We're on. Good morning, everyone. Welcome to the third and final day of the Morgan Stanley Healthcare Conference. Thanks everyone for attending. My name is Jason Russell with the Healthcare Investment Banking team at Morgan Stanley. Before I jump in and introduce Andy, a quick research disclosure. "For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. So briefly, on stage here with Andy Robbins, President and CEO of Cogent. Cogent is a clinical stage company focused on developing precision therapies for genetically defined diseases. Most advanced clinical program is bezuclastinib. I'm gonna try and pronounce that correctly. Which is a selective tyrosine kinase inhibitor that is designed to potently inhibit the KIT D816V mutation, as well as other KIT exon 17 mutations.
Bezu is being studied in systemic mastocytosis, as well as GIST. And in addition to Bezu, the company has a pipeline of targeted therapies, and we'll get to touch on that as well with Andy. We're honored this is the first year to have Andy here. You've got a series of important events for the rest of the year, so I think very timely, probably most important being initial data from the SUMMIT study and the non-advanced SM population, and then updates on the advanced as well. So let's jump right into it. Andy, maybe just as a refresher for the group, let's get right to the meat. Let's jump through, you know, the key upcoming data readouts for Bezu.
We'll come back on the asset, but let's just talk about what's coming for the remainder of the year.
Yeah, perfect. So, you know, first of all, thanks for inviting us. Happy to be here and have a chance to give an update to folks who are tuning in. And as you mentioned, I'll just remind folks, I'll be making some forward-looking statements as well, so you can refer to our SEC disclosures for a more full characterization of risk. With regard to the rest of the year, let's just sort of talk about the next four months. We do have a few important clinical updates coming up.
So until we're actually accepted at a conference, we don't typically like to front run them and say where, but we're committed to our guidance of providing the first look, the initial clinical data from the part one of SUMMIT, which is, as you said, the study of bezuclastinib as a single agent for non-advanced or indolent systemic mastocytosis patients. So that'll be exciting. And also in the next few months, potentially at a similar time point, we would provide a what we're kind of calling a full update from the part one dose exploration study of APEX, which is bezuclastinib as a single agent for the patients with the advanced form of the disease, systemic mastocytosis.
Those are two, I would say, fairly substantial clinical updates that we're looking forward to seeing, not just how the drug performs, but potentially how it's differentiated from some of the available therapies for this patient population.
Great. Maybe picking up on that thread, you know, both the readouts, I think the advanced population and the indolent population, but particularly the indolent population, that'll be the first data that we're getting from you in that population. Could you help characterize what you've said and what you want people to understand as the bar for success?
Yeah, absolutely. So this is a disease, the indolent or non-advanced systemic mastocytosis of morbidity. These are patients that have a fairly normal life expectancy, but their life is severely impacted by the symptoms that are caused fundamentally by the mutation, the driver mutation in the KIT gene, known as D816V. And so, up until very recently, these patients had no biologic intervention that actually got to the heart of the disease, why that they were experiencing symptoms. And so what they're looking for from an unmet need is a drug that can target the mutation, that can help downstream improve how they experience life and reduce the symptoms that they experience every day.
What we're trying to demonstrate in this initial clinical data set is there reason to hope that in subsequent trials, that a drug like bezuclastinib can help do exactly that? Can it help these patients live a better life? While they have a normal length or life expectancy, we want to improve the quality of their life during that time. So, in this initial data readout, obviously one of the first things you want to look for is a safety and tolerability profile that's conducive to chronic type dosing. Does bezuclastinib at the doses we're studying deliver a tolerability and safety profile that you can imagine patients taking it for years, not for months? Number two, some of the well-known measures of success in a systemic mastocytosis population are what are known as surrogate biomarkers.
So measures of how much serum tryptase, which is a marker of mast cell activity, is in the patient's body, a measure of how many mast cells are aggregating in their bone marrow, and then a measure of how many mast cells circulating in the blood are exhibiting that mutation we spoke about. So we will we hope to demonstrate that in the clinical data, reductions in all of those surrogate measures. And then kind of the third part of the triangle is, how does that translate into symptomatic improvement? So do patients feel better? You know, if they have a positive safety and tolerability profile associated with a therapeutic intervention, and these surrogate markers are going down, does that translate into a better quality of life as measured by improvement in the symptoms that they're experiencing?
That's really sort of, on a triad, what we're looking to present in the initial clinical data set.
... Wonderful. I think you may have touched on it, but just remind us, how many patients approximately?
In SUMMIT part o ne, which is our dose exploration, it's designed to have 48 total patients. What we've said at this initial clinical data readout is it'll be a subset of that 48, and we've characterized it as a relatively robust subset, so it won't be three or four patients. But as we get closer to where we are intending to provide that clinical update, we'll get closer to unblinding. This is a blinded study with a control group of placebo, and so as we get closer to that meeting, we'll be able to dial in exactly how many patients will be into that initial clinical readout. But we think it'll be robust enough that we can start to have a good conversation around the performance on those three aspects of clinical performance I just walked through.
Okay, great. And maybe just going back on a comment you made, until recently, these patients had no intervention to actually, particularly the indolent population. I think it was a big focus event earlier this year, and there's another company that has a drug that did get approved in this area. Help us understand and characterize why it's still very important for you to be focused here. First of all, what kind of differentiating characteristics do you hope to have or could improve on? And also, you know, a perspective on why having that leader out there is perhaps harmful or helpful to you.
Excellent question. So certainly we congratulate our colleagues at Blueprint Medicines for being, the first company to get an approval in this patient population, to provide patients with hope and something that they can take to try to get their disease under control. Their medicine is called AYVAKIT or avapritinib. What's interesting about the development of that specific compound is, if you look at the history, it was developed first, similar to what we're doing in the advanced form of the disease, at a dose of, 200 milligrams, a daily dose of that medicine, and then subsequently, they were approved in the indolent form of the disease at a dose of 25 milligrams, so approximately a 90% reduction in dose intensity.
Our opinion, and I think folks in the world of mastocytosis, is the reason they reduced their dose is based on some of the off-target toxicity and safety issues that are present at those high doses when they're really potent and hitting the target, which are not acceptable in a disease population like the indolent or non-advanced systemic mastocytosis. So, kudos to Blueprint for determining that going to a very low dose of their medicine would deliver an acceptable safety and tolerability profile, but our observation is that it probably leaves a significant opportunity for another medicine that doesn't have some of those off-target liabilities to provide the appropriate level of target engagement and drive increased symptomatic improvement.
So that's really the opportunity that we're going after with bezuclastinib, is, avoiding some of those, the inhibition of other kinases or avoiding the, strong penetration into the CNS tissue that's, I think, associated with that specific molecule, where it's not associated with bezuclastinib, to, to give us an opportunity to do that. Now, your second question is, what does it mean to Cogent to have, another company with another medicine already out there? I think it's, it's great for us, it's great for patients, great for physicians, because I think what Blueprint will do over the next, several years since they were approved in, in May, is really drive disease awareness, disease education, drive the knowledge among several different physician types.
This is a disease that is, I think, highly underdiagnosed in the United States and around the world because it is typically diagnosed as a symptomatic disease. And really, what you need to do is drive to a genetic diagnosis of this disease. So working with allergists, gastroenterologists, immunologists, hematologists, a whole variety of subspecialties among the physician community, to understand why it's important to find these patients not just symptomatically, but genetically to diagnose them. And then if we can demonstrate that bezuclastinib has a better performance or potentially drives higher symptomatic improvement, I think we'll benefit from all of the work that, you know, impressively Blueprint is doing now in the near-term future.
Andy, that's great. I mean, maybe just to pull on a thread a little bit, I think that's a discussion point in this area frequently, is where these patients found? You know, who has control and care of these patients, and where do diagnoses happen? You touched on it a little bit, but I'd love if you'd elaborate further, 'cause I do think it's an important debate.
Yeah. Within, again, the realm of systemic mastocytosis divided into the advanced form of the disease and the more indolent form of the disease, our understanding in, you know, talking to many physicians out there is most of the advanced patients are treated by hematologists or physician experts in major academic medical centers. So that is a sort of a typical KOL-type call point for that subset of the disease. The indolent form of the disease, to your point, is, I think, very dispersed, and it... Typically, patients have a journey where, until they're diagnosed, they go through 5, 6, 7 referrals at different physician specialties because there's not a lot of awareness about this disease and there's not a lot of prevalence of next-gen sequence genetic testing at allergists, community allergists, community gastroenterologists.
So these patients typically get, you know, a series of medications that are designed to try to treat the symptoms that are presenting to the physicians without really understanding the, the underlying biological basis of the disease. So, across those subspecialties, and really, if you look at a pie chart of where these patients seem to be treated, it is a lot of slices, again, across allergists, GI specialists, immunologists, hematologists. But I think we need companies like Blueprint, Cogent, potentially other companies down the road, to drive that disease awareness, through programs to say how important it is to genetically diagnose these patients, so they can be matched with appropriate therapeutic intervention.
Okay, just to tie that out, and then we'll switch gears. Is there a good analog? I mean, obviously, oncology is the best analog. We've seen how that's progressed as patients get genotyped and we get better and better at getting the right medication to the right patient. But, you know, beyond oncology, is there another analog where we've seen a market progress to what you just described?
Yeah, I think there's a couple. I mean, there's probably several instances of rare diseases which the patient population is underdiagnosed until there becomes a therapeutic reason to go try to find them. I think some of the ones that you know, we take a look at from a historical analog basis are drugs like Jakafi in the JAK space, you know, with PV and some of the lessons we learned from what Incyte had done with that story. And then, from the Alexion story with PNH, what they did with Soliris, of taking a disease that's not well understood, needs to be diagnosed specifically and matched to a therapeutic intervention, and over time, those medicines grew into significant blockbusters with you know, thousands of patients benefiting from those discoveries.
Okay, great. Maybe moving on from mastocytosis, your most recent data disclosure was at ASCO in GIST, same drug, obviously, a different, you know, therapeutic intervention. Could you just touch on that program? You know, what you disclosed at ASCO, and then we'll dig in a bit.
Yeah. We're, we're really excited about what we call the PEAK study, which is an ongoing global Phase III trial of bezuclastinib in combination with a well-known drug called sunitinib, which is the current standard of care in the second-line treatment of gastrointestinal stromal tumor patients. For us, again, you mentioned in your overview, we're a company that's very focused on trying to treat patient populations which are defined by genetically driven diseases, so going where the science takes us. And when you have a very potent KIT inhibitor, especially one that hits specific mutations, in this case, bezuclastinib is highly potent against what are known as exon 17 and exon 18 mutations within the KIT gene, that is a classic signature of resistance for patients who take an amazing drug in the first-line setting for GIST called imatinib.
Gleevec was the brand name. I think folks are well aware of that drug. But almost all patients with GIST eventually develop resistance to Gleevec, and in many cases, that resistance is based on mutations in those exon 17 and 18 compartments of the gene. So taking a drug like bezuclastinib into that patient population makes a lot of sense biologically. The difference that our program is relative to some, I think, recent and well-known failures in this second-line GIST space, is that we adopted a "If you can't beat them, join them" clinical strategy. So the resistance is not only in exon 17 and 18 mutations.
In many patients, that resistance is conferred through mutations in exon 13 and 14, which our drug and many of the new generation KIT inhibitors are not very potent at covering, where Sutent is or sunitinib is very potent at those mutations. So adopting an approach, instead of going head-to-head against Sutent, of adding on to it, in the control arm, we think that Sutent will do quite well at helping patients that have only exon 13, 14 mutations. But in the active arm, the combination arm, we think we'll be able to broaden the coverage using the combination strategy to essentially help all patients that have developed resistance to imatinib.
So not only having the right drug, but having the right strategy, and learning from others, frankly-
Exactly
... because of the, as you noted, some of the, the negative developments. Okay, great. Maybe just going back to both GIST and SM, and we touched on some of this, but let's start with GIST. You know, opportunity for patients, you know, some perspective around how many patients there are, you know, second line, how do you, how do you look at that opportunity commercially?
Yeah. For us, as I said before, almost all patients eventually progress on first-line treatment with imatinib. We're estimating that in the United States, there's probably somewhere around 2,500-3,000 patients every year that develop that resistance. They're looking for longer and better performance of drugs. The current standard of care, sunitinib, has about a 7-8 months median progression-free survival, depending on which study is your favorite, and objective response rate of around 10%, maybe even slightly less than that. So, unlike many other solid tumor cancers, where there are several lines of therapy that have 20%, 30%, 40%, 50% response rates and longer durations, really, these patients have a high unmet need once they develop resistance to imatinib.
In the United States, we think that second-line patient population from a sort of a commercial potential is about a $700-$750 million peak sales market. And what's interesting, unlike many other solid tumor oncology indications, there really is not a lot of development outside of what we're doing in our ongoing Phase III program. We acknowledge that our colleagues at Deciphera are developing ripretinib in a small subset of second-line patients. About 15% of patients have the genetic signature that they're looking to treat. But really for, frankly, all of the patients, including that subset, we think that the combination of bezuclastinib and sunitinib could become the new standard of care in that setting. And there really isn't any clinical candidates behind us.
Unfortunately, you know, for patients and physicians, our colleagues at Theseus announced recently that they're going to stop developing another KIT inhibitor due to some toxicity that arose in that program. So now, even looking backwards, I don't think, you know, for the next 2, 3, 4 years, there's really any clinical competition coming behind us.
Great. So, so just to, unpack that just a little bit. So front line, well-defined. Second line, you said 10%? Or-
10% objective response rate, yeah.
Yeah. Okay. So clearly... And what did you report at ASCO?
At ASCO, it was an interim report of two groups of patients. One was designed to demonstrate in a new formulation of bezuclastinib, which was really that program was designed to reduce the pill burden for GIST patients, which I think we successfully did, that we have similar exposures to the original Phase I, II study. Again, I think we demonstrated that. So that allowed us to go forward into the Phase III portion of the trial, and then a separate portion of patients to demonstrate the, you know, potential interactions between sunitinib and bezuclastinib, which, you know, we need to let that data mature a little bit, and that'll be coming out in the future as well.
But across that 40 patient subset, I think what we showed is, and these patients are predominantly third, fourth, fifth line patients, just to get them into the study, relatively impressive duration of therapy on the combination, ongoing, hadn't yet met a median progression-free survival, had evidence of several patients who had met response. So as an immature data set, I think there was a lot of interest there, specifically in the safety and tolerability of these two drugs. I think one of the concerns going into that data readout was if you put two kinase inhibitors together with an already well-known, sort of slightly messy safety and tolerability profile associated with sunitinib, was that going to be too toxic for patients to tolerate?
I think what we demonstrated is that adding bezuclastinib to sunitinib doesn't seem to exacerbate the underlying sunitinib safety profile, so that was a positive. I think a lot of early green shoots about what is that combination going to look like when the data matures.
Okay, great. And obviously, the hurdle rate for success in actually helping these patients is pretty low. So,
Yeah, we, we're looking forward to, you know, certainly, the enrollment of that Phase III trial and the readout, just from a timing perspective. We're deep into the enrollment of that study. We're on track with our plans. We would expect to complete enrollment of our Phase III by the end of 2024. So what's that? 15 months from now, something like that. And then, because the primary endpoint is progression-free survival, we'll have to wait for the events to accrue. It's one of those classic, the longer it takes, maybe the better the data is, but we'll see what that looks like. We're estimating it'll take about a year for those events to get to the top line result cut point.
By the end of 2025, we would hope to bring forward, potentially data that describes a new standard of care for that patient population.
Awesome. Pardon me. Quickly switching to back to systemic mastocytosis. Let's look at the two arms. You know, how do you think about the opportunity in both populations?
Yeah. If you look at the epidemiology of systemic mastocytosis, the vast majority of patients underlying the population have the indolent form of the disease. I think the estimates are about 90% of patients present with that non-advanced systemic mastocytosis. So when you work out the numbers, we estimate there's around 2,500 ± prevalent patients with the advanced form of the disease. And then when you look at ISM, if you just back into that 90%, that sort of implies there's about 25,000 patients. It's a spectrum of severity, so many patients have mild symptoms that are probably well controlled with over-the-counter, simple things that you can get at your neighborhood pharmacy. Those are probably not candidates long term for chronic therapy like avapritinib low dose or potentially bezuclastinib.
But the moderate to severe patient population, which we do think is kind of in the bull's eye for patients that need an intervention to help improve their quality of life, we estimate that to be around 7,500 patients. Again, the trick here is most of those patients are living with the disease and don't know the name of the disease that they have. So over the next several years, hopefully, with Blueprint's efforts and, you know, as we emerge through our clinical studies, our efforts to help, we can drive awareness for this disease and the need to have a drug like a potent KIT inhibitor to help these patients.
Great. Obviously, the company is more than just BEZU. So, want to spend a few minutes on what else you're up to.
Sure.
I'll leave that open to you to—
Yeah, one of the exciting things about Cogent is, yes, we think bezuclastinib is can become an amazing medicine to help lots of patients across these different diseases, but we have designs and strategies to turn Cogent into a much bigger company with many other products. So over the past couple of years, we've really built from scratch what we think is one of the best small molecule research teams in the industry. We're up to about 60-65 scientists now out in Boulder, Colorado, many of whom came from a well-known company that was also, you know, quite adept at creating small molecule kinases. That team is now focused on many internal research programs, only two of which we've talked about publicly.
The first is a selective FGFR2 inhibitor that we announced in, I think, August, in our Q2 earnings, that we had finalized and selected a clinical candidate, and now that clinical candidate is moving through the IND-enabling study process. So that would put us in place sometime in 2024 to put our first Cogent invented molecule into clinical trials. Certainly very excited about that program. Admittedly, that's for a relatively narrow population of patients that have a disease called cholangiocarcinoma, which is a disease, essentially a cancer of the bile duct that's driven by fusions and translocations in FGFR2. There are other drugs that are used, but we think each of those sort of has a liability similar to the KIT story with avapritinib that we hope to improve upon.
Sometime probably in the next several months, we'll be able to describe fully exactly the characteristics of our clinical candidate at a scientific meeting, so we look forward to describing exactly how the profile of that drug could potentially differentiate from some of the either on-market or in-development drugs that are targeting that patient population. And then the other program that we've talked about publicly is a selective and potent ERBB2 inhibitor. ERBB2 inhibitors, I think most people in the industry understand, you know, how that target has been used in the past with antibody approaches in breast cancer.
With the small molecule approach, one of the things we think we can do, and admittedly, other companies are trying this as well, so it is a bit of a competitive race, is to dial up the ability of that compound to get into the CNS tissue. One of the big unmet needs in metastatic breast cancer is to help patients who have metastasized to the brain, to the CNS tissue, extend their lives, and potentially down the road, help prevent the spread of the disease into the brain. So really focusing that program on potently inhibiting mutations associated with ERBB2 and providing activity in the CNS tissue. So looking forward to describing again potentially later this year, how that program is advancing.
We also have a whole bunch of as-yet-not-disclosed, exciting programs that we think have the opportunity to do the same thing that we're describing here, is look at well-known diseases that have, either drugs that are approved or drugs in development that might have a problem, a liability, and then design a rational approach that can, address those problems and potentially give a better patient experience, either through efficacy or safety or, delivery of the medicine, to patients with whatever that disease and targeted genetic, problem is.
Great. Just a couple minutes left, but I do think you raised a couple interesting points, and you're in a unique position as a company. I mean, you're a small molecule company. Your lead asset is going after multiple indications. I would... You know, it's a topic we talk about with management teams all the time. You know, what is your perspective on how IRA, you know, which is the topic du jour for the past year, impacts you, impacts the industry? You know, I would love to hear your candid thoughts there.
Yeah. You know, as much as I want to pretend to understand what goes on in geopolitics, really, our position on this as a company is, our job is to make medicines that help patients, and if we can do that successfully, then we can figure out how to navigate whatever party is in place, whatever the rules are, whatever the reimbursement system is. If we don't make medicines that help patients, then none of that matters. So that's really what our focus is, getting these candidates into clinical trials to determine are they safe and well-tolerated, do they help patients, and if they do, then we think we're confident we can navigate that space.
I do, sort of as a personal aside, think that the, the inequity between large molecules and small molecules doesn't seem to make a lot of sense. That feels like that's gonna be corrected at some point, probably in the future. But, but overall, as sort of a political statement, I do subscribe strongly to belief that, you know, drugs should be priced for value. Patients should have access to drugs, whether they're in the United States, Europe, Asia Pacific. So again, that is gonna be solved by much bigger companies with, you know, lobbyist groups. For us, our focus is about the science. It's about the patients. It's about developing medicines that can help these patients.
Well said, and let's hope, for everyone's sake, that they figure this out-
Yeah
... in a good way. All right, great. Thank you, Andy, for joining. I think that's all the time we have.
Awesome.
Appreciate you being here.
Thanks for having me.