Good afternoon, everyone. It's the final countdown to the end of our Annual Healthcare Conference. We saved some of the best for last. We're very happy to have with us Andrew Robbins from Cogent. Got a lot going on. He had a lot going on last year. The company's in a new phase now, pre-commercial. Congratulations on all the success last time, last year.
Great. Thanks, Andy, and appreciate you inviting us, and glad to be at your conference, and I look forward to a good discussion today for sure.
Great. Can we get a overview of Cogent?
Sure. Just to remind folks, I'm gonna probably be making some forward-looking statements, so make sure you take a look at our recent SEC docs for a full disclosure of risk associated with the company. Again, for folks that are new to the company, I'm Andy, I'm the CEO. Cogent is a biotech company that's focused on the discovery, development, and hopefully very soon the commercialization of novel small molecule targeted therapies for patients with rare diseases that are driven by mutations. Our lead asset is a drug called bezuclastinib, and that is being developed in three patient populations, two forms of systemic mastocytosis, the non-advanced and the advanced form, as well as in gastrointestinal stromal tumors.
Each of those three patient populations, we ran a pivotal study over the past several years, and each of those pivotal studies read out positively in the second half of 2025. At this point, as Andy mentioned, we're getting ready to be a commercial company. We're going through the process of submitting each of those trials through parallel new drug applications to the FDA. We expect based on how the FDA decides to grant review times that we would launch somewhere between one and all three of those indications by the end of the year. At the latest, we would be commercial in all three indications in early 2027. Really looking forward to that.
In addition to bezuclastinib, which I'm sure we'll spend most of the time talking about today, we're also inventing and developing a host of pipeline assets that are each targeted to different patient populations based on those specific mutant drivers. What we try to do is create the best-in-class assets to precedented targets, designing molecules that have very specific scientific hypothesis about how to solve some of the liabilities with more advanced or earlier or more mature products from competitors in the pipeline. We might be able to talk about a few of those as well today.
Absolutely. Just a little bit of your background. This is obviously not your first rodeo. You wanna give the audience.
Sure. In my personal background, for several years I worked at a little company called Pfizer in the Oncology Division. Really, you know, sort of cut my teeth and learned about the pharmaceutical industry there. Also worked for a company called Hospira, which is now part of Pfizer, working across a host of different products and technologies focused in rare disease patient populations, oncology predominantly. Most recently, I was the Chief Operating Officer of a company called Array BioPharma for about the last eight years of its existence before I joined Cogent. If you followed that story, Array was very well known as an excellent chemistry company, developed many successful products that are now in the hands of patients around the world.
In addition to the MEK and the BRAF that is most probably best well known for associated with Array, that team of scientists also developed all the drugs for Loxo Oncology, Mirati Therapeutics, several other drugs for Seattle Genetics, Celgene, Genentech, et cetera. Part of me coming over to Cogent, much of the research division at Cogent now has its roots and legacy with my old colleagues at Array BioPharma. The folks who are inventing the next generation of Cogent Biosciences drugs have a lot of experience and expertise at designing best-in-class chemical molecules for other organizations, including Array.
Great. Well, thank you for that. Why don't we dive into each of those indications now? One of the things we like also about Cogent, it's definitely one of our top picks this year, is besides the fundamental value of having validated commercial opportunities, there's a lot of strategic value because there's been a number of deals in similar settings, right?
I mean, I don't have that job. I did at one point, was on the buy side of a strategic. You know, certainly you can imagine that folks that are looking for opportunities to fill either patent gaps or revenue gaps would be interested in companies like Cogent as well as, you know, other companies in the industry. But what I can say from Cogent's perspective is we're hyper-focused on commercializing bezuclastinib, building our commercial team, ensuring that our launch is gonna be excellent. While we are a publicly traded company, it is possible for, you know, larger companies who are interested to approach our board, but that's not our focus right now.
Our focus is maximizing the value of bezuclastinib, getting it into the hands of as many patients as possible, and that's we're gonna keep our heads down and focus on that.
Okay. Well, let's talk about some of those opportunities and the preparations. Let's start with ISM. I think you've previously said it's a $3.5 billion global opportunity. Can you give us some insights into those numbers?
Sure. We call it the non-advanced mastocytosis. The way that we developed bezuclastinib in what's called the SUMMIT trial was to allow patients with all forms of the non-advanced mastocytosis disease, both indolent, smoldering and bone marrow mastocytosis. We will be a little distinct from the main competitor, avapritinib, that only allowed indolent patients into their PIONEER trial. When you think about sort of the global epidemiology, there's probably around 30,000 patients with non-advanced systemic mastocytosis in the United States. That's an estimate. Not all of those patients are diagnosed with the disease.
About 6,000-8,000 of that 30,000 have what we and I think other folks that have done this work deem to be moderate to severe symptoms that would expect to result in taking a chronic therapy designed to help them lead a better quality of life. That is how we kind of see the treatable patient population. If you look at the main competitor, the only drug approved in this indication, AYVAKIT, they're probably right now treating around ±2,000 patients in the U.S.
If you kind of go back through the historical scripts, there's probably another 1,000 or so patients that have either tried the drug or a physician has tried to prescribe it to them and they've said, "No, thanks," based on some fears about the side effects associated with that molecule. The balance, the other 3,000-5,000 patients are those that both Sanofi and Cogent are gonna try to help drive more disease awareness, more diagnosis, get those patients a KIT inhibitor, which is what they fundamentally need to target their underlying disease. That's 6,000-8,000 patients in the U.S. and probably a corresponding number in Europe.
When you take some assumptions about pricing, if you look at the AYVAKIT price, which is about $43,000 a month for wholesale acquisition costs in the U.S., and obviously substantially lower in Europe, and you multiply out in this prevalence market, you get to that $3.5 billion-$4 billion total available market across predominantly U.S. and then to a lesser extent, Western Europe. We think with the profile that we've developed, and we'll probably talk about this in a minute, we are clearly out-compete across really any measure of clinical activity. If you look across symptoms, if you look across quality of life, biomarkers, patient-reported outcomes, any way you slice it, the results from the SUMMIT trial look superior to the results from the PIONEER trial.
We think that even though they have a head start, and they have a respectable installed base, and they've done a, you know, an admirable job of launching their drug, we have a lot of opportunity with an FDA approval to go in a commercial launch and really change the dynamics of the market.
Great. Well, as a second entrant to the ISM market, you know, what are Bezu's attributes, and what is your strategy for capturing market share?
I think when you really roll it back to why everything I'm about to say is true, it comes down to sort of basic science. This is a disease fundamentally of a single mutation. It's known as D816V in the KIT gene on exon 17. All these patients have evidence of having that as a mutant driver. The difference between bezuclastinib and avapritinib is that avapritinib is a highly CNS-penetrant drug, and it is also a multi-kinase inhibitor. In addition to inhibiting the target, admittedly very potently, it also hits PDGFR and to a lesser extent CSF1R and FLT3.
Bezuclastinib is different is that we're non-CNS penetrant, and we're highly selective for KIT alone, and that allows us, in this patient population, to drive the therapeutic index and hit exposure levels in patients close to that EC-IC90 exposure, which is what you're looking for in a mutant disease. Whereas in the PIONEER trial, Blueprint Medicines or Sanofi now, were forced to dose reduce from their intended exposure level by 90% to a 25 mg dose, which is really only hitting the mutant target at about an IC15 level.
While they were superior to placebo statistically in their study, if you look across trials, again at symptomatology, you can see on a scale of 0 to 110 points with similar baselines after four years, which they just presented at a recent conference at Quad AI, they can improve patients on average about 17 points on that 110-point scale. At one year, what we presented is we can improve patients' symptoms by 32 points on that very analogous scale. That's just one example of nearly a doubling of symptomatic improvement on average for patients for our drug at one year relative to their drug at four years.
If you look at other measures of disease improvement, you can look at biomarkers like serum tryptase, where about 50% of the patients treated with avapritinib had a 50% or greater reduction in that biomarker. What we just presented at Quad AI is 99% of our patients had that similar 50% or greater improvement. There is clearly evidence that our drug is more active. It shows deepening of objective response. It shows deepening of symptoms. Maybe for the first time, and most importantly, from a disease modification perspective, we can show linkage between if you can really change how many mutant cells are in a patient, you can really drive symptomatic improvement.
There is a correlation between those two things, and I think what's gonna happen with bezuclastinib's, you know, impending launch is that more and more physicians will really buy into that scientific story where in this mutant-driven disease, what you want is a powerful drug that can target those mutant cells, get rid of them in the patient altogether, and really good things are gonna happen as patient-reported outcomes in that, in that patient population.
Great. Well, AYVAKIT is approved at 25 mg, and I think you mentioned there are some doctors, a fair number of doctors are escalating to 50 mg. You know, what does that mean to you in terms of Bezu, and what are some of the limitations that AYVAKIT has experienced when they escalate above 25 mg?
Yeah, we certainly hear that anecdotally from physicians in the commercial setting is 25 mg of avapritinib, per the results I just cited from their trial, doesn't seem to be powerful enough to drive symptomatic improvement in patients. Right now, with one drug on the market, their choice is to try to chase that efficacy by increasing the dose to off-label doses. The challenge with that drug, if you look at their PATHFINDER study in the advanced form of the disease at a two hundred milligram dose, they have a significant number of patients who have evidence of intracranial hemorrhage. They have 80% incidence of periorbital and peripheral edema. They have greater than 40% incidence of cognitive impairment in those patients.
The trade-off of trying to chase that efficacy of the power of a KIT inhibitor is the off-target CNS penetrant, off-target kinase side effects. When you go to 50, many patients start to experience the edema. Some patients start to experience cognitive impairment. When you chase it up above that, what you really don't know is at what level are you gonna take a patient with a disease of morbidity like non-advanced mastocytosis and put them at risk of a true safety issue like intracranial hemorrhage. I think when there's another drug, another option available that doesn't have that type of safety risk, or we have truly no clinical sequelae safety issues, there's gonna be a clear option, a clear switch in the minds of the physicians that are trying to treat these patients.
Yep. Certainly, we've heard some anecdotal experience, which I shared with you from some of the doctors at ECNM that are actually saying they're gonna use Bezu as the first drug that they reach for, which I think is interesting given that they've had a lot of experience with AYVAKIT. These are doctors that have had a lot of experience with AYVAKIT. Have you been hearing the same thing?
Yeah, absolutely. Especially over the last several months, first at ASH and then at Quad AI recently, both first with the hematologists and then with the allergists, which are the primary specialties who prescribe these drugs and treat these patients, they really see this scientific story that's emerging with the deepening of symptomatic benefit for patients over time related to that scientific story of objective measures of disease improvement, first with serum tryptase, with variant allele frequency, with mast cell burden in the marrow, with some of our investigators and advocates, a very well-known pathologist, Dr. Tracy George, who presented a really compelling paper on the pathobiology of what bezuclastinib can achieve, where she notices that in about a third of patients at six months, the bone marrow biopsies show on the pathology report no evidence of disease.
What's starting in these discussions that we get to witness among the key opinion leaders in the field is them talking about what does a functional cure mean? What does it mean to completely remove the presence of mutant mast cells from the patient? How can bezuclastinib kind of get to that level, which is a discussion that has not been present with avapritinib, given its inability to get to that depth of response.
Okay. Now, Blueprint had another KIT inhibitor that's in development. I was wondering your thoughts about whether that's gonna be relevant commercially.
Yeah, it's interesting. Back when Blueprint was a, you know, an independent company, they talked a lot about BLU-263 or elenestinib and, you know, starting what's known as the HARBOR trial. They are developing it in a slightly different way. They're doing a much longer trial, a 48-week primary endpoint, where there's a one-year randomization period on placebo. I think that's gonna be challenging for patients, especially with the availability of both avapritinib and then soon bezuclastinib commercially to stay on a placebo for a year. So that might complicate that study. It's also gonna take a little while for them to get to the end of that trial. They haven't even finished enrolling it yet, so the results and then a subsequent approval is gonna take some time.
Elenestinib is, if you look structurally, almost identical to avapritinib with one sort of change on a head piece of the molecule that is designed to prevent it from crossing the blood-brain barrier. It is possible that that drug can solve some of the cognitive problems that avapritinib faces. But we also know that in our models, we would have expected them to study the drug at a much higher dose in a pivotal study, where we think that based on some of their off-target kinase liabilities similar to their parent compound, they may have had to sacrifice some dose intensity with elenestinib as well. We'll wait and see the results of that trial when it comes out.
I think, I mean, one thing that I've had never really gotten a clear answer from is, you know, obviously, if it crosses a blood-brain barrier, that probably leads to the cognitive effects. The intracranial hemorrhages, it doesn't necessarily mean it's a direct effect of that drug. It could just be the effect on platelets, which we know it has in a coagulation cascade. You could still see even where the drug doesn't cross the blood-brain barrier, you could still see intracranial hemorrhages.
Yeah, it's interesting. If you look at the kinase profile of elenestinib, it's at least as potent, if not more potent, on the off-target kinases as its parent compound. Some of this, you know, aggregation of hitting CSF1R with KIT, hitting FLT3 with KIT is implicated in things like thrombocytopenia. You would expect the elenestinib, once it gets through its trial, to have a similar profile as avapritinib, assuming it's dosed at a clinically efficacious dose. I agree with you. I don't think it potentially removes that liability.
Okay. Why don't we switch to the commercial-
Sure
...infrastructure you're building? Blueprint definitely had a very sophisticated hub assistance programs, so forth. What, you know, what have you learned from their efforts, and what are you doing at Cogent to be commercially ready to when you're approved?
Yeah. First of all, you know, we're trying to currently attract talent to the company. We've hired around 40 folks, starting with the Chief Commercial Officer and then across the key functions of, you know, marketing, analytics, access, and sales leadership. We have not hired our actual sales force, the sales reps as of yet. That's gonna be some number of months prior to the planned PDUFA date, the planned launch, so that they can be onboarded, trained, introduced to their, you know, accounts, et c. We're in really good shape as far as identifying talent, bringing talent into the company.
We agree that in these rare diseases, both in mastocytosis as well as in GIST, one of the keys for us is gonna be to make it as easy as possible for when a physician decides to prescribe our drug for the patient to get the drug, both as soon as possible when that decision is made and then as soon as possible to have the financial assistance from, the patient's own payers and insurance companies, as well as anything Cogent can do to help, offset the expense of the therapy. We are planning to put in place all programs that are known about, as well as some new ones that we're thinking about to make Cogent the most rare disease patient-friendly company possible.
We really think that driving access is gonna be incredibly key to getting patients on drug, keeping them on therapy from a compliance, especially in these chronic settings, and really being competitively advantaged over a company like Sanofi, where we're razor-focused on one drug and, you know, a couple indications as opposed to a portfolio of a hundred things across many different therapeutic areas.
Okay. You've submitted the application. You should hear back from the FDA imminently. I guess what are the expectations? I know investors are worried about black box, potentially a REMS for liver monitoring. What's your base case at this point?
Yeah, our expectation based on the data that we've delivered, not just in SUMMIT, but across all of APEX, SUMMIT, and PEAK, which is, you know, over 800 patients with experience on bezuclastinib, is that we don't have serious liver clinical consequences. All of the adverse events that have been reported are reported as lab abnormalities. In all cases, what we've seen is patients either organically dosing through it or in certain cases with dose reductions or in very rare cases with dose discontinuation, that all of those transaminase fluctuations return to baseline.
Our expectation is it's possible that there could be language, general language in there around the need to monitor, especially early in treatment course, the first several months of treatment. We do not see, or do not have an expectation that anything like a black box or a REMS would be relevant here, especially without any of those clinical sequelae that you would commonly see in those cases.
Okay. Some investors also questioning, you know, whether you'll get a priority review, a standard review. I know, you know, the FDA. We've had several of the FDA staff here this week, and
Did they tell you?
We got different messages. 180 degrees. I think, you know, there definitely seems to be an impact from DOGE and some of the exiting at the FDA. What's your sense about whether you'll get a priority review or standard review?
I mean, in our humble opinion, it certainly qualifies to get a priority review based on the quality of the data and the importance of getting this drug into the hands of patients. What we hear, 'cause we ask lots of folks as well, is that the adjudication of priority and standard is probably less these days around the drug and more around resourcing. In whichever division you're asking for review, it's very dependent on how many parallel reviews that division is conducting about whether or not they feel comfortable signing up to a six-month or a 10-month review. We'll have to wait and see. I'm hopeful that our division is one of the lighter ones, so maybe we'll get a priority review.
Okay, I think we should shift to GIST-
Sure
...which is probably, to me, one of the more exciting opportunities. What have you shown in GIST and how big do you think this market could be?
Right. Gastrointestinal stromal tumors, if you think about the current standard of care, everybody diagnosed with metastatic disease receives imatinib, which is an amazing drug, especially for patients that have an exon 11 mutation. Those patients do very well on imatinib. Unfortunately, like with many tumor types, eventually all of those patients will develop resistance. We see in the second line setting, the current standard of care is sunitinib. The expectation historically is that sunitinib would do around a 10% response rate, around a six or seven-month median progression-free survival.
With the results we showed in the PEAK study, moving the combination of bezuclastinib with sunitinib based on sort of the complementary action across the common resistance mutations, which are typically in activation loop and ATP-binding domain, each of our drugs covering one of those groups of mutations. When you put our two drugs together, because of the selectivity of bezuclastinib that enables that tolerability of the combo, what you see is a median progression-free survival of 16.5 months with an objective response rate approaching 50%. Never before in history has a drug shown statistical significance on an efficacy endpoint relative to an active comparator in any line of GIST, and not in 20 years has a drug been approved in the second line setting.
We believe, based on conversations with many GIST-treating physicians, both in the United States and around the world, that as soon as the combination of bezuclastinib and sunitinib is commercially available, it will very rapidly become the standard of care in the second-line patient population. With a mean duration of treatment that we're seeing estimated from the PEAK trial approaching or potentially exceeding 19 months, we really see this as a very, very large commercial opportunity, potentially even larger than the mastocytosis opportunity and sort of have a single product that has multiple billion-dollar-plus commercial opportunities all launching this year.
Right. Why don't we talk about that 19 months a little bit because I think that's interesting. It's a unique. I guess the impact of the drug is unique in that there is a tail, that some patients do a lot better. Median PFS, which is what a lot of investors, including us, use a lot of times to estimate the duration of treatment, which is a key lever on this revenue opportunity, is significantly different than the median, right?
I think what we're seeing is that when you have a GIST patient who has a response or has a very durable, stable disease and goes past a year, goes past 16 months, that there becomes a higher and higher likelihood that they will get past other milestones like 20 months, 24 months, 30 months. We have these very, very long, very durable responders, which we actually had in the phase I lead-in trial for the PEAK study as well. It's just the sample size was much smaller, so you couldn't see it in such a big population.
We're expecting a pretty healthy minority of the PEAK population to get benefit for two, three, potentially four years on the combination, which really drives that average duration of therapy, which is what you use to try to do the commercial modeling. The median is important, obviously, for statistics, you know, clinical comparison in the trial, but it's really the mean that's used to drive you know, sales estimates based on how long patients are going to keep taking the drug.
What percentage of the patients are in that long tail?
Well, we don't know yet. We do know that there is still a very sizable but minority of patients who are on the trial, and they're still getting the combination on study. They haven't progressed yet. It's going to take some time, and hopefully a very long time on behalf of those patients for them to continue getting benefit of the combination for, again, potentially three, four plus years. The longer that they stay on, the more that kind of tail will drag the mean duration of treatment longer and longer.
Okay. Expanded Access Program, how important is that going to be?-
Well
...for these early launches?
Yeah, for both, GIST and mastocytosis across both indications, in the U.S., we now have active expanded access programs where patients can get access to bezuclastinib before approval, for free, as long as they find a site that's participating and are treated by one of these investigators who sign up for the EAP. While we don't kinda track it on a regular basis as though it's a launch, it's really to try to give bezuclastinib to patients that have a very strong medical need right now, and they can't wait for the approval. I can tell you that there's a lot of demand from both the physician community and the patient community to get access right away and not wait for the approval.
Okay. CMC, you ready yet?
CMC, we're good. We're locked. We completed an entire NDA, including Module 3. The CMC, both from an API and finished drug product, is nearly identical between all the indications, save for the final size of the pill. We have 75 mg pills and 50 mg pills, which will be used for the different indications. All the way up until that point, it's identical, so we feel very solid about where we stand with that.
Okay. I promised you I'd let you. ...talk about the beyond Bezu.
Beyond it is so, you know, not to sound like a pivot, but we do have a portfolio of very exciting pipeline assets, five that we've disclosed, three that are in clinical studies, and two that are planned to go into IND this year. What we want to communicate to investors is that we're going to be very responsible and, in some cases, ruthless about investing in these assets because bezuclastinib is the focus. Commercializing bezuclastinib is where all of our energy is going to go for 2026, but we also have an eye towards how we're going to build Cogent into a much bigger organization over the next five to 10 years, and that's going to come through hopefully one or two of these pipeline assets. We know we're not going to succeed in all of them.
As an example, each program that we put into clinical studies has a very specific target product profile, and we're looking to exceed it in very early, efficient clinical trials. What I can tell you today is our initial program, which was an FGFR2/3 inhibitor, we've actually decided to deprioritize that asset based on that early clinical experience, which for a couple reasons has made us decide it's probably not where we want to continue investing. Maybe the most important part is what we've learned is that the resistance conferred from some of the pan-FGFRs is not what we thought it was going to be.
We thought it was going to be driven predominantly through FGFR2 gatekeeper and molecular brake mutations, and what we're seeing from the clinical results and from the patients enrolled in our studies is that, quite often resistance is conferred through other pathways like RAS, like mTOR, like AKT. Our drug that's designed to be a very specific FGFR2 inhibitor is really not helping those patients. They need other drugs. It's shrinking the patient population. It's making it harder to find patients that have that specific genotype that would be relevant. We also are seeing that the FGFR2, adverse events, on-target adverse events, are showing themselves, especially the hand-foot syndrome and some of the epithelial tox.
For those reasons, what we would really need is that drug to be extremely well-tolerated, extremely durable in a very small population of patients. We've decided it's just not where we're going to spend our time, and we're going to focus on our other pipeline assets. Appreciate, you know, being able to share that with investors today.
Thanks for sharing that with us today. Definitely opportunity costs and cost of capital are important.
Absolutely
Especially when you have other fish to fry.
Yeah. Thanks, Andy. Appreciate it.
Thank you.
Awesome.
From the audience before we wrap it up. All right. Thank you, Andy.
Awesome.
Congrats on all the progress.
Great. Thank you.