Okay, yeah, great. Let's get, let's get it started here as we're right at the top of the hour, or half-hour mark. But thanks, everybody, for joining us here at Piper Sandler Annual Healthcare Conference. I'm Joe Catanzaro, one of Piper's Biotech Analysts. It's my pleasure to kick off this session with the team from Repare Therapeutics. We've got Lloyd, CEO; Mike, CSO; and Maria, CMO. Always great to have you guys. Obviously, a fair amount to discuss in these next 25 minutes, but maybe first, I could give you a minute or two. You could sort of give an intro to the company, what you guys have been up to, and what we have to look forward to. Great, and thanks for having us, Joe. We always love to come to the Piper conference. Repare Therapeutics is among the leading, if not the leading, small biotechs, clinically in the precision oncology space and focused on synthetic lethality and DNA damage repair medicines. We were founded in 2016, and virtually everything we do, and everything we've put into the clinic and lined up for the clinic is built off our platform, which is a CRISPR-enabled system that's proprietary to Repare, that allows us to identify not only very high potential new targets for synthetic lethality, DDR, genome instability drugs, but allows us to overlay that once we've got chemistry on how to select patients that are going to be far more likely to respond to those drugs. Ultimately, that's what makes us a very differentiated Precision Oncology company. It's allowed us to fill our pipeline with these Precision Oncology drugs. Most advanced drug, as you know, is our ATR inhibitor, camonsertib, which we think is the best-in-class compound. Almost two years ago now, we had great data in Phase I ovarian cancer that we shared. It seems like a lifetime ago. We subsequently partnered that program with Roche. Roche now owns camonsertib globally, except for a carve-out for us for our second drug, which is a PKMYT1 inhibitor. We were the first in the clinic with a PKMYT1 inhibitor. We think we have a best-in-class PKMYT1 inhibitor that is now in the clinic. We showed at ENA just recently in October, really phenomenal data with a combination of, It's called lunresertib with camonsertib, and that's a proprietary combination to us. We carved out of the Roche relationship. That data was, very, very small numbers, as you know, but spectacular, potential there. We had, among 10 women with gynecological tumors at the, RP2D, a 50% RECIST response. So as you might imagine, we're pretty excited about the potential there, and we're, certainly digging in to see how that, plays out over the next couple of three quarters. And then, to finish off, we just announced a week and a half ago two new compounds going to the clinic, a PLK4 inhibitor, which will be first-in-class, and we think potentially best-in-class, and a Pol-theta inhibitor a little later next year, which again has all the profile that we look for as a potential best-in-class compound. So Lloyd, I think I ask you this every year about sort of DDR synthetic lethal space and where sentiment lies. It feels like it's a space that's seen its ups and downs, so I want to just sort of ask you where you think it stands. And maybe relatedly, one thing I've been thinking is it seems like these next-gen DDR inhibitors, and I know we'll talk about this, is sort of combination strategies is where everything seems to be heading. Maybe just sort of your overall thoughts on that as well. You know, I think the story is in its first couple of chapters still, despite the dramatic success of PARPs, and even the emerging new PARP1s. I think like everything, the hype early in a new technology generates a lot of excitement, but cancer drug development and drug development as a whole, it's hard. And inevitably, you learn things in the clinic that remind us to stay humble about how drugs are developed. And it doesn't mean they're not incredibly promising. I've yet to hear of a drug that was literally a layup or a three-point shot from, you know, mid-court. It just doesn't happen in drug development. I think as DDR drugs emerge, you know, we're just regressing to the mean of these drugs. But the excitement about synthetic lethality and these kinds of drugs we're developing, if anything, is at a high point, and I think it's why our peer group has been able to invest so much in these emerging drugs. And they include the things in our pipeline, but you know, multiple other synthetic lethal drugs being developed by other companies, and more recently being bought up by pharma, which is always a good sign of the emerging confidence, you know, us with Roche, but other in, you know, USP inhibitors and other synthetic lethal agents with other pharma. Perfect. So, so maybe with that, we could jump into lunresertib. You mentioned you guys were first into the clinic with a PKMYT1 inhibitor. Seen a couple data disclosures for you guys over the last year. I guess as of right now, with, with the early data you have, what do you think we know about PKMYT1 as a target, and maybe how it compares, contrasts to other sort of DDR targets? I'm happy to take. I think, you know, we're really excited to see that, with 6306, lunresertib, we've been able to go in, modulate the target, and see the level of biomarker engagement that we were looking for, as well as the initial activity that we saw as a single agent. And ultimately, really understanding kind of the, how do I put it? The complexity of the pathways and maybe the need to hit that pathway in more than one way, i.e., with the ATR combination, giving then much more profound data, in that early release that we just had, about a month ago. I think when you compare it, one of the things that's maybe the most interesting and is still emerging was the toxicity profile seemed to be more single lineage, predominantly, the red blood cell lineage, as opposed to seeing this pancytopenia that you would see with a lot of the other DDR agents that have already been used. I think that's been offering the ability to be able to combine in a different way, and to be able to move that forward. But there's still a lot of, I think, you know, data that's left to emerge for all of these agents and to figure out the best way forward. Is there an understanding of why, and whether we've seen this before, why it's sort of single lineage effect, and why it's just red blood cells, and you don't see platelets and neutrophils? Like, again, other DDR inhibitors sort of see this broad myelosuppressive effect. Yeah, I think, you know, I'll have Maria chime in as well. But I think at the end, it looks like it's a later progenitor or a later stage in the development of the hematopoietic system. The other agents were hitting what looks to be an early progenitor, if not the early hematopoietic stem cell itself, that causes a multi-lineage effect. With ATR, we had found that it was really in effect late in that development stage of the red blood cell, and that allows for a rapid, you know, reconstitution of the red blood cell compartment, and a lot more flexibility in dose and schedule. But I think it's just really about where in that lineage you're hitting. Got it. Maybe sticking with sort of PKMYT1-related safety, I think one thing you guys disclosed, which it sounded like it was expected per the preclinical, was rash. Just wondering where you're at in terms of understanding the mechanism there. And then, as I was sort of thinking about the combinations that are going on, I think rash is also something that's seen with gemcitabine, and whether there's some how you guys are sort of managing that within the context of the ongoing combination trial with gemcitabine. Right. So the rash indeed was our original toxicity observed with PKMYT1 inhibitor, lunresertib. And very important to note, it's apropos your previous question, that we did not observe anemia much with the monotherapy. The anemia is a feature of the combination therapy. So back to the rash. Rash was observed in our initial studies, where we dosed lunresertib continuously daily, and then we observed that very short breaks of lunresertib relieving the patient from the rash. The rash is resolved. So then, when we look back at the preclinical studies, we discovered that intermittent doses, three days on, four days off, is not different in efficacy versus continuous dosing. So this was very convenient for the management of rash. Regarding the pathogenesis of the rash, we have two very prominent consulting dermatologists who are helping us understand the rash, and we also have about 12 or 15 skin biopsies of the rash to see what is the histological pattern feature of the rash. And what we are diagnosing, the dermatopathologist, is that it is indeed erythroderma similar to what is observed with chemotherapy, either gemcitabine or capecitabine. And the clinical picture of the rash is dramatically different from the MAP kinases or TKIs that is also characterized with rash, like RAF inhibitor, etc. So what we believe now is that it is indeed erythroderma chemotherapy-like, consistent with the pathology picture. But the good news is that by the introduction of the intermittent schedule, we were able to alleviate the rash to minimal frequency, and the rash is not grade 3, it's grade 1 or 2, and it's transient. Perfect. So, so I maybe want to shift to the combination of lunresertib and camonsertib. Just saw some data from you guys a month or so back. Maybe leave it high level, and then we'll sort of dig into some specifics. But what do you see as the most important takeaways within this early data set? And I could give that to you, Maria. So for the combination, the most important and satisfying is that we were able to confirm the preclinical hypothesis, that combination of PKMYT1 inhibitor and ATR inhibitor, with the very detailed scientific rationale for the combination, was able to be confirmed in clinic. How the confirmation looked is that the monotherapy lunresertib has minimal single-agent activity. When you add ATR inhibitor at half of the doses for monotherapy, you see this miraculous response rate, as Lloyd mentioned, 50% at RP2D in ovarian cancer, for example, or gynecological malignancies, and we have a couple of responders in other tumors as well. So this is a true synergy because the ATR inhibitor is given at 50% of the dose. Remember that the population of patients where the combination is employed is CCNE1 amplification, FBXW7 and PPP2R1A deleterious alterations, which are homologous recombination proficient changes, where ATR inhibitor as a agent for homologous recombination deficient tumor is not supposed to have any efficacy, and we confirmed it, lack of the efficacy. So this was the most satisfying scientifically and for patients because of the high response rate and very good safety. So, maybe speaking to safety, so I think people saw the rates of high-grade anemia sort of stood out to them. To me, I saw that as sort of validation of the, of the mechanism. But I think you guys had spoken to sort of opportunities to potentially bring that lower. What are you doing there, and ultimately, where do you think is a reasonable rate of isolated high-grade anemia? Right. So, critically, I would like to repeat your word, isolated. This was only a Grade 3 toxicity that we observed in significant number of patients with Grade 3. There were no Grade 4. And further, there were no discontinuation due to anemia, which tells you that the anemia was, despite the fact that it was a Grade 3, it was a reasonably well-tolerated side effect. And then, let's understand better the 40% anemia. Because the drug combination is very active, patients are receiving the combination for a very long time. We have patients close to a year on a study. And then how we are calculating the 40% number is we are counting, did the patient during the study have Grade 3 anemia? So if the patient had grade 3 anemia in month seven, the patient counts towards the 40%, okay? So the anemia is not, the 40% is not that every patient in week three has anemia. It is during the very long observation of this study. So that's point one. Number two, never any discontinuations. Number three, this is a insidious toxicity that doesn't occur suddenly, so the patient can be prepared. The patient knows that the anemia is a toxicity expected, and it is manageable, and the management is a discontinuation of the combination for, let's say, a week. Because it is a late-stage injury to the progenitor cells, if you stop the drug, the progenitors continue to progress, and therefore, the anemia goes away within a week. So if you compare that with other compounds, such as PARP inhibitors, or for that matter, CDK4/6 inhibitors, or for that matter, chemotherapy, the frequency, for example, with talazoparib of grade 3 for hematological toxicity in the label is in the range of 38% monotherapy. If you look at the early data for from Phase I study, which is our number, it is 55% grade 3, 4. If you look at ribociclib, the frequency of grade 3 for neutropenia is 70% in. Why is it just a number? Because the neutropenia and the anemia is in some way inconsequential, because the patient can still be treated, and the patient can tolerate it reasonably well, and we know how to manage it. So you know, it's 40%, back to your question, it's 40% a number that I love? No. Would I like to get it down to 20, 25? Yes. And we have the one left over task in our trial now, is to confirm that the regimen that we are proposing and the way to manage is successful, and that we'll be able to decrease the anemia. Yeah. So maybe that's a good segue and sort of half answers a couple last questions on the combination of lunresertib, camonsertib. Sort of where are you in selecting a move forward dose? When does that happen? And then sort of relatedly, have you sort of settled on how these expansion cohorts can potentially be designed, tumor type versus biomarker versus something else? Right. So we do have a dose that's stated. The only question that we continue to explore is where to incorporate the week off. Should we incorporate the week off therapy to every patient, or should it be in some way individualized on demand? And this is the experiment that we are performing now. With regards to expansion, we started the expansion in multiple settings. One is to ask the question whether specific alterations such as FBXW7 or CCNE1 amplification is something that we can explore pan-tumor, because as you saw at the end of presentation, we had responses across the alterations and across the tumor. So we have to follow up on the question, ask the question, is this a drug specific to alteration, or is it a drug specific to the tumor? Obviously, the tumor of major interest is gynecological malignancies, because this is where the concept is already proven, but we are also looking at others. So I mentioned sort of at the top, right, this idea of combination strategies seem to be the way a lot of DDR inhibitors going, and that seems like the strategy you're taking for PKMYT1. So beyond camonsertib combo, you have the FOLFIRI and gemcitabine, and a couple others in the works. Maybe you could speak to the type of data we could expect to see for these other combinations in 2024. So the other studies with gemcitabine and FOLFIRI are Phase I studies, and we are about to complete those studies shortly. And this will be basically mostly safety and tolerability, to see whether the drug is combinable with the combination. As you know, we are trying to use. For example, for FOLFIRI, we are trying to use the recommended FOLFIRI dose, so interpretation of the efficacy in the phase I study is very, very difficult. So the planned release of the data disclosure will most likely incorporate just safety and tolerability, and show how different it is from the combination with camonsertib, rather than interpretation of efficacy. So maybe last one on lunresertib, and then we could try and cover some of the other assets in the pipeline. And maybe one for you, Lloyd. I guess, how do you think about the long-term strategy for lunresertib versus what you did for camonsertib? I remember for camonsertib, the idea was, you know, there's a lot of different ways you can go. It's gonna take a lot of resources and effort, and Roche is, you know, much better positioned to fully explore that. So, I mean, how do you sort of compare and contrast that versus what lunresertib has on track? Yeah. Great question. I can answer it in part, but obviously, we haven't, until we share all our data, it's harder to dig in. But the short answer, Joe, is, you know, at this stage in its development, it was pretty clear to us that the footprint for properly developing camonsertib was such that we needed a global partner's heft and balance sheet. That's not yet clear to us in lunresertib. As the data plays out, as Maria described, there may be, and we are obviously hoping for this, themes that we can run into ourselves and, you know, chart a path to registration that is credible for a company at our size and stage of development. That's always the goal, but as you know from our history, we're always ready to partner things if that's the highest and best prosecution of that drug for patients and shareholders alike. Great. So maybe with that, we could shift to the rest of the pipeline. I actually want to start with Pol- theta, which you guys disclosed a couple weeks back. And I guess maybe where we could start there is sort of the rationale behind targeting the helicase domain versus other Pol- theta that are going after the polymerase domain, and what's some of the work you've done to sort of, you know, delineate those two approaches. Yeah, absolutely. So I think upfront, both of those domains from a biological perspective, we found the different genetic experiments and ultimately, the pharmacology experiments were giving the same results. So it didn't, we don't think it matters which domain you go after from a biological perspective. But what we found when we created a polymerase inhibitors is that we had this incredibly large falloff from the enzyme assay into a cell, be about 2000-fold plus or minus. And really, this just created a challenge in being able to create the best drug possible, i.e., the potency falloff meant you were in that, you know, triple-digit nanomolar range and near micromolar. And so to combine that to get the right drug was very challenging. At least with the other polymerase inhibitors that we know of out there, we believe that they all bind in the same way and have the same problem. With the helicase, we found a much more normal falloff into the cell, like you would see with any other traditional agent. And that really allowed us to get down to this really ultra-potent inhibitor with RP-3467 that we talked about just the other week. So with this asset, too, I think you guys highlighted, you know, a lot of opportunity to combine it with chemotherapy, ADCs, radioligands, PARP. For PARP, PARP inhibitors. Maybe for you, Maria, I guess, like, you know, how do you get to the quickest path towards validating that combination potential? What is your experience with lunresertib and the combination strategies? And I'm thinking more in terms of like clinical strategy and how trials are designed. And whether you have a preference for which combination you'd sort of go after first? So we did not reveal our clinical strategy, although we are working on it day and night, so do a very efficient one. So the Pol- theta inhibitor that we have, we think is characterized by extreme potency and very good safety profile. And we have it proven by several animal studies. So what it means is that we probably, with this particular agent, can start the, for efficiency, start at a very high dose, so that the dose escalation that usually happens does not have to occur or is minimized. And then we have to choose a partner, because we have the array of choices. We can do ADC, we can do PARP, we can do chemo, we can do anything. You know, we need to be practical about it, and we probably will start with the data, the strongest and the simplest, which is combination with PARP inhibitor. And try to then, again, without going into detail, try, try to solve the question of, does it work in PARP failure, which would be the easiest clinical development, or should we go for where really the unmet need is, where, where the PARP inhibitors do not fulfill the survival benefits for patients? Perfect. So maybe in this last 30 seconds, the other sort of asset you disclosed was a PLK4 inhibitor. Maybe just talk through whether, where this project started. Would it come at it from a PLK4 angle or from a TRIM37 sort of screen angle that uncovered PLK4 as a relevant target within that genetic background? Yeah. So in actuality, this came through our network in the DDR, academic arenas, where we actually found this through a collaboration through interaction with the key investigators that wrote the two nature papers, and we're able to bring that in-house. So I think, you know, this didn't come off our platform specifically, but we have been using the platform, of course, to help understand the target and to expand out patient biomarkers. Perfect. Well, with that, we're at our time. I wanna thank Maria, Mike, and Lloyd for their time, and thanks, everybody, for joining. Take care. Thanks, Joe.