My name is Chris Shibutani. I'm a member of the research team in pharmaceuticals and biotechnology. Together with my team, we are really excited to have the group from Repare Therapeutics join us here on stage for the discussion that we'll have. Joining us, Lloyd Segal, CEO, Maria Koehler, Chief Medical Officer, Steve Forte, Chief Financial Officer, and the mysterious Michael Zinda, Chief Scientific Officer. He's in the kid's chair for today, but that's the hot seat, so not to be joked about. In the ecosystem of biotechnology and companies, your genus is synthetic lethality. There are some very differentiating and distinctive features about, your approach, your philosophy, how you go about it. Set the table for us a little bit and characterize sort of what makes Repare Therapeutics, differentiated within the synthetic lethality landscape. I think there are a couple of just big ideas that capture. First, thanks, Chris, for inviting us here and for helping us enjoy this wonderful conference and environment. What are the big differentiators? I think first and foremost is our platform. I think that platform has two constituent parts that really differentiate us. SNIPRx, our CRISPR-enabled set of screens that allow us to find novel targets. That I think as we showed with PKMYT1, no one else is finding and really validate those targets to the level that, you know. I think even today, meeting portfolio managers, we're surprising people with what we can do. The second is applying that same platform to expand our patient selection capacity. Once we have chemical matter against target, the ability to then systematically find other genetic alterations in that synthetic lethal network of genes that predispose a patient to respond to those compounds. I think those things together, we proved in camonsertib RP-3500, we can really differentiate the way we develop drugs. I think the real secret sauce is in our ability to take those insights, drive them with great medicinal chemistry, and I think one great thing about the Roche deal we just printed was it validates really what we can do in terms of drug development and the team that we've got developing those drugs. I mean, I've been able to follow you guys for several years, and it has always been the complementarity of some of the unique capabilities, you know, really shepherded by the folks that you have on this team. Maria, with your background from Pfizer, et cetera, tremendous scientific credibility as well, has been really important. You've also done a number of things now as we sit here in June, from a sort of strategic business model and structure standpoint, right? I think you've been more thoughtful than many companies in terms of considering ways that you understand and recognize where your value is, figure out how you prioritize what you retain, and then also where value can be generated, leveraged, recognized, secured through different partnerships. Within that, for a company of your history and scale, you have quite a bit of variability. There's a whole mixture of partnership structures that you have. Let's start with the Bristol relationship that came prior to the IPO, right? I think that's a target discovery partnership there. With Ono, you have a selected target, which we'll talk about a little bit as well. Then most recently with Roche, this is, the structure is now a licensing with an opt-in. I think having all of these different, variables in there, it really sort of almost weaves together a certain element of strength to the story, and I think investors are starting to see that as well. At a high level, and we'll get into these partnerships more in specifics, how do you think about the pros and cons and the benefits as you're figuring out what do you retain and, you know, how is that value? How did you get to this point? Yeah. I think if there's a unifying element to all the great deals that you described, and by the way, I think the leadership of our Chief Business Officer, Kim Seth. Yes. Who I know you know has been a core part of that is we have a bespoke approach to how to constantly partner and exploit our assets for the benefit of patients and shareholders alike. You know, if you're talking about the first deal that we executed, it was the Ono deal. That was 2018. You know, we were in early days, and in that case, it was generally an inbound interest, and Ono just really believed in POLθ. It made for a very straightforward partnership and alliance for us giving up, you know, just Japan and ASEAN countries, which are, you know, Malaysia, Taiwan, Hong Kong, Singapore, and we still retain China. We just thought it was a phenomenal deal in its time for how early we were. Fast-forward to May of 2020, and as we shared with you back then, you know, we just saw that we were discovering more potential synthetic lethal targets than we could ever exploit. It was just about asset mobility. We didn't want stuff sitting on the shelf because someone else was eventually gonna make that observation. That was why the BMS deal was so transformational for us because it assured us that at the widest end of the funnel, nothing was going unexploited. Still allowed us, as we think we'll prove over time, that we always have more compounds that we can put into our pipeline. The Roche deal that we recently announced. This is only two weeks old still, so it's fresh. To us internally, it's actually been a while. We came to the conclusion in 2021. The way to win in ATR inhibition was going to be with a global partner who had the same conviction about ATR potential, you know, as we did. That's how we ended up with Roche. It was a systematic process that we drove in 2021, long before the market deteriorated. I don't mind telling you, I'm glad now that we did it, because we would have had less options available to us. We were on track for that partnership anyways, and we ended up with Roche as the best possible partner. We think that our, for our patients, for our shareholders, for our team, the probability that we'll win in ATR inhibition is far higher with Roche as partner, given their level of conviction and commitment. You've spoken, particularly at the time of the announcement, about the level of alignment that you had in terms of thinking, mindset, approach, et cetera. Maybe talk to us a little bit about how this came together, and you also commented the process was quite rigorous that you went through with several different parties. Specifically, what about the Roche approach, their capabilities? Yeah. That pushed them to the top of the list? Yeah. I don't know if Maria is best to talk to that. Yeah. I think the shared vision that Maria and Kim drove across the organization is really. Roche, as you know, is having a lot of resources. That's obviously big pharma partner. One of the things that Lloyd said, that we could not give justice to the opportunities that the ATR inhibitor could give the patients. We need money and capabilities of developing, doing large trials that the drug would require. That's one. Number two, Roche is known for precision capabilities and love for precision oncology. They have Foundation Medicine that they acquired a while ago, to have the tools that we are developing as well, which means NGS to find these patients. We are going to collaborate with them also in this space, in addition to our assay that we disclosed actually all the details at ASCO this year. The third is they also have a opportunity with Flatiron to do studies that are real-world comparisons for the rare populations, if they want to go to rare populations. Finally, and lastly, they have something that only large pharma can do, which means the platform studies. The platform studies include either by tumor or by alteration, big trials, which are multi-arm trials. For example, you can take a tumor, let's say hepatocellular carcinoma or colorectal cancer, and look within these tumors all possible alterations and develop multi-arm treatment trials using different drugs, staying with the same tumor. The opposite of it is to take one alteration and develop it in multiple tumors. They have these Morpheus trials, TAPISTRY trials, and all these other things which our compound is very suitable because we gave them the 16 alterations. Where they can search for the opportunities. Now really last is that, as you know, Roche is not a company known for synthetic lethality. By purchase of our compound, they are entering the very hot space that everybody now is sort of entering. Definitely this is one of the agents that they will develop either as monotherapy or combinations, and they have this big portfolio. Of immunotherapy and targeted inhibitors are off patent very shortly. There's multiple opportunities what they can do. Yep. Many layers of strategic logic for Roche. Let's get the compound on the transcript. We're talking about the Roche partnership for camonsertib. Is that an. Camonsertib, yes. Okay, terrific. What can you share in terms of what clinical data that Roche may have seen, the level of any interactions on the regulatory front just to, you know, help them with their diligence? The due diligence was extremely intense. We know that it was both. This was a late-stage development deal, which was led by both Roche and Genentech. We had a combined team, which included members from Basel and members from San Francisco. We had several in-person meetings as well as countless zooms. We had a database set up, a data room set up where we were, as the data come, we are putting the data in the data room, and they had real-time access to the data. There is no data that they did not see, both from the preclinical perspective, all our preclinical studies related to camonsertib, PK data, translational data, genomic data, and obviously also the clinical data. Got it. Now, obviously every sort of action taken and particularly with this asset, is gonna have a cascading effect in terms of the rest of the pipeline. Maybe Steve or anybody who can talk to sort of why the structure and with this asset, how did this make sense in terms of how it would reflect on what you would be able to do and the impact that this deal would have on the rest of the pipeline for you? Sure. I think very simply, just to kind of reiterate the terms of the deal, $125 million up front and $55 million in near-term milestones. We've stated that provides us now with runway into 2026. This puts us in a great position where we can prosecute the remaining parts of our portfolio at full speed. Our priorities now shift toward RP-6306. As you know, we have four ongoing trials. On RP-6306. We then have our POLθ inhibitor, which we hope to share some news in the very near term. We've guided to IND-enabling studies in the first half of this year. Then as Lloyd Segal alluded to, I believe earlier, there's another compound which we hinted toward at our June 2nd, event, and that's another asset that we'll be able to keep working on. Then there's the remaining part of our portfolio, and we hope to be able to continue with our very strong track record there of bringing new compounds eventually into the clinic. We've stated a goal of an IND every 12-18 months. As you know, we had achieved an IND for RP-3500 around the middle of 2020. Middle of 2021, we had achieved the same thing on RP-6306. I've just discussed POLθ and this additional compound. That really is kind of the core of our strategy, and we hope to be able to prosecute that now with the expanded resources we have. The last remaining piece is with this partnership with Roche. We're going to continue to complete the ongoing studies, namely ATTACC and TRESR for chemo and surgery. Okay. Yeah, no, we'll go a little bit more into those assets. To complete a little bit of the discussion around some of the mechanics of this partnership that you have with Roche there, can you talk to us a little bit about what are some of the triggers for Roche to begin the next stage of clinical work that they'll do, and how will the opt-in work for you? You know, what is it that you're gonna be looking for to feel confident about what you'd be getting into if you did do the opt-in? We haven't disclosed the specifics around what would trigger the opt-in, except to say that it's some form of a registration or AD trial. We haven't described the trial, and frankly, there's some freedom to shift that around. Why we love that opt-in structure is because, you know, why anybody likes optionality, right? Sitting here today, we can't say for certain what the final financial model on that trial will look like for us. We love the fact that at that point in the future, when Roche indicates to us, "Okay, we're going ahead, you have to make a decision," we can look at the model at that time based on the probability of success that we see, 'cause we're gonna have complete visibility into the data. Be able to say, "Okay, you know, the NPV is massive. We wanna go ahead and do this." Or, "You know what? We're happy to continue to prosecute whatever our pipeline looks like then," which I think should look even richer than it does today, and ride on a phenomenal set of milestones and royalties. That Kim and the team, achieved in the deal. I think it's a kinda heads, we win, tails, they lose. Not really, right? We win either way. I think that's the elegance of that part of the deal. Great. Let's talk about some of the data that we have. The last update was April, the AACR meeting. We had some phase I data there. You showed a 25% response rate, ovarian cancer patients, predominantly, PARP and platinum chemo failures. This prompted some speculation that this would potentially be some of the initial regulatory focus. What are the pros and cons, advantages, disadvantages of having that be the initial focus? Can you talk a little bit about that, Maria? It is indeed pros and cons. Pros is the fast. The cons is small. You know, if you look from a perspective of a larger pharma, they don't necessarily need fast, they need large. One of the attractiveness of the deal with Roche was that we, as Repare, could only afford the fast, but they can afford the big. Without talking about details of the clinical program, which we definitely participate in development very satisfactorily, it is going to be in their hands now, and we are very happy with the development. I can tell you that it's way above the. More ambitious. More ambitious than just doing the platinum-resistant, PARP-resistant. Right. No, that is very logical in terms of the potential of the platform that you have. Right. In the data, the signal for ATM-deficient patients was strong, right? And you've also noted opportunities for more precise patient enrichment strategies, right? Can you talk a little bit about that, in terms of you know, are there improved ways to ensure true loss of ATM? Also when you think about what others in the class have shown to this point, what do you think are the right settings for this? Right. You know, how I would like to answer the question, because we cannot really talk about what will happen with the compound in the context of of the smaller segments where it could be developed, is I talked about the TAPISTRY trial, which they have, where they are going to look for the small population, et cetera. But that is about that. What is extremely satisfactory with this development is that we showed with RP-3500, number one, that we know what we are doing. Number two, that we know how to do it. Which means how to find these patients. We developed a diagnostic that is really, really cool and very, very advanced. We showed that there is more advanced way to characterize the losses to biallelic losses versus protein losses and all these other things. We are actually preparing a very nice publication on all that with more details that was presented at AACR. Our translational team is extremely strong. We have various collaboration with academia to help us sort of bring it to life from a patient perspective. What is completely most important for me is all the learning that we got as a team. About the biology, about how to go about the small population, how to find the patients. All the clinical team, operational team, how to talk to regulators about it, all these learnings. Sure. This is something that is very precious and that we will bring to our next sets of portfolio. Extending beyond that, talk about the conclusions that you've drawn from the data as well in terms of thinking about the potential to address the other step two genes. Right. Which is inherent in your platform, right? Tumors that might be outside of ovarian cancer. That is that. The other validation of the platform. Also how we went about finding the dose, and we are sort of not to brag about it, but we are famous for finding a new way to establish the Project Optimus variation. We will bring all these learnings and what is very important and why Roche was interested in it, that it was a very solid proof of concept. Very solid proof of safety. Right. We didn't cut any corners, and we sort of did it the right way. Still did 120 patients in 14 months. Uhuh. Right. Into the trial. Certainly, the safety profile looks very promising. Right. Relative to others in the class. Yeah. If you were to think about a potential ability for that evidence that we have thus far about the safety profile, how do you envision how it might, sort of manifest itself in terms of relative competitiveness in the actual clinical arena? Right. You know, the secret here is that you can only predict the safety of combinations to a certain degree. The fact that the drug is the best in monotherapy does not automatically cover for lack of safety issues in combination, because it's always the synergy. If you select the patients right, you are paying the price of the synergy as well. This is another learning that we learned. We learned an unbelievable amount of things. It's, you know, the most important is, does it help patients? Is it promising for future development? These are the questions that we answer. Right. With the Roche partnership, it's as if camonsertib has now gone off to college, has in-laws or something. Yes. Let's shift gears a little bit, talk about RP- 6306. Perfect. Now, you know, it gets the biggest bedroom in the house, wholly owned. Talk about some of the data points that we have so far. Preclinical learnings, and just tell us a little bit about this asset, sort of just in terms of what the targets are. You know, what are these preclinical learnings that are starting to shape your initial approach to this? Yeah. I think, obviously, it's a novel target, right? That's been discovered for a new synthetic lethal paradigm to treat Cyclin E1 in FBXW7 patients. I think, you know, the things that we've been learning going through there are doing a lot of the in-depth work to understand the mechanism of how the synthetic lethal interaction was working. We published on that now in nature last month. The real bonus of doing all that academic work, as you could look at it, was really it helped form key combinations. The mechanisms by which they're working to give us further insights into potential synergy and the best ways to help develop the molecule and which questions we wanted to ask in the clinic. You know, the key data that we saw initially was across a range of different tumor types in both Cyclin E1 and FBXW7 as a single agent. We see tumor growth inhibition stasis that was due to a combination of both cells dying as well as cells growing in the tumor. How that manifests as you move into patients is something that we're in the clinic to understand. Whether that leads to regressions or if that looks exactly like we see preclinically. We also highlighted several different mechanistic interactions for gemcitabine and irinotecan. Both agents which are helping to further augment that S phase perturbation that was caused by Cyclin E1 or FBXW7 and drive deep regressions in the preclinical setting that we were looking at m ost recently, we started the camonsertib combination, i.e., ATR plus RP-6306, which works differently in a mechanistic way, as they both converge on r egulation of CDK1, and then enhance and show additional synergy in that study. Really looking at these different opportunities all at once in the clinic, or at least as close as we can get to all at once. To be able to determine what's the best impact on patients' lives, and which one of those do we want to bring forward most aggressively. In terms of maturity, just to be clear, for this investor audience, we're gonna see initial clinical data this year. Let me say that again. We're gonna see initial clinical data this year on the wholly owned asset RP-6306, monotherapy chemo combination as well. Talk to us about what we can learn, how we should really be thinking about it. Candidly, it's always a struggle with this initial clinical data, right? I mean, triple meeting is frankly like, you know, a bit of a white knuckle experience often, right? For the investment community, these are necessary growing pains and paths that we go through. What's the right filter that we should be thinking about with that initial clinical data there? Then maybe hint to us when we might be able to see it, what form? Just one important clarification is that the guidance is that we're gonna share that initial clinical data in the second half of this year, not the combination. We guided just to the monotherapy. I think. I think if every moon and star possible would align. Which, you know, certainly doesn't look likely today. We could share some combination data. What are we really aspiring to? Remember, as excited as we are about the novelty of prosecuting a brand new target in cancer with the validation that we have for that target so far, we have to be a little bit more deliberate. The light speed that Maria moved at with the team and our collaborators with RP-3500, 120 patients enrolled in less than 14 months, I think had a lot to do with the fact that our investigators knew and understood ATR inhibition across a number of different clinical compounds. In the case of RP-6306, our ATR inhibitor or sorry, our PKMYT1 inhibitor, a little bit more deliberate, a little more slow, a little more careful. I think that's the ethical and appropriate thing to do, and that's how, like, that's how we're approaching this trial. The guidance that we're very clearly and I'm unambiguously giving is that this phase I exercise, and unlike TRESR, this is just a phase I, not a phase I/II. The focus and endpoints are safety, tolerability, PK, any PD. We're looking at a number of PD data points, and any factors that we can find for recommended phase II dose and a schedule. Using the same sort of, I think, brilliant framework that the team used in a very optimistic, friendly fashion. Uh, f or RP-3500. No, I think that certainly makes sense. The stage of the data that we're at, it's gonna inform biology and pharmacology. I think investors should have that perspective here, and hopefully that'll be something that will, you know, continue to be ingrained in terms of setting expectations. I think there's an exciting opportunity with RP-6306. Help us a little bit with any KOL interactions with regulatory discussions here as it applies to RP-6306's strategy, particularly in terms of pursuing tumor agnostic or histology specific kind of development paths, right? I mean, there's some navigating here that can happen, that is a process that's unfolding, that you're very much involved with being at the forefront of? Right. I just wanted to make sure that from the very beginning, we were saying that we are not planning for tumor-agnostic development. The reason for that is that for tumor-agnostic indication, you need to have a very high response rate. That's number one. Number two, you probably can register based on single-arm study, and then you have to follow up with the randomized study. You cannot do randomized study in multi-tumor. The example of that is either entrectinib that registered in lung or MSI pembrolizumab that then eventually registered in phase III study in colorectal cancer. This really does not give you. Where are they making money? In the single tumors. Okay? It's not because it's an exception for development rather than a new rule for development. We are sort of not going there. Another reason why we are not going there is that we don't want to add additional variable, because we know that the tumor background for each alteration is contributing to the success of the drug in the tumor, and we all know exactly how the drug works, really, in patients. We would like to focus on gynecological malignancies for the CCNE. Upper GI for CCNE and possibly FBXW7 and definitely FBXW7 for colorectal. These are the initial tumors that we will focus on, which does not mean that we would eventually not do a basket with all possible tumors to see how it looks. It is too much risk for a new agent to go that way. Right. I answered this question. Okay. I encourage you just to get at the underlying biology that Maria's describing, that Mike was referring to. I encourage you all off our website. We enabled the direct download of the Nature paper from three weeks ago, and it's a really comprehensive piece that backs up this exciting new target. Okay. Terrific. Always science driven. POLθ, you reminded us a little bit about the history of this, the relationship with Ono starting back, several years ago. Long sought after target. Remind us what rights you retain, what's in it for Repare? It's, I think it would be easier to describe the limited set of rights that Ono got than what we retained. Okay, fair enough. You know, Ono, great partner. They've been wonderful collaborators. What they sought was the rights to commercialize any product eventually that we were able to create here in Japan, Taiwan, South Korea, Singapore, Malaysia, Hong Kong. That's what we gave up. There's royalties tied to the sales that they would make there. We think it's just a really wonderful deal given at the time. I mean, this was 2.5 years ago. We were, I wanna say, very earliest stages of that project. It's not a secret in the DDR synthetic lethal community that POLθ is on one hand an incredibly exciting target with more and more good rationale for development which has been incredibly tough to target. There are two enzymes, and the field doesn't necessarily even agree on which enzyme is the right one to target. Mike will get the chance to give you the winning answer when we are prepared to enter the clinic with that one. He's very excited about that. I believe we do have a sense of timing for that. That's gonna be first half of next year. Maybe, Mike, you can help us a little bit with the status of the compound portfolio there. What still remains to be determined in terms of your being comfortable advancing a specific, you know, target through these IND-enabling studies, et cetera? Yeah. Absolutely. I think we've gotten to be in the position to start IND-enabling studies the first half of the year, which clearly we're well into that and nearing the end of that. We'll release exactly where we're at in the 10-Q in August. I'd say we're very comfortable with where we're at. We've been able to look at both inhibitors of both the polymerase and the helicase domain, use that information, what looks most drug-like, what is the best biology that we thought and are taking forward one of those into the clinic that we think has the most potential to help and benefit patients. Got it. To close, I think when you made the announcement of the Roche deal, you made sure to put a couple of extra pages in our passport. Yeah. Some breadcrumbs to another asset that could be coming there. Yeah. You're smiling, Mike, and my team always thinks that you're kinda cagey. On the details, obviously we'll be waiting for that. Yeah. Anything you can share about the potential opportunity here? What might the goals look like? You know, help us anticipate some of the shape of what the update could be there? Yeah. I'll continue to be cagey, I think is the reality. Apologize for that in advance. You know, it's an extremely competitive field. I think, you know, we want to retain that competitive edge until the point where we're starting to head into filing the IND. That's when we'd really come out and talk about the target, where we've got to look at it. That's not only from competition, but it's also from just being pragmatic, right? It's again, another novel target. Never been through a GLP study before in history that we're aware of. You know, there's just lots of unknown unknowns. We wanna make sure that we're guiding and leading people down the right path, and also retaining as much of our competitive edge in a very competitive environment of oncology. Okay. To close, I think for many of us who've been zooming with Lloyd and the team over the past couple of years, Lloyd often sits there in front of his well-carved wooden desk, leaning forward, elbows are on the desk. There's always a certain amount of verve but also some anxiety. Now I see you sitting back. I think about you now because we talked about cash run rate through 2023. Now we have into 2026 with the Roche deal. Good place to be, right? From now to 2026, what can you accomplish with that? Leave us with some thoughts to inspire what that positioning that you have now with all the deliberate work you've done from a business structure standpoint. Where can we get to in 2026? It's really straightforward, Chris. We wanna build the best pipeline of drugs in biotech in the DDR synthetic lethality space. I mean, we've got a lot of work ahead of us to do that, but I think we haven't missed a step yet, and we've shown that we can execute as well or better than anyone in our peer group. Appreciate all of you coming to join us here. It's fantastic to have you all in person. Wishing you a lot of progress and success going forward. We look forward to next year as well. Great. Next time you should have a desk so I can lean on it, lean forward. Okay. We'll give it a try. Okay, thanks, everybody. Thank you.