Good morning, everyone. I'm Andy Berens , Senior Biotech Analyst at Leerink Partners. Welcome to day three of our healthcare conference in sunny Miami. We're very excited today to have Andy Robbins from Cogent with us, CEO of the company. Thank you, Andy, for joining us.
Great. Thanks for having me.
Why don't we start with an overview? You guys have a very big year, and we're going to go into the different programs. We only have half an hour, so we may not get to cover all of them. An overview of the company for those who may not know Cogent.
Yeah. Again, thanks for inviting us to the conference. I'm excited to be down here, as you said, in sunny Miami. I just want to remind folks I'll be making some forward-looking statements. Please refer back to our recent filings for a careful elucidation of the risk associated with Cogent. For those that aren't aware, Cogent is a small molecule company focused on creating best-in-class therapies for patient populations with rare genetically driven diseases. Our lead asset is a molecule known as bezuclastinib. It's a selective and potent KIT inhibitor that's designed to help patients with both systemic mastocytosis as well as gastrointestinal stromal tumors. We are complete now in enrolling all three of our pivotal studies across two different forms of the mastocytosis indication and the second-line GIST indication.
All three of those trials are on schedule to read out the pivotal trial results during calendar year 2025. This year is a very busy and exciting year for us, with planned results from our first study, the SUMMIT trial in the non-advanced mastocytosis indication, on slate for July of this year. Subsequently, in the second half of the year, we plan to release the results of our advanced systemic mastocytosis trial known as the APEX study. Finally, sometime before the end of the year, we're expecting results from the PEAK phase III trial of bezuclastinib in combination with sunitinib for patients with, again, that second-line gastrointestinal stromal tumor indication.
In addition to bezuclastinib, which I assume we'll spend most of the time today talking about, we're building what we consider to be one of the best-in-class small molecule pipelines, highlighted by our FGFR2-selective compound that has recently gone into first in human phase I dose finding study. We are excited to now have a second compound in clinic, with plans to put potentially two additional programs into at least IND filing by the end of this year.
Great. I think why don't we go in the order that the data sets are coming? I think that may be just as one of the ones a lot of people are interested in, but hopefully we can spend some time on that also.
Sounds good.
Obviously, ISM is a big focus of investors. There's a drug that was approved recently for ISM by Blueprint. I am just wondering, I guess, what you've learned from the launch of AYVAKIT, what they showed in the clinic versus kind of what they're seeing in the real world and how it represents a potential opportunity for you guys.
Yeah. As you said, this is a patient population estimated to be upwards of 20,000 patients in the United States that until very recently had no drugs that actually treated the disease. These are patients that have a host of symptomatic issues as a result of a genetic mutation known as D816V in the KIT gene on exon 17. Those symptomatic issues were really physicians just tried to tamp them down with various symptomatic therapies that treated individual symptoms. For the first time, and we give credit to our colleagues at Blueprint, they brought along a drug that hits the same mutation, D816V, known as avapritinib, or AYVAKIT. They were approved at a very low dose relative to where they've shown clinical efficacy in the more severe patient population.
What we know from both their clinical trial and the real-world experience is that it provides limited symptomatic benefit to patients. It's admittedly well tolerated at the low dose, but these patients are searching for a drug that can give them deeper, faster, and more sustained symptomatic improvement. That is the design of our SUMMIT trial, studying our KIT inhibitor, which is similarly potent to avapritinib, but at the clinically effective dose. The reason we can do that in this patient population is that we spare many of the off-target kinases that avapritinib also targets, like PDGFR, CSF1R, FLT3, and our drug is not CNS -penetrant, unlike avapritinib, which allows us to dose that clinically effective dose without the cognitive impairment that is resident with that drug at, again, the clinically effective doses. What we've learned from their launch is that this is a very large patient population.
While it's clearly a rare disease, I think their recent guidance is that they plan to sell around $700 million this year, predominantly in the U.S. They're definitely on track to being blockbuster status billion-dollar drug. That is important for us as they're demonstrating that this is a very commercially attractive market, especially in a setting where these patients are not completely resolving their symptoms. In May, at the time that we have our results and then subsequently hopefully get approved, we'll be looking for a therapy that can bring them to deeper, faster, more sustained symptomatic improvement.
Okay. What's your sense when I think of this patient population? It's chronic disease. It's not malignant. These patients live a long time. Do you think that patients are going to and physicians are going to stick with one drug? I mean, right now there's AYVAKIT and then there's a lot of over-the-counter drugs that are not approved in ISM that are used. Do you think that there's another alternative? You're going to see patients and doctors switching different therapies and seeing which works?
We think that these patients and physicians will operate like many folks across many different diseases, where if you have situations where individuals have complete resolution of their symptoms taking low-dose avapritinib, then they may want to stick with that long term. That makes perfect logical sense to us. From our conversations with Patient Advocacy Groups, with patients themselves, with physicians, both hematologists and allergists, we have really not yet found patients that are completely resolved of their symptoms while taking low-dose avapritinib. For the vast majority of patients who are on low-dose avapritinib, we think that they still have symptomatic issues and that they would be very interested in considering another drug that potentially would come to the market with outsized efficacy benefits. That is sort of how we see the market shaping up in the future.
If bezuclastinib can demonstrate deeper, more rapid, more sustained symptomatic benefits, then we don't understand why a patient who isn't completely resolved and isn't cured of their symptoms wouldn't want to try a new offering that has that outsized symptomatic relief.
Right. I think, and I'm sure you've heard, like we've heard, there are anecdotal experiences of patients switching from ava to bezu and getting more relief. Will you have a fair number of patients, you think, in SUMMIT that are switchers?
Yeah. It's a very interesting aspect of our trial is we allowed for patients who have prior experience with avapritinib. We think most of the time patients have come off of avapritinib into the SUMMIT trial for that lack of symptomatic improvement. We'll have a minority of the patients in SUMMIT, but sort of a noticeable minority where we'll be able to do a subset and show what might it look like for you as a patient if you've been taking avapritinib for six months or 12 months or two years commercially. Here's a cohort of patients that look like you and what is their clinical benefit and the improvement that they've experienced on bezuclastinib.
We think that could be very powerful when we get to the market and we have conversations with physicians about what do I do with patients that have been trying ava for a year or two and they have not quite got to the level that they want to get to.
Right. What percentage of patients do you think could get better efficacy or better safety tolerability that are on ava currently?
If we look back to avapritinib results from the PIONEER trial on the primary endpoint of improvement in total symptom score or the composite of symptomatic improvement on a placebo-adjusted basis, they measure improvement on a scale of 0 - 110, and they showed a placebo-adjusted improvement of 6.4 points on a 110-point scale. There is quite a bit of room for a new drug to come and improve upon the level of symptomatic benefit that avapritinib demonstrated in their pivotal trial. In our humble opinion, most, if not close to all, of patients on avapritinib will not be resolved, will not be cured of their symptoms, and would be candidates looking for something that could help them achieve better symptomatic improvement.
Okay. Is it fair to say you don't think that their first mover advantage is going to be an impediment?
It's always better to be first, but it's best to be best. We very much look forward to seeing the results of the SUMMIT trial in July of this year. Again, thinking about that six-point placebo-adjusted improvement on a 110-point scale, what is the potential for a drug that more potently hits the target, demonstrates that with the pharmacodynamic effect, and translates that into a symptomatic benefit? What is the potential for a drug like bezuclastinib that's actually doing what these patients want to do, which is making them feel better?
Right. I would assume that there's also an advantage to being a fast follower with a potentially better molecule that let your competitor establish the market, establish pricing, and then coming into the market with another option.
As we sort of kicked off this conversation, we're certainly complimentary of Blueprint's launch. They are doing a great job with disease awareness and education, and especially with hematologists and what we call the more sophisticated or complex allergists in the U.S. treating the more complicated allergy cases. I think that those physicians really understand the need for a potent KIT inhibitor in this patient population. We look forward to bringing them a new option that hopefully will show better symptomatic benefit.
Okay. They recently put out a revised number of $4 billion as the potential market. Is that something that you think is a realistic number based on your research?
Yeah, it's an interesting question. While we would like to sign up to the $4 billion number, I don't even know if you need to get to that level to make an investment in Cogent, an attractive investment. Our numbers are probably closer to the $2 billion total available market. That is just for the moderate to severe non-advanced systemic mastocytosis patients.
I think if you really kind of unpack their number, they're probably extending that to the more mild cases, looking to potentially move their drug with a profile of very well tolerated with sort of minimal symptomatic improvement to those patients that are on the more mild end of the spectrum that have either episodic or low-level symptomatic issues, where I think a drug like bezuclastinib, with its potency and its hopefully higher level of symptomatic benefit, could be more of a match for those moderate to severe patients.
Right. Before I forget, you mentioned the six-point delta. What do you think is a clinically meaningful delta in that scale? I mean, there's obviously a lot of noise to some of these PROs, but what do you think is kind of the delta you'd like to see to say, hey, this drug is really helping patients a lot more than six points?
Yeah. I mean, if we just look at the market reaction, again, credit to Blueprint for potentially selling $700 million predominantly in the U.S. in 2025, that seems clinically relevant. It seems like the treating physicians have sat up and taken notice and are prescribing the drug. We think incremental benefit above that would be better. When we look at the PD effect of bezuclastinib, when we look at the phase I symptomatic improvements, not just on the composite total symptom score, but also things like the percent of patients who get to certain thresholds, the one that seems most clinically relevant both to the investigators and to the regulators is a 50% improvement from baseline in symptoms for patients. When you look at the results of the PIONEER study, they had just under 25% of their patients achieve that threshold.
When you look at the results that we've presented recently from our phase I at our recommended phase II dose, we have north of 75% of patients getting there. Certainly a tripling of effect size, I think in anybody's estimation would be clinically relevant. I don't even know that you need to get to that level. I think if you can show a 50% improvement on what they've done, 100% improvement on what they've done, I think that physicians and patients will set up and take notice.
Right. It sounds like they're getting 25% over that 50% improvement in symptoms. It could mean that the other 75% of patients are open to an alternate therapy.
Yeah. Even the patients that get a 50% improvement, if you look longer term out, they haven't shown the data the way that we show it with our waterfall plots of how close to the 100% are you getting, where does the baseline start, where do you get to? When you look at things like most severe symptom at baseline, we're showing probably a doubling of effect size, admittedly our smaller phase I study compared to their pivotal trial. Across the board on the composite endpoints, symptomatic improvement, whether you measure it as total symptom score, threshold analysis, most severe symptom at baseline, individual symptom improvements, the data that we've shown so far is somewhere between doubling and tripling what they showed in their larger registration trial.
We definitely are looking forward to seeing the results of our larger 179-patient pivotal study, the SUMMIT Part 2, that's slated again to read out in July. Once we see those results, then we'll have a much better sense for what does that look like compared to the results of their trial.
Okay. They recently presented some data, quote, you guys did too, but I think their data set was interesting. It was patients, around 60 patients that escalated to 50 mg and obviously relevant to AYVAKIT and the dynamic that they're seeing in the marketplace, but probably equally relevant to you guys. What did you glean from that presentation? What were the main takeaways?
Yeah. We're familiar with the presentation that you're referencing at AAAAI . I think a lot of the narrative was there's maybe some confusing safety and tolerability data associated with what Blueprint presented at the higher dose. We hear anecdotally, and I'm stepping away from that poster for a second, as patients' dose escalates, some of those off-target effects start to manifest. When you dose up from 25 mg to 50 mg of avapritinib, we hear anecdotes of periorbital and peripheral edema as a consequence of increasing the exposure of avapritinib. We hear incidents of cognitive issues at those higher doses.
Certainly, as you dose up avapritinib, given some of the safety issues that they've shown relative to platelets and bleeding risk, I think you automatically bring on any sophisticated physician treating them the need to monitor for level of platelets on a regular basis to try to avoid some of those more serious consequences of bleeding risk, including intracranial hemorrhage. I think the strategy is at 25 mg, avapritinib is not achieving very impressive symptomatic improvement. One thing you can do with a medicine is try to increase the exposure, increase the dose. The issue with that drug and its therapeutic index is as you increase the dose, you start bringing in some of those safety concerns.
It's a pretty narrow window to try to find what we're hopefully going to show with bezuclastinib is at a much higher exposure and target engagement of this monogenetic-driven disease, you can have that therapeutic index that allows patients to achieve the really robust symptomatic improvement. Again, we're looking forward to that in literally a handful of months.
Right. Now we've heard the same mostly anecdotal experiences that a fair number of patients that dose up to 50 mg, the two things that we hear that some of them can't tolerate is the edema, probably number one, and then the cognitive stuff, number two. Number two, I think your drug, it's obvious that it doesn't penetrate the CNS, so it should have a benefit on the cognitive aspects. The periorbital edema is interesting because I do remember that being something they highlighted versus another company that was recently acquired, Deciphera. They always highlighted that as a KIT aspect. What do we know about the periorbital edema and why would you not see the same thing being a more potent KIT inhibitor?
Yeah, it's a good question. We see the edema as associated very closely to inhibition of PDGFR. If you look at the cellular potency of avapritinib, they're equivalently potent on KIT, mutant, and PDGFR. When you review their data that they presented from the PATHFINDER study in the advanced population at what we acknowledge is a very clinically effective dose of 200 mg, they have close to 80% incidence of periorbital and peripheral edema. We spare PDGFR. We do not inhibit that kinase. You can see that our rates of edema at our IC90 type concentration are 10% or less, sort of background noise in a single-arm trial of advanced systemic mastocytosis patients. When you dose avapritinib down from 200 mg down to 25 mg, all of the edema seems to have gone away, which is, I think, evidence that they're not hitting PDGFR.
When PDGFR and KIT are equal potent and you're sparing PDGFR, you're also probably sparing the KIT benefit at that dose level. We definitely look forward again in a few months to reading out our data and much rather be talking about our data. I know it's not time yet, but we're very excited about the potential for a drug that can get to that IC90 type inhibition of this mutant-driven disease while sparing some of those off-target issues of the first-generation inhibitor.
Yeah. Why don't we talk a little bit about the data? You had an update at AAAAI . You want to summarize what you guys showed recently at the meeting?
Yeah. At AAAAI , what we did is we took the data that we had shared at ASH from our subset of patients that had received the recommended phase II dose and said for the patients that had received it for at least a year, 48 weeks, what is the improvement or do we have sustained improvement on symptoms? We showed that, in fact, yes, we do. On the composite endpoint on total symptom score, about a 65% average improvement over that 48-week period. When you look at patients that had received bezuclastinib at the intended take-forward dose for 48 weeks, nearly 90% of them achieved that 50% improvement in symptomatic benefit.
I think showing again, rapid response, deep response, and then at AAAAI , the sustained response of using bezuclastinib over that 48-week period where you're starting to have some of the investigators talk about complete resolution of symptoms for patients, which is not obviously going to happen in every patient, but it is an encouraging goal for this long-term chronic treatment to really return these patients to a normal lifestyle.
Okay. When we see the data in July, can you just give us an insight into what we can expect from the top-line release? I'm sure you'll want to present it at a medical meeting, but will there be enough detail in the top line to make an assumption of how efficacious the data are?
Yeah, another really good question. Kind of previewing, we would expect to obviously have a press release on the day when we're in possession of those results. We would likely invite a friend or two who can speak to the clinical relevance of the results of the trial, a key opinion leader in an analyst call that day. Really what we'd be focused on is, of course, the primary endpoint. The primary endpoint in these trials is a 24-week assessment of total symptom score compared to active arm versus placebo. Obviously, safety and tolerability would be part of that presentation. Then to your point, trying to ensure that we hold back enough of the data to allow ourselves to present at a medical meeting.
I think what we've said to investors along the way is we might take a page out of our colleagues at Blueprint's book when they brought out their pivotal PIONEER data, which I think was August of 2022, really focused on the primary endpoint, some of the PD endpoints and the safety, and then some of those secondary endpoints saved for later at a medical meeting. We'll see when we get a chance to see the totality of the data.
Right. No, it sounds like it'll be a fairly comprehensive day. That is great. Thank you for doing that. PIONEER had, and you highlighted the six-point delta, they saw an increase in the placebo response from Part 1 to Part 2. Do you understand why they did that? Is that something we should expect to see in your trial?
Yeah, it's a common question. We need to go back in history a little bit. PIONEER Part 1, and this is not, Blueprint didn't do this to be sneaky or anything. PIONEER Part 1 wasn't blinded. They were disclosing to patients at every visit their level of tryptase. When your level of tryptase doesn't change when you're getting a KIT inhibitor, you're functionally unblinding the patients. It's not surprising that the placebo effect in PIONEER Part 1 was essentially zero. You can read this through their protocol updates and some of the summary basis of approval FDA communication. They took steps to ensure that patients in PIONEER Part 2, the registration trial, were not told their tryptase levels or any of their lab values. Therefore, they did an effective job at blinding PIONEER Part 2.
In PIONEER Part 2, you saw a nine-point performance on that same scale for the placebo patients. That is highly consistent with the placebo effect that we've seen in our blinded SUMMIT Part 1. Interestingly, in Blueprint's backup compound, elenestinib, HARBOR Part 1. In all of the non-advanced mastocytosis studies that have been truly blinded for the patients, the placebo effect has been very consistent. It is only in that PIONEER Part 1 where it was not really a blinded study that you saw a difference.
Right. I would assume, because I think if I recall, PIONEER Part 1, they were using multiple doses. They probably saw the edema, which I guess is hard to mask that versus placebo, right?
Yeah, in the higher, the 50 mg and 100 mg cohorts.
Yeah. Okay. We do not have much time left. I guess just quickly on ASM, they have had difficulty building that market, I think. I would like to hear your view on if you had a drug that could be used in combination with treatment for associated hematologic neoplasms , how big could ASM be?
Yeah. ASM is admittedly a smaller indication than the non-advanced setting. It's probably about 10% of mastocytosis patients are diagnosed with the advanced form of the disease. Within that admittedly smaller subgroup, a majority of those patients present with an associated hematologic neoplasm, the AHN component. Many of those patients are being treated with interventional therapies that have their own list of side effects. What physicians are unwilling to do is put two drugs together that both have significant hematologic toxicity. When you dose avapritinib at its potent IC90 type dose at 200 mg, you see an awful lot of grade three, four thrombocytopenia and neutropenia. When you try to put that together with a drug like azacitidine, which has its own struggles with sort of high-grade hematologic toxicity, it becomes a problem.
What we're looking forward to out of our APEX study later in the year is can we demonstrate that same level of potency against the mutant-driven target, which to their credit, they have a high response rate. We expect to have a similar response rate, but without some of those liabilities on the safety side, including those high-grade hematologic toxicities, which may unlock the ability for bezuclastinib to be used concomitantly with some of those AHN directive therapies. If that comes to pass, I think the ASM market can approach $300 million by itself in the U.S. I think that that market would be very nicely matched with a drug with a profile like bezuclastinib.
Okay. Just on GIST, there's been a number of trials in GIST. People, I think, underestimated the incumbent therapies. Some of those trials have failed. There have been some later line approvals. What are you guys doing differently? How do we have confidence that your approach is going to actually be differentiated versus what happened with avapritinib in the third line and Deciphera's QINLOCK in the second line?
Yeah. Fundamentally, what we like to do, we're a curious company. We like to understand to the best of our abilities what happened with those trials you cited, I think, VOYAGER and INTRIGUE respectively for avapritinib and ripretinib. When we look at the profile of avapritinib and ripretinib and bezuclastinib with regards to the mutants that are common in the refractory GIST population, each of our drugs, I would say, is similarly potent against patients that have exon 17 and 18 mutations. I might be able to argue our drug is a little bit better, but I think we're all in the same ballpark. Interestingly, I do not believe any of our drugs is very effective at covering or helping patients that have tumors that are being driven by cells with an exon 13, 14 mutation.
What we believe happened in both the VOYAGER and the INTRIGUE trials is when you take an exon 17, 18 inhibitor like an avapritinib or a ripretinib, and you run it head-to-head against a drug like regorafenib or sunitinib that do have activity against exon 13, 14, you sort of race to a tie. The patients that present with a primary 13/14 driver, they do well on the control arm and not so well on the active arm, and vice versa. The patients with the 17, 18 do well on the active arm and not on the control arm. What we've done that's a little bit different and is allowed by the really, really high degree of selectivity of bezuclastinib is it enables us to combine with sunitinib.
If we ran our phase III GIST study as a single agent bezuclastinib against a drug like sunitinib or regorafenib, we would probably meet the same fate that VOYAGER and INTRIGUE met. We would probably be active in the 17, 18s and not so much in the 13, 14s. Because of our advantage, non-CNS penetrant, do not hit the other class three RTKs, we can put bezuclastinib on top of sunitinib without exacerbating any of the tolerability of sunitinib. That combination of having all of the coverage across exon 13, 14 and 17, 18 is what we believe scientifically will lead us to a win when comparing to the control arm of exon 13, 14 inhibition alone.
Okay. How quickly has that trial enrolled? I mean, that approach, is that something that you think clinicians are open to doing?
Yeah. When you go back in time, those other trials we cited, I think, had enrollment periods of 24 months and 29 months for those two phase III trials in refractory GIST. We enrolled our study in just under 20 months from very late 2022 when we had the last patient first visit at the end of July of 2024. What we're projecting from an event PFS rate is the results will be available by the end of this year. The study is powered to show about a three-month advantage working on the assumption that the control arm will be highly analogous to the INTRIGUE study of around eight months for SUTENT PFS. What we're hoping to do is kind of push up or potentially above that year of PFS in the second line benchmark.
We think that that would be both approvable and clinically relevant and potentially establish bezuclastinib in combination with sunitinib as the new standard of care globally in a billion-dollar-plus cancer market with really no competition. SUTENT, as we all know, is now generic. It's been around for 20 years. Giving these patients that have waited 20 years for a new therapy, a new combo that would push forward their progression-free survival is very exciting, obviously, to the patient community and to the investigators.
Maybe one last question. I know we're a little over, but if you're successful in the GIST trial and establish that as an option, maybe the new standard of care in that setting, could somebody come in and run another trial against SUTENT, or do you think that that's, I mean, is that going to be a tough trial to enroll? If it does enroll, what would be the implications of beating SUTENT as a monotherapy?
Yeah. I think there's a question about IDRx, which was acquired by GlaxoSmithKline. They claim that their drug is a pan-KIT inhibitor all in one. They also are a broad class three RTK, hit PDGFR and CSF1R, FLT3, KDR, etc . From a regulatory perspective, you can absolutely run the trial you're talking about. I think it would be challenging in developed markets like the U.S. and Western Europe to ask patients who would be unblinded to stay on a drug like SUTENT monotherapy as a control arm when it's already been demonstrated that there's a new, more effective, longer survival therapy available to those patients.
We don't know what they're going to do, but they have to take that into account that patients may withdraw consent knowing that they're taking a drug that has been proven to be less effective at helping them as an individual live longer.
Would these patients potentially know that they have exon 17, 18 that are enrolled in the SUTENT arm?
They probably wouldn't know their genotyping. Again, we don't know GSK's plan for how to do these studies. Based on the time and the logistics, especially on a global study, it's very hard to use genotyping for baseline inclusion criteria. Typically, the patients only find out subsequently, not right in the beginning.
Right. Thank you, Andy. Congrats on the progress. Big year for you. Thanks for joining us and walking us through the story.
Appreciate it. Thanks, Andy.
Thanks everyone for joining us.
Yeah.