Cogent Biosciences Inc Aktie

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama, I'm one of the Senior Biotech Analysts here at JPMorgan. I'm joined by my squad, Rati Pinge, Joyce Zhou and Priyanka Grover. Our first presenting company of the day is Cogent, and presenting on behalf of the company, we have CEO, Andy Robbins. Andy?

Great, Anupam. Thanks so much. Thanks for inviting us to the conference. We're happy to be here. My name is Andy Robbins, I'm the CEO of Cogent Biosciences. I'm going to do probably 20, 25 minutes of prepared remarks with a little presentation, and then maybe Anupam will ask some questions. We'll see if anybody in the audience has any questions.

Before I get started, just to remind folks, I will be making some forward-looking statements. So we just tell you to take a look at our recent SEC filings for a full disclosure of all the risks associated with the company.

Okay. So as much as I want to spend the whole day today reviewing what happened last year, which was certainly a pivotal year in the history of Cogent, we're going to really look forward about what's going to happen with Cogent in 2026 and beyond. But just to pause for folks that are new to the story, our lead asset, bezuclastinib, which is a potent and selective KIT mutant inhibitor, in 2025, read out 3 pivotal trials, all of which were positive, which was a really exciting year, not just for the company, but obviously for the patients in -- who are fighting these diseases, gastrointestinal stromal tumor and systemic mastocytosis.

We're going to spend most -- or I'll spend most of the presentation today talking about bezuclastinib and these 3 trials. So maybe we'll wait to get into those details. What we're doing this year really after that success is focused on a sort of rapid execution as we can to get those 3 studies filed. So the first NDA for the non-advanced systemic mastocytosis indication or the SUMMIT trial was submitted at the end of December. And the other 2 NDAs will go in, first, the PEAK NDA for the gastrointestinal stromal tumor indication in April of this year, and then followed rapidly in succession by APEX. So in the first half of this year, we'll have all 3 of our NDAs submitted for bezuclastinib, and that puts us on track to launch the asset in the U.S. in the second half of the year in at least the non-advanced systemic mastocytosis indication, but as many as all 3 of those indications commercialized by the end of the year, pending discussions with the agency.

The other thing that's important that we did from a corporate perspective really near the end of the year was put ourselves in a very strong financial position to build that commercial organization, to file those 3 trials and then get ready to launch. So now as of the start of 2026, we have about $900 million on the balance sheet, and that will get us deep into 2028 from a cash runway and really get us towards that conversation around profitability given the timing of these pending commercializations.

In kind of the background for what we talked about most of the time is our burgeoning pipeline. So if you remember, Cogent has what I consider to be one of the best research small molecule chemistry teams in the world, a legacy from a past company that I used to work at and now really focused on building Cogent's pipeline of novel agents. I'll go in depth on 2 of the programs that we're really excited about, our pan-KRAS(ON) inhibitor and then our JAK2 V617F inhibitor that we disclosed late last year.

So now coming back to the lead asset, bezuclastinib and the 3 pivotal trials. So across GIST nonadvanced systemic mastocytosis and advanced systemic mastocytosis, this represents about an $8 billion annual opportunity. If you get really deep into these diseases, you'll know that there's very limited competition for this $8 billion commercial opportunity in systemic mastocytosis. We're really talking about one company, Sanofi that owns a drug called AYVAKIT, and then a backup compound that's in development before us. In GIST, you're really talking about us and us alone. There is really no competition in second-line GIST. We're the first drug ever to show activity against an active comparator in this patient population, first ever, and also plan to be the first drug approved in second line GIST in over 20 years, hopefully later this year.

The other thing that I think is a little bit misunderstood, and I have a slide on the next slide about this is our sort of intellectual property position or protection against generics. We see ourselves as having a very long runway of this opportunity into the mid-2040s based on our intellectual property position, and we're continually thinking about ways to enhance that. So here on Slide 5, you can see from a composition of matter with patent term extension, standard Hatch-Waxman, will be protected into 2039. And with our formulation patent, which uses proprietary technology that we're waiting on a pending patent to grant, we will be protected through 2043. So with an approval pending, hopefully, later in 2026, you're looking at 15-, 18-year runway for bezuclastinib really around the world to be protected from generics.

So coming back to the GIST indication or the PEAK trial. Again, just to reiterate, first time ever in history that a clinical trial in GIST showed an advantage against an active comparator. Every other drug has been approved against placebo. And in the second line, since 2006, first time a trial has been positive with any design.

Some of the, I think, key numbers you see here on this slide, a 16.5-month median progression-free survival. It's really pushing forward the expected benefit for patients, also matched with a very high response rate nearing a 50% confirmed objective response rate in this patient population when historical drugs are approved with single-digit response rates in imatinib resistant GIST, the other thing we pointed out during our study from an overall survival perspective, way fewer overall survival events occurred at the time of the PFS analysis than we were projecting. So I think it just from an efficacy perspective, exceeded all expectations across all of the endpoints that we're studying. Again, we're giving formal guidance that we expect to submit the NDA for this trial in April of this year, so not -- in the not-too-distant future.

And then when you think about the size of this market, and I think this is also an area where both the sell-side present company excluded and the buy side are kind of continuing to learn about what the opportunity here looks like. What you really need to take away is in our trial, the average duration of therapy, and this continues to evolve because obviously, patients remain on the combination, looks like it's going to be minimally about 19 months of average duration of therapy for these patients.

And in a rare oncology disease, second-line setting, where the old benchmark was 7, 8 months of duration of therapy, this dramatically changes the commercial potential for this patient population. So what we're looking here across U.S. and Western Europe predominantly is with about 6,000 patients becoming resistant to imatinib on an annual basis with some of the benchmarks on the slide of what other KIT inhibitors have priced at and are priced at in the market today. This could potentially be a $4 billion market alone for second-line GIST. And again, without really any competition, so we look very well poised to capture a significant proportion of that total available market.

Now pivoting to the, the other 2 pivotal trials that read out in 2025. Well, first SUMMIT in nonadvanced and then APEX in the advanced setting for systemic mastocytosis patients. What we demonstrated here is for a KIT inhibitor who can achieve a therapeutic index based on its selectivity and its inability to penetrate the CNS, you can really drive very exciting results in this patient population.

So for the first time in the nonadvanced systemic mastocytosis patient population, we demonstrated that there is a clear link between hitting the mast cells in the body, the mutant mast cells and translating that into symptomatic improvement. For several years, another company said that there was no correlation between those 2, but that was likely because they were dosing their drug in a mutant-driven disease at about an IC15 concentration.

With our drug, based on its tolerability profile, we could really drive that target engagement up to close to that IC90, more historical full target coverage level. And what that showed from a mast cell burden perspective is rapid and deep reduction in these measures of mast cell burden. You can see here, tryptase -- patients achieving at least a 50% improvement across tryptase, variant allele fraction, bone marrow mast cells, all 90% plus.

And what that showed is that, if you look over on the right side, about 90% of our patients achieved what's known as pure pathological response. So a measurement of that mast cell objective measures of disease. And that translates into, first, at 24 weeks, an outsized improvement in overall symptoms, it translates across the domains, across the individual symptoms and noticeably better resolution in symptoms. And then even sort of that preview that we did at ASH of what does this look like at 48 weeks, those symptomatic effects improving even more deeply. So really excited about the potential for bezuclastinib to become the standard of care in the nonadvanced mastocytosis setting.

And then kind of finishing and off in the advanced setting, again, this matters based on how the competitor has positioned itself. So the standard of care currently is being dosed at that more traditional IC90 type target inhibition. But with that, for a nonselective CNS penetrant drug for avapritinib comes a lot of liabilities, high frequency of peripheral/periorbital edema, high frequency of cognitive impacts and noticeable numbers of patients with intracranial bleeding. What we showed in our study is that you can achieve the same level of potency, drive those deep rapid responses, but spare the liabilities of all of those side effects.

And so again, when given a choice for patients, we think that a much, much better tolerated option to drive that same sort of clinical activity is going to be rapidly adopted as a standard of care. And then taken together, we certainly acknowledge the impressive work that, first, Blueprint, and now Sanofi has done to drive awareness of this disease, diagnosis of this disease and the patient population is growing.

The number of patients that are coming forward and being diagnosed with non -- specifically nonadvanced systemic mastocytosis, we think we'll benefit from that because in both of these settings, we have noticeable advantages against the standard of care, AYVAKIT. And so this $4 billion opportunity completely distinct from GIST also is going to be essentially a 2-drug battle between Cogent and Sanofi.

One thing that I think we want to make clear is that we're not kind of done investing in bezuclastinib. While there aren't clearly other diseases to pivot into within mastocytosis and gastrointestinal stromal tumors, we are going to generate additional clinical data, which we think can help us expand this market potential. So if you look here on Slide 11, and the orange is really focused on the GIST, and the sort of more teal colors are focused on systemic mastocytosis, I think folks are familiar that we are -- we had announced a while ago a collaboration with SARC, which is a co-op group in sarcoma to run a third-line trial to try to investigate the utility of the combination in patients who had progressed on Sutent in the past.

So it's not really fair to say that we're going to forget about all those patients who are still fighting GIST. So we think that, that will be helpful certainly in the beginning of the launch of bezuclastinib to see if those patients have benefit of adding bezuclastinib even if they've already progressed on Sutent.

And then maybe more excitingly, we haven't presented the full data from the PEAK trial yet, but we plan to do so in the first half of 2026. And as part of that, we'll have kind of the full breakdown of the genotype subgroups. What we've said publicly is that unlike other historical trials that didn't meet the primary endpoint, our trial was not driven the success by an individual genotype subgroup. It looks like patients across genotypes, all had very impressive benefit from the combination.

But when you think about going into the first line, and we've said this before, imatinib has been established as a standard of care in first-line GIST for a couple of decades. It's a very impressive drug, but there are genotypes in first-line patients, specifically exon 9 patients that don't respond as well to imatinib. So what we're going to do in actually just a few months is initiate a first-line cohort of patients of the bezuclastinib, sunitinib combination to demonstrate what does that look like in that exon 9 genotype frontline group, which is approximately 15% to 20% of newly diagnosed GIST patients. So this represents an opportunity to kind of migrate upstream from what we expect to be a second-line approval.

Now pivoting to the mastocytosis setting, I think, again, folks are probably aware of that bottom study that concomitant use, which was part of the APEX design, trying to determine the utilization of the benefit of bezuclastinib with azacitadine in patients with the associated hematologic neoplasm disease, which is about 3/4 of the ASM population, that trial continues to enroll, and we expect to have results from that around the time that we launch.

But that kind of darker blue-teal study there in the middle, the switch, we think that this could be really important for the commercialization of the asset. So we're running this Phase II study in Europe. We expect to complete enrollment of about 40 patients in the middle of this year, which would put us on track to present that data by the end of the year.

And really, what this shows is that you find patients who are currently on avapritinib, you get to measure their symptomatic control while on avapritinib, then you run a washout, then you see if bezuclastinib can deepen the reduction in symptoms. So this will really inform for patients who are the "installed base" on the standard of care, would it be worthwhile trying a new drug when it comes to the market, which we think will be very important.

The other thing, and I think folks are aware of this, but we want to sort of reiterate it, is we have an ongoing expanded access program that provides access to patients in the United States of bezuclastinib for both gastrointestinal stromal tumors and mastocytosis. Currently, right now, if they are at an investigational site, which is supporting this EAP for free, and so this will get us a lot of experience. It will get the investigators more experience with the drug in advance of the full commercial launch. And so we see this as a really important part of a rare disease launch prior to a full FDA approval.

Getting ready in 2026 is going to be one of the most important things for us to have a very successful commercial launch. We have already hired all of the senior commercial executives in the team. I think the last one we announced in our press release yesterday, the Head of Sales. We already have, obviously, our Chief Commercial Officer, Head of Access, Head of Analytics, Head of Marketing in place long ago. They are in the process of building out their teams.

What we've guided to is that for both of GIST and mastocytosis in the U.S., we see this as about 100 employee or less total build-out, including home office and field-based employees. We're going to be very, very focused in a rare disease fashion on, number one, access, ensuring that when a physician decides to prescribe, it is the easiest drug to get their patients on in these 2 diseases; and number two, the patient community, again, in these rare diseases, understanding what patients are looking for, how to match them to the drug, how to get them excited about the opportunity to be on bezuclastinib is going to be critically important to succeeding in the launch. So that's kind of where our head space is at. And certainly, through 2026, we'll give more updates as we prepare to launch.

Now just a couple of words about non-bezuclastinib. You can see here sort of a reimagining of the pipeline splitting into to 2 franchises, 2 therapeutic areas. So focus on hematology or rare hematology assets and then sort of the more classic solid tumor oncology, really anchored by our lead asset, bezuclastinib, which is going to have a presence in both of those franchises. But then in hematology, announcing late in the year that we have what we believe is the most selective JAK2 V617F versus wild-type asset that -- with plans to go into the clinic or to IND in 2026. And then coming to oncology, a host of what we believe, best-in-class targeted therapies for specific populations from FGF down to ErbB2 down to alpha-selective PI3Ka, and then maybe highlighted by our pan-KRAS(ON) inhibitor that, again, is on track for IND in 2026.

So just quickly, obviously, there are other companies that are participating in the KRAS or pan-KRAS field. We presented a poster at the triple meeting in the fall, where we use our colleagues at Revolution Medicines as sort of the benchmark for activity in preclinical models. The difference quite frankly with our drug and their drug is that we spare activity on HRAS and NRAS. So we see that there is the potential for drugs with HRAS and NRAS to have epithelial toxicity, which may limit their therapeutic index. The hypothesis here is that if you could build a drug that has similar potency on the K variants without that activity on H and N, you could push that therapeutic index. So that's really the experiment that we're going to try to judge in our Phase I studies.

And then looking again very recently at ASH. For the first time, we announced we have a JAK2 V617F inhibitor. Again, this is for patients with that mutation across MF, PV, and ET, probably one of the big unmet needs in those MPN indications. And while a lot of folks also have programs within this umbrella, what they presented is selectivity over wild type of somewhere between 3 and 8 fold, we're 3 to 8x, and we're looking at over 100-fold selectivity over a wild type.

So again, if you think from a clinical future expectation that selectivity over wild type in this mutant driven disease is going to be important. That's our opinion, and we're excited to see that hypothesis tested in the clinic.

So just to round it out before I let Anupam ask some questions about the company in the future, kind of bringing it back to the high level, what are we going to do in 2026. With bezuclastinib, we're going to get the 2 other NDAs filed. So now we would have 3 NDAs submitted by the first half of the year, that would lead us into hopefully, FDA action PDUFA dates in the second half of 2026 with a commercial launch. That is the dramatic focus of the company. That's what everybody at Cogent is pulling our ores on. At the same time, the research organization is helping us get by this time next year, hopefully, 5 Cogent invented assets into the clinic across FGF, ErbB2, PI3Ka, pan-KRAS and JAK selective.

And then from a corporate perspective, certainly, the focus is on finding those excellent new commercial colleagues to help us succeed in our launch, but also at the same time, going through a process to figure out exactly how we're going to execute the commercialization of the asset around the world, specifically Europe, which is probably a partner or a build, and then outside Europe, which is definitely a partner from a commercialization perspective. Just underlying that with a very, very strong balance sheet. We're excited about our opportunity to execute, not just in 2026 into the launch but even further than that without the need to raise additional capital.

So maybe I'll pause there and turn it over to Anupam to see if there's anything I didn't cover that would be helpful.

Thanks, Andy. So I'll ask the first couple of questions, but then I'll also open it into the audience for questions. So feel free to raise your hand when I do.

So my first question is on the SUMMIT data in non-advanced, I think you're supposed to give an update in the first quarter. What within that data would you kind of point us to that would continue to kind of underscore the benefit that we're seeing of bezuclastinib in nonadvanced patients?

Yes. And they can hear you, right? I don't need to repeat it?

No. [indiscernible]

Okay. Yes. We do have a plan to share additional data or first data from all 3 of those pivotal trials within the first half of 2026. So SUMMIT is certainly a part of that. For SUMMIT, because we shared the data at ASH in about 6 weeks ago, the next time we share it will really be about the longitudinal data. So what do patients look like after 48 weeks when we really did a comprehensive description of what they look like after '24. And what I think is going to be most exciting, and we've already kind of previewed this in some of our corporate decks is that the symptomatic benefits for bezuclastinib don't stop after 24 weeks.

So if you look at avapritinib from the PIONEER trial and the long-term follow-up and they presented strangely a poster at ASH that shows the symptomatic benefit at year 2 and year 3 is actually worse than at year 1. So their effect wanes over time, our effect is going to continue to deepen.

And so I think what we want in a chronic disease therapeutic is that patients continue to get benefit over long periods of time. And so that's really what we're going to try to demonstrate in that presentation of the SUMMIT data.

And Andy, while you're at it, like, what about the updates for APEX and PEAK? What additional data we'll be getting at a medical conference?

Yes. So I think probably from the PEAK perspective, the most important data, the thing that we get the most questions about is sub setting. So I think that there's not a lot of confusion about the excitement of generating a 16.5-month median progression-free survival as the primary endpoint and nearly a 50% objective response rate, but there are questions about in genotype X or genotype Y, how does your combination look. So that will probably be the highlight of sharing the full results of the PEAK data.

From an APEX perspective, I think we did a pretty good job sharing the preliminary data. What we said in December is that the patients on APEX had been cut with about 9 months of follow-up. So I think we'll have an opportunity in a single-arm trial to continue to follow some of these patients and see if the response rates mature over time. One of the things we said at the top line results is there are several patients who are either in unconfirmed or still have the potential to become responders on the APEX study. But really, the tolerability of that APEX readout was quite impressive to the mastocytosis community. So we're -- even without additional data, I think we're positioned to rapidly become the standard of care in the advanced setting.

Question from the audience? So just thinking about regulatory dynamics here. You're going to have 3 filings at the agency basically at the same time. How do you think about the regulatory dynamics there and what has been an unpredictable agency?

Yes, it's hard for any individual company to predict what's going to happen with a large government agency, given the dynamics that are going on today. But what we can do is we can take these 3 studies, which each have extremely clear results. In the case of PEAK and SUMMIT in a randomized fashion against well-documented standards for how you design trials in those patient populations with highly statistically significant primary endpoints and key secondary endpoints and put a package together that is as clear as possible, that really helps the agency even in a world where there's resource constraints and how do they prioritize. If you can really put together a story that is for rare disease patient population, clear outperform against standards of care or well-documented control arms from a regulatory perspective, it gives them an easier file to approve on a rapid basis.

So that's kind of our position. The other thing I'll kind of point out or I will point out is that we were granted breakthrough designation for a few subgroups of the SUMMIT population, while breakthrough doesn't necessarily confirm that you're going to get a priority review. I think if you look back over the last several years, almost all of the drugs that have breakthrough designation have achieved a priority review.

Questions from the audience? So you've got all this data in hand. And one of your slides kind of broadly touched on this, but maybe I was hoping you could dig into sort of some details on what the key medical initiatives, pre-commercial activities are going to be happening as you look to your first approval towards the end of the year?

Yes. It's a great question. So the team, both from a commercial and a medical perspective are already very active. Even at conferences like ASH, we probably had conversations with, I don't know, 100-plus hematologists about the data that we presented across both SUMMIT and then the top line data for the APEX pivotal trial that was available at that same time, getting those folks aware of it, getting them activated on the expanded access program, getting them experienced, treating patients.

So obviously, the investigators in the trial already have that, but expanding that into physicians who are interested and treat these patients via the EAP, we think that using bezuclastinib is the best opportunity to convince people that this is an outcompete against avapritinib in mastocytosis.

In the GIST community, the conversations that we've had with really dozens and dozens of just experts have been this combination becomes a standard of care at approval. There's really not a lot of confusion or parsing or comparing. No drug has been approved in 20 years. It's the first time you've ever seen and outcompete in a clinical trial against an active comparator. So the GIST community, both the physicians and the patient groups are very excited about the combination of bezuclastinib and sunitinib. It's our job to take these data, communicate them, share it with the physicians and the patient groups and then make sure that all of the sort of ancillary machine of the U.S. commercialization of pharmaceuticals is teed up and ready to go for our FDA approval.

I've got one more question, but final call for anyone in the audience. One of the most common questions that I get, Andy, is you've got these 3 positive studies clearly building out this commercial team. Different doses across all of the studies, right? And so how do we think about pricing?

Yes. So we have the luxury of waiting until we're approved to decide what the price is. And of course, given what's going on in the world with geopolitics and most favored nations, other companies, pricing their drugs, we're going to use as much information as we can up until that sort of last moment where we set a price.

What we can tell you is that in these 2 patient populations, there have been recently approved KIT inhibitors that have provided benchmarks here in the U.S. So originally Deciphera, now ONO Pharmaceuticals with QINLOCK or ripretinib, they just took a price increase. So now they're at about a $46,000 wholesale acquisition cost in the U.S.. And then Blueprint first and then obviously, they are acquired by Sanofi, is right around $41,000 wholesale acquisition cost.

So those provide, I think, interesting benchmarks. When we do those global commercial opportunity slides, we use 40,000 as an easy math to get to those numbers. If you were to price higher, obviously, those -- the commercial opportunity gets even stronger.

So we'll continue to monitor this. Our position is that the results from PEAK, SUMMIT and APEX put us in best-in-class territory for our drug in the KIT class across all of the diseases as opposed to chopping it up that this drug is for this disease, this one is for another one, this one is for another one. When you have a KIT mutation, we see that bezuclastinib is going to be the preferred choice across all of the patient populations. And I think that puts us in a very strong position from a pricing perspective.

Looks like we have a question in the back.

You're going to have a busy year this year here in the U.S. When you would consider looking outside of the U.S., please?

Yes, just in case folks couldn't hear it. I think the question was, very busy year coming up in the U.S., but what about outside the U.S. and maybe specifically Europe. So just quickly outside of Europe, so Rest of World, outside of Europe, we are definitely exploring actively partnerships from a commercial perspective to find organizations that want to prioritize investment in bezuclastinib in Asia, South America, Australia, Middle East, et cetera, et cetera.

Europe is an interesting question because I would say 7, 8 weeks ago, I would have just lumped Europe into that comment I just made that outside the U.S., we're really going to rely on partnerships in order to commercialize. But with the PEAK data specifically, with the strength of that data and the duration of therapy in an early line setting in a cancer population, it's one of those situations where a U.S. biotech company really can make the numbers work for investing and expanding into Europe itself.

So as part of our ongoing partnership discussions around bezuclastinib outside the U.S., we're going to be very selfish around the U.S. rights and launch that ourselves. As part of those ex U.S. partnership discussions, we'll determine, are there -- is there an organization that wants to prioritize bezuclastinib in Europe and provides the economic terms that make it challenging for us to match that by building it ourselves. But if not, then we would be ready to go ahead and do that ourselves.

Any final questions? Great. Thank you, Andy.

Thanks, Anupam. Appreciate it.

Good morning, and welcome to the Cogent Biosciences webcast. I will now turn the call over to Christi Waarich, Senior Director of Investor Relations.

Thank you, operator. Today's call will cover our SM updates announced over the weekend and this morning. You can find the press releases in the Investors and Media section of our website at cogentbio.com.

Before we get started, please be reminded that remarks made during this webcast may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about our planned regulatory submissions and time lines as well as our anticipated commercialization and market opportunity for bezuclastinib.

Please refer to our most recent filings with the Securities and Exchange Commission for a full discussion of risks and uncertainties associated with our business.

With that, it's my pleasure to turn the call over to Andrew Robbins, President and Chief Executive Officer. Andy?

Thanks, Christi. Good morning, everyone, and thanks to everyone for joining our call today. It's certainly been a very busy weekend for us down in Orlando, and we're excited this morning to review the full results from the SUMMIT trial that we're presenting at this year's ASH conference as well as announced for the first time positive top line results from our APEX pivotal trial.

Joining me on the call today are Cogent's Chief Medical Officer, Jessica Sachs; as well as our special guest, Dr. Lindsay Rein, Associate Professor of Medicine at Duke University. Dr. Rein will review the SUMMIT results that she shared at ASH on Saturday afternoon. And after highlighting a few additional takeaways from the SUMMIT study, I will walk this through the APEX top line results.

Before I turn the call over to Dr. Rein here on Slide 4, I would like to take a moment to recognize the amazing progress we've made at Cogent since this summer. In just the past few months, we've reported positive results from all 3 pivotal trials of bezuclastinib.

The SUMMIT trial of bezuclastinib in non-advanced systemic mastocytosis patients, the PEAK trial of bezuclastinib with sunitinib for second-line GIST patients and this morning, the APEX trial of bezuclastinib for advanced systemic mastocytosis patients.

Based on these results, bezuclastinib has emerged with a profile that positions it for market leadership across all 3 patient populations with a global annual market potential of over $7.5 billion. We are moving forward rapidly to build a fully capable commercial organization and with plans to submit all 3 NDAs within the next several months, we are on a path to launch bezuclastinib in both systemic mastocytosis and GIST by the end of 2026.

What I'd like to do now is invite Dr. Rein to help walk us through the very exciting SUMMIT clinical trial results that she presented on Saturday afternoon at ASH. Dr. Rein?

Thank you. So again, thank you for the invitation this morning. I'm going to walk you through the results from the pivotal SUMMIT trial data. If we go to the introduction slide, this will be Slide 7. I don't need to remind you, but non-advanced SM for the purposes of this study includes indolent moldering and bone marrow mastocytosis subtypes.

As we know, SM can be associated with debilitating symptoms, which affects quality of life and can be life-threatening, and those are listed there. And as a reminder, bezuclastinib is an oral potent and selective TKI, which has minimal brain penetration and spares closely related kinases due to its high selectivity for the D816V mutation. This allows us to minimize off-target effects such as bleeding, cognitive impairment and edema.

If you go to the next slide. So this is the outline of the SUMMIT study, which I won't focus on too much. I think everybody has seen this, but for the purposes of this presentation, we looked at the Part 2, which randomized patients in 2:1 fashion to bezuclastinib 100 milligrams daily versus placebo. Patients then rolled over into an open-label extension. We know that the primary endpoint, which was statistically significant, was the mean change from baseline in the MS2D2 total symptom score, and what I want to focus on a little bit more today is the key secondary endpoints.

Again, all statistically significantly different, which included those listed there, greater than or equal to 50% reduction in various markers of mast cell disease and then additional descriptions of the symptom change.

So if we go to the next slide. These are the patient demographics that were represented within the context of the SUMMIT study. I think I'm going to point out just a few pertinent populations. So number one, this study did include smoldering the systemic mastocytosis patients, which is important. If you go to the bottom left, you'll note that a population of patients did receive prior KIT inhibitor therapy, that was slightly overrepresented in the bezuclastinib group in comparison to placebo, and the other notable difference within the context of this study was the fact that patients who received bezuclastinib did have a slightly higher baseline mean total symptom score as measured by the MS2D2. So again, that was 57.1% in comparison to 52.6% in the placebo-treated group.

So if you go to the next slide, I'll review this quickly, but I think this has been discussed. So the primary endpoint was achieved within the context of the study through a rapid, durable and statistically clinically and clinically meaningful symptom improvement for patients. So you can see here the mean change in total symptom score at week 24 was approximately 9 points improved in patients who received bezuclastinib in comparison to placebo with a p-value of less than 0.001.

If you go on to the next slide, we can look a little further at this and look more specifically at the proportion of patients who achieved either a greater or equal to 30% or 50% reduction in their MS2D2 total symptom score, again in comparison to placebo. So on the left of the slide, you'll note the patients who received bezuclastinib. In blue, you'll see those patients who achieved at least a 30% reduction in their total symptom score. And on the green bars, you'll see those patients who achieved at least or greater than a 50% reduction. This is in comparison to placebo. And again, these differences are statistically significantly improved for patients who received bezuclastinib.

If you go to the next slide, I think this is an important piece of information to note that the improvement in mean total symptom score change as measured by the MS2D2 was not specific or due to one domain of symptoms or one symptom, but rather occurred in totality across all symptoms that were measured as part of the MS2D2. So here, you'll see all of the symptoms collected as part of this MS2D2, including those that were utilized to calculate the total symptom score as well as additional symptoms.

The baseline mean score is listed on the top of the slide. And you'll see with the green bars, statistically significant improvements in the mean total symptom score across a majority of these individual symptoms for the patients. And so again, indicating that the change in the primary endpoint change was due to a change across all symptoms.

If you go to the next slide, we'll take a look a little bit more in depth at the markers of mast cell disease burden. So this is Slide 13. We note that bezuclastinib significantly reduced serum tryptase, which again is a core indicator of mast cell burden. We see here that 95.4% of patients had at least a 50% or greater reduction in their serum tryptase. This was in comparison to no patients who received the placebo. And I think interestingly, if you look to the bottom table there, you'll note that almost 78% of patients normalized serum tryptase values within the time frame of the study in comparison to no patients who were treated with placebo. So an important change there.

If you go to the next slide, you'll see the changes in bone marrow mast cell burden and the abnormal mast cell phenotype, again, significantly improved in bezuclastinib-treated patients. You'll note that 88.2% of patients had at least a 50% reduction in mast cell aggregates or clearance of those aggregates. This is in comparison to 25% of patients who achieved the same marker in the placebo-treated group. One might ask why there is a change in patients who received placebo, and I think the way to think about this is to look at the blue circles underneath the patients -- underneath the lines of patients.

So this is indicative of CD25 staining. As we'll note, patients with mastocytosis have abnormal CD25 staining. In the patients who received bezuclastinib, we see that a majority of these patients had a reduction in the abnormal CD25 staining, indicating effects of bezuclastinib on abnormal or diseased mast cells. This is in comparison to only 3 patients treated with placebo who saw the same change, which would indicate that bezuclastinib is acting on the abnormal mast cells. And the variation we see within the placebo group is due to marrow sampling in that heterogeneity, which we do see.

If you go to the last slide, we'll round this out with changes in KIT D816V variant allele frequency, or VAF. And again, you can see here 97.5% of patients achieved at least a 50% reduction when exposed to bezuclastinib. This is in comparison to 0% of patients who received placebo. So I think global response across all markers of disease burden and those key secondary endpoints.

If you go to the next slide, which is Slide 16, I want to highlight 2 particular patient populations. So this is the patient population for smoldering systemic mastocytosis and then also the patients who received prior avapritinib. Although small, these subgroups are important and patients here did demonstrate meaningful improvements, again, both in symptoms and objective measures of disease consistent with the global population that was seen within the context of the study. So nice and consistent data here.

If we go to Slide 17, I think you'll see an interesting and important correlation that has come from this study. So given the large size of the data sets available and a large number of patients, we were able to correlate some of the changes in symptoms with the degree of mast cell burden. And what we find is that the greater reduction in the markers of mast cell disease, so serum tryptase, bone marrow mast cells and KIT D816V VAF, the greater the change in those markers was significantly correlated with greater reduction in symptom severity, again, as assessed by the MS2D2.

So this is really the first description of this type of correlation within a cohort of patients, again, given the size of the population available to be able to do this and really suggests that there is a relationship here between symptom improvement and what we're seeing in terms of bezuclastinib's effect on the pathophysiology of the disease.

We're going to go one slide further and look at the safety profile. So again, bezuclastinib demonstrated a favorable and manageable safety profile. If you look at the AEs, you can see they're listed in the table to the left. The most common AEs we saw, again, we see across many TKIs or hair color changes in altered taste. A majority of the treatment-emergent AEs were low grade and reversible with cessation of therapy. We saw that 11% of patients required dose reductions of bezuclastinib related specifically to changes in ALT and AST, so those measures of transaminases.

5.9% of patients ultimately discontinued, although we will note that these, again, changes in AST and ALT were reversible, did not result in any hospitalizations and were not associated with any significant change in synthetic liver dysfunction. So again, I think supporting a favorable toxicity profile.

So if you go to the last slide, just to summarize, bezuclastinib really does represent a promising new treatment with evidence of disease modification in this patient population of broadly non-advanced SM patients. This includes smoldering SM in patients with previous KIT inhibitor therapy. We see, as we note that the study met its primary endpoint, and we see further reductions and significant reductions in objective markers of disease listed there. This is the first demonstration of a significant correlation between this reduction in objective measures of disease and improvements in symptoms. And we see ongoing tolerability of bezuclastinib in this patient population with most treatment-emergent AEs being low grade and reversible.

Great. So Dr. Rein, thanks very much for that excellent presentation and for helping us as an investigator on the study. So now I wanted to look here on Slides 21 and 22. I'd like to encourage everyone listening to spend some time, later this afternoon listening to Dr. Tracy George from the University of Utah in ARUP Laboratories present a very thorough review of the SUMMIT pathobiology results, focused on the impact bezuclastinib has at a cellular level in non-advanced systemic mastocytosis patients.

Broadly speaking, Dr. George will present evidence that treatment with bezuclastinib reduces dense mast cell aggregates, decreases the overall quantity of mast cells in the bone marrow and targets the removal of neoplastic mast cells from these patients as evidenced by reduction in cells with CD25 and CD30 expression. These data are expected to stimulate a conversation among the mastocytosis community about the importance of using objective measures of disease burden in non-advanced patients as a key component of goal-directed therapy.

To expand on this point, on Slide 22, you'll see that 55% of patients treated with bezuclastinib achieved a level of improvement so dramatic that they no longer meet the diagnostic criteria for the disease. This is an amazing finding in a majority of SUMMIT patients treated with only 24 weeks of bezuclastinib.

Moving to the right panel on the slide, you'll see over 2/3 of bezuclastinib patients meet the complete remission definition of pure pathological response. These data are highly impressive and suggestive of the rapid and deep benefit bezuclastinib is providing these patients at a cellular level.

Bringing Dr. George's presentation together with Dr. Rein, Cogent is excited to be the first to show that objective measures of disease burden appear clearly linked to symptomatic improvements reported by the patients.

Now turning to some of the most exciting SUMMIT data, I'd like to share a brief preview of our upcoming 48-week long-term follow-up from the study. Here on Slide 23, bezuclastinib shows clear continued deepening of symptomatic improvement throughout the first year of treatment as measured using total symptom score. You can see this impressive effect juxtaposed with avapritinib's 48-week total symptom score results, which show a flattening or plateauing of effect on symptomatic improvement beginning by week 28.

In fact, this weekend at ASH, much longer follow-up data from the PIONEER trial showed no significant additional symptomatic benefit in avapritinib-treated patients after 3 years of therapy with mean TSS reduction at 3 years of only 19 points from baseline. Bezuclastinib's symptomatic improvement of 32 points at week 48 is the type of differential magnitude that non-advanced systemic mastocytosis patients are looking for as they search for a treatment that can return them to a normal quality of life.

Then on Slide 24, we look at the broad impact bezuclastinib is having on the lives of these patients with 86% of patients treated with bezuclastinib reporting a clinically meaningful improvement in symptoms by week 48. As you can see, 56% of patients on bezuclastinib report greater than a 50% improvement in their symptoms at the same time point.

Next, on the right panel, you'll see that patients originally randomized to placebo also show rapid notable improvements in symptoms were once crossed over to bezuclastinib therapy. Adding all of these results together result in the bezuclastinib profile showcasing a very active, well-tolerated option for patients, which we believe has the opportunity to become the preferred standard of care following approval.

Now turning to the results from APEX, our registration-directed trial of bezuclastinib in patients with advanced systemic mastocytosis. Here on Slide 26, you'll see contained within the blue line, 81 patients were enrolled in Part 2 of the APEX trial at the 150-milligram daily dose, 68 of whom reported measurable C-findings at baseline and therefore, are evaluable for response on the modified IWG MRT ECNM criteria.

On the subsequent slides, you will see a total of 81 patients analyzed for PPR and safety, while that subset of the 68 patients with measurable C findings will be included for analysis of the primary endpoint.

Turning to Slide 27, you will see the patient demographics and characteristics, which are generally representative of the broad ASM patient population. Of importance, the APEX trial enrolled a slightly higher proportion of aggressive systemic mastocytosis and mast cell leukemia patients, along with a higher rate of patients with the SAR mutations compared to prior studies in the same patient population. Also of note, the APEX trial did allow a small number of patients with prior avapritinib treatment to enroll.

On Slide 28, you'll see the impressive clinical activity demonstrated by bezuclastinib in this patient population. On the primary endpoint of modified IWG-MRT-ECNM response, bezuclastinib achieved a 57% response rate, including 49% objective response rate when considering the subset of patients who achieved a partial response or better. It's important to note that these data were cut with a median duration of treatment of just over 9 months. And at the time of data cut, multiple additional patients were in unconfirmed response pending further assessment.

Looking at performance on pure pathological response, a key secondary endpoint of the APEX trial, you'll note that 80% of patients achieved a partial response or better, reflective of the rapid and deep activity bezuclastinib has on serum tryptase and mast cell burden in this patient population.

To dive deeper into bezuclastinib's effect on these objective measures of disease burden, you'll see here on Slide 29, a very impressive waterfall plot showing that nearly all patients have reduction in their mast cell burden. And looking across the bottom of the slide, you'll see this impressive activity applies also to bezuclastinib's effect on serum tryptase and D816V variant allele frequency with 89%, 89% and 91% of patients achieving greater than a 50% reduction on these objective measures of disease burden.

Now turning to possibly the most exciting part of the APEX results for advanced systemic mastocytosis patients, the safety and tolerability profile on Slide 30. You'll see here that in the trial, no patients treated with bezuclastinib needed to discontinue treatment for related adverse events and only 14.8% of patients even required a dose reduction of bezuclastinib.

With low rates of Grade 3 thrombocytopenia and anemia, coupled with the non-hematologic safety profile presented in the table, we look forward to offering patients a new treatment option, which delivers the powerful clinical activity they are looking for without the trade-off of high rates of edema, cognitive impairment and bleeding risks associated with the current standards of care.

Of particular note here on Slide 30, only 1 patient reported a Grade 3 transaminase elevation and with dose reduction, that patient remains on bezuclastinib today.

To summarize the APEX results, bezuclastinib showed a 57% ORR on the primary endpoint as measured by modified IWG criteria, along with an 80% ORR on the key secondary endpoint of PPR, but what makes bezuclastinib stand out in the advanced setting is the safety and tolerability profile, which should allow patients to enjoy the rapid and robust activity of a potent KIT inhibitor without all the risks associated with currently available treatment options, which lack the selectivity of bezuclastinib.

The potential for us to unlock the ability to treat SM-AHN patients with bezuclastinib and in AHN-directed therapy is of particular interest for investigators in this community. We are excited to submit an NDA for bezuclastinib in advanced systemic mastocytosis patients during the first half of 2026.

Now before I open up the call for questions, I'd like to reiterate just what an amazing journey the last several months have been for Cogent. Bezuclastinib has now demonstrated across 3 separate pivotal trials that it can provide clear clinical benefit to systemic mastocytosis in GIST patients, all while delivering a well-tolerated safety profile reflective of its highly selective targeted approach.

With an opportunity to submit 3 NDAs in the next several months, putting us on track for multiple launches in the second half of 2026, Cogent is positioned to make the leap to a profitable commercial biopharma company in the very near future.

To finish up today, I would like to congratulate my Cogent colleagues on all the recent successes and particularly thank all of the investigators and patients who participated in the SUMMIT and APEX trials and believed in the potential of bezuclastinib.

So now, operator, I think we're good to open up the line for some questions.

[Operator Instructions] And I'm showing our first question in queue coming from the line of Andrew Berens with Leerink.

Can you hear me?

Yes, we can hear you okay.

Great. Congrats on the data and all the progress. I guess on ISM, Slides 12 to 15 are particularly striking and suggesting that these have a broad effect on symptoms and the biomarkers correlate with symptoms. It's different from what AVA shown in the past. I'm wondering if the doctor could comment whether she thinks this is going to translate into an improved quality of life for the ISM patients. And when both of these drugs are on the market, how will she decide, which drug she's going to use when a new patient that's naive to therapy presents to her clinic? And then I have a question on ASM after that.

Okay. Dr. Rein, do you want to maybe tackle that one?

Yes. So I think the first part of that question was how do these findings translate into improved quality of life. So I think they translate in various ways. So as somebody who treats patients with SM, I think, obviously, the data that we've presented looking at the change in total symptom score says right there that patients do have an improvement in their quality of life, right?

So if people feel better and are able to do the things that they want to do, go to work and function, spend time with families, do the activities they enjoy, that oftentimes inherently improves quality of life. And so I think what I find encouraging about this data that we present is that we see the change across symptoms, again.

So it's not one specific domain or symptom driving this improvement, but rather a global change, and that is important because, again, specifically within ISM, we do see such a heterogeneous disease presentation in these patients. So I think that's important. I think the other key takeaway as you kind of tie it into the decrease in changes in mast cell burden, as an oncologist, for a lot of diseases, we have markers of disease that patients follow very closely. And I think there is a certain level of comfort from a patient perspective. I know from my own personal experience and then as a treating physician that patients really do feel comfort and some feel better seeing positive changes in disease, and I think that's very logical.

So I think from a quality of life and just well-being perspective, I think oftentimes seeing your tryptase go down, or seeing your mutation go away, I think that positively impacts a patient experience of their disease, which is really important for chronic disease. So I think that answers the first part of the question.

I think the second part of the question was how would you choose between agents? Is that correct? I just want to clarify that.

Yes.

So I think that is an excellent question. So I will say first, I think the most exciting piece to this entire process from my perspective is the fact that this is the potential for patients to have options. So I think I like facts and figures. And I think what we've presented and what I've shown here within the context of this date -- of this data is that, again, there is a significant improvement in symptoms. There is a significant improvement in markers of disease. There is a correlation between those 2, and there is a tolerable safety profile.

So I think when you talk to patients and when I talk to patients about this, what I typically review is the facts and the figures. I review the data in a patient-friendly way. And then we make the choice for the patient to decide on an agent that is going to be effective and then also well tolerated. And I think, again, the tolerability is important because these are chronic diseases and patients do stay on these medications for a long time. So I do think the safety profile, which we've presented here is quite encouraging.

Okay. And then just on the ASM data, just wondering if, Andy, if you can give us a little more color on the unconfirmed patients, the number of patients that have had a response, and maybe that haven't confirmed yet, but still may confirm. And then when we might see the 20 patients, the combination patients presented and if you think those patients may eventually end up in the label?

Okay. So thanks, Andy, for the question. I'll take the second part of it first. The cohort of patients that is allowing for concomitant use of bezuclastinib with AHN-directed therapies continues to be open for enrollment. We would expect to have data from that cohort probably closer to launch. It is not meant to be part of the registration trial. So we'll have to stay tuned for that later in 2026 or early '27.

With regards to your first question, without putting a specific number on it, what we can tell you is if you look at that chart on -- I'm going to get the slide number wrong, let me see. From the APEX data, Slide 28, that shows you the sort of disposition of response by patients at the time of data cutoff, there's quite a few patients on the modified IWG column that are in stable disease or clinical improvement.

I can tell you that a lot of those patients are already in response, several of whom are in complete response per the pure pathological criteria, and they're waiting resolution of C findings. Now some of those C findings are due to the underlying mastocytosis disease. Some of them are probably due to the AHN disease. So it's hard to predict exactly, which ones of those patients will eventually become responders. What I can tell you, there's -- of the patients that are on study remaining in stable disease and clinical improvement, we've gone through them sort of one by one. There are many that have the opportunity to still achieve a response per modified IWG.

So we'll wait and give those patients some more time. They're assessed on a Q 3-month basis up through the first year and then a Q6-month basis afterwards. We have seen patients in our dose escalation portion of the study respond for the first time as late as 16 months into therapy. So we're going to give those patients a chance to get to their response before we try to report out on them.

Congrats again on all the progress and execution.

And our next question coming from the line of Anupam Rama with JPMorgan.

One for Dr. Rein. Look, this question was almost just asked of you, and I know you called it a loaded question on stage on Saturday morning. I was just wondering if you could dig in a little bit on how you think about the segments of patients that might be more appropriate for bezuclastinib in both the non-advanced and advanced setting versus AYVAKIT based on the totality of what you know today? And then Andy and team, congrats on all the progress, man. Like just wondering what are the final gating steps here to getting that NDA submitted in non-advanced and the SUMMIT data? I think you've reiterated that, that's happening this month.

Yes. So Anupam, I'll just take the second question quickly, and then I can ask Dr. Rein, I know people want her to say that she's going to prescribe bezuclastinib to everybody. So maybe we'll hear what she has to say. So the NDA for ISM is definitely going in, in December. So the gating at this point is honestly just editing to make sure everything is TS crossed and is dotted, but we're at the very, very home stretch of getting that submitted. So that will be sort of an any day type of thing.

So Dr. Rein, do you want to sort of speculate on in the future, assuming bezuclastinib is approved and the FDA gives us the green light, how you would make decisions, understanding that you already answered that it's going to be a patient involved decision on an individual basis. But globally, do you see bezuclastinib becoming a big component of your treatment in the future?

I think -- so to answer the question, I think you kind of hit the nail on the head. So what -- I think the question asked is what is the patient population for this. And I think what the SUMMIT study, what we showed and what is shown so nicely in that slide, and I get you the slide number, how is that? Slide 16. I think the important takeaway for me is that this particular agent has activity across a broad patient population for non-advanced SM. And so we have not included previously in studies patients with smoldering SM. These tend to be higher-risk patients. These are the folks that you watch more closely with higher concern for disease progression.

This particular -- the SUMMIT study also included patients who had prior avapritinib exposure. And so I think the take-a-home message for me when I think about future use is really that this is potentially applicable and is applicable to the entire population of indolent SM patients, so a global population. So when I think about who's appropriate, I think the answer there is I think it's appropriate to consider this when you're treating patients with indolent SM.

Maybe I'll add one thing. And Dr. Rein, we were discussing this offline at some point over the weekend. As we get further down the line and we show longer and longer-term follow-up of bezuclastinib in SUMMIT, I think we have the opportunity, as I sort of presented a preview of the 48-week data to show more clear differentiation as what we're seeing from avapritinib over time is there's essentially no deepening of response outside of the skin domain, and what we're seeing preliminarily from bezuclastinib is continued deepening of symptomatic response across the domains, including as we saw here for the 24-week data and as we can hopefully present in the not-too-distant future, the 48-week data, bezuclastinib is having a broad effect, not just within the skin domain, but the skin domain with the GI domain, with the CNS domain, with fatigue, with most severe symptom at baseline.

And I think that's going to be very compelling for patients of do I want a drug that has a quick bump on one domain? Or do I want a drug that's going to help me across all of my symptoms deeply and continue to improve over time. So look, we're at the beginning stages of this journey with the SUMMIT data, but we're certainly encouraged and excited to show how those data emerge in the future.

And I think that's exactly what you share with patients, right? So I think from my perspective, again, facts and figures, I think what you show speaks -- the data speaks for itself.

Our next question coming from the line of Michael Schmidt with Guggenheim.

Congrats on the data as well. Maybe just a follow-up on SUMMIT. So just obviously, not great to see consistency in effect really in treatment effect across all symptom domains. But are there any particular subsets in the score that is particularly burdensome for patients, particularly impactful to have improvement perhaps relative to AYVAKIT as we look at symptomatic improvement. So that's my first question and anything that stands out there?

And then yes, on the correlation with -- of PD markers essentially and outcomes on Slide 17, really interesting to see the correlation, especially with some of the measurable things like serum tryptase reduction. And I was just wondering in clinical practice, just having that correlation can that be used to guide therapy in any way, for example, seeing perhaps serum tryptase reductions first, but not yet a clinical response and keeping patients on longer on therapy, having that additional measurement, can that be used in clinical practice to guide therapy was the other question I had.

Great, Michael. I appreciate your questions. And I'll certainly ask Dr. Rein to comment a little bit on the second half of -- or actually both questions. Maybe I'll take a step first. So I think what we've heard over the last several years from our competitor is that there's really not a lot of good reason to look at the biomarkers. And really, what you should do is focus exclusively on symptomatic improvement and dose a drug based on how a patient says that they feel, but I think what our data set is suggesting, and we acknowledge that this is the beginning of this journey, and it's going to take a while to adopt is that there is a very strong reason to measure what's going on at a cellular level inside these nonadvanced systemic mastocytosis patients to see if the drug you're using is having the intended effect.

So fundamentally, we are prescribing these patients inhibitors of KIT mutations. Their disease is driven by a KIT mutation, there go, it follows that you would want to measure is that drug doing its -- what's intended to do, which is remove the cells that have a KIT mutation. And we think absolutely, we think that the data we're presenting this weekend and later this afternoon is highly suggestive that you would very much want to measure those things in the future as they will correlate over time with symptomatic improvement, but certainly interested to hear what Dr. Rein has to say.

With regards to your first question on particular symptoms, I'll just remind folks that at baseline, we do measure what's called the most severe symptom in these patients. In our study, and I think it was consistent in PIONEER. The most frequent most severe symptoms are really fatigue as well as sort of the collection of skin symptomology in these patients. And then after those first 2 across the gambit of certainly patients reporting CNS and GI and some of the other symptoms as the most severe. We're really encouraged by the level of improvement we're seeing on the most severe symptom at baseline, matched to the broad improvement across domains, and we're excited to show how that emerges with longer-term follow-up.

I think what Dr. Rein said before is it's nice to have a drug where you don't have to make a choice among several drugs depending on which symptom a patient has, but instead, a drug that has that broad activity. So regardless of the most severe symptoms that are bothering a patient, you know that, that drug is going to help whatever that most severe symptom is. So maybe I'll ask Dr. Rein if she wants to comment on either of those.

Yes. So I'm going to -- I'll piggyback on that -- on the first part of the question, the symptoms. So I think that hits the nail on the head. So I think this speaks to the heterogeneity of patients with indolent SM. No one patient is alike. We do have folks who have mainly skin findings. We have folks who have mainly GI or gastrointestinal findings. And so again, I think this data shows in a lovely way that you get broad improvement across symptoms. And there really is not one specific symptom that is contributing to that change in total symptom score, the mean change in total symptom score. So for me, from a clinical perspective, this broad improvement, I think, is actually very important. So that's the first part of the question.

The second part of the question was addressing the correlation and how we use it clinically. I don't know that we would use it or I would use it as a marker of disease or in choosing. I think what I take from this, the takeaway message for me when I look at the correlation between symptom improvement and change in markers of mast cell disease burden, I think to me, it just speaks to the fact that, again, the agent is active not only in the symptom domain, which is highly important for patients' quality of life, but also is modifying the -- what's driving the disease.

So as a hematologist and obviously, as an oncologist, I think both aspects of that are very important and the correlation for me suggests that this is really -- the therapy is targeting the -- what is driving the pathology driving the disease.

Our next question coming from the line of Christopher Raymond with Raymond James.

Maybe one for Dr. Rein on the treatment choices here. I know you've answered a couple of previous questions on how you choose between these drugs once they're both on the market. But maybe just a question here on another wrinkle. A big part of the treatment decision tree with AVA is whether to updose from 25 to 50 milligrams. We've heard from a number of treating physicians that this can be an issue for patients who are worried about cognitive effects, et cetera. So maybe with both drugs on the market, how big of a factor is that for you? And how important would it be to not have to deal with that? And then I have a follow-up for management.

All right. So I'm a role follower by nature. So I prefer to prescribe per label. So I think for me, that's a consideration. So my general preference is to prescribe per label. So I think thinking about how I will utilize available agents, I will typically prescribe per label, which is how I would think about things moving forward.

Cell. Okay. And then maybe, Andy, so you guys now have objectively a superior drug to AYVAKIT in both non-advanced and in ASM here. I think we all know the price that's been set for AYVAKIT. And I know you're not going to sort of talk about price specifically, but you have flexibility here now given the different doses. Should we be thinking about a meaningfully different price point for these indications?

Yes, it's an interesting question, Chris. And as you know, Blueprint and now Sanofi have avapritinib priced in a flat strategy. So whether you order a bottle of 25 milligrams of avapritinib or 200 milligrams, it's the same price. It's a price per bottle, not per dose. We'll definitely monitor how this all evolves as we get closer to launch and put as much information as we can into the decision. And it's not just in our little corner of the universe within mastocytosis. It's broadly within all of the things that are going on with drug pricing, both in the U.S. and globally, thinking about the best way to maximize the value of bezuclastinib.

I will -- I know this weekend is really about ASH in hematology and mastocytosis, but I can't help but point out that we also have a very exciting finding in second-line gastrointestinal stromal tumor patients. And that, as you know, is at a significantly different dose of bezuclastinib in combination with another agent. So it's a little bit complicated, but I think we're very prepared to move forward and come out with a price that is very competitive to what's available given the clinical data that we've generated for bezuclastinib.

And our next question coming from the line of Sam Slutsky from LifeSci Capital.

Great work on the update. Just 2 for me. Just on the correlation between the PD markers and symptom benefit in non-advanced SM, any hypothesis on why your data shows this versus avapritinib didn't? And then I guess, to this point, could it be possibly because you have more data points at deeper reductions to contribute to the analysis? And then the second question is for the patients who had prior avapritinib in both your advanced SM and non-advanced SM studies, just any general statements on how they did?

Yes. Sam, thanks for the questions. So I will -- I think I'll take both of these and see if Dr. Rein has anything to add. I mean the most obvious answer to your first question about differences in non-advanced mastocytosis AVA versus bezu is -- first principles is that avapritinib reduced their dose by 90% in order to spare the side effect profile that they generated in the advanced setting, which is the only acceptable way to develop that drug in the non-advanced or the indolent systemic mastocytosis population at 25 milligrams, and we've discussed this before, we see avapritinib on D816V as about an ICEC15 level inhibitor, whereas at our 150 or 100-milligram dose in the SUMMIT study, we're probably tickling IC90 concentrations.

And so I think that's reflective of the tryptase data that they shared from PIONEER versus the tryptase data we've shared from SUMMIT, where we're hitting the target and engaging the target. And at the 25-milligram dose, they just aren't, which is also, I think, reflective of their strategy to try to stimulate use of their drug off-label at higher doses when patients are not seeing that symptomatic benefit, it's, in our opinion, due to the fact that they're at a dose that's far below what would be required to hit the mutant cell target.

With regards to the prior AVA patients, I think we present -- or Dr. Rein presented the prior AVA patients from the SUMMIT study looking highly consistent from a magnitude of effect size. That's encouraging because you'd expect that those prior AVA patients would have gotten some benefit from AVA before they entered the study and would have had some of their symptoms improved, albeit needing a washout period before starting.

From the prior AVA patients in the APEX study, I can say that, again, they performed consistently with the overall patient population. So we don't see any reason why you wouldn't want to give bezuclastinib to patients that had seen prior AVA, but I think there's also a lot of evidence building, especially some of that longer-term data from SUMMIT that there's no reason why you want to give AVA first and then wait to reserve bezu for later. So I see the profile of bezuclastinib as a clear preferred choice long term post commercial approval, of course, as a first-line agent in these patient populations, but it's also a very interesting choice for patients that are currently or had previously taken avapritinib and either didn't tolerate it or didn't see a deep benefit as a potential option to try bezuclastinib as well. So Dr. Rein, anything to add to those two?

Yes. I will just echo the prior avapritinib exposure patients. Again, very consistent data, very consistent response. So again, suggestive that this is a subpopulation who will respond as we've seen nicely outlined in that data.

Our last question is coming from the line of Clara Tong with Jefferies.

This is Ding Shi on for Clara. So our question is regarding the APEX trial. So could you elaborate on the time to responses, like the median time to responses? And how do you expect the ORR to evolve over time with longer follow-up?

Sure. So thanks for the question. And I think this is probably going to be our last question. So thanks, everybody, for joining the call. And certainly, thanks to Dr. Rein for spending her time at a very busy conference with us this morning.

With regards to time to response, I think you saw in our press release this morning that we said the median time to response in APEX was 2 months and that the duration of response is not yet mature, which suggests that these patients are having a deep durable response. I did reference earlier in the call that from our dose escalation portion of APEX, we did see patients responding for the first time as late as 16 months on therapy. So we are going to give the patients on the registration trial a little bit more time.

Obviously, they get as much time as they want, but from us to judge the response rate, we did mention that there are multiple patients who at the time of data cutoff on APEX were already in unconfirmed response. That is additional over the response rates we reported, not part of the response rates importantly. So I do believe that the PR or better modified IWG response rates, I would expect those to migrate into the 50% to 60% range from the APEX trial.

And again, what we were expecting from APEX, given that avapritinib from PATHFINDER ran that trial at their clinically relevant dose of 200 milligrams, I would expect that bezu and avapritinib at their equivalent clinically relevant doses would achieve similar levels of activity.

The key difference on APEX that we presented today is a safety profile that looks significantly better than what avapritinib at 200 milligrams can deliver with notably lower levels of dose modification, dose discontinuation, noticeably lower levels of tolerability challenges that those patients face. And so that is really the key for the APEX study is providing a potent KIT inhibitor without all that off-target toxicity that has been managed by investigators, physicians and patients over the last several years. We're hoping to bring a choice that you don't have to manage those tolerability concerns and still achieve that same level of activity.

So hopefully, that answers your question. I appreciate you calling in. And again, to Dr. Rein, thanks for spending time with us today. And I think we're going to wrap up the call at this point. So thanks, everybody, for tuning in and listening. Appreciate it.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.

Good morning, and welcome to Cogent Biosciences' webcast. I will now turn the call over to Christi Waarich, Senior Director of Investor Relations.

Thank you, operator. Today's call will review the positive results from our Phase III PEAK trial in GIST. These results were shared in a press release earlier this morning. You can find the press release in the Investors and Media section of our website at cogentbio.com.

Before we get started, please be reminded that remarks made during this webcast may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about our planned regulatory submissions and timelines, future presentations of clinical data and financial projections. Please refer to our most recent filings with the Securities and Exchange Commission for a full discussion of risks and uncertainties associated with our business.

With that, it's my pleasure to turn the call over to Andrew Robbins, President and Chief Executive Officer. Andy?

Thanks, Christi, and good morning, everyone. As I'm sure many of you have already read this morning in our press release, today is a historic day for Cogent Biosciences, and more importantly, for patients fighting GIST around the world.

After analyzing the results from our PEAK Phase III trial of bezuclastinib in combination with sunitinib, I am very pleased to share that the results show a clear, dramatic, statistically significant advantage over sunitinib alone in patients fighting imatinib-resistant or intolerant GIST, as measured on our primary endpoint, progression-free survival.

With a 16.5-month median PFS, a 46% objective response rate and a hazard ratio that shows a 50% reduction in the risk of progression or death for these patients, the profile generated by the bezuclastinib combination has positioned it to rapidly become the standard of care for second-line GIST patients.

Taken together with the results previously reported from the SUMMIT trial of bezuclastinib in non-advanced systemic mastocytosis patients, bezuclastinib has emerged as the best-in-class selective KIT mutant inhibitor in a $7.5 billion global market with a path toward approval in both patient populations by the end of 2026.

Now here on Slide 3, I'm very happy to introduce both Dr. Jessica Sachs, Cogent's Chief Medical Officer; and Dr. Neeta Somaiah, our special guest today, who is the Department Chair of Sarcoma Medical Oncology at the MD Anderson Cancer Center and a key investigator on the PEAK trial. Dr. Somaiah will take us through the results of the PEAK trial and join us for Q&A at the end of the call.

Before we get to the peak results, here on Slide 4, I would like to remind us all of the current treatment landscape for patients with imatinib-resistant GIST. While imatinib demonstrates very impressive durable responses in the majority of first-line patients, the current treatment options for patients who develop resistance to imatinib have demonstrated much more modest clinical activity. There are currently 3 FDA-approved products for the treatment of refractory GIST, including sunitinib, regorafenib and ripretinib. Each of these products garnered an approval based on a pivotal trial, which demonstrated median progression-free survival of 5 to 6 months and drove responses in less than 10% of patients on those trials.

Sunitinib was originally approved for second-line GIST in January of 2006 and has remained the standard of care around the world in this patient population for the past 20 years. With advances in quality of care, it is now generally associated with an 8-month median progression-free survival and an expectation of approximately 20% of patients demonstrating evidence of response.

Keeping this current treatment landscape in mind, I'd now like to invite Dr. Somaiah to provide us with some background on this disease as well as describe the PEAK trial and the exciting results we have to share today. Dr. Somaiah?

Good morning, everybody. It is my absolute pleasure to be walking through the next couple of slides about the GIST overview and the topline results.

So moving on to Slide #6. So gastrointestinal stromal tumor is a rare disease, but it is a common sarcoma that I see a lot of, more than 6,000 new cases diagnosed annually in the United States. And over 80% of GIST tumors express KIT mutations, which is typically in exons 11 and 9. They can occur anywhere in the -- all along the GI tract from the base of esophagus all the way to the rectum, but majority of these tumors arise in the stomach and following that in the small intestine.

While imatinib, as Andy has said, provides disease control in the frontline setting for majority of patients, at least 60% of patients with advanced GIST will develop resistance within 2 years. And this is primarily due to mutations in the ATP binding site of exon 13 and 14, or as we call it, the activation loop, which is exon 17, 18.

And as you have seen, while there are additional FDA-approved sequential lines of therapy that includes sunitinib, regorafenib and ripretinib, they are effective only against the subset of -- effective only in a subset of patients, and this is because their activity is limited to a subset of the resistance mutations that we see and eventually disease progression results because of clonal heterogeneity.

Next slide. So this is the key slide that talks to -- that excites us as investigators because there is a great rationale for combining bezuclastinib and sunitinib. So as you see here, no single TKI inhibits all the KIT mutations when we look at imatinib, regorafenib, IDRX-42, ripretinib and sunitinib. They have activity against the primary mutations, exon 9 and 11. But when you look at the slew of secondary mutations that can arise, we have regorafenib, ripretinib are skewed more towards the activation loop activity, including IDRX-42. And sunitinib is the only drug that we have that has strong activity against the ATP-binding pocket, especially exon 13. So when we combine bezuclastinib -- and bezuclastinib has more focused, targeted activity on the activation loop exon 17 and beyond mutations, so when we combine both of them, you do have a broad inhibition that covers the full spectrum of secondary mutations.

Next slide. So moving on to the trial design of the Phase III portion of the PEAK study. Patients were randomized 1:1 to receive either bezuclastinib 600 milligrams once daily, along with sunitinib 37.5 milligrams once daily, and there were 204 patients on that arm. And sunitinib alone, 37.5 milligrams once daily, and there were 209 patients randomized to that arm. Crossover was allowed following blinded independent central review, confirming progression of disease. So it was a very -- actually, it was a great design. So it was a simple to accrue to study. Hence, the accrual did proceed fairly quick.

The patient -- key patient eligibility included age greater than 18 years. Patients needed to have locally advanced unresectable or metastatic GIST with at least 1 measurable lesion per RECIST 1.1. And they had to have documented disease progression prior to entry or documented intolerance to imatinib, which is rare, but we do see that a couple of times. So the primary endpoint was progression-free survival per blinded, independent central review.

The key secondary endpoints were objective response rates per BICR, overall survival. And other secondary endpoints included progression-free survival per the investigator assessment, disease control rate, time to response and duration of response.

Moving on to the next slide, Slide 9. Here, we can see the Part 2, which is the Phase III portion of the PEAK study, the population that was represented in this part. When you look at patient demographics, when you're looking at the sex, male versus female, median age and the ECOG performance status across the 2 arms was fairly balanced, slight male predominance. The median age was around 63, 64, and majority of patients were between ECOG 0 and 1.

When looking at the distribution because this study was open across multiple regions, there was a fair distribution among both the arms between -- of course, majority of enrollment was in North America and Europe, and the numbers were lower in Latin America and Asia Pacific.

Other baseline characteristics, the KIT mutation profile, so the KIT mutation was per the molecular pathology report that was any time prior to enrollment in the study. When you look at exon 11 only, majority of the patients fell into that bucket because that is the most predominant GIST type. Then, following that was exon -- any exon 9 mutation. And then there were patients who had neither reported exon 9 or 11, and some had reported other mutations in KIT. And then, some had no mutations either detected or not reported because it was not a requirement prior to entry.

Looking at the treatment -- prior treatment history, imatinib intolerance, as I had mentioned, is fairly rare, but was balanced across the 2 arms. Prior radiotherapy, now radiotherapy is not used often, but we use it sometimes for localized treatment for -- if they had focal progression on imatinib, they might have received this, but fairly low numbers. And then prior anticancer surgery. I think majority patients might have had this for their initial presentation or after response to imatinib, but they did have progression at the time of entry.

Moving on to Slide 10, which is the most exciting slide. It shows that the combination of bezuclastinib and sunitinib extends PFS with a 50% reduction in the risk of progression or death. As you can see from these Kaplan-Meier curves, once the curves separate, which they separate early on, they seem to run parallel and remain separated. The median PFS was 16.5 months for the combination arm. And for sunitinib alone, it was 9.2 months with a hazard ratio of 0.5 and a p-value of less than 0.001. And this was the primary endpoint.

Moving on to the next slide. This is also very exciting for us investigators. The response rate in the second-line setting for the combination was almost 46% for bezuclastinib and sunitinib and 26% for sunitinib alone. The difference in the overall response rate, the P value was less than 0.0001.

And looking at complete response for the -- was higher in the combination arm with a 6.4% complete response rate for the combination and the 39.2% was a partial response rate. And the reason I say this is exciting and important, we have seen, and there is data for treatment with imatinib. When they have focal progression or some residual disease, we do normally take them to surgery or have other means for focal-targeted control of focal progression. And those patients derive actually a much longer PFS or a time on imatinib that eventually extends their survival.

So if we can extend that same high response rate to the second-line setting in patients who have developed resistance, I think it is quite possible that we will be offering them similar local control measures for focal progression that will allow them to stay on this combination for much longer. And this was not allowed as part of the study. However, in clinical practice, we might see that.

And now moving on to the next slide, it is important -- again, you're using a combination, so I think everybody would be wanting to know whether it was well tolerated or not. What we see here is the combination is generally well tolerated and the safety profile not very different from sunitinib alone. The incidence of treatment-emergent adverse events and treatment-related adverse events was similar between the treatment arms.

And you can see here, there was slightly numerically higher grade 3 treatment-related adverse events in the combination arm and also the serious adverse events. But when you look at -- there were no treatment-related deaths in the combination arm, 1 on the sunitinib-alone arm. And reductions of either drug due to the treatment-related adverse events were around 56% for the combination and 44% for sunitinib alone.

And treatment-related drug reductions required for adverse events. It's not uncommon in our practice of treating patients with GIST. So that is acceptable. What is good is that the discontinuation of study treatment due to these adverse events was fairly low on both arms. And if you look at the adverse events that lead to discontinuation of either drug in more than 1 patient, this is mostly neutropenia in 2.9% patients; ALT/AST increased, 1.5%; and diarrhea in 1%.

Moving on to the next slide. This is a table that lists all the grade treatment-emergent AEs that occurred in more than 20% of patients. And you can see it's fairly balanced between both the arms. The reported frequency was higher than 15% for the combination arm included ALT/AST increase, taste disorder and hair color changes. So that, of course, the ALT/AST increase are the only ones that had a higher grade. The others are usually low-grade events.

What is very interesting is the treatment-emergent AEs reported less frequently in the combination arm. So there were ones that were less frequent in the combination arm, included plantar -- the PPE, plantar-palmar erythrodysesthesia, which is also known as hand-foot syndrome, stomatitis and thrombocytopenia. And these are frequently associated with sunitinib alone, and we can see lower rates in the combination. And hence, the safety profile of bezuclastinib combination is generally consistent with the known safety profile of sunitinib alone, and there were no new risk factors that were identified with the combination.

Moving on to Slide 14. Here, we can go a little deeper into the grade 3 or higher TEAEs that occurred in more than 2% of patients. And as you can see, they're balanced across the arms. Majority of the Grade 3-plus TEAEs were reported at a similar rate in both the arms, except for ALT/AST increase and anemia that were reported. Those were the only 2 that were higher in the combination arm. And as you can see that, there are some that are higher in the sunitinib alone arm as discussed previously. There was no increase in the frequency of severe events observed in the combination arm for hypertension, neutropenia or diarrhea.

And the ALT/AST elevations that led to bezuclastinib dose reductions in 12.7% of the patients, and only 1.5% of patients discontinued. So all Grade 3 ALT/AST events resolved, and no Grade 4 elevations were reported across the study. So again, discontinued -- I mean, most of the times, when you reduce the dose, we were able to get through the higher-grade LFT elevations.

And then, I will move on to Slide 15. And the next 2 slides are going to be my patients of mine that are -- demonstrate nicely the efficacy of this combination, and then, I'll turn it over to Andy after. So this particular patient is a 66-year-old male with metastatic GIST. So he was diagnosed back in 2020. He had -- I mean, I call it, he had adjuvant imatinib. It was a little advanced at presentation, but imatinib worked, and he underwent debulking surgery in 2022 because there were some areas that were still residual. And thereafter surgery, imatinib was reinitiated. But unfortunately, he had disease progression around September-October 2023 with multiple peritoneal nodules.

And this is the time, he was consented on to the PEAK study. He was, otherwise, well. He had some obesity, hypertension, anemia at baseline, some elevated ALT and creatinine at baseline, and he had noted some abdominal distension. He also had long-term leg swelling, some back pain and GERD, but all were well controlled. He enrolled on the study. And as you can see from this graph, right at the first restaging at Cycle 3, he was noted to have a partial response, which is very exciting.

The images here, of course, are only showing the first -- the 2 nodules that you see there, but he did have multiple nodules in the abdominal cavity. And then, at Cycle 9, which is somewhere around April of 2024, he achieved a complete response, and that complete response continues until Cycle 26. He actually was on both full doses for quite some time, and sunitinib was reduced to 25 milligrams, I think, only recently.

Moving on to the next slide. This is a 69-year-old gentleman who was diagnosed with GIST back in 2015. He did have some progression, had surgery in 2021. The imatinib dose was increased thereafter, but then he continued to progress and was enrolled in the PEAK study around end of 2022.

This gentleman had a partial response achieved at Cycle 5, but the reduction in tumor was noted right at the first restaging. And that partial response has continued slowly to increase. And this gentleman is now on Cycle 36. He did have a dose reduction for sunitinib down to 25 milligrams as well, but has continued on the 600-milligram dose of bezuclastinib. He did have a dose interruption because of a Grade 3 anemia, neutropenia at one point. But after the dose reduction of sunitinib, he has continued. And as you can see, the treatment-related adverse events with the maximum grade reported are also on the slide. But again, nothing unusual that we don't encounter with sunitinib alone.

And I think with that, I will pass it on back to Andy, and I will be available for questions thereafter. Thank you very much.

Excellent. Excellent. So thank you, Dr. Somaiah, for your great review of our data, including maybe most importantly, your own experience treating patients with the bezuclastinib combination. It's really just amazing to see patients responding so dramatically, and that with this combination, we may have to start measuring patient duration in years instead of months.

So now turning to Slide 17. I'm going to pause here and emphasize a few points that Dr. Somaiah covered in her presentation. So first, the clinical activity of the bezuclastinib combination outperformed even our loftiest expectations for this trial: 16.5 months of progression-free survival, including a 50% reduction in the risk of progression or death compared to the current standard of care, a 46% objective response rate with 13 patients on the combination achieving a complete response with no evidence of original target lesions. A safety profile across 400-plus patients, which uncovered no unique safety risks of adding bezuclastinib to sunitinib. And for some known sunitinib-related adverse events, including, as Dr. Somaiah walked through, PPE, stomatitis and thrombocytopenia, evidence that the combination treatment may even show signs of reduced frequency and severity of these adverse events.

Second, as we continue to review and analyze these amazing results, it's important to note that 73 of the original 204 patients originally randomized to the bezu combination arm remain on combination therapy as of the data cut. When we project their treatment course, we estimate that the mean treatment duration for patients on bezu combination is expected to exceed 19 months. The clinical benefit and durability of this novel combination continues to impress.

Third, as we look forward, the Cogent team is already working diligently to put together a new drug application for bezuclastinib in GIST with plans to complete that submission in the first half of 2026. If granted priority review, bezuclastinib could be approved for GIST patients as early as the second half of 2026. But in the meantime, Cogent is committed to providing access for the bezuclastinib combination for GIST patients in urgent need as part of our already active no-cost bezuclastinib expanded access program.

There are already several expert GIST physicians around the country, including Dr. Somaiah herself, who are participating in this program. Additional information about eligibility can be found on the bezuclastinib patient assistant website.

Now on Slide 19, I'd like to remind everyone that we are still just crafting the beginning of the bezuclastinib story. We are weeks away from the results of our third pivotal study, the APEX trial in patients with advanced systemic mastocytosis. We plan to share those results in December and hope to demonstrate that potent inhibition of the KIT D816V driver mutation without off-target kinase inhibition and without CNS penetration can lead to robust clinical responses while sparing side effects that are associated with the current standard of care, including frequent edema, cognitive impairment, frequent high-grade hematologic toxicity and a demonstrated risk of intracranial bleeding.

Separate from APEX, we are also on track to submit our first bezuclastinib new drug application in December based on results from the SUMMIT trial in non-advanced systemic mastocytosis patients. We're excited to have 2 oral presentations at ASH during which full results from the SUMMIT trial will be presented as well as the opportunity for Cogent to describe for the first time our novel, potent, selective JAK2 V617F inhibitor, which will also be shared at ASH. Certainly, a busy finish to 2025 for Cogent.

And now finally, on Slide 20, I would like to take a look at the big picture as it relates to bezuclastinib. Five years ago, we acquired this product, informed Cogent around the idea that bezuclastinib's molecular profile, a potent and exceptionally selective KIT mutant inhibitor that did not cross the blood-brain barrier was ideal to develop and position as the best option for patients with both systemic mastocytosis and GIST.

Now, with the results of the SUMMIT and PEAK trials, this vision is coming into focus. The global opportunity for these indications is north of $7.5 billion annually. And with very limited competition, Cogent is poised to transition into a rapid growth commercial stage company in 2026. With a strong patent protection plan through 2043, we are confident and excited at the opportunity in front of us, and we'll continue our focus on high-quality urgent execution against our goals.

Before I open up the call for questions, I'd like to do a few things. I'd like to recognize the amazing team of Cogent professionals that we have assembled over the past 5 years who have worked so hard on behalf of patients to put us in this amazing position today. I'd also like to congratulate the PEAK investigators around the world, including Dr. Somaiah, who has graciously volunteered to join us today for their help conducting a PEAK Phase III trial that has delivered an exceptional result for GIST patients. And finally, and probably most importantly, to the GIST patients and their families who trusted in Cogent in the PEAK study, you did it. You are amazing, and we are forever grateful for your courage and bravery.

So operator, we are now ready to open up the line for questions.

[Operator Instructions] Our first question comes from Anupam Rama with JPMorgan.

Congrats on the data. Not really sure what to ask, even given this mic drop. But I'll ask one to the KOL here, which is, how do you think about incorporating this combination into your treatment paradigm given everything you know today? And would you consider using it in maybe even more refractory patients like third or fourth line, given the unmet need? And then one for the company, just you mentioned the EAP program, can you give us a sense of what demand has been like here in the early innings? And where do you think that could go?

Great, Anupam. Thanks for the question. And I'll take the second one first, and then, I will ask Dr. Somaiah to opine on how she thinks she's going to use the combination.

So with regards to the EAP, we opened that, I think, this summer officially, and we have several, several patients who have already taken advantage of the opportunity to get the combination. But to be fair, until about 1.5 hours ago, those patients were signing up based on, I think, the advice of the investigators who already believed the trial would be successful. I think based on our announcement this morning, we expect many, many more patients might be interested in trying to figure out how to get access to this combination based on these results. So we've seen very good early demand for the combination. I would imagine we're in a different conversation now with the results of the PEAK trial that we've shown this morning.

So Dr. Somaiah, do you want to opine on maybe how you think about using this combination? I'll expand on Anupam's question, certainly in the second line, but across the treatment landscape for GIST patients, both later lines and then even potentially, if you want to comment on, can you imagine using this in any first-line patients?

Well, okay. I'll take all those questions. So firstly, to follow up on your EAP, we have that open, and we were allowed from our institution initially only 10 patients, and we enrolled that so far. So we're going back to ask for increasing the enrollment to at least 30 at our sites. And we are enrolling not only second line, but later lines as well, bringing to the point that do I -- where do I foresee this?

So firstly, once regulatory approval is obtained, I think this will become the preferred standard second-line treatment option for patients who are progressing on imatinib. There are still ongoing clinical trials in the phase -- in the second-line setting, and I think they will continue to enroll, as we learn more about the GIST mutation and treatment landscape. But I don't see any reason why this would not be adopted as the standard second-line option after approval.

To the point of what beyond second line, I do think this combination is very effective even beyond second line. I mean, I know we will hopefully later see data on the crossover part of the study. I do think it works. And we have data from the initial Part 1 of the PEAK study that shows activity in patients, and those patients were not second line alone. A lot of my patients were on that part of the study as well who really benefited beyond second line. So I think it is really important to look at that population. And I hope with the expanded access program, you'll be able to generate more data in the later line setting so that patients will be allowed to get on this combination even after the second line because we have a lot of patients who are past second-line treatment right now who should get access to this combination.

Our next question comes from Michael Schmidt with Guggenheim.

It's Paul on for Michael. Congrats on the terrific results today. My first question is on safety. So could you provide any additional details on how the bezu-related adverse events versus SUTENT-related adverse events were adjudicated in a combo? And how that informed dose modifications for one versus the other on the study?

And then my second question is, you mentioned the 19 months duration of treatment, which is longer than the median PFS that you're seeing. How are you projecting that number? And is there a particular subset of patients who are seeing more outsized benefits who are driving some of that duration? How confident are you that, that will translate to the real-world setting?

Great. Thanks, Paul. And I'll do my best to take these, and then, I'll ask Dr. Somaiah if she has anything to add. So with regards to during the conduct of the trial, how investigators determined dose modification for the combination drugs, the final answer is it was left up to the investigator locally with the patient to determine the right course of action and right care. Of course, Cogent did our best to educate -- Dr. Somaiah doesn't need our help, but across the world, physicians about what you might do if you see a specific adverse event or not.

I think we are now in a very different position based on the results of the trial. So I'll give you an example. You can see in the slide that Dr. Somaiah walked through that one of the most frequent, albeit still at only 2% of patients, reasons for discontinuation of the combination bezuclastinib-sunitinib was for neutropenia.

But then, if you move and look at the rates of neutropenia between the single-agent sunitinib arm and the combination arm, you'll see that the rate of all grades and Grade 3 is identical between sunitinib and sunitinib-bezuclastinib, which I think speaks to going forward in the future, maybe less likelihood of discontinuing bezuclastinib in a patient that presents with neutropenia.

So, potentially, based on the results that we've shown in a very robust Phase III setting, maybe more likelihood to first reduce or discontinue sunitinib and maybe leave bezuclastinib in place to see if that's a possibility. So, hopefully, that's helpful.

Number two, with regards to the mean duration of treatment of 19 months, I think, when you see oncology products that have long median progression of survival, you typically see a minority of patients getting very, very, very durable benefit. So 2 of the patients were described by Dr. Somaiah today with currently ongoing after 2 years and after 3 years. And so while they're not constrained to the responders, what we do see is that patients that have a response tend to be very durable. And so what we're doing here is projecting not the median duration of treatment, but the mean and that, that percentage of patients, call it, 25%, 30%, 35% of patients who get past 2 years and 3 years are really driving that utilization of the mean treatment duration, pulling the average, the mean much further than the median of progression-free survival.

So I don't know if -- Dr. Somaiah, do you want to speak on anything else about how you determined dose modifications for the individual drugs on the trial and then maybe your thoughts about how that could change now that we have the results of the study?

Yes. No, I do hope it does change. So yes, when you -- on study, I think when there is a side effect, it's difficult to -- when you're assigning and the patient is on both drugs, I can imagine why people had assigned the relationship to both drugs in most places. But when you look at the side effect profile, it is clear. So majority of the times, I have not had to actually discontinue drug. I was just able to reduce the sunitinib dose down to 12.5 in some of the patients that were -- that had cytopenias, which was one of the reasons of needing to hold drug. We were able to continue patients with that lower dose sunitinib and bezuclastinib.

So as you saw, of course, I think the liver function increased. That's one, if its high, might need reduction of both drugs because you don't know which one is the major driver. But for majority of the other side effects, I believe now in clinical practice, people will make an attempt to lower sunitinib first before lowering bezuclastinib.

Also, I think -- and the good news is we did not see a drop in efficacy and that, I think, points to perhaps sunitinib, even a lower dose, being effective against the exon 13 resistance mutations and not affecting the efficacy much. So again, we'll see more once more data in the secondary mutation space comes out, but I think we should not have as many both drug dose decreases or discontinuations in clinical practice moving forward.

Our next question comes from Andrew Berens with Leerink Partners.

This is Amanda on for Andy. Congrats on the data. We'd like to get more information on the breakdown of patients that have the KIT exon 13, 14 mutations versus the 17, 18. Or is there any color that you can provide on these segments of patients?

Yes, it's a great question. And the simple answer is there's just a ton of emerging data from this trial that we're going to continue analyzing and be able to bring forward at a medical meeting. And one of the things we're doing on purpose is trying to preserve a lot of those results so that Dr. Somaiah and her colleagues get a chance to stand at a -- in a big room with a lot of people at a medical meeting in the future.

What I can tell you, though, is we have looked preliminarily at it. And maybe most importantly, when we look at the baseline characteristics in the secondary resistance mutation genotypes, the population of the PEAK trial looks highly analogous to the population of the INTRIGUE study. So I think from a frequency of 13, 14, 17, 18, the mix across those 2, we're going to be looking at a dataset that we can do a nice job comparing, and we will have robust sample sizes from each of those genotype subgroups.

And then at a very, very high level, I think what's potentially most exciting about the future is the combination, as Dr. Somaiah nicely walked through on that, mutational coverage grid slide earlier in the presentation that the science of this combination is that when you give patients bezu and SUTENT combo, it should help all of the genotype subgroups. And I can tell you broadly, that's what the finding is going to look like. We're not constrained to an outsized effect in a small group of genotype. This combination is really going to provide benefit across all of the genotype subgroups.

Our next question comes from Sam Slutsky with LifeSci Capital.

Congrats on the great data. Just 2 for me. I guess, first, any thoughts on eventually going into a frontline study, just given how strong these data are in the second line?

And then, on safety, obviously, adverse events like PPE, thrombocytopenia, stomatitis look better with the combo than with sunitinib alone. How much of that do you think is associated with the DDI where you do lower sunitinib exposure a little?

And then for Dr. Somaiah, I guess, how appealing is it to lower these specific AEs with sunitinib such as PPE, thrombocytopenia and stomatitis?

Great. So, Sam, thanks for the questions. And again, I'll kind of dive into that first one. But Dr. Somaiah, I'm curious to hear your thoughts on essentially all these questions. So what I can tell you is, obviously, imatinib is a very, very effective first-line therapy for GIST patients. I think we all have heard the story of Gleevec. It's probably one of the most impressive drugs ever developed in the drug industry from 25 years ago. But we have already had conversations, not since this data, but even leading into this data with investigators on both sides of the ocean interested in exploring the utility of bezuclastinib as a potential combination drug in the first-line setting.

I think what we can sign up for is generating data in potentially smaller exploratory groups of first-line patients, doing something like bezuclastinib combinations in a handful of first-line patients to see what the activity looks like. I think there's really interesting scientific questions around, would you use a bezuclastinib combination in exon 9 primary mutation patients, where maybe imatinib is not as effective as it could be in exon 11? But look, we're just digesting these data, and those are really going to be fun conversations to have with the GIST community moving forward.

On your second question around the -- what's going on, and how does adding bezuclastinib make some of these side effects look improved, which is obviously exciting for patients? I do think that there is a nice scientific hypothesis about that CYP3A4 drug-drug interaction that we reported a couple of years ago, where in combination with bezuclastinib, sunitinib exposure gets, I'm going to call it, smoothed out a little bit. And I think Dr. Somaiah has already talked about this during her comments.

We, of course, always love the idea of some of these tolerability challenges for patients like PPE and stomatitis specifically that patients obviously feel getting less frequent or maybe less severe. But maybe I'll turn it to Dr. Somaiah for her thoughts about what the dynamics might be there and whether that's clinically relevant in her practice.

Perfect. Yes. And I'll take the BDI, the side effect question first, and then, I'll move on to the first-line setting.

So with regards -- I think with sunitinib and just these TKIs that follow imatinib, the palmar-plantar erythrodysesthesia, the PPEs, is one of the most problematic quality of life affecting side effects. So -- hypertension is also a problem, but people don't feel it unless it goes really high. Liver function abnormalities, it's standard practice that we monitor these every 2 weeks initially because that's when we see it, but patients don't tend to feel anything. So reduction in the PPE actually is quite a good effect of the combination that allows patients to stay on it long term.

And even with sunitinib, as I said, most often, we're able to control that side effect by dose reduction. But, of course, with the combination, it allows -- it reduces the growth of these tumors, so allows patients to stay on the combination for much longer even with the lower dose of sunitinib. So I think that is a definite advantage. And I think the DDI reported is probably what is driving that.

With regards to the first-line setting, I do think so this combination in the frontline might be a bit challenging just because imatinib works very well and -- looking at sunitinib plus bezuclastinib frontline, would only be possible if the patient had really bulky disease and already known secondary mutations with -- that we detected maybe perhaps in a liquid biopsy. But, otherwise, I think imatinib will still be frontline.

Now, bezuclastinib has the benefit of being similar to imatinib in the sense it does not affect wound healing and patients can still go to surgery even if they're on the bezuclastinib. So combining bezuclastinib in the frontline setting with imatinib is a thought. And I think probably it will take a little bit more of patient selection because there are patients who have primary exon 17 mutations or certain combinations of mutations upfront. But if we are able to do that without increasing toxicity too much, I think that is definitely reasonable.

Our next question comes from Chris Raymond with Raymond James.

Congrats from us as well on this really groundbreaking data. Maybe first for Dr. Somaiah. Just a question for those patients that you have that are maybe just starting SUTENT that haven't progressed yet, just with this benign and maybe even improved safety profile of the combo, would there be a scenario where you would add bezu for those patients already initiated with SUTENT monotherapy?

And then maybe for the company and for Dr. Somaiah. So -- I'm hearing you guys talk a lot about a potential dose reduction regimen here with SUTENT. This sounds a little bit like maybe there would be a need here for -- to develop some kind of formal maintenance regimen. Any sort of plan there? And congrats again.

Thanks, Chris, for your question. So, again, to your second question, I guess, my quick answer is we are literally like a couple of days into analyzing this data. And there are -- based on the results, like 100 questions and hypotheses we have about how can we move this forward as a standard of care, what can we do to help the GIST community, how can we partner with folks like Dr. Somaiah to do additional studies to really dial in the exact way we want to use bezuclastinib combo in these patients going forward. So I think yes to all your thoughts. I'll ask Dr. Somaiah to opine specifically on your question.

And then with regards to the addition of bezuclastinib to sunitinib, one thing that Dr. Somaiah has already referenced, and we don't have these data yet, but we will bring them to light is part of the trial included a crossover where you add bezuclastinib for patients who have formally progressed on sunitinib, and we're going to get those results to see the performance of those patients. But I think your question might be why would you wait until somebody progresses who's currently receiving SUTENT, why not just add the bezuclastinib right away, both today on EAP and then in the future in a commercial setting for sort of that installed base of patients? I personally think that's a really good idea, but maybe we'll turn it to Dr. Somaiah to see what she might do in her practice.

Yes. It's a good question. And I think we need -- as the data evolves, I think that answer will get clearer. So what I will do currently for my patients, it would be very patient-dependent because it is also dependent on the bulk of disease. We get a sense of how long these patients are going to potentially stay on this monotherapy. And as I said, I had a lot of patients that crossed over and derived benefit after crossover as well. So again, we have to look at the data to see. And, of course, I think the OS, because the patients did very well, will take a long time to read out. But we'll have to look at the overall benefit of that sequential. So -- I mean, if the patient is on SUTENT and is tolerating it well and responding and doesn't have very bulky disease, I might not, might just continue them on it. Whereas if it is easy and it's available and there is access and they have bulky disease, it might make sense to add the combination or add them back on bezuclastinib right away.

Now, the point is when they're on sunitinib, they don't stay on it long enough. So eventually, we will have to add the bezuclastinib. What I'm getting at is I don't know if early addition has benefit -- has a significant benefit or not. And I think, as I said, looking at individual patients, if it's a patient that I want a better response, so I can take them to surgery, those are the patients I would want to add them -- add on the second drug right away. And as we see with no worsening of side effects, I think there might be a lot of investigators who would do that or a lot of treating physicians who would do that.

Okay. I think we're going to have time for one more question. And before we get to it, I just want to recognize Dr. Somaiah for her willingness to be with us very early to describe this very exciting data. It's incredibly helpful to have somebody who treats patients and is a deep expert to help us put this data in context. So thanks, Dr. Somaiah, and now, I think we'll take one more question and then wrap the call for this morning.

Our final question comes from Clara Dong with Jefferies.

Congrats on that really remarkable data. So one for Dr. Somaiah. How do you expect the mean treatment duration of over 19 months to translate into real-world practice from your perspective, maybe where factors like dose modifications and patient adherence also come into play?

And then also a question for Andy. You referenced a $4 billion market opportunity globally for GIST. Maybe could you walk us through the key assumptions behind that figure, like patient population sizing and pricing, et cetera?

Sure, sure. So thanks for the question. I'll take the first one -- or the second question first, and then, maybe we can hand it to Dr. Somaiah to talk about her experience treating patients and durability.

So when we talk about the global opportunity here, we're really kind of focused on the United States and Western Europe. I think outside of those territories, of course, there's also potential upside from a commercial potential over time. But if we look at just the epidemiology, and Dr. Somaiah already referenced this in her comments, each year, there's about 6,000 new patients diagnosed with GIST. I think there's about 85% of those with confirmed KIT mutations. And then, each year, about 60% of patients develop resistance or intolerance to imatinib from the first-line setting. So that gives you, on an annual basis, around 3,000 patients as sort of classic second-line patients on an annual basis.

The current -- or the most recent drug approved in GIST is ripretinib, or QINLOCK, which is priced at about $43,000 a month WAC pricing. And based on the estimates from the PEAK trial of around a 19-month average treatment duration, you can multiply those up to get to that global number of about a $4 billion market with essentially no competition. As we know, SUTENT was approved now about 20 years ago. It's a generic drug. There's nobody promoting it. And quite honestly, we need sunitinib as part of our combination for the scientific and biologic reasons that Dr. Somaiah has gone through.

Bezuclastinib is an excellent inhibitor of activation-loop domain mutations and some of the primary mutations, but it does need an ATP domain mutation partner, of which sunitinib is the best one available today. So looking to launch this drug in late '26. I think there is an excellent opportunity for Cogent partnering with investigators around the world to really rapidly penetrate this market with bezuclastinib combination as the emerging standard of care.

Maybe I will hand it over to Dr. Somaiah for her opinions about durability of the combination. Again, I think we walked through how we've calculated this 19-month mean treatment duration for patients on the study. We do think that there is going to be a very large fraction of patients who have these very, very long durable responses like the patients that Dr. Somaiah used to exemplify her experience treating in the case studies. So maybe Dr. Somaiah, if you want to add anything to that.

Yes. No, so again, of course, there are some patients who eventually will progress and will need to go on. But those patients who are responding and continue to respond, the response seems quite durable. The other interesting thing in my -- there were some patients who came off due to focal progression. And as I said, the study did not allow us to do focal treatment or maybe liver-directed therapy or a resection of the progressing lesion and continue them on it because when those patients went on to the next lines of therapy, the progression was much faster and patients really wanted to get access and go back to the combination again for at least more -- a more sustained control. They were actually doing better on the combination. And I'm just saying that from my personal experience. So it will be great to have this option available, and I think patients will stay on it. And as I said before, when you have a great response and a deep response, we will -- all investigators will figure out how to keep patients on it longer. And if we see some focal progression, how to treat it and continue therapy?

With regards to compliance, of course, patients on clinical trial are a motivated bunch, so their compliance is always higher. However, I will say that patients, once they have progressed on imatinib, I think they do come to a realization because if they have not been compliant with their imatinib and had progression, they are -- I have this talk with my patients all the time, it's like come to grips with what is reality. And when they're struggling with why we'll have to take this all the time, and this and when they're actually progressing and they're dealing with what comes next, their worldview and their ability to stay on drug changes. So compliance second line and beyond actually is better than in the front line. Of course, it will be very important to ensure access to medications so that patients can continue getting access without big cost burden, and all of that will also play into their ability to stay on the medication long term.

This concludes today's conference call. Thanks for participating. You may now disconnect.

Good morning. Thank you for coming to the 2025 Citi Biopharma Conference in Boston. I guess let's get started here.

Next up, we have Cogent. Cogent has had some news recently. If you could just kind of introduce yourselves, perhaps talk about the company, the mission and your overall path to this point.

Yes. Great. So David, thanks so much for inviting us to your conference. My name is Andy Robbins. I'm the CEO of Cogent Biosciences. Cogent is a company that's focused on the discovery, development and hopefully very soon commercialization of targeted therapies for patients with rare genetically driven diseases.

Our lead asset is a drug called bezuclastinib, which we believe is the best-in-class selective potent KIT inhibitor for patients whose diseases are driven by mutations in the KIT gene. Those groups are typically divided into patients with mastocytosis. That disease is further divided into several subgroups grouped mainly into the advanced form of the disease and the non-advanced form of the disease as well as a completely different disease driven by KIT mutations known as gastrointestinal stromal tumors, which is a malignancy or rare sarcoma. We've, several years ago, kicked off pivotal studies across all 3 of those patient populations.

As you mentioned very recently in just this summer in July, we read out the first of those 3 pivotal trials known as the SUMMIT study in the non-advanced systemic mastocytosis population with what we believe are very positive data, speaking to the potency, the favorable safety profile of our drug, and we believe will lead us to our first FDA submission and ultimately approval in 2026.

In addition, the other 2 pivotal trials known as the PEAK study in gastrointestinal stromal tumor patients and the APEX study in the advanced form of mastocytosis are slated to read out later this year. So certainly a very busy 2025, looking at those products. In addition to bezuclastinib, which I believe we will spend most of the time talking about today, Cogent is also building a portfolio of early-stage early clinical and predominantly nonclinical at this point, best-in-class programs for other targets, including FGFR, ErbB2 and PI3K as well as KRAS or pan KRAS. And while we won't talk about those programs today, we're certainly very excited about the future of the company, building what we believe to be a broad portfolio of many, many best-in-class therapies for these patients with high unmet medical need.

I guess to start, could we just talk about the mechanism itself of targeting mutant KIT has a long history, a lot of trials through multiple indications. And what about the mechanism itself is attractive for each of these diseases? What have been the challenges that the various competitors have had? And use that to kind of move into bezuclastinib and how that molecule is designed and how it might be different to actually achieve something that some of these other molecules have not been able to achieve.

Yes. I think as with many other targets and many other genetic mutations, one of the keys to finding a best-in-class drug for these patients is really focused on potency, how well your drug can engage the target and the cells that have the mutation as well as selectivity, how well your drug does at avoiding off-target effects with these patients that have very specific genetically driven diseases. I think we can all get behind the science of trying to find a program, a molecule, a drug that can hit that target and not do a lot of other things.

There's other sort of drug properties that think prospectively around either designing in or out depending on the specific disease. And in the case of mastocytosis, this is all of the immune system where mast cells have a specific mutation in the KIT gene known as D816V. Mast cells typically don't aggregate in the CNS tissue. And so when you're designing a therapeutic, you want to design out the penetration into the CNS tissue.

And so some of the elements of differentiation for bezuclastinib in mastocytosis are not being CNS penetrant unlike a very well-known predecessor compound that's already approved known as avapritinib, which is significantly CNS penetrant as a liability of that compound and then also being very selective. So if you look at the track record of KIT inhibitors past and present, almost every other KIT inhibitor that has been characterized clinically is essentially a pan- Class III receptor tyrosine kinase inhibitor. So in addition to hitting the KIT gene, they also all hit PDGFR as well as many other kinases such as CSF1R, FLT3, VEGF, KDR.

And in diseases like mastocytosis and then GIST, bringing along inhibition of those other kinases simply brings along off-target side effects. It doesn't bring any benefit to those patients. So having a drug like bezuclastinib, which is very specific and selective for only KIT and spares all of those other Class III receptor tyrosine kinases is exactly the type of profile you want in these patient populations.

Got it. So let's start diving into systemic mastocytosis. I know that it's really broken down into multiple segments. I know the Street tends to look at it as to advanced and nonadvanced or ISM indolent. Could you tell us about the disease as a whole, the spectrum, frankly, in more detail than we usually get into the Street of what is the mild side of the disease and what is the severe side of the disease? What are the differences?

Right. So I think you got it right. Typically, folks think about mastocytosis in 2 large buckets. And then within those buckets, there's definitely subgroupings of patients depending on severity of disease and prognosis. But in the advanced form of the disease, that really is a disease of mortality. So again, both of the -- all patients in mastocytosis are fundamentally driven by the same point mutation in D816V. But in the advanced patients that arises sort of a more serious mortality disease where in addition to mast cells having mutations circulating in the body, they tend to aggregate in large numbers in places like the bone marrow, in the spleen and the liver and cause significant challenges for patients ultimately left untreated, shortening significantly.

In the nonadvanced form of the disease, the mutant mast cells continue to proliferate probably don't aggregate nearly as much in places like the bone marrow, the spleen and the liver, but cause significant symptomology. So the non-advanced form of the disease, you can think about it as a disease of morbidity, where the patients that have this disease tend to live a normal lifespan, but their life is compromised significantly on a spectrum of symptomatic severity with a host of different symptoms, probably most commonly symptoms of skin in the GI tract, but also leading to issues with pain, with fatigue, with CNS issues like anxiety and somnolence, depression, cognitive symptoms, et cetera, et cetera, et cetera.

So while the sort of manifestation of the diseases is quite different, advanced form of the disease mortality, nonadvanced all these patients are driven by the same mutation. And so when you look across mastocytosis, there's a very good scientific basis for having a potent selective KIT inhibitor that can turn off cells that express this mutation in the body.

When we drill into the non-advanced side of themselves, there's a whole host of symptoms you start talking about relative to the disease. which are the most problematic -- clearly, skin is the most prevalent, which are the most problematic, which are the symptoms patients to go see doctors and actually begin them within the kind of diagnostic process to be identified as systemic mastocytosis?

Yes, it's an excellent question. And over the past few years, we've gotten to know many of -- many patients with the non-advanced form of the disease and of course, interacted with many investigators. And one of the biggest issues and challenges right now is that there are thousands of patients with this disease, but only a handful or a fraction of patients have affirmative diagnosis of the disease. It is a challenging disease to diagnose. And many of these symptoms when a patient presents to a primary care physician or a community gastroenterologist or immunologist or allergist are not well known among tens of thousands of physicians.

And really, it's a patient struggle over probably years and multiple physician referrals before they finally find themselves in a physician's office like a hematologist or what we call a sophisticated allergist who really understands how to see those signs and how to affirmatively diagnose a patient with this disease. When you look at the patient populations that we've enrolled, and I think it's consistent across some of the other clinical trials that have looked at non-advanced mastocytosis, probably the most severe symptoms tend to aggregate either in the skin. So things like skin redness, itching, wheels, rash, it's about 30% to 40% of patients suggest that those are the most significant or bothersome most severe symptoms. And another 30%, 40% probably in fatigue.

So just debilitating tiredness as a result of their disease, inability to sort of interact with society, hold a job, interact with people outside of their world. And then there's a whole host of others that make up the last 20% to 30% of most severe symptoms at baseline, including some of those CNS symptoms, some of the pain associated with this disease.

And really, that's the symptom side of the disease. There's also -- I think it's important to point out for these patients, this constant fear and the potential of a severe anaphylactic reaction as a result of overactive and proliferating mast cells, which can be brought on by a host of different environmental triggers. And so you can sort of see how this constellation of symptoms, along with that sort of underlying fear on a constant basis of severe anaphylactic reaction leads to significant morbidity for these patients.

And they are really looking for options to address how do I keep all of these things under control and not just stick Band-Aids onto the symptoms, but really searching for a therapeutic option that can get to the heart or the root of what their disease is caused by that can lead them more towards really broad resolution of the symptoms. And I think for the first time after we presented data this summer, there's starting to be talk of what does true disease remission look like from an agent like bezuclastinib that can potentially bring hope to this patient population.

So if we look historically before avapritinib came out of the market, these patients basically had to run through the antihistamines, some got up to Xolair, which would have been off-label. And of course, avapritinib came along. To this point now, how do you think the market has changed with Ayvakit there versus these other medications, which are almost certainly because they're cheap, probably still easily used. And what is avapritinib done to change it?

Yes. So we acknowledge that avapritinib represented a very important step forward for the first time patients had an approved KIT inhibitor, albeit at a dose that's significantly below the target exposure that you would look to in a mutant-driven disease for resolution of symptoms and clearance of the objective measures of disease. But as a step forward, what avapritinib can offer at the 25 or even a 50-milligram off-label dose is some symptomatic improvement in an oral pill, right? And so that's a great option for patients to take, but we know that patients very rarely on lower dose avapritinib can achieve full resolution of their symptoms.

So they can get some improvement, which we, again, acknowledge is an important step for this patient population, but it leaves these patients still searching for something that can bring them all the way to resolution of their symptoms. The challenge with avapritinib, as I think folks know, is as you increase its exposure, you bring in some of the liabilities of that molecule, namely that it hits many other kinases in addition to KIT as well as its potency in crossing the blood-brain barrier.

So patients have a trade-off with that molecule of as they want to dose up to get the benefits of removing mutant mast cells, D816V KIT mutant mast cells, you have to take the trade-off of nearly ubiquitous periorbital and peripheral edema, frequent cognitive symptoms and then the risk of things like intracranial hemorrhage due to the off-target effects of avapritinib.

So SUMMIT Part 2, you announced top line data earlier this year. Could you talk about what you saw in that data versus what we know about avapritinib? And how much closer are we to full symptomatic resolution?

Yes. I mean we're very excited to demonstrate a clear statistical win in the SUMMIT Part 2 data, bezuclastinib compared to placebo. We acknowledge that for basically a blueprint-driven reason of wanting to trademark their patient-reported outcome scale, we at Cogent created a new patient-reported outcome scale in concert with the FDA and working with investigators. When you look across trials and what we do to make it easy for folks is we score our data using the speed improvement is noticeably higher, deeper, better, faster with bezuclastinib compared to what you're used to seeing in the PIONEER study at low-dose avapritinib.

And that is really backed up in the data by what we showed with the objective measure of disease response, namely circulating serum tryptase, which is a protein marker of mast cell activity, where we showed close to 90% of patients getting what was considered a response, a greater than 50% reduction in serum tryptase at 24 weeks compared to low-dose avapritinib, which is closer to about half of patients getting to that measure.

So backing up sort of the potency, the exposure, the target engagement of a stronger KIT inhibitor and then translating that into faster, deeper, more pronounced symptom resolution, sort of all those things are tracking in the same direction to make sense for what we believe will become the standard of care in the non-advanced mastocytosis patient population.

Got it. So if you look back at the PIONEER data, they eventually got to start releasing the more details of the data, getting into the actual specific symptoms within the TSS itself, the total symptom score. What were the areas of strength that you saw? I mean, it was hard because you start spreading it out into symptoms, the powering goes way down naturally because of patient numbers. What did you see in there? And where could we see differences once you ultimately get to the more detailed updates?

Yes. So we're speaking at the PIONEER data, and this has been presented and published across many conferences in journal papers. If you look at individual items, which are things like fatigue or redness in the skin or any of the individual symptoms themselves or you looked at the aggregated sort of sets, which are domains on no individual symptom aggregate of all the symptoms together did avapritinib sort of squeak out a win statistically over placebo. To be fair to avapritinib and just based on lots of conversations with investigators, with patients, low-dose avapritinib does seem to have some benefit in the skin symptomology.

So patients that have rash or redness or wheels or itchiness, when they take low-dose avapritinib, some relief is gained with 25 mg of ava. But really, people don't have a lot of anecdotal evidence that -- or stories about patients whose fatigue or CNS symptoms or GI symptoms or pain is resolved with low-dose avapritinib. And so I think the standard practice that we've seen emerge is to try to titrate avapritinib up to higher doses and try to find that balance between driving to exposure in a mutant-driven disease against the target, where at 25 milligrams, they're below IC20 on target engagement.

And so I think science would tell you, you want to push that dose up until you can engage those mast cells, the mutant cells and get rid of them, but balancing that on the titration with bringing in the PDGFR inhibition, bringing in the CNS penetration, trying to avoid replacing symptoms with side effects. So that is where Cogent and bezuclastinib come in.

If you look at the profile that we've delivered and you think about the symptoms -- the side effects that are symptomology for patients, patients feel, we have very infrequent, especially compared to placebo, side effects that patients experience as replacement to symptoms.

And so that allows us to dose bezuclastinib in the SUMMIT trial up to 100 milligrams, which is just around IC90 target inhibition of the KIT gene and really show that through the objective measures of disease like the serum tryptase where 100 milligrams of bezuclastinib is dramatically different than 25 milligrams of avapritinib at removing the bad actor mutant mast cells from the patient.

Got it. So I guess, fast forward, specifically with respect to the safety profile, what types of tolerability issues have been observed with bezuclastinib? I know that certainly the Street had concerns about it after the first update, which was, I guess, 1.5 years ago now. What were the expectations originally? What are they now? And how have they evolved?

Yes. If you look at the safety profile that we presented in July, we're certainly very pleased as I think are the investigator in the broad systemic mastocytosis community. So if we rewind back to when we had our Phase I results, we can sort of with hindsight, understand from the investment community why there may have been concern with reporting a handful of patients with higher than grade 2 elevations in liver function tests because the concern in a small Phase I study is that when you see those and you show up 2 years later into a larger pivotal trial, will those manifest into true liver toxicity.

And so again, putting ourselves a couple of years ago, maybe that's a rational concern, but now that we've read out the pivotal data and that did not occur, there are no patients that had any liver side effects other than lab abnormalities reported in the trial, treatment emergent completely across the board, nor are there any patients that have true liver consequences, no hospitalizations, no DILI reported as adverse events, no liver transplant, no liver toxicity. This is really truly confined to lab abnormalities in LFT numbers moving up and down, all of the patients, whether without dose mods, with dose mods and in rare cases with discontinuation have had their liver enzymes return to baseline very rapidly.

And we've even extended that a little bit further by saying across all of our clinical trials, including the PEAK study, which is dosed at 6x the dose in patients that have fundamentally compromised livers, which is one of the main sites of metastasis of second-line GIST patients, we, again, have no significant liver toxicity findings, albeit in a blinded basis at this point. So look, where we are now, I think it's pretty clear that the profile of the drug, we will with bezuclastinib have patients with fluctuating liver enzymes. We have no evidence that, that will lead to true liver toxicity or consequence. Beyond that, the safety profile looks very close to placebo.

Probably the only other thing that you can point to is that patients, which is an on-target effective kit have their hair grow in sometimes with white color. That is an easy to fix side effect. If you care about white hair, there are cosmetic ways to fix that. And so we think the profile of bezuclastinib at the appropriate target engagement in this mutant-driven disease, reaching that ICEC90 type drug concentration is exactly what these patients are searching for.

As a consequence of removing the bad actor mast cells from the body, we see a direct correlation to symptomatic improvement. And while our predecessors, now Sanofi, but before Blueprint had told a story of really no relationship between the objective measures of the disease and the symptoms of the patients, Cogent is going to tell a different story, and I think a story that makes more sense scientifically.

So one more question on non-advanced, and that's regarding the actual process of treatment. Avapritinib, when they go in patients essentially for the first few doses, they have to be -- they're monitored for a period of time. I would expect that you assume that practice would continue at least at the beginning of any prescription and then eventually, that would kind of dissipate once patients are beyond the initial few months.

Yes. So the question is about monitoring. So in the practice of treating mastocytosis patients with KIT inhibitors, let's start with avapritinib today. Number one, you want to monitor patients for signs of disease improvement, not dissimilar than in a cancer treatment setting, the idea of never providing patients with a solid tumor, a scan again after initiating treatment to see if their tumor is changing size or shrinking, that seems sort of strange as it would be for us to never take blood from a mastocytosis patient to see if their tryptase or their variant allele fraction is changing.

So there's a positive reason why you want to monitor patients to see if the treatment you've chosen and that the patient has accepted is doing something beneficial to the patient. So on a regular basis, physicians are going to monitor for things like tryptase and variant allele fraction. From a safety perspective, starting at 25 and definitely in an off-label higher dose avapritinib setting, it's a responsible thing to monitor those patients for their platelet counts because we know the history of avapritinib when the patients' platelets drop they puts them in significant risk for bleeding events, including intracranial hemorrhage.

So on an ongoing and I think indefinite basis, patients with avapritinib are going to be monitored for platelet counts. We have shown that on bezuclastinib with regards to liver function tests, it's probably a good idea to measure patients' LFTs for the first several cycles of treatment. There are going to be a small number of patients based on the SUMMIT data, it's probably a small single-digit percent number of patients for whom bezuclastinib might not be the long-term chronic treatment.

For the other 95% plus of patients, they will not have issues. They will not have to dose M. They will be able to get through the first several cycles without any LFT issues. and continue on benefiting from the drug. So we don't see any practice changing for bezuclastinib's hopeful approval next year to the frequency or sort of underlying reasons for monitoring patients receiving KIT inhibitors for non-advanced mastocytosis.

So let's move over to advanced. Tolerability also pops up there, but for different reasons, just like the non-advanced and overall, there's different -- there's a spectrum of disease. Could you talk a little bit about how bezuclastinib can differentiate from what avapritinib has been able to do? And it seems like a lot of that is connected to that tolerability profile.

Right. And again, this is important from a history perspective. So we just spent some time talking about avapritinib, which we acknowledge is a good step forward, a good first step for patients with non-advanced -- the downside of 25 milligrams of avapritinib is that it doesn't actually have the potency to remove all the mast cells from the patient. In the advanced form of the disease, which was their first indication, they dosed their drug at their ECIC90 dose, which is 200 milligrams.

So almost 10x the dose of the non-advanced dose. And we acknowledge that, that dose is highly potent, highly effective at removing the bad actor D816V mast cells from advanced patients. The consequence based on the profile of that drug is that 1 in 20 patients died from a fatal adverse event. So they have a greater than 5% fatal adverse event rate at that dose.

In addition to that sort of headline, about 80% of patients experience periorbital or peripheral edema because that drug is a very potent inhibitor of PDGFR. About 40% of patients experienced significant cognitive side effects because that drug is exceptional at crossing the blood-brain barrier and aggregating in the CNS tissue. In addition, they have about 25% incidence of Grade 3, 4 thrombocytopenia, neutropenia and anemia because that drug is a Class III RTK pan inhibitor. So it hits many of the kinases required for formation of healthy blood cells.

And when you put that profile together of that CNS activity with the detriment to the platelets, what -- you saw as a consequence is in over 20 confirmed patients during their clinical program was evidence of intracranial bleeding. And so bezuclastinib in the profile that we've delivered has very low rates of grade 3, 4 heme tox, has very infrequent, if ever shown any cognitive side effects, has very low rates of edema, similar to placebo, does not lead to fatal adverse events at our dose.

And so we think that the profile -- again, we have to wait to see the data out of the APEX study. But if we can match -- simply match the activity and the potency of 200 mg of avapritinib without all of the drawbacks of that level of toxicity associated, I think we're going to have a very strong commercial profile for those patients.

Does this open up the possibility of moving into the associated hematologic neoplasm patients where avapritinib has kind of not been able to get used as much?

Yes. It's a great question. And now we get into kind of the subgroups of the subgroup. So within the advanced population, you really divide it into 3 forms of the disease, mast cell leukemia, which is a pretty rare and very severe form of the disease, the aggressive mastocytosis, which is patients that have just D816V mutation, just the mastocytosis.

And then about 3/4 of the patients have the advanced form of the disease with another unrelated or call it an associated hematologic neoplasm. So a disease like myelodysplastic syndrome or CMML or potentially myelofibrosis, something else that's happening in their body at the same time as mastocytosis. Now those diseases, many of those have therapeutic options to treat but those options are typically associated with significant heme toxicity. And so treating those patients concurrently with those therapies like azacitidine or ruxolitinib or chemotherapy concurrently with avapritinib that has its own high rates of Grade 3 heme tox is really dangerous for patients.

And so it's uncommon to try to treat avapritinib concurrently with those drugs. Now in that 3/4 of the ASM population, if bezuclastinib has a profile with significantly lower risk of hematologic toxicity, then to your point, that potentially opens up that concurrent treatment of bezuclastinib with the AHN-directed therapy. And obviously, Cogent is very interested in that patient population. And so we're running what's sort of seen as a side cohort or a protocol separate than the registration APEX trial, where we're allowing concurrent dosing. And so while that cohort won't be ready at the time of the APEX top line results, we're hoping to have many of those patients dosed concurrently by the time we would be approved as part of a commercial strategy.

How much larger would the market be including those patients versus excluding?

Well, about 3/4 of patients with ASM have SM-AHN as that subgroup. So that's 75%. There are patients with SM-AHN where you make a tough choice and you say the SM is the most challenging part of my disease today. So I'm going to take avapritinib and not the AHN-directed therapy. So it's probably not all 75%, but I think a pretty healthy chunk of that patient population would want to try to achieve therapeutic treatment for both of the diseases that they're fighting at the same time.

Got it. And then the readout for that is coming up pretty soon.

The readout for APEX, the sort of the pivotal study is coming up by the end of this year.

Got it. Jumping over to GIST. Certainly, there's been a handful of -- I wouldn't call them outright failures. They've had minor successes in areas of GIST for these KIT inhibitors. But you're doing it differently, again, because of differences in the tolerability profile. The kind of stuck to monotherapy later lines, you're actually stepping into combination therapy in the second line. Could you talk to us about the upcoming trial and what the differences are and what we could expect to see?

Right. So great question. And this really, again, gets back to science and fundamentally, what is driving disease progression or tumor growth in GIST patients who have progressed after trying Imatinib, which is an amazing drug, probably one of the biggest successes of our industry. So patients whose disease progresses after Imatinib typically show mutations in the KIT gene in either the activation loop and/or the ATP domain.

So exon 13, 14 and/or exon 17, 18. If you look at the history of KIT inhibitors that have been developed across avapritinib, a drug known as ripretinib, which is now approved in the fourth line for GIST sunitinib, regorafenib, maybe most recently bezuclastinib, there really is no individual molecule that can effectively cover all of those mutations. And so while we agree with you, there's been a couple of notable failures recently, probably the most notable are the Phase III trial of avapritinib versus regorafenib in the third line and then more recently, the Phase III failure of ripretinib versus sunitinib in the second line.

Essentially, what those trials showed is that when you take a drug that covers half of the mutations and you measure it against another drug that covers the other half of the mutations, they have a very similar median progression-free survival and therefore, the new drug -- the tie goes to the incumbent. The new drug won't get approved.

Our strategy is to acknowledge the science behind this disease and to acknowledge that bezuclastinib, if we ran it as a similar trial design, bezuclastinib versus sunitinib or versus regorafenib, we would probably meet the same fate where our drug is highly effective at treating patients with mutations in exon 17 and 18, but really not effective at treating patients with exon 13, 14 mutation. And conversely, Sutent is -- which is the current standard of care in the second line. It is now a generic drug. It's been on the market for over 20 years. That drug is very effective at treating patients with 13, 14 and not with 17, 18.

So instead of going forward with a similar design that has failed in the past, we chose a different clinical strategy, and that's enabled by the selectivity of bezuclastinib because unlike avapritinib, unlike ripretinib, we are a selective KIT inhibitor. We don't bring in activity against the other Class III RTKs. And so it enables us to combine with sunitinib. So the safety profile of bezuclastinib in combination with sunitinib does not noticeably worsen the safety profile that sunitinib has as a single agent. And the benefit you get from activity against the disease is that the combination of bezuclastinib and sunitinib can cover all of the known KIT secondary resistance mutations. And so the design of our trial is the combo of our drug with sunitinib in one arm covering all of the mutations compared to sunitinib alone in the control arm, which is really only effective at covering patients with about half of the mutations.

So expectations would be reasonable that efficacy should be improved. The question is, is the tolerability burden acceptable?

I think that's a fair question. We've presented data to date on 60 patients with GIST with full dose sunitinib and bezuclastinib. And across the safety profile, what you see is a very similar combination safety profile of bezuclastinib and sunitinib to the sunitinib monotherapy safety profile. So as much as we would want, we don't solve the tolerability issues of Sutent. Those are probably most notably high-grade hypertension, fatigue, some of the GI and skin toxicities associated with pan-kinase inhibitors.

So that will continue as part of the sunitinib safety profile. But really what bezuclastinib adds on top is sort of similar to what we've already talked about in the mastocytosis population. Maybe some of these patients will grow additional white hair. It's possible some of these patients will see fluctuating LFTs. But now we bring it back to this patient population from a risk benefit. These are metastatic cancer patients who are looking to extend their survival.

And so even more so than in the patient population of non-advanced mastocytosis, refractory metastatic GIST patients, I think, are definitely going to be okay with the cosmetic effects of white hair if it can translate into longer survival.

So the update for that is coming in before the end of this year as well.

That's right.

I know I'm getting ahead of myself here because we have to see this data first. In theory, if it's covering all the mutations, depending on the efficacy data you see. Is this something that could be moved into the combination into a frontline trial against the current standard? Or would that be a heavy lift?

It's definitely a heavy lift. People have speculated about this. What we -- here's what we don't know. So Imatinib, as I mentioned before, is the current standard of care in frontline. That trial was run in the late '90s, very early 2000s, and the quality of care has advanced significantly since then for all cancer patients, but of course, for first-line GIST patients.

What we don't know is how good and how long would the PFS look for Imatinib in the control arm in 2027, which would be when you'd be running a Phase III trial. I think folks have speculated that might be 30 months. It could be longer.

And so a first-line trial might look like more than 1,000 patients. It might look like 5, 6, 7 years, a different strategy for a company like Cogent and for a drug like bezuclastinib it might be to generate some clinical data in a group of first-line patients as opposed to a formal registration trial, which would be, as you mentioned, a pretty heavy lift.

Got it. Thank you very much for your time. Appreciate it, and look forward to chatting again soon.

Awesome. Thanks, David.