Good morning, everyone. Thank you for joining at Jefferies Healthcare Conference. My name is Clara, one of the biotech analysts here. Please join me in welcoming Andrew Robbins, CEO of Cogent Biosciences, for this presentation. Andy, why do not I hand it over to you?
Great. Thanks very much. Let me just adjust these mics. Okay. Good morning, everybody. It's good to see you all. It's good to be with you. What I'm going to do today is walk through—normally we do a fireside chat, but today, given how close we are to seminal data event for the company, what I'm going to do is actually present a prepared set of slides. A little bit different twist on the normal Cogent presentation. I'll just start by reminding folks that I'll likely be making some forward-looking statements. I would just refer you to recent SEC filings for a full characterization of risk associated with the company.
Again, just to orient folks, here in June of 2025, we are at a very exciting point in our company's history with all three of our pivotal studies for bezuclastinib, which is a potent selective inhibitor of KIT, enrolled. Those are namely SUMMIT, PEAK, and APEX. We're going to spend a lot of the time today talking about SUMMIT, as I think folks that are familiar with the story know that we're planning on unveiling the unblinded results of that pivotal study in about a month in July. We are very excited about where we stand with relation to that trial. We'll also talk a little bit about PEAK and APEX as well.
In addition to bezuclastinib, which again, we're going to spend the bulk of the time today talking about, we have a very robust and growing pipeline of what we consider to be potentially best-in-class targeted agents for a variety of rare diseases, most notably oncology of the programs we've discussed, but some of the undisclosed programs would also be non-malignant rare diseases. We have just under $250 million as of the end of Q1, and that cash is sufficient to fund us into late 2026. Again, here on slide four, and we will post these slides so folks will be able to review these after this presentation. Just a reminder for bezuclastinib about the commercial opportunity here.
With SUMMIT and APEX going after both forms of a disease called systemic mastocytosis, the non-advanced form and the advanced form, together, that represents somewhere between $2.3-$2.5 billion opportunity in the U.S. alone. PEAK, which is designed to help patients with gastrointestinal stromal tumors, a rare form of sarcoma whose disease has progressed following treatment with imatinib in the first line, that represents north of a $1 billion opportunity in a completely separate patient population. Altogether, well in excess of a $3 billion total available market for the indications we're pursuing. Again, all three of these pivotal trials have been enrolled long ago, and we are really in 2025 waiting for the right time to assess the primary endpoints and then report those results out to the world.
What I'm going to do today is kind of go back in time a little bit, remind us how we got to where we are, and then try to set some expectations about what would success look like if we roll forward a month into July. On this slide, on slide five, I want to, for this part of the presentation, look at the right half of this slide. In systemic mastocytosis, there are really two companies that are developing products for these patients: Blueprint, or now Sanofi, and Cogent. You can see the three drugs that are well known and have been in clinical development for several years listed here and the differentiation profile from a scientific basis. We acknowledge that each of these three drugs is in preclinical assays, both enzymatic and cellular assays.
Each of the three drugs is highly potent against the target. This is a monogenetic disease driven by a point mutation in the KIT gene known as D816V. All three of these drugs can knock that down. Really, there's no other drug that has the potential, even partially selectively, to hit this mutation potently enough to serve as a clinical candidate. There's no other drugs really seriously being studied clinically for these patients right now. The difference comes from some of the things that you don't want to have for a monogenetic disease. The ideal candidate would be a drug that all it does is inhibit D816V as a point mutation and does nothing else. That is very close to the profile of bezuclastinib. We're about 10x selective for KIT mutant over KIT wild type, but we spare everything else.
Unfortunately, for Sanofi, that's not the case for the other drugs. avapritinib is both highly potent against off-target kinases, including PDGFR, as well as inhibiting CSF1R and FLT3, sort of across the board on class three receptor tyrosine kinases. It is also among the most CNS-penetrant small molecules for any disease and any target ever discovered. That is a liability in this patient population. What they did long ago is they developed a drug that lost that property. They designed a molecule around their CNS penetration to block its ability to cross the blood-brain barrier, and they developed a drug called elenestinib . That drug is now a couple of years behind bezuclastinib in clinical development. What they did not solve with elenestinib is their kinase selectivity.
Elenestinib still is a highly potent inhibitor of PDGFR and also hits many of the other class three receptor tyrosine kinases, and that will cause off-target liabilities for that drug as well. One thing that we've noticed over the past three, six, nine, 12 months is that while we can all acknowledge that avapritinib was certainly a step forward for the non-advanced or indolent systemic mastocytosis patients, the first drug ever approved in this patient population, I think among the buy side and frankly the sell side, there's a little bit of sort of misremembering about exactly what happened in its pivotal trial. I think people would describe AYVAKIT as well tolerated and effective. We just want to remind folks about what that exactly means.
Going back to the actual product insert or the results from the avapritinib PIONEER pivotal study, and this is a straight screen grab from their labeled insert, you can see that on the primary endpoint, what they showed is a 5.7 point placebo-adjusted benefit at 24 weeks, again, compared to placebo. They beat placebo on statistics with a very modest benefit and a sort of close call on statistical significance. That is right now what ISM patients, that's their choice. They can take a drug that has a modest benefit of 5.7 point placebo-adjusted improvement at six months on a patient-reported outcome scale. If you look at it a different way on the same chart, same trial, oftentimes in studies of looking at patient-reported outcomes and improvement in symptomology, you want to look at a threshold and how many patients got a certain percent better.
What the FDA, what I think clinicians around the world have sort of established as a clinically relevant cut point in this disease is what fraction of patients can achieve at least a 50% improvement while taking an active agent. You can see here that avapritinib at six months had about a quarter of their patients achieve this threshold, 25% of patients getting at least 50% better compared to 10% on placebo. A 15 point absolute point delta. We want to remind people what the bar looks like, what a patient is experiencing, and what would be an expectation for what a new generation and next generation of better drug might look like. We will come to that in a minute. Just a quick word, because I think quickly we say, well, AYVAKIT's well tolerated and on to the next topic.
We do want to remind folks. I popped up their safety and adverse event table again from the label and highlighted some of the maybe more macro-level safety bullets on the right side here. Even at 25 mg, and we'll get into why they dosed it at that in a second, what avapritinib delivered in PIONEER part two was over 20% of patients experiencing grade 3 adverse events, almost 10% of patients having to dose reduce from 25 mg, and 5% of patients experiencing a serious adverse event. This is all on the avapritinib arm of PIONEER part two. Again, we acknowledge a well-tolerated drug, but it is not without some warts. Now, why did Blueprint study the drug at 25 mg?
If you remember the chronology, they first studied avapritinib at what we would acknowledge and stipulate is the clinically relevant dose of this medicine at somewhere between 200-300 mg daily dose in more serious patients, both in GIST patients as well as the advanced systemic mastocytosis patients. I think we know the history in GIST that the drug did not work, didn't meet the primary endpoint. In the advanced systemic mastocytosis, again, it's a very potent drug. It hits the target. It gets the job done. If you look at the sort of highlights of their safety at that dose, the story is quite a bit different. At these 200 mg and above doses in the EXPLORER and PATHFINDER trials, 50% of patients had serious adverse events. One in 20 patients had a fatal adverse event on these studies. Not one in a million.
One in 20 had fatal adverse events. They had to dose reduce in the vast majority of patients with an average time of between the first and second cycle. This is not a fun drug to take at the clinically relevant dose. That is why Blueprint was forced to reduce the dose intensity by almost 90% to take the drug forward into the indolent systemic mastocytosis population. That led to, sure, an improvement on the safety and tolerability, but the modest symptomatic improvement benefit that we walk through with a 5.7 point delta over placebo on the primary endpoint. Another thing we hear is, you guys use a different scale, and there is no way to compare these things. We just want to walk through this a little bit.
What we've done here is try to make this a little bit easier to show these mysterious scales on the same slide. They're not mysterious. They're both derivatives of the same sort of starting point of mastocytosis activity scale, which was long ago developed by clinicians. It was just never validated for regulatory purposes. The symptoms, the items, the domains that are included on these scales are a direct result of interviewing and collecting patient-specific information on baseline symptoms in both Blueprint and then Cogent's clinical trial settings. If you look again at these groupings of the items that we include for composite endpoints, they're highly analogous. You look at the skin, you look at the GI, you look at the CNS, you look at some of these systemic, there's really very few differences.
What we are prepared to do and what we've done in the past is we collect data on things like diarrhea and dizziness. It's just when we validated our scale, when we met with the FDA to align on our scale, we both agreed that the frequency and severity of items like diarrhea and dizziness did not rise to the level of inclusion in a composite total symptom score patient-reported outcome endpoint. That same feedback was provided to Blueprint in the summary basis of approval. They chose to ignore it. We chose to incorporate it. We go a step further. If you look at the data on the left side of the screen, those are live clinical data from the SUMMIT part one trial of the patients at the recommended phase two dose.
This is the classic total symptom score chart that shows how much better patients report that they feel over time. The green line is how our patients did using our tool. The dotted line is how our patients did using the items from Blueprint's tool. What we are showing here is that regardless of which tool you use, when you have an active agent, the results of what patients say are nearly identical. We will do this again when we see our SUMMIT part two data. We are happy to show that there is not some sort of subterfuge of us choosing different items in order to make it look better. We chose the items that are the most frequent and severe for these patients, and we have aligned on this with regulators.
Now we get to what are we expecting this to look like and what maybe how do we sort of define success? How do we define what would be potentially practice changing? We've had lots of conversations with investigators, with clinicians, with physicians, with patients, with advocacy groups, with all the key stakeholders in this patient population. We really deeply understand what moderate to severe non-advanced systemic mastocytosis patients are looking for. They're not looking for a drug that is slightly safer. They're looking for a drug that helps them return to a normal life. They want symptomatic improvement. They want potency, powerful. They want a drug that can help them live a normal life.
What we're putting forward here is that in this patient population, we're defining success on the primary endpoint as a home run would be a 50% improvement over what is currently available to these patients on a placebo-adjusted basis on the same endpoint at the same time point. If we could deliver a doubling of the effect, and again, this doesn't happen very often in drug development where one drug is approved for a disease and the next drug comes along and doubles it from an efficacy perspective, we would consider that a grand slam. We've tested this thoroughly with physicians and patients, and I would say that these constituents agree that if you can bring them a new drug which improves their symptomatic benefit by 50%, that opens their eyes. If you can improve it by 100%, that drops their jaws.
That is really the expectation we're setting for July about what the primary endpoint would look like to drive practice changing behaviors in this field. From a safety and tolerability perspective, we understand we've had lots of conversations about the safety profile of bezuclastinib, both from SUMMIT part one as well as APEX as well as the PEAK lead-in. Our drug, we've characterized this, the safety profile of our drug will do essentially two things. It will turn patients' hair white, and that is a spectrum from individual strands of hair to eyebrows to sideburns to more hair in certain patients. That is a cosmetic effect that can be addressed if patients choose to do it. Number two, it will cause fluctuations in transaminases, specifically AST and ALT.
We have looked across the safety database of all of our current patients on bezuclastinib, including the blinded patients on the PEAK study, which is being dosed at six times the dose of SUMMIT in combination with sunitinib, which also has an association with fluctuating and elevated transaminases, similar to other tyrosine kinases. Across all of our patients, we can tell you that there are no DILIs. There are no HISLA. This drug does not seem to be associated with true liver damage. This drug is associated, as almost all kinases are, with fluctuating transaminases. The safety profile that we would put forward as an expectation as a positive a month from now in SUMMIT part two would be to demonstrate no new safety signals. I think everybody has digested what SUMMIT part one looks like. We know there's going to be patients with white hair.
We know there will be patients with fluctuating transaminases. No new safety signals. Specifically, our expectation with regards to liver function tests is that we will continue to show no DILI, no Hy's Law. It does not translate into true liver toxicity. All of these events will be asymptomatic and reversible. In the vast majority of patients, these will be fluctuations. They will be reversible without dose mods. In a small number of patients, you may have to dose reduce, and rarely you may have to discontinue the therapy if you want to get those LFTs to baseline. In all cases, they will be reversible. Finally, what I can tell you is in conversations with prescribers, those are the most important pieces of the conversation around transaminases.
We understand for the buy side, looking at clinical data in a rapid news feed, it's nice to have some bars and some benchmarks. We would say that less than or equal to 10% of grade three, less than or equal to 10% discontinuation. Single digits of these things will put us in a very favorable position, competitive positioning relative to avapritinib, assuming you can demonstrate differentiation on the top of this slide. That's really what we are expecting, what we would like from a target product profile to, in our humble opinion, be highly competitive and be a drug that non-advanced systemic mastocytosis patients will want to take and will want to take rapidly.
With a few minutes left, I'm going to pivot at this point and talk about the fact that while in the summer of 2025, specifically June and July of 2025, most of the eyeballs that are on Cogent are on Cogent for the SUMMIT readout. I do want to politely remind everybody that we also long ago finished enrolling a 413-patient phase 3 oncology pivotal trial for a disease, second-line gastrointestinal stromal tumor, that has not had a new drug approved in over 20 years. If we can demonstrate statistical significance and clinically meaningful results on this phase 3 trial, we will very rapidly be adopted as the standard of care in a billion-dollar-plus oncology market in the US alone with no competition. The competition is a generic drug that nobody promotes any longer, and it would be used as part of our combination.
When you look at how did we get here, what is this trial about? Again, gastrointestinal stromal tumors in the vast majority of patients are driven by mutations in the KIT gene. If you look back at the history, a drug like sunitinib is quite good at hitting part of the resistance mutations, the exon 13, 14 mutations. The newer agents like ripretinib, to their credit, like avapritinib, to our drug like bezuclastinib are quite good at hitting mutations in exon 17, 18. When you take a drug out of the new and you run it against out of the old head-to-head, what you do is you miss this crisscross. The patients that have 13, 14s are well treated by sunitinib and not by ripretinib, and vice versa. The patients with 17, 18 mutations are well treated by ripretinib and not sunitinib.
Again, coming back to the profile of bezuclastinib, being highly selective, having a safety profile that allows for combination, this unlocks a new strategy for us. Instead of having to run our drug head-to-head against a standard of care like sunitinib or regorafenib, in which if we're being transparent, we would likely meet the same fate that Deciphera met with their INTRIGUE study, we have a completely different clinical approach where we can add on. The combination of bezucl astinib and sunitinib will allow us to cover all of the known resistance mutations. That is really why we think the result of the PEAK study will be different than what others have seen in the past. Just to remind folks again, this is a large global study with 413 patients randomized one-to-one against the combination of bezuclastinib again at 600 mg daily dose.
That is meant to really push the dose to cover a wide variety of resistance mutations, not a single mutation like is the case in mastocytosis against the standard of care with a primary endpoint of progression-free survival. We enrolled the study in early August of 2024. We look at blinded events on an ongoing basis. We are confident that those blinded events are still leading us to a top-line result by the end of 2025. We are very excited at the opportunity to see the results of that study. I will remind folks, we did include several classic second-line patients in a couple of different proof of concepts and lead-in studies. If you look at this chart here on slide 15, these are the data of all the second-line patients that we have treated with full-dose combination of bezuclastinib and sunitinib.
If you first look at the very bottom left in gray, and it's sort of hard to see maybe up on the screen, you'll see the benchmarks for what does progression-free survival in the second and third line look like for approved standard of cares as well as some of the recent large phase three studies. You can see it ranges in the third line in the sort of four to five months to the more contemporaneous INTRIGUE study, which Deciphera lost to Sutent, where both arms did around eight months of progression-free survival. If you look at the combination of bezuclastinib and sunitinib, in an aggregate from a median perspective, we delivered a 19.4-month PFS, admittedly in a small N, not a ton of patients. What we're looking for here is about a three-month advantage to show clinical meaningfulness in this setting on PFS.
When the benchmark is around eight months and your proof of concept data are 19 and there is a strong scientific rationale of why that occurred, again, nothing is ever certain, but we feel very confident that later this year we will unveil a new standard of care in a billion-dollar cancer market without competition. I think I have come to the end of my slides. Maybe just to repeat, we are on the precipice of reading out what is potentially the most important pivotal study for our company in about a month. It is definitely going to happen in July. We think that there is a very high likelihood that we will deliver a profile which is significantly better on efficacy and symptomatic improvement for these moderate to severe non-advanced systemic mastocytosis patients, which is exactly what they are looking for with a safety profile that is very positive.
Really the only difference between low-dose avapritinib and what our drug can deliver is fluctuating transaminases. The final thing I'll say is I popped up that slide about what avapritinib looked like in some of those higher doses. If you go back and check on PATHFINDER and EXPLORER, they actually have higher rates of transaminase elevations than we do. To be fair, those are not a concern. They did not change their dose to avoid those. By changing their dose by 90%, they certainly got the benefit of all of the safety effects, but also got the benefit of leaving efficacy on the table.
Maybe I'll wrap up for today, but certainly appreciate your attention and really, really are looking forward on behalf of all the Cogent employees and on behalf of the patients that are waiting for this data to see what this looks like in about a month. Thanks for your attention. Thanks for your time. Appreciate it.