Good morning. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim, and the first presenting company here is Cogent Biosciences. With me, I have Andrew Robbins, CEO. Andrew, welcome. Thanks for joining us.
Thanks, Mike, for inviting us. Glad to be here.
Andrew, we were just talking, Cogent is obviously weeks, if not days away from its first FDA decision, with two more to follow. How are you preparing to become a commercial company, and what does a successful first year look like for you?
Yeah. We're, as you say, imminently awaiting, hopefully, an approval from the FDA. For folks that aren't as familiar, we've been developing a drug called bezuclastinib, which is a selective potent KIT inhibitor for three different patient populations, within systemic mastocytosis, both the non-advanced and advanced form of the disease, and then in gastrointestinal stromal tumors for patients who have developed resistance on imatinib therapy. Each of those pivotal studies read out during 2025, and most of 2026 has been a process of filing the NDAs and working with the FDA, hopefully for some very near-term approvals. In addition to all the regulatory and development work that we've been doing, of course, we've been planning and onboarding a commercial team to be ready to launch the product ourselves here in the U.S., and we're very excited and waiting anxiously for the word to say go.
So, we have our entire home office, commercial team, and medical teams in place long ago. In Q3, we onboarded all of our field professionals who have territories around the country, and they have been working very hard to develop relationships, doing introductions, telling people who Cogent is, and getting ready for the day when they are ready to sell the product. So, hopefully that is not too much longer.
Again, the first PDUFA date for the GIST opportunity is November 30th. I guess, what is your confidence at this time in an on-time approval as we get close to the date?
I never like to speak in definites about things in the future, but we feel very confident, as confident as I think we can be, that it is literally a matter of days until we get the green light from the FDA. And the team is ready. I know the investigators, the patients are certainly ready to get access to an important new drug in the treatment of gastrointestinal stromal tumors based on the data from the phase III PEAK trial. I think everybody is ready. Now it is just in the hands of the government to let us know when the right day is.
There has been some investor focus on the label specifics around the GIST label, liver enzyme warnings, or potentially monitoring around bezuclastinib. What is your view on how the label might impact the opportunity potentially?
Yeah. Also, the label, as folks know, is usually the very, very last thing, literally in the days leading up to an approval. So, again not being able to give you a definitive answer. What I can tell you about gastrointestinal stromal tumor patients is that for the last 20 years, the standard of care has been a drug called sunitinib, and GIST physicians are extremely familiar with a drug that carries its own language around transaminase monitoring. The protocol for treating GIST patients today, and last year, and 20 years ago, has always been to monitor for transaminase. So, we don't see any language that would suggest you need to monitor for transaminase as anything different than what these physicians, both here in the U.S. and around the world, are used to doing already.
We've said for years, since we characterized the profile of this drug, that it's probably going to be a good idea to monitor transaminase in these patients. What's important in the clinical studies, and this persists till today, is we don't have any adverse events reported clinically as hepatic adverse events. All of our adverse events are lab abnormalities. All of our patients across the studies, APEX, SUMMIT, and PEAK, either had no problems at all, or the ones that had higher grade transaminase had either dose reductions or, in very, very rare cases, discontinuation of drug with a complete return to baseline.
We think that this drug has an amazing profile from an activity perspective, and we acknowledge that it's a good idea to monitor patients in a metastatic cancer population, and specifically in second-line GIST, we don't see that as being any different than what's been done for the past 20 years.
Yeah. When we speak with sarcoma specialists and oncologists in general, they're obviously very familiar, and it's very common for many cancer drugs to monitor for enzyme elevations. But given that SUTENT has a black box for that, do you expect it to carry over into the bezuclastinib label?
It's a great question, and unfortunately, there's not a simple answer to that. So, when you look at the history of products approved for the first time in combination with another product, there are many cases where you see some of the warnings and precautions or safety language from the on-market product carry over to the new product. There are other cases where you don't. And so, I think there's not a hard and fast rule about how that's going to be handled. In our case, we have bezuclastinib being developed as a monotherapy at lower doses in a different disease, where you also see the benefit of monitoring transaminase. So, I think we feel pretty confident, we acknowledge it's the right thing to do for the clinical care of patients to check transaminase.
But what's important, again, is that in no patient has it led to any serious clinical outcome.
Yeah. In the past, you've characterized GIST as a $4 billion global opportunity. When we speak with physicians, equally, they're equally excited. They expect the drug to be used in essentially 100% of their patients that are in the second-line setting. Maybe walk us through how you get to the opportunity. Sometimes it's difficult for investors to understand the TAM without a branded product being on the market that they can point to.
Yeah. It's doubly hard here because what we think the combination of bezuclastinib with sunitinib is going to do is turn a disease of incidence, where today the expected average duration of a standard of care is somewhere in the seven months plus or minus range, to a disease of prevalence because the results of the trial that we ran, the PEAK Phase III showed the average duration of therapy, the mean, which is how you want to think about commercial potential, is now over 21 months. So, patients on average take the combo for over 21 months. And so, what you see when you do the how many patients develop resistance to imatinib each year in GIST, we're modeling that in the U.S. and then similarly in Western Europe at about 3,000 patients on each side of the Atlantic Ocean develop resistance to imatinib.
But if you fast-forward to 2032 or 2037, when you're thinking about peak sales, you're not just thinking about the patients who develop resistance in that calendar year. You're thinking about the patients who started your combination the year before and are still taking it, and then patients who started two years before and are still taking it. So over time, and of course, a prevalent story doesn't emerge in the first or second quarter of launch, but over time, we think the benefit of the combination will allow patients to stay on for multiple years, and that will create a total available market which is much larger than the current incidence market.
Did you have an experience with an early access program, EAP, and maybe talk about how extensively that was utilized or has been utilized?
Yes. One thing that's very important to us as a company is to ensure that patients who are in need get a chance to access our drug. I think it's going to be very easy in the United States. in a short number of days once we have a commercial approval. But after the phase III trial results, while we were submitting the NDAs, we set up an expanded access program across all three indications. So patients with advanced, non-advanced systemic mastocytosis and GIST could all access bezuclastinib or the combo of bezuclastinib with sunitinib prior to approval at expanded access program sites.
We haven't quantified how many patients are on, how many sites are on, but we can tell you is that it's doing a great job helping us educate the community, educate physicians, educate patient advocates, patients themselves about the availability, and there have been many patients who have taken advantage of this program, as well as many patients who for, in most cases, logistical reasons of not wanting to have to go three hours or get on a plane to get to a site, are now aware of the drug and are ready to take the drug once it's commercially available.
Okay. How quickly can you launch the drug once approved in terms of supply availability, CMC inventory, et cetera?
The team is ready to go. It's probably a matter of a day or two would be my guess from the time we get the green light. There's some logistical things about having to move from place A to place B, which you can only do once a product is released and commercial, but it is literally a handful of days, and we would start taking orders immediately.
Okay. What's your plan for ex-U.S.? Maybe talk about the regulatory application there and then potential launch plans.
Yeah. What we've committed to is pivoting now to submitting the MAAs, the European Medicines Agency version of NDAs as soon as we can, so probably in 2027. And that'll give us a little bit of time because that process, similar to the U.S., takes a minute to work through the submission and the review of the files. The files will be relatively similar. They'll be based on the same data sets as we use for the NDAs. What we've noticed, and this is not dissimilar than a lot of both big pharma and biotech companies that have made comments on this recently, is working with potential partners outside the U.S., if we wanted to, we could sign a deal right away. And if it was 2018, we may have already done that.
I think the trick now with MFN is it's very hard for a company like Cogent and our peers to give pricing control to another organization in Europe based on how currently and how maybe in the future European prices might impact the U.S. I think we've decided unless and until partners outside the U.S. are willing to give pricing authority back to the innovator in the U.S., we'll continue to march down a path of really focus on access, probably really focused on the GIST opportunity in Europe. I think an early line of metastatic cancer therapy with very impressive data is the type of drug that you can effectively launch in Europe still. And so, we'll focus on that ourselves, again, unless and until a partner comes forward who's willing to do the terms that we would need.
Yeah, that makes sense. How do you think bezuclastinib is positioned long term in the GIST market? We're getting questions sometimes on other KIT inhibitors that are being developed in this disease, including one from Glaxo. How do you think bezuclastinib is positioned given sort of emerging competition being developed?
Yeah. The first thing is, of course, we're a company that's very focused on patients, and we're intimately familiar now with this patient population. We've been working with GIST patients for five years. We've been hearing their stories, their family's stories, the physicians who help them. First of all, we would love there to be more drugs that are active against that disease to give patients an opportunity to live longer. Specifically with regards to [avapritinib], it's a little puzzling for me because we've profiled the drug long ago when the innovator, Merck Serono, decided that they didn't want to develop it. They didn't see the strategic value and out-licensed it. At that time, we said that this drug looks sort of like ripretinib, maybe not quite as good.
But eventually, it found its way into the hands of a big pharmaceutical company, and now that they're investing aggressively to develop it doesn't have a pan-KIT mutational profile. So, we're a little confused at why GSK is pushing it so aggressively. We'll see, and hopefully, it provides some benefit to a subset of patients. Specifically, we don't think it really hits exon 14 at all, and it's probably not quite as potent of an exon 17/18 inhibitor as either ripretinib or bezuclastinib, but it does have some activity anti-KIT. And so, depending on if the right patients fall in the right times, it'll show some activity, I think.
And so, how do you think about first-line GIST? Glaxo has a study up and running there, but I know that you started some work in the frontline setting as well.
Yeah. So, we sort of reiterated in our Q3 earnings last week that we are running this 40-patient cohort, and now it is open to any mutational profile first-line patient. That is a data collection or a clinical information collection study with the goal of moving into a more formal registration program. We are continuing to work very closely with global KOLs on what that study would look like. We can tell you is when we showed up to ASCO to present the PEAK results, that is the same meeting where, again, this drug that GSK is developing presented their phase II results. I think that there was an expectation that a true pan-KIT inhibitor would have had noticeably better results in phase II.
And what that did is it led the KOL community to rapidly shift back to Cogent and say, "We need you to figure out a way to develop your combo in first line." And so, I think in the not-too-distant future, we will have some very specific and formal guidance on what that might look like. But we do see the utility of a combination like bezuclastinib and SUTENT that covers all of the primary exon nine and 11 mutations, as well as the ATP domain and activation loop mutations in the second line, effectively out-competing a drug like imatinib, which is an amazing drug and is one of the most important drugs ever invented, but by definition, doesn't cover the resistance mutations. They all exist because of imatinib's inability to cover it.
So, I think a head-to-head trial of sunitinib and bezuclastinib, while it would be large and it would take a long time, I have a lot of confidence it would be able to beat imatinib head-to-head.
What do you need to see to potentially do a large phase III study in frontline?
I think the most important thing for us was the receptivity and support of the global KOL community, as that's the sites that you would use to run such a study. And I think we have very strong support from those folks. I think we're heading in that direction.
Okay, great. A few questions on systemic mastocytosis, which is your second PDUFA date towards the end of the year. In this market, unlike in GIST, you're competing with a similar product that is already on the market. Maybe talk about how you think bezuclastinib could gain share in the non-advanced systemic mastocytosis space.
Yeah. As you said, there's a lot of important distinctions here. Maybe one of the ones that is most important to investors is the non-advanced mastocytosis, for us launching in hopefully very late 2026 or early 2027, is much more of a prevalence story than an incidence story. What I mean by that is, it takes a very long time for these patients to be diagnosed. The average number of physicians that a non-advanced patient has gone to prior to their affirmative diagnosis is seven or eight physicians, right? They have to go through a whole referral process until they find someone, and it's almost always a hematologist who can do a confirmation bone marrow biopsy to tell them that they do have this disease. And so, if you think about, as you mentioned, there's a drug called AYVAKIT, which was invented by Blueprint and now owned by Sanofi.
That was approved coming up, I think, on four years in February. They have had a long time to educate the market, find these patients, and really, the non-advanced systemic mastocytosis patient population is broken down at this point into predominantly three buckets. It is patients who are still taking avapritinib, patients who used to take avapritinib and stopped either because it was not working or was giving them side effects, and the third bucket is patients who are afraid to take avapritinib because of some of the CNS side effects that that drug has. In that case, what we would be doing when we get the green light from the FDA is really communicating to each of those three patient subgroups.
Probably the number two and number three would be the easiest, as patients who are not currently taking a therapy or afraid to take the current standard of care as the way that we would penetrate that market. Just as a reminder, what is important about bezuclastinib relative to avapritinib is mainly two big things. Number one, we're very much more selective from a pan-kinase perspective. Not only does avapritinib hit KIT mutant, KIT wild type, PDGFR alpha and beta, as well as a little bit CSF1R and FLT3, and that leads to a very complicated safety profile at clinically relevant doses. But number two, they are one of the most CNS-penetrant small molecules for any disease and any target ever found. They are actually preferential for CNS tissue over systemic delivery. Bezuclastinib is neither of those things. We are exceptionally selective for KIT mutations, and we are not CNS penetrant.
That provides us a lot of therapeutic index to dose to a more potent level and really demonstrate at a molecular level that we are eliminating the mutant clones in non-advanced patients, which I think ultimately will be the goal, shifting away from making patients feel a little better to trying to eliminate all presence of mutant mast cells in the body.
Yeah. With relatively newer markets like non-advanced SM, it can be a favorable setup to be second as opposed to first on market in terms of building the opportunity. When you think about that, how should investors think about the potential launch trajectory, and where do you expect to make most inroads early? Will it be more on the new patient side or perhaps on patients that have already seen avapritinib?
Yeah. In a classic prevalence market, the incidence population is probably a significant minority. The number of brand-new patients that are diagnosed for the first time in any given week or month is a fraction of the number of patients who are currently on avapritinib or have decided for various reasons not to take avapritinib. So, for us, I think that that is really the focus of the commercial launch. And what's really exciting for Cogent, and I think for these patients as far as clinical information, is we have a whole new clinical study which was designed to speak specifically to this issue, where we take patients who are currently on avapritinib, either the 25 mg or the 50 mg dose, and we measure them on our TSS symptomatic scale while they're taking avapritinib.
Then we wash them out for a brief period, give them bezuclastinib, and we see, is there any benefit to taking bezuclastinib as a switch? We haven't presented that data yet. I think some of that in our press release will be available at ASH by the end of the year. Some more will be rolled out early in 2027. But if that shows even any numerical benefit, then you have to think to yourself as a patient, "I've been taking this drug, avapritinib, for," you pick your number, "six months, 12 months, two years, and I feel somewhat better, but I don't feel all the way better. Do I want to keep taking this drug where I feel somewhat better, or do I want to try a new drug that has evidence that in people like me, their symptoms improved even more?
Do I want to try that?" And that's sort of the commercial strategy is, do you deserve to try something that'll make you even better? A seven out of 10 is better than a 10 out of 10 on severity, but wouldn't you rather be a two out of 10?
Yeah. We get asked sometimes, will you market bezuclastinib as a different brand in SM compared to GIST, or will it be under one brand?
Yeah, we haven't said that yet. At this point, I don't even really actually remember why we didn't say it, but we'll say that very soon. I think as soon as we get an approval, we'll be able to explain what our strategy there is. There's reasons why you would do both. Avapritinib, for instance, has the same brand across a very rare form of cancer as well as mastocytosis. But I think there's also benefits to having separate brands for non-malignant diseases and malignant diseases. So, at the right time, we'll kind of unveil our brand name strategy.
Okay. How important is advanced SM? It's a relatively smaller market, but obviously, you had a positive registration data set there as well, which is in front of the FDA. How important is that for the franchise?
Yeah, advanced systemic mastocytosis, as you say, it's only about 10% of the overall systemic mastocytosis patients. The bulk of the patients are diagnosed with a non-advanced form of the disease. But the advanced patients, that is a disease of mortality. Those patients without treatment prior to TKI development had an average of about three-year lifespan from diagnosis. So they're desperately in need of intervention to help them. The reason why bezuclastinib is so important for that patient population is that you need to drive potency. In that disease, it is clear you want to remove the mutant cells from the body. At high doses or appropriate clinical target engagement doses of avapritinib, that drug is somewhere between hard to tolerate and dangerous. They have multiple grade five fatalities that are related to drug in their small clinical trials.
They have dozens of patients who have had evidence of intracranial hemorrhage taking 200 mg or higher of avapritinib. None of these things are characteristics of our drug. So I think there is a clear out-compete safety advantage of bezuclastinib relative to high-dose avapritinib. So, we think that those patients deserve to live longer without the risk that a drug like avapritinib presents to them.
Yeah. And then how do you think bezuclastinib is positioned in the SM market longer term in context of Sanofi Blueprint working on a next-gen KIT inhibitor as well?
Yeah, it is a little harder to track now that it is in the hand of a big pharma company. That elenestinib is, I will call it a non-CNS penetrant version of avapritinib, but it still has that same off-profile kinase promiscuity. So we expect that they will still have significant amounts of edema at clinically relevant doses, as well as heme toxicity at clinically relevant doses because they hit other kinases. We would have expected long ago that trial to have been enrolled and completed, but I think in the transition, maybe it is a little bit deprioritized in the hands of Sanofi, so we'll see. Certainly, the last we have heard competitively, that trial is still enrolling. They have a 48-week primary endpoint, so we are at least several years away from approval of that drug.
Okay. And the last question. You do obviously have a pipeline beyond bezuclastinib with a couple INDs coming up soon. So, how important will the rest of the pipeline become for the company in the coming years?
Yeah, we understand from an investor perspective all the focus is on executing a great commercial launch, and that is what we intend to do over the next, hopefully, days, weeks, and then quarters ahead. We also have aspirations to become a large biotech company, so we have two assets in clinical development. By the end of the year, we'll have another two. So, if any of those drugs work, then we will be very well positioned for sort of next horizon growth after bezuclastinib.
Great. Well, thank you, Andrew. We have to wrap up here, but appreciate your time this morning.
Great. Thanks, Michael. Appreciate being here.
Thanks.