Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeffrey Hung, one of the biotech analysts. 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. For this session, we have Repare Therapeutics with CEO Lloyd Segal and CSO Mike Zinda. Welcome. Great to be here. Thanks for the invitation. For those who may not be as familiar with Repare, can you provide a brief introduction? Sure. Repare Therapeutics is among the leading, clinical stage companies focused on broadly synthetic lethality, DNA damage repair, and genome instability, and that's kind of where we like to play. Everything we've built in this company, is has a foundation in our, CRISPR-enabled platform discovery, that we call SNIPRx. And it, it's a real edge for us both, and that allows us to identify brand-new, targets in DDR synthetic lethality that we have for, close to eight years now been prosecuting. And, it also allows us to, do a really innovative brand that is unique to how we approach discovery and development to identify broader, genes that could enrich our patient populations for drugs once they're advanced in development. We have two clinical stage compounds, camonsertib, an ATR inhibitor that we partnered a little over a year ago with Roche and which they are now prosecuting globally, and I think far more aggressively as of recent times. Lunresertib, which is we're currently the only one prosecuting a PKMYT1 inhibitor that was discovered off our platform and is now going to have its first, I think, really important readout at a major medical conference upcoming in the fall. That's not in Madrid. That is, I think, a big event for us coming up, that hopefully we can expand on a little today, but probably won't be able to talk about a lot. We have a pipeline of exciting things beyond that. We have guided that we'll introduce RP-1664 into the clinic in the next, you know, four to six months. And that, and our Polθ inhibitor, which will follow that by about six months, are really expanding out our overall clinical footprint in a fairly sizable way, that I think is sort of game-changing for us as a company You kind of touched upon these two, so maybe I'll try to ask if you can just dive in a little bit more, talking about the SNIPRx platform and the step two screens and how they help expand the patient populations. Absolutely. Yeah. So I think as we highlighted, the SNIPRx screens are our methodology and our platform for finding novel synthetic lethal targets. And in particular, we've been focused on genetic alterations in cancer that drive genome instability, because they're very early events, and we think we can get greater durability, in the responses that we're looking at with those inhibitors. But basically, that platform was put into place using pairs of normal cell lines that are very clean backgrounds, where we can then knock out one gene of interest, and compare that to the wild type cell. Therefore, when we knock out all the genes in the genome using our CRISPR library, we can find those that are selectively killing the mutant cells and not the wild-type cells. We then go through an extensive set of validation in a discovery effort to then bring those to the patients that are in the clinic. It's distinct from some other platforms that are looking across panels of cell lines, which we still use and think are very exciting, but it's allowed us to find a number of targets that you can't find from those public databases, and really be able to bring forward and execute them and help support our collaboration with BMS, as there were too many targets for us to execute by ourselves, and so we found a partner to help make sure we could bring all those together. Great. Let's start with lunresertib. Can you just go over the rationale for targeting PKMYT1? Yeah. So as we talked about when we did the screens, one of the early lesions that we looked at was cyclin E1 amplification, because it's a patient population that has a high medical need, but also it was a genetic alteration that's driving genome instability. And it does so by pushing cells into the S phase of the cell cycle, where they're replicating the DNA early before they have all the building blocks. So now the cell is trying to build the DNA and build the building blocks at the same time, which expands out that S- phase of the cell cycle and created this alteration where we could come in, do our CRISPR screens with the SNIPRx platform and identified PKMYT1. What we found in the end is that PKMYT1 is really important at holding a key factor, Cyclin B- CDK1, at bay during that S phase until the cell has completed that replication and then can undergo mitosis and become two cells. So it was really this really key factor that it's holding the cells at bay, and it's specific to these genetic alterations, cyclin E1, as well as FBXW7 and PPP2R1A, which are all causing this extended S phase. Now, how is lunresertib differentiated from WEE1 and CDK2 inhibitors? Yeah, a great question. ... So, we'll start with WEE1 first. So when you think about WEE1 and PKMYT1, they've been drawn next to each other in a line for a couple decades, and so everyone kind of defaults to thinking they're the same thing. But in fact, they do have one thing in common, is they both phosphorylate CDK1 at two different sites and hold it at bay so that the cell doesn't undergo mitosis at the wrong time. So it's really two different breaks for a very important part of the cell cycle. That's really the only place where they're similar. They're different in that PKMYT1 is in the cytoplasm, and it's phosphorylating CDK1 in that space through different signals at different times. That then has to be removed, enters the nucleus, and WEE1 is like a secondary break, so it can come in again and now inhibit it after it's been activated. In addition, WEE1 also regulates the G1 to S- phase transition of the cell cycle, so it has multiple roles. Whereas PKMYT1, to the best of our knowledge at this point, is really just focused on CDK1 and that cytoplasmic mechanism of action. On the flip side, CDK2 is really the partner to cyclin E. So in those cells where cyclin E is amplified, CDK2 is its partner, and inhibiting it directly is what's helping to block the cells then from entering S- phase, and holding the cells at bay, with Pfizer and, Blueprint and a few others actually working in that space. We think it's very exciting. It's people been worked on this 25 years ago. It's been very challenging to find truly selective inhibitors. It's exciting, but I think it's different, right? So it's not the same mechanism, and we don't think it's gonna have 100% overlapping populations. And we think that different types of combinations will be essential to see the full phenotype in these different settings. Now, your step two screen identified new sensitizers to PKMYT1 inhibition. How frequent are FBXW7 and PPP2R1A mutations compared to CCNE1? So I think the first and most important part is that these different genetic alterations are mutually exclusive with one another in the vast majority of patients, with only a small percentage of hypermutators showing them. So they're distinct populations. But in particular in the gynecologic oncology settings, you see a preponderance of cyclin E, so like in ovarian cancer. In endometrial cancer, you see all three at a very high frequency. And in the upper GI cancers, you're seeing both FBXW7 as well as cyclin E. And then finally, when you look at things like colorectal cancer, it's about 13%-15% of colorectal cancer that have FBXW7, things like non-small cell lung cancer, squamous subtype. And really, if you're looking at all the populations of the top indications, it's about 65,000 patients. If you look across all cancers, it's about 90,000 patients with these genetic alterations. Great. Can you just walk us through, like, the monotherapy data from the phase I MYTHIC study and early insights from the combination studies that you've reported on earlier this year? Yeah. So earlier this year, in June, we gave out the first data on lunresertib as a monotherapy and then gave a, I think a teaser, kind of a little bit of an insight into what we hope to be able to present this fall. And so up front, I think, you know, again, we showed it was a potent and selective PKMYT1 inhibitor. It's first in class in this setting, and so the first time any clinical data has come out on PKMYT1 inhibition in the clinic. We found that it was highly tolerated, and we think, differentiated from the profiles that you were seeing with some of those other agents that we talked about, WEE1 or CDK2 inhibitors, where we had very little, hematologic toxicity, and rash was, the more of the dose-limiting toxicity that we were seeing at the time. In addition to that, we went through, and we were able to show that we blocked the target by looking at the direct biomarkers downstream, and seeing that they were, inhibited to a level, that was similar to what we were seeing in the preclinical models that was necessary to drive maximal efficacy, as well as some further downstream markers showing that DNA damage was being induced. And demonstrated some efficacy where we were able to see a complete, or, sorry, a confirmed PR in one patient on the monotherapy, as well as several patients that had a durable response out to 11+ months and ongoing in that study. And then we ended that particular presentation by highlighting some emerging data around the combination with camonsertib. And in that setting, we were able to show that when you looked at the depth of ctDNA response across patients, that on the monotherapy, that we saw a nice, you know, reduction with about, I think it's three to four patients that went below the 50% mark. But when you looked at that in combination, you saw that most of the patients were going down, all except one, and a large percentage were going down below that 50% mark, and then showed just three examples, not all the examples, but three examples, of PRs based on RECIST response, each in a different genotype. So cyclin E, PPP2R1A, and FBXW7, just highlighting that we're seeing a broader range of activity from that early data that we showed and hope to expand on that at an upcoming meeting. Now, you identified two different dose schedules. What do the different dose schedules offer you? Yeah. So I think the, the easiest answer to that is, is flexibility, right? And so one thing is Project Optimist. They want to see different doses and schedules to understand that you're getting the maximum amount of benefit with the minimum amount of toxicity, so it plays into that. But it also gives us flexibility when we're leading into the different combinations, where we expect to have to do more dose schedule work. So we understand exactly how this compound is working, how it works when it's on an intermittent schedule, on a BID schedule, on a QD schedule. And so it's really been very informative to help us both in the monotherapy, but also as a lead-in to that combination therapy. As you guys mentioned, you plan to present additional MYTHIC Module 2 combination data at a medical meeting. You know, what should we expect to see, and what do you need to see to consider that a positive update? Yeah. So, I mean, the foundational things that we absolutely expect to share are the safety and tolerability, and as Mike was referring to, at least a couple of RP2D plus schedule options to be as optimist-friendly as we tend to have been in the past. ... I think beyond that, I guess Mike mentioned in terms of the teaser data that we shared in June at our Investor Day, you know, our aspiration for this data set is that, you know, unannotated, you know, we should be able to set an expectation for our investors that they can see a path forward with this combination if the data justifies it, and that's, of course, always what we're aiming for. So it's frustrating for us. You know, we'd love for the meeting to be this morning and to be up here talking about the data, but, you know, we've got to be a little patient as our investors have been. Great. Let's shift to camonsertib. You know, that's partnered with Roche. So how is camonsertib differentiated from other ATR inhibitors? Yes, so I think as we showed as we were coming into the clinic, we really focused on potency and selectivity upfront. So we think we are unique in driving that perspective. But the other part was, again, building out and making sure we were asking the right question clinically, right? So we were picking biallelic patients that have both alleles lost, something that wasn't being routinely done, and we're selecting for patients in that phase I. I think the phase I also showed and demonstrated very clear differentiation on the how would I put it? The tolerability side, where really anemia was the only thing, and that was about 14.5%. On the other side, where we were seeing efficacy that I think, you know, was clearly differentiated in a positive perspective, from any of the competitors, to date that have been showing their data. Now, this fall, you're expecting initial gemcitabine combination data. Can you just talk about the study and what the bar for success is to that data? Yeah, so the gemcitabine data is the fourth module of TRESR. The final part that we're getting done, it will be presented at an upcoming meeting here in the not-too-distant future. And again, really the main focus of that is understanding dose and schedule, right? Being able to go in, understand what's the right dose and schedule that we could use and progress forward. With regards to what the success is, I think, again, at the end of the day, this is now in Roche's hands, and so I don't think we can speak to what you know is the exact thing that they would be looking for, but we'll hopefully be able to give a clear view of what that combination could do. I think it really informs, the street on what a likely path forward is for Roche with that combination, if at all. Again, you know, the data will be what it will be, and it's I think it's at the same meeting, right? So, at the same meeting- This fall ... not in Madrid. Now, multiple of your studies have combinations with PARP inhibitors. You know, so what have you seen in the data on the benefit with PARP inhibitor combinations? Yeah, so we have the two different studies, both one of the modules within TRESR and then the ATTACC study, that are both looking at a combination of ATR inhibitor with talazoparib, olaparib, and niraparib, and really trying to understand what it looks like in combination with all these different agents. We were able to present on that study a little bit earlier in the year. And I think, you know, it was really several pieces of excitement that came from that. One is, yes, you can combine these together, driving a safe and tolerable way forward. But also showing that there was actually an increase in the ctDNA that was being seen across the board in the combination that was better than seen in monotherapy. I think some early signals that were showing up, particularly in the ovarian cancer space, where there was a demonstration of seven plus months of PFS, and that was in the platinum-resistant setting. Comparing that to the best benchmark that we had at the time is the ORIOLE study with olaparib in the platinum-sensitive setting, where it only saw a 5% or five months of PFS. So I think there were lots of things that were showing that this was an active combination. And then the work that's ongoing now is to continue to flesh that out, understand that in specific patient populations, and then really close out the TRESR studies, and 100% hand over things to Roche. Mm-hmm. Now, Roche recently added the camonsertib-based arm to both its phase II TAPISTRY study and the phase Ib/II MORPHEUS-Lung study. You know, what do these mean to you and the potential future direction of camonsertib development by Roche? Yeah, I think we've been saying pretty clearly the real thing you should read from those two study starts that we shared at the last Q are that Roche is moving forward. I think and looking at us in terms of we're a proxy for camonsertib now with Roche as the partner, you know, we didn't just elucidate these new study starts, but guided very specifically to a $40 million milestone with the TAPISTRY start in Q4. And I think the meta message here is Roche is getting going on a much broader plan that is up to them to share with the street. It was interesting, several of our shareholders picked it up on clinicaltrials.gov, and your team did, too, before we even announced it, because that, you know, Roche is going to file when they file. Mm-hmm. This is the thin edge of the wedge. Great. Now, you're hosting an R&D day in the fourth quarter. You know, what should we expect to see during that presentation? And will you disclose a target for 1664 then, or might you wait until it enters the clinic in early 2024? So our expectation, just because it's coming up really close, is that we will share the target on RP-1664. That could be an IND as soon as kind of like very late this year or very early next. So, you know, our tendency has been to, you know, really justify the capital allocation decision when we're ready to make that clinical commitment, which in RP-1664, we are. And the reason for holding back there was competitive, right? We didn't want to inform potential competitors that we think might be there with a similar target, if the same, not the same target, that we were in this space. So yes, that investor day will focus on that. We're also gonna focus on sharing as much as we think we reasonably can on RP-3467, which is our new Polθ inhibitor. You recall, RP-2119 was our lead pony. We made a decision in the spring to switch that out for RP-3467, and I think we're going to put a spotlight on the whys of that, and we're just incredibly excited about this Polθ compound. And you know, we'll share as much as we can then. We're hoping some of our competitors, you know, have some data out there on their Polθ inhibitors, because what we really like to do, and you remember from camonsertib, where we were—I think we were able to portend how ATR inhibition would play out with us winning, by showing sort of the chemical and preclinical advantage, and we can't do that until others share their own data. So- Mm-hmm. We're excited about that. Now, you just talked about RP-3467 and how that's your second Polθ candidate, and you had RP-2119, and that you're gonna talk about it at the R&D day. But I'm gonna ask you anyways, like, how, how is RP-3467 different from RP-2119? Yeah, so we haven't released the information, but I think what I would say is we will make that clear when we have the R&D day and really kind of compare and contrast. And I think it'll make it very clear that, you know, it's a very competitive environment in the POLQ space, and we want to make sure that we had what we think could be a best-in-class approach. And so I think the data will demonstrate why we're excited about the new compound and why switching those key lead horses was a critical factor for us. Okay, great. Maybe one last question. What, if anything, do you think investors most misunderstand about Repare Therapeutics? You know, I think it's the breadth of what we have. And the good news is, I think once we get a chance to talk about RP-1664 and RP-3467, that'll start to change. But, it's in our DNA not to talk about things until we're not hand-waving data, you know, comparative information. And, you know, it's funny, just today at your conference, you know, we're talking with some of our most longstanding investors, and it's what they appreciate most about us. We tend not to get out of our skis and not to hype things before we have data to back them up. I'm not sure we've changed, but I think it's. It means the street is slower to come around to appreciate the value in the company. You know, we're doing everything we can to execute to change that. Great. Let's leave it there. Thanks so much for your time. Thank you.