Okay, let's go ahead and get started. Thanks, everybody, for being here. My name is Chris Raymond. I'm a senior biotech analyst at Piper Sandler. Very pleased to announce our next presenting company, which is Cogent Biosciences. We have with us the CEO and President, Andy Robbins. Just to go over the format, this is a fireside chat format, so it's meant to be very informal and actually participative. So if you guys have any questions in the audience, just raise your hand. I'll make sure it gets asked and answered. I got a ton of questions, but before we delve into those, maybe, Andy, just for folks who might not be familiar with Cogent, if you could just level set the conversation, give us the story and the setup on Cogent, and then we'll jump into Q&A.
Sure. So Chris, thanks very much for inviting us to be here today. We're certainly excited to be at the conference. Again, just very briefly, I'll probably be making some forward-looking statements today, so please take a look at our recent SEC filings for a more thorough characterization of risk with the company. Again, to your point, for folks that aren't familiar with Cogent, we're a company that's focused on creating small molecule inhibitors that are best-in-class potential for targets that have unmet need in diseases that are driven by genetic mutations. Primarily rare diseases, including oncology. Our lead asset is a drug called Bezuclastinib, which is currently in three clinical programs, each designed to lead to a registration and approval if successful.
Two different subpopulations of systemic mastocytosis, and we'll talk about these trials later, the APEX study, which is for the advanced form of the disease, and the SUMMIT study, which is for the non-advanced form of the disease. And we'll have updates from each of those trials from the phase one or dose escalation portions just in a matter of days at the ASH conference this weekend. The third program is in second-line metastatic GIST for patients that have progressed on imatinib as the first-line standard of care. And that program, we announced back in August that the 413-patient randomized global phase three study had finished enrollment. And so that study's primary endpoint is progression-free survival, and now we are waiting for those events to accrue.
The guidance for each of these pivotal programs is that we would have the results of the ASM or APEX study in mid-2025, the results of the non-advanced systemic mastocytosis trial or SUMMIT in the second half of 2025, and the results of the second-line GIST PEAK study by the end of 2025. So as we approach the calendar flip to 2025, next year is going to be a very exciting year filled with clinical catalysts for the company.
Yeah, so obviously just lots of really important events here setting up for next year. Maybe before we get into the specifics of the indications and the programs, Andy, if you could, maybe just talk about the TPP or the target product profile in ISM, in advanced SM, and then GIST.
Sure. So when we look at the landscape, which is fundamentally important in how we are developing the molecule, there are a handful of other KIT inhibitors, probably most notably a drug called Avapritinib from a company called Blueprint, as well as a few other drugs like Ripretinib from Ono Pharmaceutical in GIST. The way that Bezuclastinib was designed was really to create its best-in-class potential in two ways. One, by being exquisitely selective for KIT over all the other class three RTKs, including PDGFR, CSF1R, FLT3, VEGF, KDR. It really is, to date, the only pure KIT mutant inhibitor, as all the other drugs I mentioned, and even some of the new drugs very early in development hit those other class three RTKs.
And then secondly, to spare CNS penetration or CNS activity, which in the diseases that we're developing the drug is seen as a liability and has been shown clinically to lead to side effects like cognitive impairment. So having a drug that does not get into CNS would be advantageous for mastocytosis and GIST patients. So the profile that we're trying to deliver is a drug that has a therapeutic index that you can dose up to engage the target fully while sparing a lot of the off-target toxicities that other pan-TKI inhibitors that include KIT are associated with.
Excellent. Okay, so obviously an important data event coming at ASH next week, and we all saw the ASH abstracts from early last month. You guys, just to review, had two abstracts, one from the phase two APEX study in advanced SM and one from the SUMMIT study in ISM, so maybe let's just start with SUMMIT. We're expecting the full data from 18 patients, I think at 100 mg, and this is over a 24-week period. Maybe to start, maybe for those who aren't familiar, just quickly go over that design and the efficacy outcomes in each part.
Sure. So as you mentioned, SUMMIT Part 1 was a dose escalation study that was looking at a variety of different doses of Bezuclastinib as a single agent in the treatment of patients with the non-advanced form of the disease. The design, very briefly, was separated into two parts, 1A and 1B, looking at doses of 100 and 200 of an older formulation of the drug and then 100 and 150 milligram daily doses of the optimized formulation of the drug. That formulation was optimized for the cancer indication, which we can talk about later, but we wanted to harmonize it across our programs.
The patients were followed in the randomized portion against placebo cohorts of the active versus placebo for 12 weeks to judge a variety of endpoints in a dose escalation study, including safety and tolerability, but also pharmacodynamics, as there are a handful of biomarkers that are very important in the treatment of mastocytosis patients, and then ultimately symptomatic and quality of life improvement, which are measured with patient-reported outcome questionnaires, and so really what we wanted to accomplish and what we did accomplish in SUMMIT Part 1 is to pick a recommended phase two dose, and we announced that in February around the Quad AI conference last year that we believe the optimal dose of Bezuclastinib for non-advanced SM patients would be the 100 milligram dose going forward.
And we launched immediately into a registration-directed study called the SUMMIT P art 2 study, which was designed to enroll just under 160 patients. And we set out to do that in about 18 months. So our guidance was we wanted to complete that study by the end of Q2 2025. We've already updated that guidance with confidence that we will land the enrollment of that study a quarter earlier in Q1 of 2025. So we're not that far away from completing enrollment. And what we can say about that is the demand, certainly based on the clinical data we've already presented from SUMMIT Part 1, has been very strong from the investigator and patient community around the world to get access to Bezuclastinib.
So I don't want to necessarily go back and rehash a lot of the history, but I think it's important to sort of frame what we're going to see at ASH. There was some confusion at ASH last year. Part of this issue is you've got competing, dueling, if you will, scoring systems that are hard to, virtually impossible to compare across trials. I think you guys went a long way in clearing that up at AAAAI when you provided your scoring system and then did an ISM-SAF-like measure that, at least in our view at AAAAI, that sort of drove it home, that you've got an activity profile that appears, at least from that data, to be superior to Avapritinib.
But just kind of, again, this is probably not something you would do in the poster, but will you provide an ISM-SAF-like scale when you update this data again?
Yep. So following or around the same time of the ASH conference, we're planning to have an investor call on Monday morning, December 9th, including one of the prominent KOLs in the field to review and discuss the results that we're planning to present at the conference. And during that presentation, I'm more than happy to share what the performance of our drug looks like on a scale that is analogous to the ISM SAF scale, which is the name of the questionnaire that Blueprint had created and then trademarked.
Yep. Great. Okay, so we'll have that. And then maybe let's also put into perspective the stock obviously had a negative reaction to the abstract release, and I think, at least in our view, was misplaced and a reaction to stuff that wasn't necessarily new. But just maybe put that into perspective and what your KOLs are saying with respect to, or your investigators are saying with respect to AST/ALT elevations.
Yeah, I think that the way that the investigators and the physicians who understand the severity of the disease see this is it's not a liver tox issue. These are lab abnormalities, and they are a signature of many kinase inhibitors within and outside of this class of therapies, but certainly including other KIT inhibitors that you infrequently see patients that have transient increases in AST/ALT. Very rarely will you see a patient that has increases in bili. And what we're very confident in saying is both in the data we've already presented, the data that we'll be presenting soon, and the data that we know from much larger patient data sets in a blinded fashion, we have no evidence of liver toxicity leading to clinically relevant liver toxicity outcomes.
And so that's really what we want to drive home is that the profile of our drug, number one as a kinase inhibitor, number two as a KIT inhibitor, similar to other drugs in our broad class and then narrow classes KIT, will have asymptomatic reversible transaminase elevations. That is on target for the drug and drugs of this class. The important thing is that we do not have any signal of irreversible transaminase elevations. So in the significant majority of cases when patients, and this almost always occurs in the first several cycles of therapy, have increases in AST or ALT, regardless of what that increase is, in the majority of patients, they can resolve to normal baseline levels without dose modification. In a smaller number of patients following a dose reduction, they too can resolve to a normal level of transaminase enzyme levels.
And then only in rare cases following a discontinuation do all patients return to a normal baseline level of transaminases. So delivering a profile to non-advanced systemic mastocytosis patients and physicians that has a characteristic of asymptomatic and reversible in all cases is completely understood by the physician investigator community and seen as not problematic to prescribing to these patients.
Okay. And so we viewed success at ASH this year as just a continuation of what you showed at Quad AI. Not to lead the witness here, but longer-term follow-up and just holding up that sort of treatment benefit differential. Again, symptom score reduction, I guess in broad strokes, right? You showed 50%-ish versus 30% Avapritinib. Again, cross-trials is difficult, but is it your view that just holding that sort of efficacy from what we saw at Quad AI is sort of the goal here, or is there some other thing we should be thinking about?
Yeah, from our perspective, the unmet need now that there is a drug approved in this patient population is to find a drug that actually improves the symptoms of these patients. So we commend Blueprint for developing their drug, taking a step forward to having something for patients to take. But now what we know by talking to the advocacy groups, by meeting patients, by enrolling folks on our study, working with the investigators, is that there continues to be a need to actually demonstrate deep responses and return these patients to a normal healthy life. And so the numbers that we look at from a primary endpoint in non-advanced mastocytosis, you're looking at mean improvements in total symptom score at 24 weeks. Chris, as you mentioned, Avapritinib in their pivotal trial showed about a 30% mean improvement at 24 weeks.
That's certainly a number that we're going to be keeping in the back of our mind when we look at the performance of Bezuclastinib. Another number that is very important, clinically relevant to physicians, is the percent of patients who achieve at least a 50% improvement in their symptoms. We know from, again, Pioneer at the low dose of Avapritinib, only one in four or 25% of patients got to that threshold in the Pioneer study at 24 weeks. That's another number that we're going to be keeping in mind as we look and judge the performance of Bezuclastinib at the upcoming ASH conference, where we will be able to report actually from a larger number than you mentioned before because there are placebo crossover patients, but all patients who are receiving the recommended phase two dose at 24 weeks, how do they perform?
How does Bezuclastinib help them get back to leading a normal life with symptomatic improvements?
Great. Okay, so maybe let's talk about SUMMIT part two. This is obviously not a 100% hard and fast rule, but generally when enrollment is going better than expected, there's a signal perhaps that physicians like what they're seeing and there's demand. You mentioned this, Andy, that enrollment, you guys pulled enrollment forward by a quarter based on the demand and investigator demand and patient demand. Just maybe contrast how that timing sort of compares to the Pioneer experience and sort of, again, as qualitatively as you can, maybe talk about the demand and experience as you've enrolled sites and talked to docs about this.
Yeah, I'm certainly very impressed by, number one, our own Cogent Clinical Development and Operations team for the work that they've done to get the study active at so many sites so rapidly and to stimulate demand for investigators and patients to get onto the trial. But also so impressed with the non-advanced systemic mastocytosis community, with the patient advocacy groups, with the investigators and the support that they've given in the face of a newly approved drug for the first time in the history of the disease, which, again, commending Blueprint for their work, took them about two years to run their pivotal study from start to finish. We set out to do ours, and as I mentioned before, just under 18 months, 16, 17 months, and we've already pulled that back to a target of about 15 months.
Shortening the enrollment time dramatically relative to our competition in light of the fact that their drug is commercially available when during their trial there was no commercially available choice. What I can say is that across the U.S. and Western Europe, which is going to be the vast, vast majority of the patients enrolled in the SUMMIT study, we have had no issues finding patients who are naive to Avapritinib who are willing to consent directly into the SUMMIT trial. This is based on the knowledge that 25 milligrams of Avapritinib, while approved and well tolerated, does not seem to offer significant symptomatic improvement to the patients. The investigators and the patients are searching for something different.
That gives us a lot of hope for if we can deliver on this promise of pushing forward those bars, that 30% improvement, the 25% of patients getting to a 50% improvement. If we can dramatically or noticeably push those milestones and thresholds higher, then I think we set ourselves up to be the drug of choice, assuming the drug is approved by the regulatory agencies.
One of the questions I get from investors, and it's kind of died down recently since you've been moving forward with enrollment, et cetera, but it was around the validity of scoring systems. To your point, Blueprint has the ISM SAF, they trademarked it, nobody else can use that. Yours is MS2D2, and you almost need a cheat sheet to remember all the acronyms for these scoring systems. But to your point, also they seem to be relatively similar, but I think you guys incorporated some refinement after talking to the FDA in light of ISM SAF. I'm just kind of curious in a commercial setting how you feel that that scoring tool maybe differentiates you guys commercially in having a more refined symptom score, how that matters actually in the trenches, docs.
Yeah, it's a great question and from a practical perspective, we see the application of complicated scoring questionnaires in a post-approval world as being used, we'll call it infrequently, if ever. The way that we understand the practice of medicine in this disease is that physicians like to have conversations with their patients about how they feel, what's getting better, what's getting worse, what their side effects are, as opposed to asking them to complete a complicated questionnaire on a daily basis for a long duration of time, so while we understand that demonstrating in a very controlled fashion in a clinical trial using a rigorous scoring process is important to determine the safety and activity of a drug, in a commercial setting, we don't expect that either of these questionnaires will be used very often.
Instead, what we see from physicians is that measures like 50% improvement in symptoms or the improvement in the most troublesome or most severe symptom at baseline, so remember, again, this is a disease where there's many different domains from fatigue to dermatologic issues to GI issues to cognitive issues to pain, on and on and on. Not every patient has every one of those symptoms, and what physicians who are treating these patients like to look at is how good is a treatment at helping my patient who has this specific problem, and so both to their credit, Blueprint and Cogent have started reporting the improvement in the most severe symptom at baseline, which could turn out to be among the most clinically relevant measures.
And so you'll see that again coming up at ASH as how do we do, how does Bezuclastinib do at treating whatever it is that's bothering that individual patient the most. That's when we get down the road into the commercial setting. I think what will be most impactful is when a physician tries Bezuclastinib, do they see a dramatic difference in improving symptoms of their patients relative to what they've been used to for the past couple of years.
Excellent. Okay, so let's maybe pivot to advanced SM. We spend all this time talking about ISM, it's obviously the bigger market opportunity, but your more near-term pivotal event is mid-year when we get that data. So maybe just frame for folks how treatment goals in the advanced SM setting sort of differ from indolent or smoldering SM.
Sure. So in the advanced setting, it's a disease fundamentally of mortality. Left untreated, these patients before the advent of KIT inhibitors had a median overall survival of about three years. So it's very analogous to a malignancy or a metastatic cancer indication where you're trying to improve survival as opposed to necessarily just improved symptoms or quality of life. What we see from the available therapy, Avapritinib, is that it has a very high level of activity. And remember, in ASM, it's dosed 90% higher than it is in ISM, where it actually does clinically engage the target.
The challenge at that dose is that it leads to significant safety concerns, including intracranial hemorrhage, nearly ubiquitous periorbital and peripheral edema, high rates of grade 3, 4 heme tox, and a contraindication for patients who have a low level of platelets based on the risk that it could turn into intracranial hemorrhage. They also, based on the fact that they're a highly CNS penetrant drug, have about a 40% rate of cognitive impairment. So this is a, while it's a very active drug at 200 milligrams and does a very commendable job of delaying progression of patients' disease with ASM, it is not a very pleasant drug to tolerate. That's where Bezuclastinib in our profile at ASM comes in.
So what we're looking to do is match the level of efficacy as measured by a complicated objective response scoring system in this disease, but without all of those things I just talked about, without intracranial hemorrhage, without cognitive impairment, without the edema, without high rates of grade three-four heme tox. And we think that when patients have a choice between two drugs that deliver the same type of high-level response and durable response, one with safety risks and one without, we believe we know what we're going to do. Just as a postscript, which we find interesting, at that level of 200 milligrams of Avapritinib per the label, they have rates of over 40% transaminase elevations, including over 40% rates of bilirubin elevations. So again, evidence that this is a class effect.
The reason that you may see lower rates in Avapritinib in ISM is based on the fact they reduced their dose by 90%, where they sacrificed all of that potential efficacy or symptomatic improvement relative to what Bezuclastinib can accomplish.
Maybe one follow-up question on that, kind of intrigued that you allow in that study the inclusion of patients that have been exposed to prior Avapritinib treatment. Maybe just talk a little bit about how we should be thinking about those patients, whether they were non-responders or intolerant to therapy. Just from a commercial perspective, having data in Avapritinib experienced patients seems to be an interesting setup.
Yeah, great question. And just to be clear, both in SUMMIT, the non-advanced, and in APEX advanced, we allow for patients who have had prior Ava. Our experience is that the majority of patients who have come into both of those studies have come on for intolerance. So they've decided to move off of commercial Avapritinib based on side effects or adverse events, and that's why they've decided to enroll in each of those trials. I agree in a commercial setting, having a subset of patients with that experience can be very powerful to generate that switching behavior in physicians.
Okay, excellent. I have a whole list of questions on GIST, but I have no more time, but just maybe one sort of question.
Sure.
So you mentioned year-end, you get your PEAK study in GIST. As I talk to investors, almost nobody's given credit to this opportunity. Why should we be thinking about GIST as a real value driver here?
Second-line GIST is about 3,000 patients in the U.S., and based on recent new commercial oncology product launch prices, we haven't chosen a price yet. We will once we get closer to approval. It is a total available market of well north of $1 billion, with the standard of care being a generic drug that will be part of our combination. So there are very few small-cap biotech companies that have already completed a global phase three study in an oncology indication with no competition with a $1 billion potential. That's the pitch I would give for GIST.
It's a pretty good pitch. All right, well, we're out of time. Thanks, everybody.
Thanks, Greg.
Thank you.