Absolutely. Appreciate the signal it sends. Excellent. Welcome, everybody, for our next session here at the Goldman Sachs Healthcare Conference. My name is Chris Shibutani. I'm one of the research analysts in the biopharmaceutical space, and we're very pleased to have Repare Therapeutics join us to see our CEO, Lloyd Segal. And Lloyd, a lot has been happening with the company. Perhaps just a little bit of a brief overview, and we're sorry that Maria couldn't join us. She's always full of spit and vinegar and opinions. I always love talking to her, so you're going to have to do your best Maria impersonation when we start to talk about some of the clinical programs here. But just maybe just level set for everybody who's here, what's going on lately. Great. Well, thanks for inviting us, and sorry that Maria had a last-minute conflict, but we're really pleased to be here at the Goldman Sachs, Florida, conference. A quick sort of overview of Repare. We are a company focused on applying our unique capabilities of CRISPR-enabled discovery to find novel targets that are synthetically lethal. In other words, targets that have an inherent prediction of a genetic alteration linked to a target that together allow us to really focus on targeting specific tumor cells and not other cells associated with the same target. We've been doing this since 2016. We have, I think, the most advanced pipeline in the field. And despite synthetic lethality being sort of broadly of interest to everyone from AZ to a host of very high-quality competitors in our field, I think this is still early days for synthetic lethality. Today, we have three clinical compounds, all homegrown, targeting PKMYT1, ATR, and PLK4, and a fourth that we expect to enter the clinic later this year, which is our Polθ inhibitor. And I think together it represents what we believe is the most compelling portfolio of synthetically lethal DNA damage repair agents. Now, synthetic lethality is always a very cool term, really sort of like had its proof point of being for real, probably with PARP inhibitors. And so then the quest became, where else can we go with this as a plan of attack? And you guys actually have a proprietary platform. Talk a little bit about your methodology. You referenced it quickly in the opening sentence here, but there's an element of kind of specificity and diligence that you have in your approach. Kind of what is the Repare secret sauce for prosecuting this whole plan of attack, synthetic lethality? So I believe that what really makes our platform distinct, aside from finding new targets, is that we have an ability between our initial target focus and what we call our STEP2 dimension, which is our platform. We apply our platform once we have a target in chemical matter against that target to expand out to understand the network of other genetic alterations that predict a response to inhibition of the target itself. And so what that's done in virtually every program we put into the clinic is allow us to expand out the genetic alterations we seek beyond the initial lesion that we query with our platform. And so, I mean, the best example I can give is in our PKMYT1 programs in lunresertib, we're not just looking at cyclin E1, which is a lesion associated with some pretty aggressive disease, but we've identified PPP2R1A and FBXW7 as alterations in that same network that we showed at ENA last fall predict a response to PKMYT1 inhibition. I think that's the secret sauce in many ways of what we're doing, is expanding that out. And so as we see more and more competitors, large and small, showing up with cyclin E1 selected patients, we feel a lot better about having FBXW7 and PPP2R1A to expand out the populations that we're exploring efficacy with our drugs. Yeah. There's always kind of this tension, I feel, as if precision oncology has faced. If you think about the journey and the mindset of investors, there was a bit of an initial love affair with precision oncology because it felt like, wow, the right drug for the right patient at the right time and the higher probability of success. When I'm looking at ORRs, I want to see the numbers start at least in like 40%, 50%, 60%. None of this like, oh, if we could just get 20%, that'd be amazing kind of thing, right? Which IO learned us to be very sanguine about. Then there was a sense of an awareness of like, oh, actually the precision has kind of more precisely defined our TAM, which means kind of a smaller TAM. Let me choose a slightly italic font, perhaps, here. And yet I think one of the underlying premises of the synthetic lethality approach is, as you described, this whole prediction of being able to possibly unearth what nature has been trying to hide, looking for that other leg of the stool to use some of the synthetic lethality metaphors here and to think about that. As you've taken this company and turned it into more of a kind of a business, a research business, how is that playing out relative to your expectations? Is it tougher than you thought it would be? Is it about what you thought? Because you have a scientific mindset. But just understand, because I'm asking in the context of investors who kind of went through this love affair and then reality hit, but there's still opportunity very clearly. You have all these things in the clinic and the premise is there, but has it been tougher? So, you know, Chris, it's a great question. And I think the short answer is it almost always takes longer than you think to prove things out. I attended a conference where Arie Belldegrun was speaking. He said he woke up that morning and heard a report from BioCentury on ADCs and RLT being the hottest thing, and he thought it was 1996, right? Proving things in our business, particularly in oncology, takes a long time. That said, we are very focused on data. And the data from every one of our programs, from ATR inhibition through to PKMYT1 inhibition, and I think at the ENA data that we showed in the fall shows unequivocally that we have an active compound that is delivering an unambiguous early signal. And our job is to keep our heads down and focus on generating the data that proves that early signal. My mentor in this industry taught me that data will set you free. Data, data, data. We have a phenomenal four quarters ahead of us, as you know, of data. We're just really excited to see this data come to fruition. I think when you put on your armor and you're willing to explore down novel paths, you're going to come up with first-time, first-in-class, undrugged targets, et cetera. And so I think what you have is a portfolio that's pretty replete with that. Let's talk about the first one, RP-6306 PKMYT1, lunresertib. What do you really call that at home? There are some of us who are lunresertibs, but we can't stop the lunresertibs. It's all the same. Really? There's no shorter nickname? Okay. Well, I'm going to struggle up here. So 6306. Tell us what we should expect, because I think we're actually pretty actively engaged and we're going to be able to turn some cards over. Where is the program? When will we learn some stuff? So I think it's a particularly cool time for lunresertib. There are five cards that we're going to turn over in the next four quarters or less, just to enumerate them. In our lunresertib-camonsertib combos, we have an ovarian and endometrial. In each of those, a phase II-like arm of somewhere between 20 and 30 patients. We're really going to expand out on that incredibly exciting signal we had. Remember, this was from ENA last year. We had 10 patients who were at RP2D with gynecological tumors. We saw 50%, now five out of 10, a very small number, with a RECIST response and six out of 10, if you included one biomarker, one CA125 response. So we're expanding that very interesting early signal into those two ovarian and endometrial, respectively, arms that will read out in the fall. We just reaffirmed in May, we're very much on time for that readout. In terms of a WEE1 combination, as you know, this combination has gotten a lot of attention in the competitive marketplace. We started our trial in partnership with Debiopharm, and we should read that out in early part of 2025. And then we have a gemcitabine combination and a FOLFIRI combination. The former will read out in the second half of this year. And the latter, in the last week of June at ESMO GI, we're going to share that data in GI tumors. And I think we've already hinted and the abstract is out that we have a very interesting tolerability profile that is showing a heck of a lot of promise. FOLFIRI, as you know, is a tough combination agent. I think the early signal is that a PFS potential here is possibly very large. We're looking forward to sharing that data just a couple of weeks from now at ESMO GI. That's the first of five cards that we're going to turn. The message we like to get out to investors, and more importantly for our patients, is only one of those has to be positive enough for us to feel we've got a registration path forward that we can start in 2025. That's our plan. If we see data that we really like in more than one of those, we're going to explore the possibility, but we want to take the best one forward in 2025 as a registration opportunity. So much of the journey has involved getting pre-clinical work, trying to figure out whether it's going to translate into the clinic. Then in the clinic, you have early-stage biomarker data. It's fascinating. It's confusing to me. Give us a sense for when you look at pre-clinical data and you're thinking about bringing these assets as you have successfully into the clinic, is there a lens that you think is particularly relevant in general? And then maybe specifically for this compound, for 6306, what tipped your confidence to say, let's go for it? Yeah. So we're over 100 patients into our lunresertib clinical experience. So I think as much as, and this is literally the case, that PKMYT1 inhibition, which we discovered as a clinical strategy and published in Nature in 2022, I think it was, we had a great depth of pre-clinical data for us. And if Maria were here, she'd certainly know, is the fact that the PD markers and everything else in terms of the data we've got so far establishes unequivocally that PKMYT1 inhibition is active in the monotherapy that we did. And in combination, is clearly showing we're seeing a number of responses that give us no question that this is an active drug. So I think, Chris, I would turn it in terms of looking at PKMYT1 inhibition, is the data we're going to share over the next four quarters, is any one of those cards enough of a compelling opportunity to represent a pretty exciting commercial drug with broad enough impact for patients to make a difference? Because that's what matters. That's the data that I'm talking about. And so I think we're long past talking about whether our pre-clinical data, certainly in PKMYT1, is going to predict whether we have an active drug. We have an active drug. I think the question is whether there's as big an impact opportunity for patients as we believed when we got started in this adventure. You have these biomarkers in the early clinic. The question is, how do those correlate with kind of other broader clinical markers of success, response rates in particular? Did you feel that the biomarker reduction tracks even with a small denominator so far with the responses? So it's unequivocal that gamma H2AX, which is the biomarker we identified pre-clinically, correlates with response generally. And Maria has talked with you before several times about our circulating tumor DNA responses, which again, similarly predict for response. It's clear that there's a correlation. I just think the numbers are too small now to make definitive statements, but that there is a correlation there is clear. Endometrial, cervical cancer, very significant unmet needs in the second-line and beyond setting. Monotherapy, where is monotherapy setting there? So I mean, lunresertib combo is a combination. It's combo therapy that we're focused on for that set of patients in endometrial and ovarian. But what we see in each of those is really unsatisfactory responses from first-line therapies, right? We're looking at 5%-15% ORRs, something like three and a half, four months of 3.5-5 months of PFS. Sorry, that's below this. It's 2.5-3 months PFS. It's not a satisfactory current state of affairs. So that's Maria's and the team's obsession, is to see what we can do to beat those standards. I think emerging therapies, like we look pretty closely at mirvetuximab in a diffrent domain with an ovarian cancer beacuse they are looking at platinum sensitive patients. I think it just proved to us that you can focus on a subset of patients and have a big enough impact to excite the oncologist community and we hope Wall Street. Yeah. And what has been the level of investigator enthusiasm based upon the fact that this is a novel combination? You know, our investigators have been unbelievably awesome partners with us in this. I think they have been the true believers, and I think they're doing all the things they're supposed to do. And keeping in mind that with lunresertib, with PKMYT1 inhibition, we're the pioneers. So we were out first. And I think it's always that much greater challenge for investigators to be the first one to take a novel strategy into patients. And our investigator has been fantastic. You've seen Dr. Yap talk many times before. He's been an amazing partner for us in this. And so the investigator community has been incredibly supportive. And it's why when we project that we'll be able to get 20-30 patients in each of these arms before the year is up, we're very confident that's not us. That's our investigators, very excited about that early data that we published last fall. To get into a little bit of the nitty-gritty regarding the regimen itself, thinking about tolerability, dosing, dosing schedule. I think you're now doing a three days on, four days off. The watchword here is watching the bone marrow, looking to see if we're going to get any anemia in particular. Talk to us about that schedule and any other strategies that you're doing as far as executing on the clinical plan here to try and help mitigate the risk of some of these developments here. Yeah. So I just want to emphasize that when we published last fall, the overall tolerability profile for this combination, admittedly, we had just gotten to RP2D and limited number of patients at RP2D, the overall profile was phenomenal. I think anemia was the only heme tox signal that even kind of showed up. And you compare that to other DDR agents, certainly to chemotherapy. I mean, we weren't seeing the kind of things that we were seeing in a lot of competitive regimens. That said, I think Maria and the team and our investigator partners did a fantastic job of just sort of saying, okay, how do we understand how to introduce a tailored schedule, which has precedent? Niraparib does this, which based on the entering hemoglobin level allows the physician to give an extra week of holiday for the drug in the base regimen. It's a small proportion of patients who are coming in with that very low hemoglobin level. Remember, these are incredibly beat-up patients, 3-4 lines of prior therapies, many of them more than that. And so it's not surprising that they're coming in with that state of hematological affairs, so to speak. And what we saw, and this is the data that we shared just in May, is that we were able to almost completely overcome any concerns that we had, and they were minor. They certainly weren't concerns of our investigators about anemia. And I think, again, step back, the overall tolerability profile now, I think, is beautiful. And we're solely focused now on efficacy measures as we share our data in the fall. Okay. Because you had previously talked about a low hemoglobin protocol for those patients, two weeks on, giving a week off to rest the bone marrow, so to speak. How much is that being invoked in sort of the clinical development as it's playing out now? Yeah. So in what we shared in May, what we said was that the spread of entry-level hemoglobin was the same as it was. I think we used the word perfectly analogous to what we shared in the fall. So it's not like we were seeing a lot less of those patients. In fact, quite the opposite. We just aren't comfortable ethically and in terms of how we work with our investigator partners to start eliminating whole swaths of patients who are coming in with low hemoglobin. And so the team, if you recall, I think last year at this conference, Maria talked and said very comfortably, this is what we're going to do, and this is how we're going to solve the problem. And not unusually for Maria, she was exactly right. So I'm used to that. I think just for our patients, we were just so pleased that this was the solution to ensuring that we could bring the broadest set of patients who need our drugs into our clinical trials. Makes sense. Let's shift over to camonsertib, RP-3500, ATR inhibitor. This is the lead asset from the story around the time of the IPO. It had a bit of journey in terms of a partnership with Roche. You now have that fully back in. Give us an update with, since it's been back in the fold, how you've thought about perhaps directing the strategy from the next steps of clinical development. Obviously, you're paying the bills, but then that probably forces more conviction that's needed in terms of taking those steps, right? I think the $185 million we got from Roche for what's now a wholly owned program allows us to continue to pay the bills very nicely. But maybe if you pull the lens back, you'll recall, and we sat here with you years ago when we published our initial monotherapy data at AACR in 2022, we had a very interesting signal with our 16 genetic alterations, including ATM loss in ovarian cancer. And I think for us, that was early, early POC of the monotherapy potential. We very shortly thereafter partnered the drug with Roche. Roche, in its wisdom, completely shifted to a much broader combination, IO combination, PARP combination strategy, which was appropriate for large pharma. And that's where they spent the next two years really investing their energy and capital. Now as the program has come back to us, we're a biotech company and we're unlikely to do global multi-hundred patient phase II trials to get a signal similar to what they were looking for. So we've gone back to what companies like us and what biotech does best. Where's the narrow, exciting signal and small indication that we can get clear proof of concept in a fairly rapid way? So just this morning, we announced, remember, we got this back May 7th. We announced this morning that we have first patient in our ATM loss, non-small cell lung cancer, which is a massive market. And we are going to try to reaffirm in roughly 20 patients in fairly short order whether or not we have a signal that we saw in a much smaller set of patients with ATM loss amongst the many monotherapy signals that we think are there. The backdrop, though, is also really cool when you think about ATR inhibition. It's not lost on a lot of investors that Merck Serono and more importantly, AZ are pouring considerable investments into their ATR inhibitors, which we know from history, we are pretty certain based on published data that we have the most potent and cleanest ATR inhibitor out there. And they're pouring a ton of money into their respective, well, in the case of AZ, it's Durva. In the case of Merck Serono, it's in combination with Regeneron's PD-L1. This is really heating up in terms of that combination, which is a, you're talking about very, very large markets. And Merck Serono is plowing ahead with their ATR inhibitor in PARP combinations, which is also a pretty compelling, from a biological point of view, compelling opportunity. So we've said on May 7th, when we took the asset back, we said we're going to run down the seam that we as a biotech company can best run down. And that's laser-focused monotherapy, fast signal, a clear definition of opportunity and POC. And in parallel, we're going to explore collaborative opportunities. And if people know anything about us, it's that we know how to do a business development deal. And we're going to see where the opportunity is. I think it will mean that as AZ and Merck Serono publish what I hope for the benefit of patients everywhere is good data, that the realization of we have a phase II compound with over 450 patients of data monotherapy and combination therapy, that we've got a phenomenal asset that we just have to figure out how to reposition it post-Roche. Yeah. No, I was flying out to AACR and Kim Seth, your head of business development, was sitting in the row right behind me. So I felt like he was looking over my laptop the whole flight. And then I kept on bumping into him at the Hyatt Manchester in San Diego. We're crossing paths. So he was working hard. So just to be rest assured that absolutely accurate in terms of Repare. With the STEP2 mutations, the 16 STEP2 mutations, talk a little bit about that, because we made reference to that at the beginning, how your proprietary platform allows for potentially prosecuting a broader TAM there. What should we know? Yeah. So I think we published, and I was asking Robin this morning, I think there's at least 11 STEP2 mutations where we've shown either molecular or actual responses suggesting that we've selected the right ones. We didn't get to completely prosecute that work because our Roche partners, when they were our partners, shifted the focus, right? So we're back to where we were focused, which is looking at those 16 STEP2 mutations. We're starting with ATM loss, but we are deeply observing others, both in the work that others are doing and in the data that we have that we're still analyzing because we hadn't really thought about our monotherapy work since we partnered with Roche in, I think it was May or June 2022. Okay. Polθ, let's talk about that a little bit there, RP-3467. How's Polθ feeling since camonsertib came back home to live? It's like our children. Exactly. It's like the boomerang. It's just like, didn't you get your master's? I am just so excited about the Polθ program. And I mean, from one perspective internally, we have said to several folks, we think we've got lightning in a bottle. Why? Our preclinical data, which Mike has shared a couple of times now publicly, in combination with RLT in unselected models, in ADCs and both PARP1-2s and PARP1 selective agents, has just, it's been about as good animal data as any of us have ever seen. And not only is the data really compelling preclinically, but there is virtually no additive tox, right? So it's very rare in a world that's increasing. You're spending a lot more time with your cancer companies talking about combination agents. Inevitably, you start talking about, okay, well, what kind of tox are you adding and are you creating a very, very narrow therapeutic window? The data Mike has shared has really, really wonderfully shown that in three, as we know, massively growing opportunities, or at least two of them are massively growing opportunities. PARP is a different thing with PARPs coming off patent and PARP1s getting a lot of energy. We've got an agent that combines really nicely, really, really pristine preclinical data. We're pretty excited about getting this into the clinic in the second half of this year, which is very much on track and playing a role in what we believe is going to be a very large, very competitive marketplace across RLT, ADCs, and PARP combinations. Remind us who else has been tackling Polθ. And I say this in part because often with these novel difficult targets, the stocks all perform well when somebody succeeds. It's like someone threw a little bit more in the tank and all the boats lift a little bit, right? There's plenty of opportunity to go into the Wall Street zero-sum game mentality of like, okay, fixed pie, who gets what portion of it? When you're at this level of exploration and really going after novelty, there's benefit to that. So just give us a sense for Polθ's ecosystem. Yeah. So GSK with a compound that they licensed from IDEAYA have an early phase I compound. So they're a little bit ahead of us. They're targeting the same enzyme. In Polθ, we are. Artios, a private company, has a Polθ compound targeting the other enzyme, which it's polymerase targeting. In our hands, we just couldn't make that work in our preclinical models. So we're informed that, but we don't know for sure that AZ has a program. We think there are probably two or three more of them out there. But with more and more pharma in RLTs and ADCs, many of them targeting the same targets, it's not a surprise that they're seeking differentiation for how they approach those. So our goal, head down, data-driven, we want to generate the data for safety data, of course. And then I think the likelihood is we'll go into PARP combinations first because we can, because we can do it in our laser-focused productive way and get the answer out there from a data perspective on Polθ combined with PARP inhibition is probably the first order of business. That could change depending on BD factors. We've got a pretty active set of conversations, and we were clear when we came out with that program that this was likely going to have a collaborative dimension to it, given that we don't have RLTs and we don't have ADCs and we don't have a PARP. So I would say watch this space very closely. Yeah. No, and I brought that question up in part because in our ecosystem, I think to the extent that you can capture the attention of the investor community and sort of say you're one of the players in an area that's getting warmer and warmer and more attention, that can be helpful. Anything to generate eyeballs around this. And we've certainly seen that between Mike and Maria. You have incredible tenacity and focus with your team, chief scientific and clinical development officers there. And so I'm glad that you guys are focused on the work, but for the stock, I think often just raising your hand and being able to sort of say, we're also navigating this swimming pool over here can be valuable. So I'm glad you humored me there. I appreciate that. I should ask you on the stock. I should ask you what the stock reaction is going to be if we beat the bar that you guys set for us in ovarian endometrial? Yeah. You know, I think there is this sense with many of the companies that are doing sophisticated platform-based work and have managed to graduate to the point you have multiple assets in the clinic. And then you look around and you should feel so proud. It's like having three kids in college. But why is it that the investor seems to have a deficit disorder? It's very important to have a lead steer, a singular shiny object that people, for better or worse, usually for better, for at least attracting inflows, et cetera, and attention to have something there. So if you can achieve that, then I would certainly say that that's a flag worth waving and really being the sentinel aspect of your platform. And then it becomes a virtuous cycle of people getting, can they do it again? Is there more behind that? So I think that'll be a very important moment. Remind us of the timelines for that catalyst. That's fourth quarter. That's endometrial ovarian fourth quarter this year. Okay. Terrific. So within the calendar 2024, folks, we all get measured by performance by 2024. So keep this ticker in mind. Lloyd, always good to see you. Thank you so much for joining.