All righty. Welcome everyone to the 42nd annual J.P. Morgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at J.P. Morgan. I'm joined by my squad, Malcolm Kuno, Laraya Hall, Priyanka Grover. Our next presenting company is Cogent Biosciences, and presenting on behalf of the company, we have CEO Andy Robbins. Andy?
Great. Thanks, Anupam, for inviting us to the meeting. It's great to be here, and I'm looking forward to the presentation and some Q&A today. So, before I dive in, just to sort of remind folks that I'll probably be making some forward-looking statements today, and I would point you to our recent SEC filings for a more thorough assessment of risk associated with the company. So encourage you to review those. I'm gonna start and use today as kind of a jumping-off year beginning recap and sort of level setting for the company, and especially our lead asset. So Cogent is a precision therapy company that's focused on discovering, developing, and eventually commercializing precision medicines that are targeted for patient populations with mutationally driven diseases.
Our lead asset is a drug called bezuclastinib, which is a potent KIT exon 17 and 18 inhibitor. It's being developed in two broad patient populations. The first is a disease called systemic mastocytosis, which is itself divided into several subgroups, which we can go through in a little bit. The other is for gastrointestinal stromal tumors, which is a rare type of sarcoma that has high unmet medical need remaining. In addition to bezuclastinib, which, again, I'm gonna spend the bulk of my time today discussing, we have built what I think is among the best, if not the best, medicinal chemistry research team in the industry, and they are working on several projects.
Three, which we have publicly talked about, are a selective FGFR2 inhibitor, a highly CNS-penetrant ERBB2 inhibitor, and a mutant-targeted H1047R PI3K alpha selective inhibitor. We've presented data on each of these programs in the past. Probably, most notably, we intend to start a phase I study of our first, Cogent-discovered product, the FGFR2 inhibitor, later in the second half of 2024. But we'll have plenty of time during 2024 and in the future to discuss these programs in detail. So again, I'm gonna focus most of my time today on bezuclastinib. We have, as of the end of Q3, just under $313 million on the balance sheet that, at our current and projected cash runway, will last us into 2026, so we are well-capitalized. And now I'm gonna launch into bezuclastinib.
So again, I'm gonna sort of present this as though we're talking for the first time. So bezuclastinib, as I mentioned already, is being developed for two distinct diseases. And really, what we want folks to take away from this is we have two very distinct and commercially attractive franchises available for the asset. The first is the systemic mastocytosis community, and that is, and we're gonna talk about the data we've presented over the past 18 months in two different types of this disease. First, the advanced systemic mastocytosis patient population. That's at the bottom of that stacked bar. About 2,500 patients in the United States have this disease, and it is a disease of mortality, so these patients, without treatment, face a median overall survival of about three years.
The non-advanced systemic mastocytosis population, also known as the indolent systemic mastocytosis population, is much larger, as you can see here. Probably about 25,000 people in the United States have this disease, but it is a highly underdiagnosed disease, as until very recently, there were no therapeutic options for these patients. Both of these diseases are fundamentally driven by a mutation in the KIT gene in exon 17 called D816V, and we feel very passionately that patients across both or all of these subtypes deserve relevant clinical exposure in a drug that is highly targeted to their specific mutation and doesn't have some of the off-target liabilities that are resident with the other drug that is already commercially available for this patient population.
It is somewhere between a $1.5 billion and $2 billion opportunity in the US from an annual sales perspective. And so again, in a very limited competitive market, really only one other company focused on developing drugs here, we're very excited about what this could mean from a value perspective. In a completely different and unrelated patient population, patients fighting gastrointestinal stromal tumors, there's a well-known drug called Gleevec, which is used ubiquitously around the world as the first-line standard of care. But once patients develop resistance to imatinib or Gleevec, there's really no good options for them. The current standard of care is a drug called sunitinib.
It's a generic drug in the second line, and we are in the midst of enrolling a phase III global pivotal study called the PEAK Trial, in which we add bezuclastinib to sunitinib in an attempt to extend the progression-free survival in these patients. Conservatively, this is a cancer indication which could be worth upwards of $700 million a year in the United States, and there is really very limited, if any, clinical competition for this space, so we're excited about both of these opportunities moving forward. Very briefly, why do you need a drug like bezuclastinib? So if you look again at this specific mutation that drives mastocytosis, listed here in the title as D816V, you can see that there's only been three drugs discovered to date that have the potency in a cellular assay to effectively hit this target.
It's our drug, bezuclastinib, highlighted at the top, as well as two drugs owned by a company called Blueprint Medicines, avapritinib, and then a backup compound called BLU-263 or elenestinib. Each of these three drugs would be sufficiently potent to hit this specific mutation in these patients.... Moving forward, though, to selectivity, which is critically important in the world of tyrosine kinase inhibitors, you can see here that only bezuclastinib spares important anti-targets, that are not related to driving this disease and are associated with troubling tolerability, in some cases, safety problems, including intracranial bleeding, different types of edema, and pleural effusion. So you can see here that while bezuclastinib is potent against KIT mutant, probably 10 times as potent as on the wild-type KIT, it really spares all of these other closely related class III receptor tyrosine kinases.
Unlike the Blueprint compounds, which are potent against not only the KIT component here, but also highly potent against PDGFR and moderately potent against other class III RTKs like CSF1R and FLT3. Then finally, when you're thinking about systemic mastocytosis, or quite frankly, GIST, these are not diseases that require a significant component of CNS tissue activity. So having CNS penetration as a feature of your drug is not desired in KIT inhibitors. You can see here on the left, in bezuclastinib, we have about 7% brain-to-plasma ratio, so it's very limited transition into the CNS tissue, while the current standard of care and market leader, avapritinib, has the reverse, a 200% brain-to-plasma ratio, so almost preferential delivery to the CNS tissue over systemic delivery, and this results in noticeable levels of cognitive impairment at clinically relevant doses for that agent.
So walking through this in sort of a different order than I typically do in these presentations, the first thing we'd like to point out, and these are data that were recently presented at the ASH 2023 annual meeting for our drug, bezuclastinib, in the advanced systemic mastocytosis population. You can see, looking at these waterfall plots, that these are not waterfall plots you commonly see for markers of pharmacodynamics or efficacy, with nearly every patient seeing significant deep responses to getting bezuclastinib. As measured by a composite objective response rate endpoint developed by world leaders in this specific disease, we have a 56% objective response rate.
Using a different criteria that is becoming more interesting to these same leaders in the field, we have an 86% objective response rate, with all of the patients at the dose or the exposure that we've selected to take forward achieving at least a partial response. So the drug is clearly active and admittedly similarly active to avapritinib, which has a very similar objective response rate in their registration trial. But now leading to what I'm gonna show here, sort of a side-by-side comparison of the safety and tolerability, the story diverges a little bit.
So using the information that is resident in the summary basis of approval in the medical review, on the left, the left chart here, you can see the relative rates of adverse events for avapritinib at the ASM-delivered doses, which is at an exposure that delivers that potent activity that you're looking for in this patient population. You can see across the x-axis, the preferred term is listed there, the same, in the same order for both the avapritinib data on the left and then the more recently presented bezuclastinib data on the right. And I think what your eye will see is that the relative rates of adverse events is noticeably better for bezuclastinib. Again, these are in different trials, so, want to give that as a careful caveat.
The other thing I'd point you to is if you look up in the rows, the table where we list the relative rates of Grade 3 adverse events, serious adverse events, reductions, discontinuations, you can see that the rates of bezuclastinib are noticeably better than avapritinib. Maybe most concerningly for this patient population, and why we think the advanced systemic mastocytosis patient population is looking for a new drug like bezuclastinib, you can see out of the 148 patients dosed in the avapritinib trials, 11 of these patients showed evidence of intracranial bleeding, and nine patients had adverse events that led to death out of the 148. This is a drug that, at the dose, labeled and intended for ASM, has significant safety consequences. So that is, again, why we think, this patient community is looking for a drug like bezuclastinib.
Now, turning to ISM, which from an investor perspective is certainly a larger commercial opportunity, we wanna highlight a couple things that we showed from an early-stage phase I study that we presented again at ASH back in December, ASH 2023. So, allowing for a similar level of exposure, doses at the similar level as we've shown in the advanced systemic mastocytosis population, given our safety profile, we could take those similar doses into the ISM population. And what we showed is that across the three major biomarker that are associated with activity in this population, that every one of our patients demonstrated at least a 50% reduction in tryptase, at least a 50% reduction in variant allele fraction, and at least a 50% reduction in mast cell burden.
May potentially most interestingly here, because the goal in the ISM setting is to return these patients' body system and mast cell activity to level of normal, you can see in the footnotes or the circles underneath the tryptase bars that 90% of the patients treated with bezuclastinib at any of these doses returned to below 20 nanograms per milliliter of serum tryptase, which is considered criteria for complete response in the ASM setting. Two-thirds of these patients actually returned to a level below 11.4, which is considered the upper limit of normal for patients that don't even have this disease. So what we believe we've demonstrated, albeit in a much smaller data set than a pivotal trial, is very encouraging pharmacodynamic and biomarker activity of bezuclastinib at these doses.
And then moving to the way that performance is ultimately judged in the indolent systemic mastocytosis or non-advanced systemic mastocytosis clinical trial setting, it's based on the improvement in the severity of symptoms that these patients experience. So ISM patients typically experience dermatologic symptoms, often gastrointestinal symptoms, pain, fatigue, CNS symptoms. And what these different tests here you see on this slide, MCQOL, PGIS, PGIC, they are measures of improvement in either patient's quality of life or improvements in the severity of symptoms. And while we're not ready to demonstrate this definitively, in this early dose-finding study, we have shown here evidence that bezuclastinib does maybe surprisingly well across all of these scales. So within 20 weeks, improving median best improvement on MCQOL quality of life by 57%.
For patients who were given placebo for 12 weeks and then crossed over to active drug, within 8 weeks, a 75% best median improvement on quality of life. Looking at these PGIS and PGIC scales, which are performances of severity of symptoms, north of 70% of the patient population, close to 80% of our patients having a clinically meaningful improvement on bezuclastinib within the first 20 weeks of therapy. This is, again, admittedly a small data set, but it is unlike the data which has been seen previously from other agents tested in this disease. So we would like to remind folks that in a very short amount of time, about 7 weeks from now, we plan to go to the 2024 Annual Quad AI Conference in Washington, D.C., and present a larger sample size of patients.
So in addition to the 20 patients that were presented at ASH in 2023, we have 34 additional patients that we're preparing to unblind from Part 1B of this study. In an aggregate, we'll have 54 patients worth of data to provide across safety, biomarkers, and pharmacodynamic looks, and again, across these measures of patient-reported outcomes and symptomatic severity improvement. So we're very much looking forward to having a larger sample size to better elucidate the safety, tolerability, and activity of bezuclastinib in this important patient population. Now, I'd like to turn to our Phase III cancer trial, which, you know, we admittedly, we feel like most of the attention paid from the investment community to Cogent at this time is in systemic mastocytosis, and we can't disagree with that.
It is very exciting and commercially interesting, but there are not many companies of our size that are developing a drug in phase III in a cancer indication with essentially no competition. We are on track to complete enrollment in our nearly 400-patient global phase III pivotal trial by the end of 2024, and waiting for the PFS events to accrue, given the design of this trial, which is essentially a randomized add-on study of our drug plus sunitinib versus sunitinib monotherapy, which is the standard of care. We project that those progression-free survival events should accrue by the end of 2025. So within the not-too-distant future, we are optimistic that we will have a new standard of care in a no-competition cancer indication, which is a rare place to be these days.
The reason we think our clinical strategy is differentiated from some of the recent failures in this field is we've adopted a, "If you can't beat them, join them" approach, colloquially. So unlike the failed clinical trials that Blueprint and Deciphera have recently run of doing head-to-head comparisons of their exon 17, 18 inhibitors versus Sutent or regorafenib, which are- have activity on other types of resistance mechanisms, putting bezuclastinib and sunitinib together, you see here at the bottom of this chart, is a combination that can address all of the known resistance mutations to imatinib. We, we do think, and we feel strongly in the scientific rationale of this study approach, and we have data which suggests the reason that this is even possible is the selectivity of bezuclastinib provides for a non-additive combination safety profile.
So you see here data we presented at the CTOS conference this past fall, where across 42 patients that we ran as a lead-in study to this phase III trial, the safety and tolerability profile denoted in the table is highly similar to what you'd expect from Sutent monotherapy. So unlike the other drugs in this class that implicate PDGFR and KDR VEGF, FLT3, CSF1R, that would potentially have additive toxicity to Sutent, we can effectively combine our drug with Sutent and generate an acceptable safety profile. And what that looks like from an activity perspective, again, this is a new slide that's looking at second-line patients. These are patients that have only seen prior imatinib in the GIST community that have been enrolled either in our original phase I/II dose-escalation study or the PEAK lead-in.
You can see very durable, excuse me, and robust responses with 4 out of 10 evaluable patients achieving at least PR, and 1, 2, 3, 4, 5, 6, 7 patients with very durable responses, much longer than you'd expect from benchmark median progression-free survival numbers from recent studies that you see there down in the bottom in gray. So with the expected PFS of Sutent of about 8 months, and many of our patients now out past 13, 14 cycles, we feel very confident and optimistic about the results of the PEAK study. So before I hand it over to Anupam for some questions, I just want to recap sort of the year ahead, specifically related to bezuclastinib, but in general, related to Cogent.
The first thing, as I mentioned, is we're looking forward in a number of weeks to presenting a brand-new clinical data set at the Quad AI meeting, further elucidating what we believe is clear differentiation or clear signs of differentiation for bezuclastinib in the non-advanced systemic mastocytosis patient community. In addition to that data release, we'll be working very hard to, number one, validate and score a novel patient-reported outcome tool that would be used for measuring the primary endpoint of a pivotal study, and then moving rapidly into the initiation of that SUMMIT-Part II pivotal study in the first half of 2024. So certainly a busy next couple of months, next 3, 4 months for the SUMMIT program.
In addition, and I referenced this earlier as well, 2024 is an important year for the other two pivotal or registration-directed trials that we're already running, namely the global phase III PEAK study, which we expect to complete enrollment by the end of the year, as well as the ongoing phase II registration-directed APEX Part II Advanced Systemic Mastocytosis study, which we also expect to complete enrollment by the end of this year. Looking to our research pipeline of very exciting future opportunities, we will and are on track to initiate a phase I study of our selective FGFR2 inhibitor, CGT4859, in the second half of the year, as well as initiating IND-enabling studies for 2 additional programs this year. The first, the CNS-penetrant ERBB2 potent and selective inhibitor, and the second, that mutant-selective H1047R PI3K alpha inhibitor.
Just again, to reiterate, we are well-capitalized at this point to execute against all these plans and certainly look forward to a robust Q&A session with Anupam.
Thanks, Andy. Just want to remind folks that there are three ways to ask a question. There's the old school way, you can raise your hand and I'll call you. You've heard this plenty of times. And you can, you know, submit a question through the question portal, it'll show up on the iPad, and I'll ask it on your behalf, or you can take an intermediate strategy and just email me. So I'll start out with, Andy, you talked about the Quad AI data coming. So what's going to be the size and scope of that data relative to the Part Ia data that we learned at ASH?
Right. Good question. So at Quad AI, we'll have an opportunity to present data from both Part Ib and then fully from all of Part Ia and Part Ib. So Part Ia was 20 patients at two different doses of bezuclastinib using an original formulation by the innovator company. Part Ib is at two different doses of an updated or optimized formulation that was really invented for the GIST program to try to reduce pill burden at a much higher dose for those cancer patients, but we feel is important to harmonize across the program. So all in all, it'll be 54 patients worth of data, including 34 brand-new patients that have not been seen before, across all of the same types of measures: safety, tolerability, PD, and patient-reported outcomes that we described at ASH.
The optimized formulation, I think there's some confusion about this. Like, how does that play out in the clinic, from an efficacy/safety perspective, or is it just from, like, a convenience perspective?
So again, the optimized formulation was really a project we embarked upon when we in-licensed the asset, about 3 years ago, when the innovator was only developing this drug for gastrointestinal stromal tumor patients. And in the dose escalation portion of that study, they escalated it all the way up to a 1,000-milligram daily dose without finding a maximum tolerated dose. The unfortunate reality is they had a 50-milligram tablet, and so that would be 20 pills per day, which we fully understand is not commercially viable or friendly to patients. So what we did is embarked upon a program to increase the bioavailability of the exact identical active pharmaceutical ingredient, but by changing the excipients, essentially the wrap around the API, and we decreased the dose in the GIST study to a 600-milligram dose with 75 milligram tablets.
So bringing the 20 pills down to eight pills a day, but with the exact same exposure. So we thought that that was quite impressive on a relatively short timeline, and using that in the systemic mastocytosis patient population will allow us to rely upon some of the patent estate we've created about around that formulation to extend the protected life of the asset by approximately six and a half years on the tail.
Questions from the audience?
Just to be more explicit, we don't expect any differences in safety or efficacy of the optimized formulation. We just expect to need to deliver fewer milligrams of optimized drug to achieve the same level of exposure as the original formulation.
Got it. Questions from the audience? What do you think are the most misunderstood parts of the SUMMIT and APEX updates from ASH?
I think APEX was fairly well understood. From a SUMMIT perspective, you know, it's a relatively small data set, admittedly. It was 20 patients. We are facing the dynamic of the competitor or the innovator in this disease area, Blueprint Medicines, having created their own proprietary patient-reported outcome tool. It's called I-SM-SAF, which they use to measure the performance of avapritinib in their pivotal study, and they've chosen to keep it as a proprietary tool and not share it with the rest or future companies developing drugs in the patient population. Not being able to demonstrate the performance of bezuclastinib on the Blueprint proprietary tool, I think, might be confusing to the investment community.
We believe that by preserving a dose that is closer to the traditional IC90 target inhibition of the driver mutation in ISM patient population, we will be able to show a noticeably better symptomatic improvement relative to, in our calculations, an avapritinib dose 90% below what they tested in ASM, which we calculate to be probably closer to about an IC20 target inhibition. So we think that there's a lot of efficacy or ability to improve the lives of patients that low dose avapritinib is leaving on the table, and that at the end of a SUMMIT Part Two, a robust, approximately 200-patient type of study, we expect that whether we have the identical patient-reported outcome tool or not, we will have the opportunity to demonstrate effectively that the symptomatic improvement and the severity reduction is differentiated from avapritinib.
I guess thinking about SUMMIT and Quad AI, if you had to just kinda define a win scenario for us, how would you define that?
Some of the important things for us is to build a larger data set so that individual adverse events are not concerning as trends, but can be seen as outlier events. So within the ASH dataset, for instance, an individual adverse event at an individual dose cohort could have been calculated as a 20% rate, when in a larger denominator safety dataset, it can be shown as a much lower incidence event. So we think that that'll be important to better characterize the safety profile of bezuclastinib at these doses in the ISM patient population. We also notably receive feedback that using averages, using different statistical calculations than Blueprint has used, is potentially troubling for investors to try to make cross-trial comparisons.
We're acutely aware of that, and we will look in larger datasets to use, maybe analogous averaging, to what Blueprint has done before. So we do see it as an opportunity, for a drug that we and the investigators that we work with already see as differentiated to build a more robust case in the minds of the investment community.
Questions from the audience? Yeah.
Thank you. So I think you did a good job laying out Part One B and the two different doses, Part One A, what we're going to see at QUAD AI. Can you go a little bit deeper and talk about what you're hoping to see in that data?
Sure. So, just to make sure people heard the question on the call, I think the question was: beyond sort of the description of Part One A and One B, what's our sort of desire for what the QUAD AI data might be able to tell us? I think what's important, number one, is to demonstrate that we have a dose that is well-tolerated for a patient population that is primarily about morbidity, not mortality. That is a different hurdle than the ASM population, so we're acutely aware of that. Number two, demonstrate that the PD effects that we saw in the small population in Part One A seem to be relatively replicated. I don't think you can get any better than 100% of every patient doing everything, but something similar to that in Part One B.
And then finally, from a patient-reported outcome, to really have a larger sample size of patients. So as an example, on MCQOL, which is a measure of quality of life, we demonstrated that on patients in Part 1 A who started on bezuclastinib, even within 4 weeks, but certainly within 12 or 20 weeks, we could move them as a population to somewhere in the mid- to high-20 range as an average score on that quality of life scale, which the feedback from the investigators was, "That is an amazing score for an ISM patient population," especially relative to the MCQOL data that has been presented by avapritinib, where even over long periods of time, it's hard to see them reducing that average score below 35.
Also, patients who were on placebo, within 4 weeks, were moved a 75% improvement on that same scale, down into that same mid- to high-20 range. So if we can have a larger population of patients that continue to demonstrate that deep, rapid effect of improvement in quality of life or symptomatic severity using scales like PGIS, PGIC, and even the mastocytosis activation scale, I think that that will be a win for bezuclastinib moving into the pivotal study. What I can also sort of share is that we've created a very impressive, I'll use the word wait list or registry of patients that are highly interested in participating in SUMMIT Part 2, both within the U.S. and Europe, based on the results that we've shown in APEX, and then, from Part 1A of SUMMIT.
So even in a scenario where there's a commercially approved drug for the first time for this disease, there are investigators and patients who are choosing to forgo prescribing with avapritinib to wait for the SUMMIT Part Two trial to start. That is the impact that we've seen and described with many of the U.S. investigators.
Additional questions? Malcolm.
Just one quick. Thank you. Just one quick one. All of those milestones are baked into your cash runway?
Yeah, so the question for the folks on the phone, if you couldn't hear it, was about the slide that's currently showing about the upcoming catalyst. Are all of these baked into our cash runway? All of these are baked into our cash runway. What our cash runway does not include is potential commercialization expenses of bezuclastinib, assuming that these trials are positive, or significant clinical spend beyond what we show for the research projects on this screen.
Great, thank you.
For SUMMIT Part Two, maybe you could walk us how you're thinking about sort of your novel endpoint for the indication, and what are the key levers or key considerations that you do have?
Yeah, so in order to build a novel PRO, there's a very specific process that is outlined by the Food and Drug Administration, and we are following that with the assistance of an outside expert PRO development firm. Essentially, the steps are to interview and collect information from patients and treating physicians in the patient population to describe all of the symptoms that could be problematic, create a very long questionnaire with questions about all those symptoms, apply it in a randomized controlled clinical trial setting, which is what we did in SUMMIT Part One, and then after you collect all of that data, use that information along with the other, more well-known and tools that are deemed anchor tools by the FDA, like the PGIS and PGIC, to validate exactly what your questionnaire should look like and weight and score that questionnaire.
So I think it's not a mystery that in the non-advanced systemic mastocytosis population, that domains like dermatologic symptoms, gastrointestinal symptoms, CNS symptoms, pain, fatigue, these are all symptoms that are highly troubling and problematic for patients to live with. And so our questionnaire, our PRO tool, will incorporate all of those types of symptoms, but the way that they're organized will be guided by the data that we collect in our clinical trial. That process will begin when we have the complete SUMMIT Part One dataset and will continue up until we meet with the FDA to align upon that tool as the appropriate tool to use for the assessment of SUMMIT Part Two.
Any final questions? Okay, thanks, Andy.
Excellent. Thanks, Anupam. Appreciate it.