Good afternoon, everyone. Thank you for attending Jefferies' London Healthcare Conference. My name is Kelly Shi, one of the Biotech Senior Analysts here. Please join me in welcoming Mr. Andrew Robbins, Chief Executive Officer for Cogent for this first chat session. Welcome, Andy.
Thank you, Kelly. Thanks for having us here today.
Fantastic. Next year is a pivotal year for Cogent, with three pivotal results coming out. Before we discuss each individual program, could you give us a quick overview of your KIT inhibitor, bezuclastinib, and how it is designed differently versus approved KIT inhibitor?
Sure. Thanks for the question and just very briefly, I'm probably going to be making some forward-looking statements today, so I'd just remind investors to take a look at our recent SEC filings for a more thorough discussion of risk. To your question, we're very, very excited about the year ahead. As you mentioned, three pivotal trial clinical readouts coming up in 2025 across bezuclastinib, our KIT inhibitor in mastocytosis and gastrointestinal stromal tumors. We're probably most excited about our drug based on its molecular profile and its difference, as you mentioned, from other available KIT inhibitors as what we consider to be the most selective, so sparing off-target kinase inhibition and its inability to penetrate the blood-brain barrier, which spares some of the cognitive problems that are associated with available KIT therapy.
Really dialing in an exquisitely selective, potent KIT inhibitor that does not get into the CNS, where for these two diseases, that's not a clinical benefit for the patients.
Great. Maybe for the imminent event at ASH, could you set expectations? What kind of data sets we could expect, and what's the implication to pivotal trials?
Right. So we're excited in just a few weeks, gosh, it's coming up quick, the end of the year, that we'll have the opportunity to present follow-up data from both of our ASM and ISM, known as APEX and SUMMIT clinical trials. This will be longer-term duration or longer-term follow-up on the same patient sets that we've presented on before. But importantly, in these diseases, demonstrating durability and the potential for chronic use will be quite important. So just to remind folks, again, unlike some of the available KIT inhibitor therapies on the market, bezuclastinib is unique in that we can deliver this very similar clinical exposure to both ASM and ISM patients based on the profile of our drug to deliver that clinically meaningful target inhibition at concentrations approaching IC90 while still having a safety profile that is very positive and well tolerated for these patients.
At ASH, we'll have the opportunity first from APEX, the ASM study, from that original about 30-35 patient cohort and the dose escalation portion of the trial to show how those patients are doing now, some of them on for several years on bezuclastinib. As a reminder, the profile that we're trying to deliver in ASM is for a very, very active therapy matching the efficacy levels that are seen in available on-market options, but with a noticeably differentiated safety profile. So sparing some of the things that plague the on-market options, like intracranial hemorrhage, near-ubiquitous periorbital and peripheral edema, 40% cognitive impairment, and nearly 30% incidence of grade 3/4 heme tox. That is what patients currently get to choose from today.
What we expect to show at ASH is a vastly differentiated, improved safety profile to deliver a similar level of high rates of response in this patient population. When turning to the SUMMIT trial, again, remembering that we don't need to sacrifice significantly clinical exposure and target engagement for these patients. We also expect to demonstrate that when you actually hit D816V clinically, you can deliver significant symptomatic and quality-of-life benefit for this patient population who struggles to lead a normal life with all of the various symptomatic issues that they face. So what we're really focused on at ASH for our SUMMIT ISM trial is to demonstrate that there is hope for a second agent in the future for these patients that actually speaks to what they're looking for, and that is symptomatic and quality-of-life improvement.
Great. And maybe we stay focused for now advanced ASM or ISM for the moment. The ASH abstract included 18 patients treated with 100 milligrams of Bezu for 24 weeks from both SUMMIT 1 Part 1A, Part 1B. And Part 1A is the original formulation, and Part 1B is the optimized formulation. Maybe first help us to understand what's the difference of these two different formulations and what actually drove the switch?
Right. It's a good question, and it's a question we get quite often about the formulation. So the good news is now all of our pivotal trials have been run from first patient to last with the formulation, which used to be called the optimized formulation. So from a historical perspective, what we really did here with an optimized formulation is improve the bioavailability by changing the nonactive ingredient mix in the tablet form. And that enabled us to reduce the pill burden for the GIST trial, which I expect we'll talk about in a little bit, getting that number of pills per day for those cancer patients down to an acceptable number. In systemic mastocytosis, we don't expect there to be really any safety or efficacy differences between the original formulation and the optimized formulation, especially at the much lower doses relative to GIST that we're giving to patients.
We feel quite comfortable on a matched exposure basis to look at data from both Part 1A and Part 1B in this trial. That's going to be the focus of the SUMMIT presentation at ASH to look at patients who are receiving the recommended Phase II dose exposure, again, from both Part 1A, Part 1B, and placebo patients who started at that level. As a reminder, that's the 100 milligram dose that we're currently enrolling in our pivotal portion of the SUMMIT trial.
OK. So just to confirm, we expect consistent efficacy and safety both from the optimized formulation.
That's correct.
OK. Great. And also, we have a question on the endpoint. So you leverage the different symptom measurement system from the system used to currently approve the drug. And so that created some debates. And then you updated you have received the FDA alignment on this. Could you help us to understand the rationale behind this modified approach and what kind of inputs you have collected to help you design this new scoring system?
Right. So this is a question about the patient-reported outcome questionnaire that is used to assess performance of non-advanced systemic mastocytosis patients. Our colleagues at Blueprint Medicines followed a process back in the day of creating a patient-reported outcome questionnaire to assess symptoms in these patients. For, I think, corporate strategy reasons, they decided to trademark that document. And so that document is not available to any other non-Blueprint companies. We would have, of course, been happy to use that. But understanding some of their strategy discussions, we were put in a position where to move forward to develop a questionnaire, we had to do it again ourselves from scratch, which we've done and completed.
The process of doing this is to collect information from patients and physicians prior to running a clinical trial about the most frequent and severe symptoms that are associated with the disease, and then test those assumptions in a prospective blinded fashion, which we did in SUMMIT Part 1 in a randomized trial against placebo, to make sure that patients who were enrolled in the study were reporting those same group of symptoms at a similar severity and frequency rate. That all occurred. To your point, we went to the FDA this past summer, demonstrated the data that we had collected prospectively, and aligned on what's called the MS2D2 patient-reported outcome questionnaire moving forward. We do acknowledge that they are non-identical questionnaires.
For anybody who reads both the ISM- SAF and the MS2D2, I think we could agree as thinking people, they're highly similar, highly analogous, but non-identical. So we understand in a situation where we had a readout that was very similar to Blueprint's, it might be challenging to say, well, they were run using different questionnaires, so very similar results could be confounded. What we plan to show, and again, we're going to do this later next year with a larger randomized SUMMIT Part 2 trial, is that the symptomatic benefit and quality-of-life benefit that bezuclastinib can show is so dramatically different and better than what Ayvakit showed in the PIONEER trial that it is impossible to ascribe that to a slightly different worded questionnaire.
Super helpful. And maybe you can give some examples for the most severe symptoms or also under-addressed symptoms. And when we think about the efficacy metrics, where do you see Bezu has the biggest differentiation compared to avapritinib?
Yeah, it's a great question. It is a complicated disease, and the assessment of benefit for patients is unfortunately multifaceted, and so it's hard to crystallize this down into one or two points. The primary endpoint of both the Blueprint Pioneer trial and our SUMMIT trial will be mean improvement at 24 weeks on total symptom score, and we use these questionnaires to assess the total symptom score. But potentially even more clinically relevant for the treating physicians in this disease and for patients are measures like what fraction of patients achieve at least a 50% improvement. Another one that physicians point to quite often is looking at the most severe symptom an individual patient experiences at baseline; how well does the drug perform on that symptom in that patient?
We are very much looking forward, both at ASH and then sometime later next year, to demonstrating our results. As an example, just for benchmark purposes, on that measure of what fraction of patients achieve a 50% improvement in symptoms, which is considered to be a clinically relevant improvement, per the U.S. label and the FDA approval of Blueprint, their number is 25% of patients. One in every four patients achieve that level of clinical benefit. What the phase one data we've previously reported shows is that 70% of patients taking bezuclastinib achieve that at half the time. That is that level of differentiation that we're expecting bezuclastinib to drive, which is very hard for somebody who looks at these independent data sets to attribute to slightly different worded questions.
Great. Maybe still early to talk about a future commercial strategy. But given that you use a new scoring system, maybe you can share initial thoughts on what's your strategy thinking about communicating with physicians and how they can reconcile different scoring systems? Or it could be more like it takes time for them to accumulate real-world experience for comparison and contrasting?
Yes, I think it's a great question, and while we probably don't have enough time to go through the entire commercial strategy, I'll give you a few very high-level thoughts, so if you sort of fast forward a couple of years, we're expecting to complete enrolling the pivotal study in Q1 of 2025, and then with a six-month endpoint, it takes a little bit more than six months to get to that analysis, and then there's a little bit of time for the NDA and the NDA review, so if we fast forward a couple of years, I think we believe very strongly that bezuclastinib will be approved for ISM patients.
And then at that point, to the credit of our competitor, Blueprint Medicines, they've done a very good job being the only drug available that actually does anything to help these patients, creating a group of patients who are now on avapritinib. What we know from talking to physicians across the country and across the world is that very rarely can you find a patient, an ISM patient, who is taking avapritinib who is completely controlled and all their symptoms have resolved. And so there will be a population of patients who have been trying to take avapritinib for six months, 12 months, 24 months without resolution of symptoms. We think that that is an excellent patient population to want to try a novel drug that has a potentially largely differentiated and superior ability to resolve symptoms.
In addition, what we also know from talking to allergists and non-hematologist treaters of mast cell diseases across the country is many of these physicians have yet to prescribe avapritinib. And we know that ISM is a largely undiagnosed disease in the U.S. today. Most of these patients don't know the name of the disease they have. They're being treated for a variety of symptoms as opposed to the underlying biology. It's very hard for a new drug and a new disease to stimulate huge changes in behavior and diagnosis when the results and the benefit of that clinical trial is modest. So we think that the rate of diagnosis and the excitement among the physician community for any disease that doesn't have many available therapies will increase when there is an option that really drives striking levels of efficacy.
OK. Already a lot of thoughts into commercial. And the last one on ISM is, could you share the latest status of SUMMIT Part 2 enrollment so far? And from the data perspective, could you help us to set a bar? What would be a winning situation for Bezu?
Right. So the SUMMIT trial Part 2 is what we call it, is ongoing. It's a 159-patient study randomized two to one bezuclastinib versus placebo designed to measure a six-month time point on mean improvement in TSS. That study kicked off enrollment around AAAAI this past year, so around the end of February, and we set out to enroll the study in about 15 months so that we had guided to a Q2 2025 completion of enrollment. We've already revised that back to Q1 of 2025 based on significant demand from investigators, and in patients, even in the face of a commercially available drug, we don't seem to have any challenges finding patients naive to avapritinib willing to consent to the SUMMIT trial.
From a bar for success, again, our goal is to provide ISM patients with a therapy that directly helps resolve their symptoms and improves their quality of life. With a current bar of about 25% of patients achieving a 50% improvement, we would say a doubling or even a tripling of that would be clinically meaningful and significant to this patient population. That's the type of efficacy step forward that we're looking for out of bezuclastinib.
Great. And now move to advanced ISM. First, where do you see the unmet needs with the current therapy?
So in the advanced setting, again, from my earlier comments, avapritinib is a very active drug at the ASM dose, 200 milligrams. It's just unfortunately a not very well tolerated drug at those doses. So first and foremost, providing ASM patients, which is a disease of mortality if not treated by a KIT inhibitor, with an option that provides them with that response rate and durability to extend their lives, but without the risk of intracranial hemorrhage, without the peripheral and periorbital edema, without the cognitive symptoms, without the grade four thrombocytopenia, that's the first step forward. And that's what we're really looking to demonstrate. I think over time, one of the opportunities for a drug like bezuclastinib, if you understand how ASM is divided, about three-quarters of patients diagnosed with ASM fall into a category known as SM-AHN, which means that they have both ASM and another hematologic neoplasm.
In many cases, that's myelodysplastic syndromes. It could be myelofibrosis. It could be CMML, and there's a host of other rare hematologic disorders that they have concurrently. The drugs that are used to treat those AHN diseases are often themselves very heme toxic, so drugs like azacitidine or ruxolitinib or chemotherapy have their own associated grade three, four thrombocytopenia, neutropenia, and anemia, so in the sort of commercial market, the challenge that physicians currently have for these SMAHN patients is, do I treat their AHN with a drug like azacitidine, or do I treat their SM with a drug like avapritinib? Because I can't give the same patient both of those drugs at the same time. It would be very damaging to their bone marrow.
Because bezuclastinib has much lower rates of these hematologic toxicities, we're exploring in a parallel clinical protocol whether you can safely give bezuclastinib in combination with a drug like azacitidine, which would unlock that 75% of the ASM market for the SMAHN patient population.
Follow the same line in real-world practice based on physician conversation. What percentage of the patients using the current therapy need a dose reduction or discontinuation due to the disease comorbidity?
Your question is about the commercially available options?
Yeah.
The interesting part is that in ASM, these patients, again, this is a disease of mortality. So prior to KIT inhibitor development, so prior to Blueprint's drug, these patients had about a three-year median overall survival prognosis from diagnosis. So these patients are willing to tolerate a lot of toxicity. These patients will continue taking avapritinib with swollen faces, arms, and legs, with cognitive disorders, with fatigue from anemia because they don't have another choice. There's no other active agent available to them. And taking the avapritinib will extend their lives. So we're very excited to move the development of bezuclastinib forward so that in a larger APEX Part 2 study, if we can demonstrate the same profile, that these patients will have a different choice to extend their lives without all of those tolerability challenges.
So to look at a safety profile comprehensively is also very critical next to efficacy for the ASM.
Absolutely.
OK. Great. Now moving to GIST. A lot of multiple programs actually running in GIST and adopting a biomarker approach. And so your second line seems like taking a different approach. Can you maybe first walk through the rationale and in terms of patient coverage, how broad it is?
Yeah, it's a great question. So I think as most people know, first-line, GIST patients are treated around the world with imatinib, which is an amazing drug and confers really, really important benefit for these patients. But unfortunately, the vast majority of patients ultimately will progress on imatinib. And then they're looking for a new therapeutic option. What we know today is that patients progress across a wide variety of mutations that are typically organized in the ATP and activation loop sites, so exon 13, 14, and/or exon 17, 18. And there really are no drugs today that do an effective job of hitting all of those mutations without being dosed to high enough levels where they're going to provide concerning tolerability or safety challenges. What we've done with our drug, remember, we're a very selective KIT inhibitor. We're exceptionally potent at hitting exon 17 and 18 mutations.
We acknowledge that similar to avapritinib and ripretinib and some of the drugs that are close to us, none of us are very good at hitting exon 13, 14 mutations. So dissimilarly from companies that have come before us and have run head-to-head studies of their drug versus standard of care, we're able to run an add-on approach of our drug in addition to the standard of care because of our selectivity and our inability to hit the CNS tissue because the addition of bezuclastinib, importantly, does not seem to add to the tolerability profile of sunitinib. So that really is the special part of bezuclastinib's profile that unlocks that add-on strategy when folks before us have really had to go for a head-to-head. And that's why we think that our phase three trial will end up in a positive outcome as opposed to what we've seen historically.
OK. So selectivity and safety is also a very critical factor, allowing this combo regimen. So in terms of efficacy, what kind of clinical evidence we have seen and how does it compare to the available therapy for this patient population?
Yeah. So in second line GIST, the current standard of care around the world is sunitinib. The best information that we have is from the recent Deciphera INTRIGUE study where ripretinib did not show an advantage over sunitinib. The sunitinib arm showed an 8.3 months median progression-free survival. So that's the assumption that we believe sunitinib will have as a monotherapy. From an admittedly small sample size in our two different phase I/II , we have 11 second line patients. In that patient population, we show the combination delivered a 19.4 month median progression-free survival. And so we've powered now 413 patient phase three trial that's already enrolled and waiting for the PFS events to accrue to demonstrate an approximately 3 and 1/2 month advantage over the 8.3 Sutent. So really anything we believe above 11 and 1/2 to 12 months in that neighborhood should demonstrate a statistical win.
Based on the data we have from our phase I/II, we have quite a bit of room for concerns about regression to the mean from that early data set to win this study. We feel very positive that in about a year, we will be able to announce that there is a new standard of care for second-line GIST patients.
Looking at disease prevalence, how should we think about from GIST to SM the market opportunity for Bezu?
Right. So we noticed that, again, our colleagues at Blueprint have set about a $2 billion U.S. total available market target for the non-advanced SM setting. We are encouraged by their first full year of launch, which will be about a $500 million top line revenue. We think that their numbers make sense to us. And so we also note that there are really only two companies developing drugs in this indication. So about a $2 billion opportunity. In GIST, it's about 3,000 patients a year develop resistance to imatinib. We calculate that's about a $1 billion opportunity on its own. And again, in GIST, there is really no competition. If we win our trial, we expect to establish the combination as a standard of care very rapidly in a non-competitive $1 billion cancer indication.
And then lastly, you already have a lot ongoing through pivotal trials in next year. But we want to touch quickly on the KRAS inhibitor. You recently announced where we are and what's the plan?
Right. So we presented at the Triple Meeting a new program. We have not yet selected a candidate. So we're working rapidly to get to that. Our program is designed to be an exceptionally potent pan-KRAS inhibitor designed in the spirit of our colleagues again at Revolution Medicines, who we think are doing a great job developing a pan-RAS inhibitor. The difference between our programs is that we plan to spare HRAS and NRAS, which we think has potential to cause some of the dose-limiting toxicity or tolerability that they're seeing, and really focus on diseases that are driven by K mutations. So more to come on that. But we're definitely excited to showcase what the Cogent research team can do.
A very comprehensive and insightful discussion. Thanks, Andy, for joining us today. And thanks to everyone for attending.
Great. Thanks, Kelly.