half months. And so if you go back to a recent large phase III second-line trial where Sutent was used as a control arm, it delivered just over eight months of median progression-free survival. So that gets you to that kind of mid-11s to 12-month range for a win on the active arm.
Perfect. So with our last couple of minutes, I do want to touch on the early pipeline. So this morning you announced the study for the selective FGFR2 was initiated for cholangiocarcinoma. Can you talk a little bit about the market opportunity here and sort of the trial design?
Right. So with all of our programs that we're going to talk about, I think a little bit briefly, our goal is to create a best-in-class version of whatever is out there. So none of our pipeline to date will be considered first-in-class similar to bezuclastinib. We're trying to improve upon the path that others have started. So with regards to our FGFR2 inhibitor, the important characteristics of our drug is that number one, it's reversible. There's a notable competitor that came before us as a covalent inhibitor and ran into some problems of off-target liabilities not being able to sort of resolve very rapidly. And then number two, pan mutant coverage. So there are very specific known gatekeeper and molecular break resistance mutations that other FGFR2 inhibitors that have come before us do not cover.
We are equal potent across all of those mutations, both the primary and resistance mutations that are known, and so we believe that our drug will confer a very high response rate, but added to very durable responses, which is the profile we're going for. In this patient population, cholangiocarcinoma is probably the best known FGFR2-driven disease. That indication alone, if you can get to a first line approval, is probably in the $500 million peak sales realm, but our drug also has the potential to go to tumor agnostic FGFR2 populations, which broadens that a little bit, and then our drug also has FGFR3 potency, and that would potentially open up other avenues later in the development program.
So we're very excited to put our first Cogent invented drug into the clinic, and we hope sometime next year to come back with some clinical data from that program.
Perfect. And then maybe with our last minute, just can you talk about the pan-KRAS inhibitor that you have and sort of opportunity in KRAS mutated cancers?
Right. So we are certainly familiar with our colleagues at Revolution Medicines and their recent data presented on their RAS(ON) pan-RAS inhibitor. The program that we're designing is a pan-KRAS. So we spare HRAS and NRAS. There's a lot of research that has been done that suggests that inhibiting HRAS and NRAS may be responsible for some epithelial tox or off-target tolerability challenges preventing therapeutic index in a true pan-RAS inhibitor. So the profile of our drug is really to be picomolar potent across all of the KRAS mutations and focus on that patient population by sparing the other isoforms and allowing us to potentially create best-in-class therapeutic index in the patient populations that are specific to KRAS.
Awesome. So I think with that, we're up on our time. So I wanted to thank you again, Andrew, for joining us, and thank you all for tuning in.
Great. Thanks, Paul. Appreciate it.