All right, good morning. Thanks, everybody, for joining Jefferies Healthcare Conference in London. My name is Clara, and I'm one of the biotech analysts here at Jefferies. Here, it's my pleasure to welcome the Chief Executive Officer, Andy Robbins, from Cogent Biosciences. It's been a really exciting year for Cogent, so I'll hand the stage over to Andy to give us a presentation here.
Great. Thanks, Clara. It's great to be here. Thanks for inviting us. I'm Andy. I will take you through some of our recent, as Clara mentioned, exciting news, focusing probably most prominently on the results of our PEAK trial in second-line gastrointestinal stromal tumor patients that we released last week, but generally talk about Cogent overall. For those that are new to the story, Cogent is a biotech company focused on the creation, invention, development, and hopefully very soon commercialization of novel small-molecule therapies for mutant-driven, rare disease patient populations with high unmet need. I'm going to be making some forward-looking statements, so I would just encourage people to take a look at our recent SEC filings for a full characterization of risk associated with the company.
At a high level, and this is a new slide, people have pointed out to us that it's a new slide, so we are trying to reframe the opportunity in light of the recent phase III data that we released for bezuclastinib, our lead, very selective, very potent KIT inhibitor in gastrointestinal stromal tumors. I think it's probably not very well understood that second-line GIST is a very significant commercial opportunity for a biotech company, especially given that there's really no competition in the space. Across the indications, and I think Cogent over the last several years has been very well known for its participation in the systemic mastocytosis competitive landscape and development of our asset in that disease. Across systemic mastocytosis and gastrointestinal stromal tumors, we see this as a predominantly U.S. and European but global opportunity of over $7.5 billion.
As a reminder, there really is only one key competitor in the mastocytosis side of the shop, which is now Sanofi with their drug known as avapritinib. On the GIST indication, there really is no competition. The standard of care in second-line GIST is a drug called sSunitinib, which was approved in 2006, the last time a drug was approved for these patients, and we're using it as part of the combination. We're adding on to the existing standard of care. There's no promoted drugs for second-line GIST patients. Now, turning specifically to GIST, and I'm going to get into the PEAK study, and it'll be an opportunity for me to put my own spin on presenting it. We were very fortunate to have the head of sarcoma from MD Anderson do that as our guest speaker on the analyst call last week.
We kind of politely review what are the patients in this indication facing today. While imatinib or Gleevec in the front-line setting is an exceptionally impressive drug, maybe one of the most famous drugs in our industry of all time, it's very good at first line, but unfortunately, most of these patients ultimately progress and end up with resistance to imatinib. When they get to second line, third line, fourth line, there are three approved options: sunitinib, regorafenib, and ripretinib, but none of them are what we would call amazing breakthroughs in the treatment of metastatic cancer patients. All approved with progression-free survival, median progression-free survivals around or below six months, and all with confirmed response rates below 10%. These patients are really searching for something new.
As I mentioned before, Sutent was approved in 2006 and is now already generic with no new drugs approved in the second-line setting. There was a very well-known phase III trial that failed a few years ago run by a company called Deciphera for a drug known as ripretinib, which is approved in the fourth-line setting. They ran a second-line trial and showed that ripretinib was numerically slightly inferior to sunitinib. Both drugs did about eight months of median progression-free survival. When we designed the PEAK trial, we had set out to show that the combination of bezuclastinib with sunitinib, which really covers across the mutations, I think we might get to that slide, is potentially going to outperform sunitinib monotherapy, and that's exactly what the trial showed. Let's go through this quickly. Just from a high-level perspective, every year in each of the U.S.
In Europe, the epidemiology is very similar across the ocean. About 6,000 new patients are diagnosed, about 12,000 patients in the U.S. and Europe with GIST. Almost all of these patients have KIT-driven GIST, about 85% of them, and almost all of these patients are given standard imatinib as first-line therapy. Imatinib is very effective, provides patients long-term duration in the first line, but unfortunately, each year about 60% of these patients develop resistance, typically in the ATP or the activation loop domains exon 13, 14, and then exon 17, 18 as secondary resistance, and imatinib does not inhibit those mutations. The patient's tumors then grow, and they're looking for new therapies.
As I mentioned before, those drugs, sunitinib, regorafenib, and ripretinib, are marginally or modestly effective at helping these patients, but they cycle through the lines of therapy very quickly with a mean duration of treatment on order of six, seven months, something like that. If you look at why this happens and you look at a map of all the different mutations that can drive the growth of GIST tumors, it's quite heterogeneous. Some patients, their tumors are driven by one mutation. Other patients are driven by multiple mutations at the same time. What you're really looking for as a treatment option here is something that can cover all of the mutations. If you look down at the bottom, the only row that is colored in all green, of course, is the combination of bezuclastinib with sunitinib.
Bezuclastinib is a very potent inhibitor of exon 17, 18. It does not hit exon 13, 14. We need sunitinib as a partner because Sutent is very effective at hitting exon 13, 14. When you put the two drugs together, then you can get this pan-mutant coverage. Our trials are relatively straightforward, large phase III cancer study. Just over 400 patients were enrolled, randomized one-to-one to receive either sunitinib as a monotherapy or the addition of bezuclastinib on top of Sutent with the same Sutent dose in both arms. It was measured as a primary endpoint on progression-free survival as well as a variety of secondary endpoints and, of course, safety and tolerability. You can see here on slide nine, the baseline characteristics and the patient demographics.
This is very representative of a classic second-line GIST patient population, very balanced between arms, very similar to a trial like INTRIGUE as far as gender, age, performance, status, place in the world where these patients were enrolled. We think it's a very well-run study and representative of this patient population. Now we get to the more fun slides. I think the expectation heading into this study is that the combination of adding Bezu to Sutent would maybe get a little bit better than Sutent, and it was on the margin of whether it was going to be statistically significant. What we showed here is quite a different story. We had the benefit of going to CTOS, the large annual sarcoma conference last year, where we met with dozens of the top GIST experts in the world who called these data revolutionary, the immediate new standard of care.
Once this is approved, every patient should get this right away. Seeing the Kaplan-Meier curve here on PFS separating very early and maintaining a separation all the way through the curve with an estimated median progression-free survival of 16.5 months relative to Sutent, which numerically outperformed at 9.2 versus 8.3. If you overlay the curve from the INTRIGUE study on top of the Sutent curve, the Sutent curves look nearly identical between the two studies, which is a really nice replication of what you'd expect for Sutent monotherapy. You can see the hazard of 0.50. You can think about that in one of two ways. Across the curve, this shows a 50% reduction in risk of progression or death by patients or a doubling of how well Sutent performs when you give the combination.
The other thing that I think was very surprising, if you remember, the FDA-approved therapies all were approved per label with response rates in the single digits. Last week at CTOS, the way that the KOLs described this, this is not a disease where they were really looking at this as a response disease. This is more of a stable disease for these therapies of how long can the patients not have their tumors grow as opposed to how many patients will have their tumors shrink. They're starting to talk about it differently after seeing these data with a response rate of nearly 50% for the combination, which is extremely outsized relative to expectations.
This is giving them a lot of excitement because it offers patients hope that getting the combination, they will actually be able on scans to show them that their tumors are reducing in size, which is what cancer patients want to see, is that that thing that's inside me is going away based on this new innovative medicine I'm taking. Also, very infrequently in GIST, even in front-line GIST on imatinib, do you see complete responses. We showed in 13 patients complete removal and no presence of the tumor anymore, which is also extremely exciting to these investigators who are treating these patients. Now turning to the safety and tolerability profile, and it keeps getting better, and the results of the trial are more and more encouraging. Sutent as a monotherapy has been used for 20 years.
Every GIST doctor around the world knows how to use sunitinib, understands the pros and cons of it. Of course, it would be nice to have a profile in a combination that did not have the tolerability associated with Sutent. We need the activity on exon 13, 14. Until a new drug is developed that can hit exon 13, 14, we are going to continue partnering with sunitinib. What we show here is across the arms, really there is a very marginal additive tolerability or safety signal of putting bezuclastinib on top of sunitinib. You can see here, I kind of take your eye to the bottom of slide 12, where you see dose reductions are only moved up slightly between monotherapy Sutent and adding the combination of bezuclastinib. The dose discontinuations are only moved up slightly between 4% and 7% of patients between the two arms.
Interestingly, and I think I can show you in subsequent slides, some of the key reasons or the most frequent reasons for discontinuation were probably made as decisions of two investigational drugs without knowing what the profile looked like at the time of the study. The most frequent reason for discontinuing bezuclastinib and sunitinib together was neutropenia. What I can show you on the next slide, and this is the adverse event table here on slide 13, the incremental incidence of neutropenia, let's just go to that one first, between the sunitinib, which was all grade 34% and in combination 34.8%, all grade grade 3, 15%, all grade or grade 3 of the combination 15%. It shows that there's really no additive neutropenia of putting bezuclastinib on top.
Now with this data in hand, and this was verified by talking to these investigators last week, I think it's much less likely that someone when they see a patient with neutropenia on the combo would discontinue bezuclastinib. There's no evidence it adds neutropenia to Sutent monotherapy. I think the discontinuation rate will actually go from seven down to something lower in the real world now that we have a 400-patient data set that demonstrates there's really not a lot of additional safety risk of adding bezuclastinib. I will point you to three things, and we've talked about this a lot. The on-target adverse events associated with bezuclastinib are asymptomatic and reversible transaminase elevations, AST, ALT, and we see that across our trials. Number two is growing white hair, which is an on-target effect of hitting wild-type KIT.
Number three, this phenomenon of altered taste where salty foods taste a little less salty to these patients, also an on-target wild-type KIT effect. Those three adverse events are really shown as the most frequent whenever bezuclastinib is given, and really after those three, the frequency of bezuclastinib-related adverse events goes down dramatically. Again, as a very selective KIT inhibitor hitting no other kinases, not being CNS penetrant, we think our drug is delivering a very attractive safety profile across the board here.
The last thing, with specifically to the higher grade, the grade 3 pluses, we have this nice tornado diagram here on slide 14 that shows the incidence of grade 3s in orange, which is Sutent alone, looks very similar to the incidence of grade 3s of the combination, which is the green bars, so the size of the bar on each side of the middle. Really, there's only one spot where it looks noticeably different for green over orange, and that's the transaminase elevations. You can see that we had 10% of our patients experienced grade 3 transaminase elevations. If you take your eye down to the lower right bullet, you can see here that we had 12% of patients had to dose modify, and most of those patients stayed on.
We only had 1% of patients who needed to discontinue, and those patients all immediately returned to baseline values of transaminases after stopping the drug. In a metastatic cancer population, this is not going to be limiting for prescriptions. I would be so bold as to say the results of this study at a 600 mg dose, which is 6x the dose that we studied in the non-advanced mastocytosis population, demonstrate a very wide therapeutic index with regards to transaminase fluctuations. There are a couple of case studies which I think are very interesting to go through. Both of these are patients on the combination in our study. This first patient is a complete response. You can see the bar chart at the bottom showing that their tumor shrinking and then having no presence of it per CT scan.
You can see that they've been on for 26 cycles now, so now past two years and doing quite well in a complete response still. You can see the second patient with a similar story with an 80% reduction in their target lesion. They're out now at cycle 38. From a duration of therapy perspective, well past three years and still deep into a response. When we calculate how long patients are staying on the study, we point out that of the 2,034 patients who randomized to the combination, 73 of them are still on with at least 16 months of duration. We don't know how long they are going to stay on the combination, but when we do some projections, and I'll take you here on slide 17 to the middle of the screen, we're estimating at least an average of 19 months mean duration of treatment.
That could get longer for two reasons. One, we do not know yet how those 73 patients are going to perform. Those two case studies show significantly longer than 19 months. Number two, in our study, we did not allow for post-progression, I am using air quotes, on progression treatment, where in a GIST patient with multiple lesions, when one lesion crossed the threshold of progression, the patients were discontinued from the study. In the real world, in a patient that had multiple lesions or had locally progressive disease, again, talking with the investigators last week, there is an expectation that if that happened after 18 months of effective therapy, they would not be so quick to discontinue the bezuclastinib and sunitinib and may just continue using it, even though in a clinical trial setting, that would be formal progression.
Again, just to kind of summarize at this point from the PEAK study coming back to some of the very, very impressive numbers, a 16.5-month median progression-free survival. I do not think anybody is expecting a number that big. 46%, nearly 50% objective response rate, also really clear evidence of high activity and synergy of the combination, a 50% reduction in the risk of progression or death, a 19-month minimum estimated mean duration of therapy, which is how you translate this into a commercial setting, how long is the average patient going to be on the therapy. We also point out that we have an expanded access program already available. It was already set up in the past. Of course, it is still working, where patients in the U.S. today can access the combination of bezuclastinib and sunitinib for free.
We have heard a lot of noise about that over the past seven or eight days, as you might imagine. We're also on track, and we provided guidance that we plan to submit our new drug application for the PEAK study in the first half of 2026. We've suggested that by the time we get to the other bank's conference in early January, we probably will be able to refine that to a more specific timeframe within the first half of the year. The full data set from the PEAK study will also be presented, assuming that they accept us for presentation at a major medical meeting in the first half of 2026.
A lot of the questions around genotype subgrouping, performance across subgroups, duration of response, all the secondary endpoints, we'll be able to provide more information on that when we get to that medical conference. I did want to talk a little bit about this because it has been sort of, I think, confusing and brand new and exciting, especially to the investment community and the sell-side community, is how big is the GIST opportunity. I think before this trial, people saw it as sort of a secondary opportunity to the mastocytosis story at Cogent. Now I think people are rethinking that a little bit, especially with that duration, average duration of treatment. You can see here on the left that it's estimated, and there's lots of sources for this, about 12,000 new patients are diagnosed every year across the U.S. and Europe with GIST.
It's split pretty much 50/50. About 85% of those patients have a KIT mutation as the driver, so the other 15% are PDGFR, SDH deficiencies. Of the population that are taking Gleevec in that front-line setting, about 60% develop resistance on an annual basis. That leaves you down in the lower left here on slide 18 with about 6,000 patients annually that are treatable in the second-line setting. Again, standard of care is a generic drug approved 20 years ago, no other competitors going after second-line patients. You can see, at least in the U.S. here, the circles in the middle, some benchmark pricing for what other KIT inhibitors are now charging. Repretinib or Qinlock, which is approved in GIST as the fourth-line drug, is $44,000 a month whack.
You can see Ayvakit, the drug that Blueprint developed and was acquired by Sanofi, is now priced at just under $41,000 a month wholesale acquisition cost. You see what I think is maybe for patients the most exciting graphic in this presentation, where the expectation in the past, even in a very recent global phase III trial running drugs that the enrollment to the INTRIGUE study was very rapid, and the investigators were excited by this study, an expectation of around eight months for how long they would be taking a drug in the second line before developing resistance. Now with our drug with the 16.5-month PFS and that minimum 19-month average duration of treatment really changing the dynamic of what second-line GIST is going to look like and how long we can keep patients from developing resistance from the second line.
If you do the math on the numbers on the screen, you get to, across the U.S. and Europe alone, over a $4 billion second-line GIST opportunity, and again, with no competition, with an NDA planned for the first half of the year. If we get priority review, which is in the hands of the agency, potentially an approval by the end of 2026. About a year until we have an approval for a $4 billion cancer market with no competition. Before I conclude my presentation, I do want to remind people, and it sounds kind of crazy, we're a small biotech company, we have another pivotal trial reading out in a matter of weeks. This is called the APEX study. It's in the advanced form of systemic mastocytosis.
This is a single-arm trial studying 150 mg of bezuclastinib, which is well into that IC90-type target engagement level in these patients. There's going to be about 60-70 patients of new data presented from APEX. It's in ASM patients, which can be either mastocytosis, aggressive systemic mastocytosis, or systemic mastocytosis with associated hematologic neoplasms, so three subgroups. The current standard of care in this patient population is that drug I mentioned that Blueprint developed and Sanofi now owns, avapritinib. Avapritinib is an incredibly potent drug at its clinically relevant dose, which is 200 mg. It just so happens that because it is a pan-kinase inhibitor, so it's a dirty kinase inhibitor, and it is massively CNS penetrant, it causes a ton of side effects and problems for these patients.
Avapritinib per label has a rate of 80% edema, periorbital and peripheral edema, 40% cognitive impairment because of its CNS activity, 25% rate of grade 3 cytopenias across all lineages, including most importantly, thrombocytopenia. They had evidence of 22 patients in their clinical trials with intracranial hemorrhage. They also have a 5% rate of fatality due to adverse events at the dose that they studied in this patient population. We don't have the data yet for this. That's next month. What would it look like for us to be competitive? They have a response rate in the 50% range, so we would be looking to match it. Again, they are a very, very potent drug at that dose. They're just not well tolerated. We're trying to match the efficacy in our trial, but then give patients a well-tolerated version of that drug.
What we'd be looking to do is show lower, much lower rates of edema, much lower rates of high-grade cytopenias, low to no cognitive impairment, we do not cross the blood-brain barrier, and then low to no, probably no intracranial hemorrhage. What we think will happen if we can deliver this profile is that you'd be looking at a choice between two drugs. Both drugs are similarly effective at controlling your disease. One drug may kill you and provide a number of challenging tolerability issues. The other drug would not. That is really the profile we're looking to achieve next month. Okay, just to come back, again, I think people are still adjusting to the new reality for Cogent of the size of the opportunity here.
Again, speaking mainly to investors on this call, across non-advanced GIST in the advanced mastocytosis settings, we're looking at globally, and really when I say globally, I mean U.S. and Western Europe, an opportunity that is north of $7.5 billion, again, with no competition in GIST and one competitor in mastocytosis. All three of these indications, if given priority review, can be approved in the U.S. in 2026. Within one year, we can be commercially selling the drug across all of these patient populations, assuming positive interactions with the agency and on our way to capitalizing on this commercial opportunity. The other thing I think not well understood, and I'll highlight it here on the bottom of slide 20, is from an intellectual property perspective. Our composition of matter with normal Hatch-Waxman extension would protect us through the end of 2038.
We also, if you followed our story, had to reformulate this drug and came up with a partner with a CDMO, a proprietary way to significantly reduce the dose and the pill burden and achieve the same exposure that we could not replicate with four other CDMOs. Because we don't see it as technically possible to match the bioequivalence with a pending patent on that formulation, that would protect this asset from generic market formation until the end of 2043. That would be a 17-year runway on bezuclastinib in these indications with very limited competition.