All right, good afternoon, everyone. Thanks for joining us on day two. We're more than halfway through our healthcare conference, first time in Miami, and hope, hope it's, enjoyable for everyone. We're very happy to have Cogent with us and Andy Robbins, CEO. Thank you for joining us.
Awesome. Thanks for having us. We're excited to be here and look forward to a good conversation today.
Great. Well, why don't we start with just a brief overview of Cogent for anyone that may not know the story?
Yeah, absolutely. Happy to do that. And just very briefly, I'm certainly gonna be making some forward-looking statements today, so I'll just point folks to our recent SEC disclosure. We just did our 10-K, so that would be a great one to review. So Cogent, for those that aren't familiar, is a biotech company that's focused on developing the research, development, and ultimately the commercialization of targeted therapies for patients with rare mutationally driven diseases. Our lead asset is a molecule known as bezuclastinib, which is a selective and potent KIT inhibitor. It's in active development now in three registration-directed studies for advanced and the non-advanced forms of systemic mastocytosis, as well as patients with gastrointestinal stromal tumors who are resistant or refractory to imatinib, so second-line GIST patients.
Each of those registration-enabling studies is, is again, in active enrollment and on track to complete enrollment in the case of APEX, the ASM study, and PEAK, the GIST study by the end of this year, and the more recently announced SUMMIT trial in the non-advanced population; we expect to complete enrollment by Q2 of 2025. And importantly, all three studies are on track to have top-line results during 2025, so we will know, by the end of 2025 how the drug performed in all three of its registration-enabling studies. So definitely looking forward to that.
2024 is a year of execution, so the team as a whole is very focused on working with the investigator and patient communities to identify and enroll patients onto the three studies, but we also will have an opportunity later in the year to provide updates with clinical data from each of the three indication programs. So, beyond that, just very briefly, we have a very exciting, what I consider to be the best in the industry, small molecule research team, who are working on a whole number of programs. The three that we've publicly disclosed are a selective and potent FGFR2 inhibitor, a highly CNS-penetrant ErbB2 inhibitor, and then a selective 1047R PI3K alpha program. Our first up, the FGFR2, will enter the clinic later in 2024, and then we'll be announcing specific timelines for INDs and phase I trials for the other two programs.
In addition to those, we have a whole host of earlier stage research programs that, as time passes, we'll get excited and start talking about those as well. But I think for now that's a good start, and, you know, we can dive into some questions.
Great. Well, why don't we start with bezuclastinib? What are, I guess, the characteristics of that molecule, so far? What have you guys shown, and how does it compare to the other KIT inhibitor that's in the market now for ISM?
Yep. So bezuclastinib, we're very excited. If you go back a few years, the company was essentially founded on one of our lead investors who are now still on the board of the company identifying an underappreciated asset at a company called Plexxikon owned by Daiichi that was unwinding itself and unlicensed the drug bezuclastinib primarily for two big reasons. One, it has an amazing selectivity profile, so other than KIT mutant and to a lesser extent KIT wild type, it really does not hit any other kinase to any consequence. So having a highly selective KIT inhibitor for these exquisitely mutationally driven diseases is very important from a target product profile perspective.
The second is it has very, very minimal CNS activity, so the drug just does not penetrate at any clinically relevant concentration into the CNS tissue, so sparing some of the cognitive problems that have been seen with earlier generation KIT-mutant inhibitors, you know, namely avapritinib that you mentioned. So, we think that there's important molecular differentiation, and that is now being borne out in the clinical and empirical data that we're generating. So certainly excited about the profile that we saw a couple years ago and now excited by the data that's being generated.
Okay. And then specifically in ISM, what have you shown in regards to the activity, the serum tryptase reductions? How much exposure data do you have to date?
Yeah. So we have recently presented two different clinical data sets. Our phase I study, essentially our dose-finding trial in non-advanced systemic mastocytosis patients, is called the SUMMIT study. We showed the first 20 patients at the ASH conference in December and then a new cohort of 34 additional patients at the QuadAI conference a few weeks ago. Across those studies, we think the data are very consistent. We're demonstrating at the dose that we're intending to take forward. Remember, this was a dose-finding trial, so we weren't trying to prove that every dose was the right dose of bezuclastinib, but we were trying to find the optimal dose. At the dose we're planning to take forward, we have a very favorable safety profile with an adverse event rate that looks highly consistent to placebo. Number two, we have very strong pharmacodynamic effects, which you referenced.
When you look at biomarkers like serum tryptase, what we demonstrate is essentially every patient has at least a 50% reduction on serum tryptase with a mean speed to normalization of serum tryptase of four weeks. So that is, I think, a very clear signal that from a target engagement perspective, bezuclastinib at this dose is getting the job done. And then when you put those two things together, from demonstrating the clinical benefit using patient-reported outcomes both on symptomatic severity, so how much better do patients' symptoms get over time, and then on quality of life, so how does a patient feel taking the drug, on both of those axes, we demonstrate what has not been shown before, very meaningful, very rapid improvement in symptoms and quality of life, which we believe is a direct correlate of a highly PD-targeting drug with a placebo-like safety profile.
You put those two things together, very good things happen from how do patients feel and perform.
Okay. And then when we look at right now, there's one drug that's approved in ISM, and we're hearing from KOLs that a lot of patients are getting higher than the labeled dose. What does that tell you, when you look at it, you know, the rationale behind that?
Yeah. It's interesting if you go back in time, so, our colleagues at Blueprint advanced a drug called avapritinib first in the advanced systemic mastocytosis population at a dose of 200 milligrams. And then based on some of the safety and tolerability challenges that patients were having at that dose, moved the drug forward in the non-advanced systemic mastocytosis population at a 90% reduced dose. So they, they went forward in what's called the PIONEER study at a 25 milligram dose, and what that delivered was, again, probably unsurprisingly, a very positive safety profile as, the, the drug is simply at a much lower dose than the, the patients at the, the ASM dose were receiving, but it also translated into a much lower pharmacodynamic effect.
So only half of the patients could achieve a 50% improvement on serum tryptase, and that's dissimilar than our trial that I referenced before, where essentially every patient was achieving at least a 50% improvement, and the majority of our patients are getting to normalize tryptase. So, I think what happened practically was the Blueprint designed the trial rationally to allow for a disease of morbidity, not mortality, a patient population that's facing quality of life challenges, to have a safety profile that allows them to get the drug but not with enough drug exposure to really dramatically improve their quality of life.
So what's happening now in the real world, not in a controlled clinical trial fashion, is we know that both the Blueprint medical affairs team as well as some of the key KOLs are suggesting that increasing the dose could lead to improved reductions in the pharmacodynamic markers, so improved reductions in serum tryptase, which probably makes sense. The challenge is how do you thread the needle for a drug that is not selective for KIT and has high CNS penetration because as you increase the dose of that drug, you're gonna implicate cognitive problems in patients, you're gonna implicate the nearly ubiquitous peripheral and periorbital edema that all the patients at the higher dose experience. So essentially you're trading off side effects for symptoms, which we're starting to hear anecdotal evidence of from some of the treating physicians around the country.
Okay. In terms of the serum tryptase reductions, I know there's been a lot of controversy how relevant that is to the clinical picture. You know, it certainly sounds like I mean, it is a measure of mast cells, but in terms of whether it correlates to clinical, the PROs, you know, what, what's been your finding with that?
Yeah. I think there's two important things to think about when you're trying to make comparisons of does changing X or Y in non-advanced systemic mastocytosis translate into Z or Q as an outcome? The first is, that the symptoms that patients experience are multifaceted, multibody symptoms. Some of the symptoms, I think we can agree very rapidly, are almost certainly caused primarily by proliferative and overactive degranulating mast cells like the classic skin rashes and skin symptomology. Other symptoms, like namely depression, anxiety, and somnolence, are almost certainly not caused by mast cell activity in the brain. They're probably caused as a secondary consequence of having a disease that is impacting your quality of life such that you can't have a normal quality of life.
So trying to correlate movements in serum tryptase, a biologic marker, to can I improve things like depression and anxiety is problematic because they are not directly related. Secondary consequences like fatigue, some of these cognitive issues, potentially pain, are almost certainly going to take longer to resolve once you address sort of the primary causes of the biological disease. So that's the first thing to think about. The second thing to think about is PROs or what people like to refer to as total symptom score, essentially the endpoint that measures how good does a patient feel on quality of life or how much better their symptoms are getting, is not a clean efficacy measure. It is a blend of safety and efficacy.
So as you start increasing the exposure of an active drug up, you will start reducing the amount of symptoms or how a patient feels. You'll start improving that. But at a certain level, when you give a drug, all drugs will have off-target tolerability challenges, and as you see adverse events emerge, those scores will come back down. Because if you tell a patient, "You come into the trial with a rash and fatigue," and I give you a drug that takes care of your rash and fatigue, but I give you confusion and dizziness or diarrhea as a side effect of a drug, the patients don't distinguish symptoms from side effects when they fill out their scores. So again, trying to correlate just an absolute composite score to a biomarker is problematic because there is not a clean dose-efficacy relationship that's linear.
The relationship is a blend of efficacy and safety. So we believe very strongly, and we plan to show this as we generate larger data sets, that correlating things like PD markers in non-advanced SM patients to primary symptomatology like derm reactions, skin rashes, wheals, redness is going to be highly correlated, whereas trying to correlate it to downstream effects like depression or fatigue is gonna be more challenging to have a straight-line relationship.
Okay. To put all that together, it's a takeaway. Do you think that patients, most patients, will be able to get the high enough doses of Ayvakit to have a meaningful change in their symptomatology in the course of their disease, or do you think there's an opportunity for another drug to come in, and more fully suppress the symptoms?
So at a very high level, it's always better to be first. But at a deeper level, it's best to be best. So when your second or third drug entering a market that is relatively new to the treating physicians, if you have a profile that is clearly differentiated on safety, on efficacy, on both potentially, I think you have a very strong case to present for not only newly diagnosed patients getting your drug as the initial treatment but also for any patient who has been trying the standard of care, the entrenched incumbent, for long periods of time without complete resolution of their disease. So we acknowledge that there may be a very small proportion of patients two, three years from now that have completely eliminated all the symptoms related to their disease and are leading a normal life as though they didn't ever have mastocytosis.
Those patients, I think, are unlikely to switch from avapritinib. We believe that the vast majority of patients that are would be taking avapritinib two-three years from now will still have residual either symptomology because they haven't gone to a higher dose or side effects from going to a higher dose, and we believe that those patients would be a very effective place for us to try to demonstrate a switching strategy.
Okay. What about a third bucket of patients that have started Ayvakit and stopped it 'cause they weren't getting enough benefit?
And those patients, to me, are even lower hanging fruit, if you will, for I have a disease that made me go to a doctor, try a new medicine, I tried it, it didn't work. Do I wanna try it again? I believe there probably are some patients that say, "You know what? I'm just gonna manage my disease," probably on the more moderate end of the spectrum, but any patient that has life-altering symptoms is always gonna be searching for something that can help them lead a better life. And so we believe with a safety profile and a PD and patient-reported outcomes effects like we saw in SUMMIT Part I, if we can replicate that in a registration-enabling study, we're gonna be an excellent choice for that patient population as well.
Okay. How high do you think that clinicians are willing to go? I mean, Ayvakit's available in 25 milligrams. Do you think they're gonna go 75 or 100 and push it there?
We've heard that there are, let's call them key opinion leaders that probably tend towards hematology specialties that are familiar with dosing the advanced patients at higher doses of Ayvakit and are familiar with the types of early signals of toxicity and safety and tolerability that have even tried up to 100 milligrams doses in non-advanced patients. Look, that's not for us to determine. Is that the right message for Blueprint to be delivering to the market? I think that the risk of generating very serious safety events at higher doses of avapritinib is real and is there. So, for the benefit of patients, we would hope that people don't push the dose that high, but we understand that there are severe symptomatic patients that are looking for any hope or optimism.
To those patients, we would say, we'd like to tell you a little bit more about the SUMMIT trial.
Okay. The flat pricing, I think, makes that a non-event in terms of escalating 'cause it doesn't cost any more.
That's correct. It doesn't cost any more than one of the most expensive drugs in the world, right?
Right. Right. With yeah, and but I do think they're giving pretty significant discounts, like 35%.
Yeah. They haven't described that publicly, but I would not be surprised that they would be needing to do something like that.
Okay. Just a little commentary, I guess, on the different dose. You tried a new formulation with this most recent update. What, what changed in it? I think you showed a PK curve that looked pretty much similar exposure but less, it's a less pill burden. Is that the main difference?
Yeah. Really, the impetus for us changing the formulation is primarily driven by the other disease that we're developing the drug in, which is gastrointestinal stromal tumor patients. So in that disease, which is a disease of many different resistance mutations across the KIT gene, we wanted to push the dose back in the original phase II studies to essentially the maximum tolerated dose to see if there was benefit there. Our predecessor company that we in-licensed it from ran that study, dosed the drug up to 1,000 milligrams daily dose without achieving an MTD, which I think everybody felt comfortable was delivering exposure sufficient to cover the KIT genetic mutations that are known. But at 1,000 milligrams with a 50-milligram tablet, that would be 20 pills per day.
So we embarked upon a project with many different CDMOs to try to reformulate the oral dose with the same active pharmaceutical ingredient to reduce the pill burden for the cancer patient indication. We were successful in delivering, number one, a 75-milligram tablet that's easy to take, and number two, bioavailability of the new formulation that reduced the equivalent exposure of the new formulation at 600 milligrams to the old formulation at 1,000. So for the GIST patients, the consequence of this project was reducing the pill burden from 20 pills per day to eight pills per day, which again, we acknowledge is not the best in the industry by any stretch of the imagination, but in a metastatic oncology indication, it's an acceptable number of pills.
The consequence of this is that as long as we continue moving forward with only the new formulation, we believe that we'll be able to rely on a formulation pattern that protects the surprising increase in bioavailability across the molecule extending the generic protection for the asset. So we've harmonized the new formulation across all of our studies, including both ASM and ISM. It was a slight improvement in pill burden. Now we're giving two pills per day to both ASM patients and non-advanced patients, which I think is exactly the ideal profile for a relatively expensive oral drug in the US. So we're happy with the consequence, but it wasn't done to fix the safety or an efficacy problem. It was really done to fix a pill burden issue with the cancer indication.
Okay. And then in terms of what we've seen with, I guess, KIT inhibition, after you guys have 12-week data, is it reasonable to expect that those efficacy responses are gonna deepen over time with more exposure?
We're definitely excited to see that. So as you referenced in the SUMMIT Part I study, after 12 weeks of placebo-controlled blinded data, we unblind all patients, and the patients on active will be given the option to continue receiving bezuclastinib for as long as they derive benefit, essentially indefinitely. The placebo patients are given the option at that point to cross over onto active drug, and then they too will be able to receive the drug for as long as possible. So, we called it the open-label extension portion of the SUMMIT study. Later in 2024, we expect sort of for the first time to robustly show data from that.
What we wanna do is have sort of a minimum amount of follow-up on the most recent patients to enter the OLE so that we can look at the totality of the data, both safety and tolerability as well as effect size. I think what we've seen from our own data at ASH in Part IA as well as our competitors' data on their KIT inhibitors, it looks like the effect size or the improvement in symptoms and quality of life does continue to improve, maybe not as rapidly as in the first 12 or 24 weeks over time, but it does continue to improve. So we're very excited to see does that dynamic apply to bezuclastinib as well.
Getting to a point where we're already improving mean 12-week symptomatology by 51%. I think we're anticipating a really exciting number at 24 weeks or 48 weeks. And certainly on behalf of the patients, we'd love to get that number to all patients getting significant clinical benefit.
Is there any risk to resistance developing over time?
We have heard that at the low doses of avapritinib in the real world that allergists that have prescribed the drug have seen, you know, early improvement in things like the dermatological effects and then sort of regressions where patients that continue on at 25 milligrams, some of their dermatologic symptoms return over time over three, four, five, six months. Those are anecdotal reports that when we talk to physicians about their experience with the drug, we have not seen any scientific evidence of resistance outside of D816V in mastocytosis patients, but of course, we will continue to monitor the space for that.
Okay. Any reason why the skin would be the one symptom that would manifest that?
I think in the minds of these physicians, that's the one that they saw improve, where some of the other domains on 25 mg of avapritinib don't see those rapid improvements like GI and pain and fatigue and cognitive. Really, the noticeable effect of that drug at that dose, I think early on, is the dermatologic effects. So I think what they're seeing is a little bit of benefit and then sort of reversal of that benefit over time.
Okay. And then, you guys also, besides not being CNS penetrant, you don't hit PDGFR alpha. And what's the benefit? Well, is there a benefit and trade-off by not hitting that?
There's no benefit in mastocytosis to hitting PDGFR. It's not implicated in driving the disease. The detriment of hitting PDGFR is I think it's well characterized that inhibiting PDGFR causes edema or fluid retention, which is, I think, very nicely evidenced by avapritinib and elenestinib, which are very, very strong PDGFR inhibitors, having at higher doses essentially ubiquitous peripheral edema across all patients. As you bring the dose down to 25 milligrams, a lot of that edema goes away, which is a function of not hitting PDGFR very hard. So I think it's a really nice PD experiment between the 200-milligram dose of PATHFINDER and the 25-milligram dose of PIONEER to see the relative rates of edema, as a function of target engagement of PDGFR.
Okay. Maybe one question on the next-generation Ayvakit. You alluded to it. It's not CNS penetrant, but it seems to have a very similar profile otherwise versus Ayvakit. I guess the question is, you know, we've seen on the label they have bleeding outside the CNS. And, do you think that could be an issue with this drug too?
We don't know. We know that bezuclastinib is being delivered at a level that appears relatively consistent on potency against KIT to avapritinib given the data they presented at ASH across their 25, 15, 100-mg groups. We know that in preclinical experiments looking at head-to-head xenograft models, you need about six times as much bezuclastinib to achieve the same tumor growth inhibition as avapritinib. So it looks like in the clinical experiment, they're approximately hitting the target about as hard as avapritinib, even though their numeric milligram doses are higher. I think their exposures are about the same.
So I would expect that the safety profile of, like, the 25-50 mg bezuclastinib would look pretty similar to the low-dose avapritinib, but I think what you also saw at ASH is that they have a very similar effect on symptomology improvement with about a 25%-30% increase in symptoms at 12 weeks, which is consistent with avapritinib at 25 mg.
Okay. For the last five minutes, I think we should talk about GIST.
Sure.
I think it's fair to say that the investors are not focused on that for you at this point. It's kind of been eclipsed by ISM, I guess, and the ASM datasets. What would you say about the upcoming dataset and your opportunity in GIST? Since you've started that trial, we've had a couple of other drugs fail in that indication, so it does seem to be, you know, you have a head start from everybody else.
Yeah. So a couple of things. There were, in the GIST community, I'm gonna talk about imatinib-resistant GIST, so second, third line. There's two very well-known phase III trials that did not meet the primary endpoint for the novel agent. First was Blueprint's avapritinib and I think the VOYAGER study that ran head-to-head against regorafenib in the third line, and then more recently was Deciphera's INTRIGUE study that ran their drug ripretinib head-to-head against sunitinib in the second line. Each of those studies essentially took an exon 17 and 18 inhibitor, which is responsible for about half of the resistance mutations in the GIST population, and ran it head-to-head against a drug that is very active against exon 13, 14 resistance mutations, which is the other half of the resistance mutations.
So both of those studies essentially ran to a tie, and the tie goes to the incumbent. Our clinical development plan is quite a bit different, which is enabled by the selectivity of bezuclastinib being able to combine it with the incumbent. So our strategy is not a head-to-head study. It's an add-on approach where sunitinib in the second-line setting is in both arms, and then in the active arm, you add bezuclastinib to it. So we've published data a couple of times now of the 42-patient lead-in study that demonstrates the safety and tolerability of the combination, again, enabled by that very hyperselectivity of bezuclastinib looks numerically similar to Sutent single agent. So we're not adding toxicity to the single agent standard of care.
That approach and allowing for all of the resistance mutations to be covered in the active arm, we believe, is going to lead to a successful outcome in the phase III trial. Just to remind folks the timing of that, we initiated that phase III study. It's just under a 400-patient study with progression-free survival as the primary endpoint. We started that in the very late 2022, and we have always had a plan to complete that enrollment by the end of 2024, and we remain on track, based on where enrollment is today to meet that goal. Because it's a progression-free survival endpoint, we are a little bit at the mercy of when those events accrue, but our latest estimate for when that would occur is by the end of 2025.
So we believe, as you referenced before, Blueprint and Decipher from a broad second-line GIST perspective are no longer relevant. There was another company called Theseus whose drug ran into some safety issues, and they stopped the development of that drug. There are a couple very early-stage programs that are probably four-five years behind where we are at this point. We think we have a clear path to a commercially attractive oncology indication with essentially no competition, which is a very rare spot for a company of our valuation to be nearing the completion of their phase III trial.
We have some data from Deciphera, where they did the analysis of where QINLOCK is effective. You know, it was a pretty striking analysis, and not only did the response rates go way up versus Sutent, which was zero, I believe, but the duration was very impressive. So what do you think the duration in the second line could be with your approach?
Yeah. So I'll kind of give you the benchmarks of what you just referenced. So in the INTRIGUE study, in the unselected population, the results were that Sutent performed at 8.3 months of median progression-free survival, and Qinlock performed at 8.0 months. So essentially a tie, and they didn't meet the statistics, obviously, for that. But in a very selected patient population with a primary exon 11 mutation and a secondary mutation only in exon 17, which represents about 15% of the second-line population, they showed a 14.4-month median progression-free survival, so an outsize effect, as you referenced. What we sort of, humbly showed the world is that in the patients that had been dosed with the combination of bezuclastinib and sunitinib that had that same genetic signature from the phase I studies, we have a 16.7-month median progression-free survival.
So I can't say, with the sample size that small, that we're definitively better, but there's no evidence to suggest that those patients would not also benefit from our combination. And so what we're seeing in the actual community around the world is very robust enrollment into the PEAK study because there's not a concern that if you find one of these patients, you would be sacrificing some sort of efficacy by giving them the combination. What I believe is most likely to happen is in the unselected population, I feel very strongly that we will show a clinically meaningful benefit on PFS, and in a subset on that same genotype patient population, we will show a similarly outsized effect because our drug, bezuclastinib, is actually a more potent exon 17 inhibitor than ripretinib.
Right. The trial that they're running in that biomarker-enriched population, if you were a patient and you were, I think it's open label. If you were given, you know, Sutent, do you think they're gonna have a hard time keeping the patients in that trial or enrolling it?
I think in the U.S., they will because in the U.S., if you're a patient and you prospectively know that you have this genotype signature and you know that there's a negative overall survival consequence to getting sunitinib, and then your physician tells you you're randomized to sunitinib, I would counsel my friend or family member to withdraw consent and ask them to prescribe me commercial ripretinib.
Right.
Yeah.
Okay. Thank you, Andy.
Yeah, absolutely.
How's that going for progress? Look forward to the data.
Thank you very much. Great, great to be here.
Thanks, everyone.