Jefferies Global Healthcare Conference in New York

All right. Good morning, everyone. Thank you for those of you in the room and those dialed in on the conference call. My name is Pastor Khashid. I'm one of the senior biotech analysts here at Jefferies, and we are here live at the Jefferies Global Healthcare Conference in New York. Really pleased to have with us the management team of Cogent Biosciences, joined here today by Andy Robbins, CEO of the company. Andy, can you start by introducing yourself and the company?

Sure. Thanks very much for having us. I'm certainly excited to be here today. So my name is Andy Robbins. I'm the CEO of Kojin Biosciences. And just a very sort of high-level introduction to the company. For those that aren't as familiar, we are a company focused on creating novel small molecule treatments for patients with rare diseases caused by mutations, both within and outside of the cancer field. Our lead asset is a drug called bezuclastinib. It is currently under active review by the FDA for our first two large indications, gastrointestinal stromal tumors and non-advanced systemic mastocytosis, and hopefully very soon will be under review for the third of our three indications in the advanced systemic mastocytosis population. As of the end of the first quarter, we had just under $870 million on the balance sheet, So we are well-funded to launch this product and these indications ourselves. The cash we have on hand lasts us well into 2028. So we're very much excited and looking forward to a commercial launch later this year. I'm sure we'll spend most of the day talking about bezuclacinib. But just the final word is we also are developing a whole portfolio of earlier-stage assets to treat other patient populations with high-end medical need and excited about those programs as well. And if we have time, maybe we can touch on a few of those.

Got it. Excellent. So starting with bisoclostinib and GIST, we just got back from the ASCO meeting where the pivotal data from the PEAK study was presented to the medical community for the first time. Can you talk to us about that presentation and the key takeaways from that?

Yeah, we were definitely excited to have the opportunity, along with Andy Wagner from Dana-Farber, who's our lead investigator on the Phase III trial, to present the full results of the primary analysis of the PEAK study, the phase 3 trial that showed that the combination of bezuclastinib with sunitinib is clearly a better treatment option for second-line GIST patients than is sunitinib alone, as measured on the primary endpoint, which showed a 16.5-month median progression-free survival versus a 9.2-month for the current standard-of-care sunitinib monotherapy, and that was highly statistically significant, had a hazard ratio of 0.5, so a 50% reduction in the risk of progression or death, which is very, very exciting for these patients that haven't had a new drug approved in the second line for 20 years. And this trial represented the first time a drug has ever shown statistical significance versus an active comparator in just in the history of the disease. So certainly a lot of excitement from the KOL community, the investigator community, and, of course, the patient community. Those numbers were known to the investment community as of last November at our top-line release. So what we showed that was a little bit new and we're very excited about was, number one, the genotype subgroups. So in this disease, after you are diagnosed with kit-driven GIST, every patient in first line essentially is given imatinib, which is an excellent drug. But imatinib doesn't cover key secondary resistance mutations, which is what usually causes patients to progress into second line, which is where our trial is conducted. And so what we showed is across all of the various opportunities for this disease to progress via different mutations, that our drug combination showed noticeable advantages over pseudonym and monotherapy. So that was nice to show the consistency across the different genotype subgroups. The other analysis we showed at the podium was an analysis of what's known as PFS2. So that's a measure of not just how long patients last until progression or death on the initial randomization, but how long from the initial randomization until they progress or have another event after the subsequent line of therapy. And the reason we showed this is our overall survival data remains very immature from this trial, surprisingly so, which is good news for patients. But as a proxy for what does it look like long-term, we showed again with a hazard ratio of 0.57 that starting on the combination appears to be better for long-term outcomes than starting on sutent monotherapy, even though the vast majority of those patients crossed over to the combination as their subsequent line of therapy. So that was also very exciting and very encouraging for patients, especially to reinforce that the patients should really start on the combination from initial progression on imatinib. And then, again, the last thing we showed, which was outside off the podium on the side, is that the mean duration of treatment for these patients is actually quite a bit longer than the median, which is demonstrating that there is a subgroup of patients, in this case a fairly robust subgroup, that have really, really long-term responses to the combination. And so our mean expected duration of treatment is now 21.4 months, which is just such good news for these patients when, if you roll back even a year or two, the expected mean duration of treatment for sinitinib is on the short side of 10 months. So adding potentially, on average, a year or potentially more to what patients in the second-line just population will be treated with is really exciting for these patients.

And then can you clarify on that duration of therapy figure from the study, did the study allow for treatment beyond progression, and would you expect that in the real world? What I'm trying to get at is this 21-month figure, would the real-world figure in terms of what we should put in our models be higher, lower, or the same?

Yeah, I mean, we certainly are happy for folks to sign up to 21.4. We think that's quite an impressive number by itself, but it's an excellent question. In the trial, we did not allow for post-progression treatment, so at Bicker confirmed progression on the combination, patients were required to discontinue treatment and choose to go on to subsequent therapy. In the real world, talking to the physicians, especially after they've seen the strength of these data, we expect that if patients have multiple lesions and a single lesion shows progression, they may choose to continue post-progression treatment with the combination because subsequent lines of therapy, while somewhat effective, are clearly much less potent and much less effective at treating this disease than the combo. So we do think that there's a possibility in the commercial setting that patients will continue to get the combo even after a single lesion or a small progression. Yes. Got it. And then, I mean, as we've come out

of now kind of the first really big medical meeting presentation of these data, how has the physician feedback been in terms of, you know, receptiveness and excitement for the drug?

Yeah, I can tell you that from both a physician and a patient perspective, because we talk to both of these groups of people, there's a lot of palpable excitement for the availability of beziclacinib and pseudonitinib, first in our expanded access program that's already ongoing, but then maybe more broadly for the pending and very, you know, we're very hopeful and optimistic Let's talk about the near-term approval with a PDUFA date of November 30th of this year. So I think the general perception among the physician community within the sarcoma docs, within treaters of GIST, is that the combination of bezuclasticin and pseudonitinib will rapidly from approval become the standard of care for second-line patients. And so we're certainly prepared to support that. We think that the uptake will be rapid, and we think that patients will get the benefit at this combination right away starting later this year.

And in terms of the rapid uptake, I've had this theory that by being a drug that's used on top of the existing standard of care that should help the early part of the launch curve, given that it can be added on to patients that are already on sunitinib. Is that a fair way to think about this?

I think that it's certainly an interesting question because we don't have data that expressly speaks to what you should do with a patient who's already on sunitinib. But I do think that the totality of the evidence from the primary endpoint to the mean duration of treatment to the very high and unexpected confirmed response rate we're seeing of the combination suggests that there's really not a great reason to continue patients on sutent and monotherapy, especially those who have been initiated on monotherapy in the very recent past. We can get behind that there are probably small populations of patients who may have been on Sutent for years and years, that you may, they may be pretty stable. But even for patients who are initiating Sutent, for example, today, by the time you get to November, and, you know, again, for a potential launch, I think that there's a very high chance that they will add

bezuclacinib to their treatment. Got it. And then talk to us about the regulatory progress. You mentioned the November 30th, Bidufa date. I know you have the breakthrough therapy designation. You're also under the Real-Time Oncology Review Program. What benefits do those programs confer, and what should we expect on a kind of more practical approval timeline?

Yeah, we certainly are respectful of the FDA, and they're a busy group of people. And so I think having the breakthrough designation in the Real-Time Oncology Review did a couple things. Number one, it allowed us to start sending them information even in advance of when we announced we completed the NDA. So, as of January of this year, we had already started communicating with them, especially on things other than the actual results of the Phase III study. So, as folks are familiar in a new drug application, it's a pretty broad document that you share with them, data all the way from preclinical, including manufacturing, including earlier stage clinical trials. And so, we were, we had the opportunity with Real-Time Oncology Review to have the review team start digesting that information even in advance of when we completed the file, which was at the end of March. The second, with the breakthrough designation and probably with the real-time oncology review, is I think that elevated the speed of review for bezuclastinib to a priority review designation, which they just communicated to us right around ASCO timeframe, which allows us to have a PDUFA action date at the end of November instead of what a standard review would have supplied, which would have been an end of March review. So I think by getting those designations and working very closely with the FDA review team, we will be able to get the commercial bezuclostinum and student-in-a-combination to patients a lot sooner than without those designations.

And if you pull the history of the real-time oncology review program in general, like a lot of these programs are approved one month ahead of PDUFA, sometimes even two months ahead of PDUFA, would that be an expectation that people should have here?

I think it's tricky to look at historical benchmarks from the FDA, just given a lot of the changes that are going on at the FDA. What I can tell you is that we are working very rapidly, and we've been prepared for a long time for that eventuality. So if the FDA wanted to work with us to find a way to approve the drug in advance of November 30th, we'd be ready to do so, and we would, of course, welcome that.

Got it. And then with respect to the, you mentioned, allude to some of the kind of changes at the FDA, like obviously investors are aware of what's in the headlines, but in terms of what you guys are encountering with the review teams and your counterparties at FDA, are there any tangible changes on that?

Yeah, we, you know, we have to knock wood here. We're happy to say that our clinical review teams and sort of the folks that we interact with on a day-to-day basis have been very consistent across both the Division of Non-Maling the hematology and the division of oncology products. And so while, you know, you see in the press a lot of change at the top at the senior leadership of the agency, the folks who we're interacting with who are reviewing our files are the same folks that we've been dealing with for a while, and we think that they are, you know, excellent partners and look forward to continue working with them.

Got it. And can you just clarify for us which group at FDA is reviewing this application, and is that separate and distinct from the mastocytosis applications?

Yes. Both of our mastocytosis files would go to the Division of Non-Malignant Hematology, and then obviously our file for the GIST indication goes to the Division of Oncology Products. So there are different clinical review teams looking currently at the non-advanced file versus the GIST file.

Hematology.

Non-Malignant Hematology.

Yeah, we'll get into the allergy hematology debate on SM. In terms of the label, one question that investors have brought up is that the drug does have some ALT, AST elevations observed in the study, what that might translate into in terms of label language, monitoring, and things like that. Can you walk us through your expectations on that? And then could you also just clarify for us at what point in the review period would you have a little bit more granular understanding of where FDA is leaning on that?

So I'll answer your second question first. I think until you kind of finalize the label, which happens late in the review period, that's really when you get full clarity on what that's going to look like. So, you know, I think that's stay tuned. On the first question, which is the more conceptual question, bezuclastinib clearly across our studies does show, you know, asymptomatic, reversible in all cases, elevations in AST and ALT. What's nice about our drug is that very rarely, across all of our studies, at all the different doses we measured, see patients have elevations in bilirubin. So, and most importantly, what we haven't seen happen is any clinical sequelae. So, we haven't seen these events lead to problematic clinical issues with the liver in patients. So, what we think is that in the GIST indication, in the advanced systemic mastocytosis indication, which are both diseases of mortality, this is really not a hot issue for treating physicians. And the non-advanced systemic mastocytosis, interestingly, we also don't think this is that big of an issue, but from a labeling perspective, we do think that there's the potential for there to be language in a label that suggests you may want to measure transaminases in patients, especially early in treatment, as I think we've disclosed previously, that all of the higher grade transaminase events typically occurred within the first five cycles of treatment. You don't see bezuclastinib leading to higher rates of transaminase elevations at late onset points. So if that was the case, if we had labeling, what's most important is it's highly consistent with the current workflow of how physicians are treating their non-advanced mastocytosis patients. They're currently monitoring patients on avipritinib on a regular basis, both for platelet levels related to avipritinib, but maybe more importantly, for efficacy, signs of efficacy. So in order to see, are you at the right dose of avipritinib, you want to measure things like serum triptase and variant allele frequency. For a drug like bezuclacinib, you also would want to measure, are you seeing those drops that you would expect in triptase and variant allele frequency? And as you alluded to a little bit ago, the vast majority of physicians who treat this patient population are hematologists. And so the idea that introducing a need to measure blood work for a hematologist is some sort of preventative problem for a drug is a little comical, since the business of being a hematologist is measuring what's going on in your blood.

Yeah, I've been telling investors that I think this question comes up because we have no other controversy to really discuss. So maybe if you think about stirring some controversy, I'm good.

I'll pass.

Yeah. But speaking of one area of question, in terms of the competitive landscape for GIST, at ASCO as well, we saw updates from the GSK-IDRX compound now called Velzatinib. Can you talk to us about what we saw in that presentation and how that makes you feel about your competitive position?

Yeah, look, it's, you know, it's, you always want to be careful because we're We're dealing with cancer patients, and cancer patients very much want to be hopeful about lots of new treatment options coming forward. But we do want to be also careful about the exuberance of early-stage data sets. And when we look at Velzatinib, or what was known as the IDRX42 compound from a private company that GSK bought, I think what you see there is you see a multi-kit inhibitor, not a PAN-KIT inhibitor and a multi-kinase inhibitor, so not a selective KIT inhibitor. So that drug has kind of two liabilities. Number one is it's off target for things like PDGFR and CSF1R and KDR. And number two is it doesn't fully cover the spectrum of KIT mutations. And so that's why bezuclastinib needed to partner up with a drug like sunitinib to really, from a biology perspective, find a way to cover across the KIT gene all of the known mutations. And so when you look at the data at the top for Velzatinib with a 13.7-month median progression-free survival and a response rate in kind of the low 30s, you notice that those numbers are numerically lower than the numbers that we presented in our Phase III trial. Now that's a little bit concerning for Velzatinib because the history of just drug development is that all of the drugs that have been developed from a recency in kit inhibition, avapritinib and then repretinib and then bezuclacinib with sunitinib, had a dynamic where they showed phase two results in second-line patients that were numerically noticeably higher than the phase three result that you saw in that same drug as you expanded to community sites around the world. So I can run through it really quickly. Ravapretinib moved from about an eight-month PFS advantage in their Phase II to a four-and-a-half month in Phase III. Repretinib moved from about an 11-month in Phase II to an eight-month in Phase III. Even our combination moved from about a 19-month advantage in Phase II to a 16-month in Phase III. So I think when you start from a 13-month and change Phase II, the expectation is you're going to underperform that in a Phase III. And when you, even if they can enroll this study, bring a 10-, 11-month PFS four years after to a patient population that's used to a 16-month PFS. That's going to be a tough sell, I think, for patients. I think the bigger concern for that trial is it's an open-label study. And when patients are randomized to sunitinib, even today on expanded access, but certainly post-approval of Bezu and Sutent, you have to think really hard about informative censoring of why a patient who is randomized and knows they're on Sutent monotherapy would choose to skip the combo of adding Bezu and potentially lose months of their life in order to stay randomized to that trial. If you see that informative censoring, the effect that will have is it will likely make Sutent perform even higher than you saw in the peak study, I think putting the statistical result of the strategist second-line study even further in jeopardy. So I think that they have a little bit of a problem. The drug clearly has some activity, but I don't know that there's a clear development path for it to get to the market.

Got it. And then with respect to the, they also recently launched a first line study as well. Does that impact your competitive positioning at all, either in second line, the core peak indication that you're aiming for approval in, or any potential future plans in first

line? One of the most interesting things that happened to cogent at ASCO this weekend was off the podium in conversations across the board with KOLs, one of the things we heard most urgently was a desire to find a way to get the combination of Bezu and Sutent into a broader first-line patient population. I don't know if that's exactly based on kind of the underperformance of what people were expecting valzatinib to do or exuberance around the, you know, how good the data from the peak trial looked. But what I can tell you is when we talk to these folks about our excitement of opening the first line exon 9 cohort, which is about 20% of first line patients, kind of across the board in these conversations, the response was, that's great, but what about exon 11? And when and how are we going to get this combination into the exon 11 first line patients. So it's very fresh, literally within the last few days, but I can tell you that it's a high priority for Cogent to determine the best route to generate clinical data of the combination in the first-line setting broadly.

And can you double-click on that with respect to what you are currently doing in the first-line setting and how that could evolve and whether there's creative strategies like working with cooperative groups or anything like that to do that in a kind of de-risked clinical and commercial type of, or clinical and financial type of way?

Yeah, so the easy answer is I can tell you what we are doing. The more complicated one is what might we do. What we are doing is we're running a 40-patient cohort of our combination, Bezu with Sutent, as a single-arm study in patients that have exon 9 at diagnosis, or within, you know, a few weeks of initiating imatinib. And what we're trying to show there is that the very exciting data we showed in second-line patients with exon-9 that showed a 25-median progression-free survival estimate for exon-9 patients in the second line, we may be even to outperform that in a first-line patient population, which would be really exciting because imatinib, while an amazing drug in exon-11 patients, is much less so in exon-9 patients. With data from a 40-patient cohort, it is possible, depending on the quality of that data to generate things like approval via NCCN pathways, compendia listing, publication-driven strategies, and maybe more importantly, to understand how to size, if you needed to run a pivotal study, the statistics for a pivotal trial. One of the things that we're very confused about is watching a company like GSK move into a first-line Phase III study without really having any idea the effect size of Either the control arm or the active arm, they are literally guessing at what that trial might do and what the statistics would be needed to show whatever that guess is. So what we would rather do is generate some proof of concept data in a first-line patient population in order to design a trial that has a much higher probability of winning to understand how to power and size such a study as opposed to just taking a guess.

Great. So we have a few minutes left, I want to talk about both ISM and commercial. So on ISM, can you just bring us up to speed on the clinical differentiation of bezoclacinib compared to Avakit, and also what the physician feedback has been on the bezoclacinib profile?

Dr. Right. So when you look at the molecules, avapritinib and bezoclacinib, in a cellular or even an an enzymatic assay, they look nearly identically potent against the target here, which is D816V mutant in exon 17. Now the issue is that the drugs are designed quite differently. So evapritinib is exceptionally brain penetrant. It's maybe one of the most brain penetrant drugs for any disease on any target ever created. It's preferential to CNS over systemic delivery. Bezuclacinib is not a CNS penetrant drug. And secondly, evapritinib is a multi-class 3 RTK. In addition to hitting KIT, it also hits PDGFR into a lesser extent CSF1R and FLT3. Bezuclastinib is a highly selective KIT inhibitor. And what that does is it gives us an advantage that allows us in the non-advanced systemic mastocytosis patient population to preserve our dose and preserve our exposure. So we can hit the mutationally-driven disease at a close to IC or EC90 concentration exposure where evapritinib, based on these off-target side effects of cognitive impairment, intracranial hemorrhage, high rates of grade 3-4 heme tox, high rates of periorbital and peripheral edema, in order to move into the ISM population, had to reduce the intended dose of their drug by, excuse me, 90%. So instead of a 200-milligram dose, which is where the drug works really well and very potently, they had to do a 25-milligram dose, and so they left a lot of exposure and potency on the table, which is what bezuclasinib is essentially solving. Now when you look across the trials, we acknowledge that we had to use a different PRO because they trademarked theirs and we couldn't, you know, step on their intellectual property, but we've scored our data on their trial. From a symptomology perspective, we, and I think the hematology and allergy community that treats this, clearly see more rapid, more durable, more sustained symptomatic improvement. And maybe most importantly, when you look at the objective measures of disease response, you see really amazing results from the summit trial of beziclacinib, including when you talk to the world's leading pathologist experts in this field, something that they've never seen before, which is in a very high percentage of our patients, complete elimination of mast cell aggregates in the bone marrow, which would lead you to say those patients wouldn't even meet diagnostic criteria for having the disease anymore after six months of treatment. That is something that you do not see with avapritinib treatment and is making the systemic mastocytosis community extremely excited about the availability of beziclastinib.

So one piece of investor pushback is, well, when you compare the two pivotal data sets in non-advanced SM, it might not be realistic because a lot of the docs might push the dose on Avakit. What is your comeback to that understanding or misunderstanding even?

So we get back to the sort of the characteristics of avapritinib. So avapritinib, as we said before, is highly CNS penetrant and hits off-target kinases. And so when you take the dose from their labeled dose up to higher levels, you are trying to find a therapeutic window between where the drug will start to work, where it doesn't vary much at 25, and where it starts to generate those off-target side effects, which often happens at 50. So they have a very narrow therapeutic index. And what physicians are doing today when there is only one drug available is they're trying to chase that window in individual patients. By moving the dose up, potentially moving it back down, trying to find for an individual patient where they can tolerate some edema, where they can tolerate some cognitive side effects to get rid of some of the fatigue, to get rid of some of the GI symptoms, bezuclacinib offers a completely different conversation where we have the best of both worlds. You can dose this at the intended dose, remove the mutant cells from the body, and not have those tolerability effects that replace the symptoms that the patients are experiencing. So I really think that the value proposition for bezuclastinib is being much better understood by the mastocytosis community, and I think that our launch is going to go very well based on the characteristics of the molecule.

And remind us, where is Evocate on commercial sales in SM? how is that done since the acquisition is it continuing to grow and and what

does metrics kind of look like yeah so as we know Sanofi acquired blueprint last summer so it's certainly gotten a little bit more opaque since that they did that they they're less you know they talk about evaprintinib a lot less than blueprinted if you look at the sales for q3 q4 and then q1 they continue to be on an upward trajectory but it's probably kind of you know falling off the the the exact slope of that curve that Blueprint had. I think even Sanofi themselves disclosed in their Q1 earnings that that might be a result of bringing that drug into their portfolio and some of the things that they've potentially agreed to about pricing dynamics. The Q1 sales for avapritinib, I think what Sanofi said, in the hands of a small-cap biotech company would have been about $2.20 or $2.25. In a quarter one, given the Medicare dynamics, a 225 rare disease oral drug is probably on track for about a billion dollar a year. So for full third year sales of a rare disease drug to hit a billion, I think that's indicative of a very attractive patient population and commercial population. I just think that we have a much better option for those patients to drive deeper

symptomatic improvement. Great. And then from a commercial launch perspective, In terms of launch preparation and readiness, what do you need to be ready to launch, and is this two separate sales forces across the two indications?

Yeah, we're very excited to answer that second question as no. We are going to have a cogent sales force or a bezuclacinib sales force that will be responsible across the indications. I sort of classically do this thing that nobody can see right now, where I show that the overlap in the physicians who treat these diseases is almost nonexistent. There is no overlap, but the physical places where they practice medicine is a huge overlap. So I think there was a misunderstanding that the ISM market was going to evolve into a primary care market. That is just not the case for several reasons. It is going to maintain and become a hematology call point, obviously just as an oncology call point. So sending a single sales force of several dozen people, this is not hundreds of people, across the country to talk to a very concentrated prescriber base is how we plan to commercialize this. I can tell you we've already identified the individuals who will be our sales force, and we're very excited based on their experience and capabilities that we're going to have an excellent launch.

Got it. One last question. One word answer, if you can. And of your four early-stage pipeline assets, if an investor comes to you and says, hey, Andy, I have time to do work on one of these, which one should I do work on?

All of them.

Oh, come on.

I think, honestly, the questions we get asked most about are our PAN-KRAS inhibitor and our JAK-617F inhibitor. Both of those are slated to have INDs this year. But I wouldn't sleep on our clinical-stage programs for CNS penetrant IRB-2 and alpha-selective PI3K. I think that they both also have a lot of promise got it. Well, thank you so much for being with us today. Absolutely. Thanks