Thank you for standing by. This is the webcast operator. Welcome to Repare Therapeutics Investor Update on its initial phase I data from its first-in-human phase I study of lunresertib, or RP-6306, also known as the MYTHIC Study. Please note that this webcast is being recorded. All participants are in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by 0. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your telephone keypad. To withdraw your question, please press star then two. Please note this event is being recorded. I would now like to turn the webcast over to Steve Forte, Executive Vice President and Chief Financial Officer. Steve, please go ahead. Good afternoon. Thank you for joining us today for our review of the initial results of the ongoing phase I MYTHIC study of RP-6306, now known as lunresertib. Today's presentation will begin with introductory comments by our President and CEO, Lloyd Segal. Dr. Mike Zinda, our Chief Scientific Officer, will provide background on our wholly owned candidate, lunresertib, including mechanistic rationale and select preclinical data. We are pleased to welcome Dr. Timothy Yap of the University of Texas MD Anderson Cancer Center, the principal investigator on the MYTHIC study, who will be presenting top-line monotherapy data from this study. Dr. Maria Koehler, our Chief Medical Officer, along with Mike, will provide preclinical data supporting the rationale for the ongoing combination study of lunresertib with camonsertib, which is one of our multiple combinations. This will, they will also provide some insights of emerging clinical data on this trial. We will then finish our presentation with some concluding remarks from Lloyd and Maria. Today's presenters, Lloyd, Mike, Maria, and Dr. Yap, will be available for Q&A after the prepared remarks. Due to time constraints and to ensure equitable participation, we would kindly ask that you limit yourselves to one question and 1 follow-up. Before we begin, I'd like to remind you that we will be making forward-looking statements during the call. Various remarks that we make during this call about the company's future expectations, plans, and prospects constitute forward-looking statements for the purposes of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are based upon our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and stage of development. There are a number of reasons why our results may differ materially from these forward-looking statements. We refer you to our latest SEC findings, where you can find a more detailed discussion of these risks and uncertainties. In addition, any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent date. We may elect to update these forward-looking statements in the future. While we may update, elect to update these forward-looking statements in the future, we specifically disclaim any obligation to do so, even if our views change. As a reminder, the audio and slides from today's event will be made available on our website later today. I will now turn the call over to Lloyd. Thanks, Steve. Welcome to today's conference call. Repare is a leading clinical-stage precision oncology company focused on synthetic lethality, genomic instability, and DNA damage repair. We're proud to have built a highly differentiated pipeline of product candidates using our proprietary SNIPRx and STEP2 platform technologies. Our focus today is to discuss lunresertib, which is the second internally discovered program that's come off of our platform and that we've brought into the clinic since our 2020 IPO. We're pleased to have this opportunity today, thanks to the efforts of our team and collaborators, to share initial Phase 1 data on our first-in-class PKMYT1 inhibitor, lunresertib, which exploits vulnerabilities caused by increases in Cyclin E1 and was not previously targeted in cancer, absent our insights. We identified a potent and selective drug candidate that demonstrated antitumor activity in tumors with specific molecular alterations, with enhanced effect when lunresertib was used in combinations across a number of tumor types with high unmet medical need. With this background, I'm happy to hand the presentation to the other presenters today, who will show you how our preclinical findings consistently translate to the clinic and share a differentiated safety and tolerability profile, along with the clinical proof of concept for lunresertib. Thank you, Lloyd. Our goal for the ongoing and first-in-class phase 1 lunresertib monotherapy study is to understand safety, tolerability, and PK/PD, which will provide important insights into future development. As an intro to the clinical data, I will remind everyone of the synthetic lethal patient populations where we are investigating PKMYT1 inhibition and provide context from our preclinical work to put the clinical data into perspective. When CCNE1 is amplified, it drives early entry into S phase of the cell cycle, resulting in genomic instability. Patients with Cyclin E1 amplification have a poor prognosis and typically do not respond well to standard of care therapy. It was these key features that drove our decision to screen for novel targets that are synthetically lethal with Cyclin E1 amplification using our SNIPRx screening platform. Our screening efforts identified PKMYT1, a key target that is synthetically lethal with Cyclin E1 amplification. The linkage between PKMYT1 and Cyclin E1 amplification was not previously published. We are the first to advance drug discovery efforts against this target to the clinic. As published in Nature, we found that PKMYT1 plays a critical role in inhibiting Cyclin E1 amplified cells from prematurely entering mitosis prior to completion of DNA replication and drives synthetic lethality when inhibited in this setting. As we demonstrated with our ATR inhibitor, there is often a network of genes that can be synthetic lethal with a given target. With this in mind, we applied our STEP2 screening process to identify the synthetic lethal network for lunresertib, our PKMYT1 inhibitor. These screens identified FBXW7 and the PP2A phosphatases, of which PPP2R1A is mutated in cancer. FBXW7 is an E3 ubiquitin ligase that targets proteins, including CCNE1, for degradation. Inactivating mutations in FBXW7 can increase Cyclin E1 levels and drive sensitivity to PKMYT1 inhibition. PPP2R1A is believed to be important in the response to replication stress. Therefore, inactivating mutations can increase replication stress and drive a dependence on PKMYT1 inhibition. Our STEP2 platform enabled us to broaden the scope of patients included in our clinical trials by recruiting patients with Cyclin E1 amplifications, as well as inactivating mutations in FBXW7 and PPP2R1A, using standard NGS panels. When we look at the prevalence of these genetic alterations across the top tumor types, there are roughly 65,000 patients in the EU4, UK, and US eligible for annual treatment. Across all tumor types, the eligibility for patients increases to roughly 90,000 patients, leading to a substantial addressable patient population for lunresertib. Notably, these lesions are largely mutually exclusive and represent distinct populations. In preclinical assessments of PKMYT1 inhibition as monotherapy in vivo, we demonstrated dose-dependent tumor growth inhibition to stasis, was achievable in both continuous and intermittent dose regimens. This demonstrated flexibility on scheduling if necessary clinically. In the model studies to date, monotherapy did not result in tumor regressions. Mechanistic combinations that synergize with PKMYT1 inhibition in key genetic backgrounds were necessary to drive deep regressions in preclinical in vivo models. Finally, to inform our clinical biomarker objectives, we investigated the correlation between pharmacokinetic, pharmacodynamics, and efficacy across a range of Cyclin E1 and FBXW7 xenograft models. In particular, we looked at the inhibition of threonine 14 phosphorylation on CDK1, the direct substrate of PKMYT1, and the induction of γH2AX, a key measure of downstream DNA damage driven by PKMYT1 inhibition using our clinical IHC assays. This work demonstrated that we needed approximately 50% reduction in threonine 14 phosphorylation on CDK1 and approximately 2-fold induction of γH2AX by IHC to drive maximal efficacy in these preclinical in vivo models. This level of γH2AX induction is similar to the induction level seen clinically following inhibition of ATR and PARP inhibitors at efficacious doses. These same assay endpoints have been used to confirm the activity of lunresertib clinically in paired tumor biopsies. I will now hand the presentation over to Maria Koehler, the CMO of Repare. Thank you, Mike. Based on the extensive preclinical and translational work, we were confident that entry to the clinic was the right next step. As the first-in-class program, there were many unknowns in the phase 1 study. We enrolled patients with recurrent solid tumors who exhausted known options for treatment. All patients in our study must have tumors with CCNE1 amplification or alterations in FBXW7 or PPP2R1A. The program was initiated in April 2021 as monotherapy, rapidly progressed to multiple combinations, as listed here. You will appreciate that consistent with our preclinical data, we continue to expand our combination program with new studies. We determined in the monotherapy study the proposed phase 2 dose for monotherapy, as you will hear from Dr. Yap in a second, are well on the way to achieve the same for other combinations, with aggressive plans for further development, as listed. With that, I would like to introduce Dr. Timothy Yap of MD Anderson, our distinguished guest and principal investigator of the MYTHIC study. Dr. Yap will be available for questions and answers following our presentation. Tim? Thanks very much, Maria. Good afternoon, everyone, and thanks for being here. Before I begin, I'd just like to quickly call your attention to my disclosures as listed here. Today I'd like to speak about the clinical experience with lunresertib, with a focus on the monotherapy portion of the MYTHIC study. I'm the PI on this first-in-human study investigating lunresertib in patients with advanced solid tumors harboring CCNE1 amplification, or FBXW7, or PPP2R1A genomic alterations. It certainly worth noting that we are always excited about new targets, as you can imagine, especially those that can serve patients with minimal toxicity, as you will see here. The MYTHIC study is an ongoing first-in-human study of lunresertib, initiated in the spring of 2021. As of the data cutoff of April 28... 2023, MYTHIC Module I has enrolled 63 patients, adult patients with solid tumors who are resistant or intolerant to standard therapies. All patients have tumors with centrally reviewed CCNE1 amplification or deleterious alterations of FBXW7 or PPP2R1A that were hypothesized to be sensitive to PKMYT1 inhibition. ECOG performance status zero, one, or two, and hematological values as stated in the slide. The primary endpoints of Module I are safety and tolerability, as well as a recommended phase II dose and schedule. Patients were treated with escalating doses of lunresertib alone with various schedules, and the study also includes Module II to test the combination of lunresertib with camonsertib, an ATR inhibitor. We plan to report the detailed results of Module II at a scientific meeting later this year and are preferentially recruiting in this combination currently. Additional endpoints for MYTHIC included pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity, such as circulating tumor DNA. The trial includes comprehensive biomarker analyses to provide a more complete picture of lunresertib anti-tumor activity. The three genes targeted for inclusion criteria are available on standard NGS assays that were then centrally analyzed for copy number variation, IHC and FISH. Direct phosphorylation of threonine 14 on CDK1, which is a phosphorylation site specific to PKMYT1, delivers evidence of PKMYT1 inhibition and importantly, proof of mechanism. γH2AX is a digital marker and an indicator of DNA damage or proof of principle. Baseline levels of γH2AX are typically 4% to 10%. If an agent causes more DNA damage, γH2AX may go up approximately 40% to 80%. For example, in the case of olaparib, one study showed that the number of cells increased in S-phase from approximately 10% at baseline to 30%-40%. ctDNA is another measure of anti-tumor effects, and while certain tumors don't shed, such as with 40% of ovarian cancers, a 50% or greater change in ctDNA allele fraction values is considered meaningful. Since ctDNA doesn't go down on its own, it is a surrogate for anti-tumor activity. As expected in a phase I trial, the 63 study participants suffered from diverse tumors. 18 various tumor types were represented, with the most frequent being endometrial, colorectal, ovarian, and breast cancers. The most prominent of the three enrollment mutations was 46% CCNE1 amplification, followed by 32% FBXW7 and 18% PPP2R1A. Not shown here is that 42% of patients had four or more lines of prior therapeutic failures. The study extensively evaluated various ways to dose lunresertib using adaptive dosing designs and sufficient cohort sizes to ensure robust MTD and recommended phase II dose decisions. Patients were given 500-600 milligrams of lunresertib once a day, every day, followed by 60 and 80 milligrams given twice a day, as guided by PK determination. We also evaluated intermittent doses, again, guided by the preclinical data. As you saw in Mike's presentation, cell cycle-related treatments may have equal benefit from both continuous and intermittent dosing. This thorough evaluation helped to establish two proposed recommended doses for future clinical trials. Repare started the combinations early, earlier than what most biotechs would, to achieve the anti-tumor efficacy where the mechanism was most effective. This approach is critical as we are focusing on combination therapies with various groups of other therapeutic. Each combination with lunresertib may require separate dose and schedules, and therefore it's useful to establish both a continuous daily and intermittent dose that can be used flexibly for future regimens. We gained significant experience by examining the drug performance this way. The only DLT on the trial was a transient rash. Any grade rash was reported in approximately 36.5% of all patients, but only 7.9% had Grade III, which improves quickly within 48 hours of therapy and resolves within a week. We successfully managed the rash with drug interruption, topical steroids, moisturizers, and oral antihistamines. Patients tolerated rechallenge at reduced doses, and an intermittent schedule successfully prevented Grade III rash and decreased the rash frequency overall. During dose escalation of the MYTHIC trial, lunresertib showed linear PK at daily doses up to 240 milligrams, which was the recommended daily dose. The mean half-life across the dose range was approximately 9 hours. The figures here show PK at the dose levels we are further exploring, plotted against the target coverage that was defined from preclinical studies. This PK data supports exploration of both once daily and twice daily dosing regimens to further understand efficacy and tolerability. Clinical monotherapy data to date have shown that evaluable patients experienced, firstly, a 50% drop in phosphorylated CDK1, indicating direct target inhibition, two, approximately twofold increase in γH2AX, which is a commonly accepted signal of DNA damage, therefore a signal of antitumor effect. These data confirmed that the PKMYT1 mechanism of action in clinical biopsies and allowed the conclusion that lunresertib acts as expected in human tumor biopsies. This is likely the most important slide in this presentation. The safety profile of lunresertib was most unremarkable, with a very favorable tolerability profile. Importantly, you will appreciate that the safety and tolerability of lunresertib monotherapy is distinct from other cell cycle inhibitors in the clinic, as you heard at ASCO, and this difference is critical both to the acceptability of this new mechanism of action for patients with cancer and in the context of planned combination development. The data presented here include all 63 patients on the left, as well as the subset treated at preliminary recommended doses. This is important for phase I studies, as the all patients profile may be misleading in phase I studies, as some patients may be treated below the active threshold. What is important is the tolerability at the doses proposed for forward testing. Here on the right side of the table, there was no Grade IV toxicity for lunresertib. Grade III toxicities were infrequent. Manageable rash that I characterized on the previous slide was the main toxicity, followed by nausea and vomiting. It's also worth noting that the nausea and vomiting significantly improved once patients started to take lunresertib with a light meal and later in the trial when there were fewer capsules taken by the patient. We believe that it is a tolerability issue that is mostly now resolved and will continue to improve with patients dose, with food, and larger content of drug per capsule. Among the 17 patients treated with active doses, here we present a case of a female patient. She is 73 years old with metastatic recurrent uterine carcino sarcoma, with both FBXW7 and PPP2R1A alterations, and she had previously received three prior lines of therapy. This patient received the recommended phase II dose of lunresertib on the intermittent schedule, and as you can see, she had a confirmed partial response based on RECIST criteria with a maximum tumor burden decrease of -41%. Her scans showed decreases in the 3 target lesions on the first and confirmatory evaluations. Metastatic recurrent uterine carcino sarcoma is traditionally very hard to treat, with known unresponsiveness to standard therapies. The patient has been treated now with lunresertib for greater than seven months, there were patients with less than 30% decrease in tumor size among those treated at higher doses but did not reach the PR status by RECIST. However, some of these patients remain on monotherapy for greater than 11 months. The study established proof of concept in clinic for lunresertib monotherapy, confirmed the differentiated safety and tolerability profile, recommended doses, and preliminary anti-tumor activity, importantly, all in line with the preclinical findings. These learnings from monotherapy were critical to the future combination effects and efforts that, as you know, started very early in the development of this clinical trial. lunresertib appears safe and well tolerated, and as a novel mechanism, it is differentiated from CDK2 inhibitors and WEE1 inhibitors, mostly in the context of limited mild toxicity, diarrhea, and fatigue. At the proposed dose and schedule, the profile is quite benign and potentially suitable for maintenance therapy as well. Preliminary anti-tumor activity was observed, including tumor shrinkage at higher doses, confirmed RECIST partial response, and several patients with long, stable disease ongoing for greater than 11 months, which gives us confidence in the mechanism and in lunresertib. Pharmacodynamic analyses confirmed PKMYT1 inhibition and DNA damage at active doses. We established recommended schedules for both continuous 240 milligrams daily and intermittent 80-100 milligrams BID weekly. We continue to enroll in this trial at the recommended doses, but the program is now focused on the combinations. Maria will now tell you about what else is planned for the program. Maria? Thank you. You saw this slide before, and, but to further just put it in context, we just reported the MYTHIC Module I monotherapy. I would like to tell you about the remainder of the ongoing trial. We would like to today specifically mention the second module in the MYTHIC study that examines the combination of camonsertib, our ATR inhibitor, with the PKMYT1 inhibitor. Mike will review our rationale for testing lunresertib with camonsertib, which entered the clinic in May last year. Thank you, Maria. When CCNE1 is amplified, it drives cells into the S phase of the cell cycle prematurely, resulting in replication stress and ultimately genome stability. This drives activation of ATR and the dependence of the cells on PKMYT1. Both of these pathways, as shown here, converge, resulting in the inhibition of CDK1, to ensure that the cells do not progress into mitosis until the DNA has been successfully duplicated. This pathway convergence provided a rationale for investigating the combined inhibition of ATR and PKMYT1. This combination approach is particularly exciting due to the ability to go after CDK1 with a dual mechanism, not only blocking phosphorylation of CDK1 by PKMYT1, but also actively dephosphorylating CDK1, driving cells prematurely into mitosis, resulting in catastrophic DNA damage and ultimately cell death. This combination synergy specifically occurs in cells sensitive to PKMYT1 inhibition. In other words, CCNE1 amplification and FBXW7 and PPP2R1A inactivating mutations, occurs at low doses of both inhibitors. When we sought to validate these findings and observed synergy in multiple animal models, including the one shown here, which is a paired cell line of DLD cells that either have FBXW7 knocked out, where we see significant tumor regression and in fact show very little activity of either agent alone, but near complete regression with the combination, versus little to no change in the wild type cells on the left with either treatment. Again, showing the specificity for the genetic backgrounds. In summary, not only did our preclinical data provide a clear rationale for launching this combination in the clinic, but it further validated our platform's ability to expand addressable patient populations by finding additional genes of interest. Maria will now walk you through a preview of clinical data from the camonsertib plus lunresertib combination that supports these preclinical findings. Thank you, Mike. We launched the lunresertib plus camonsertib combination in the clinic in May 2022, on the basis of the data that Mike just presented. To be absolutely clear, the study investigators and Repare are planning to present the module two data, along with extended data of the module one, later this year at the scientific meeting. I am pleased to present you a very preliminary look at the early set of patients from the combination for whom the plasma DNA is available. We believe ctDNA is a good measure of drug activity, and while this data is quite limited still with regards to numbers and it's pretty early, this picture is quite compelling. Our MYTHIC trial included, as you heard, module one for monotherapy and module two for combination with camonsertib, with identical eligibility and very similar patient profile. We track the ctDNA response in evaluable patients every three weeks. While the chart on the left shows some monotherapy activity based on molecular response, the module II combination on the right part of the chart has more significantly deeper and more frequent ctDNA response, as seen by the rate of best median variant allele frequency decrease. There is obvious decrease on treatment in the mVAF in all but one patient receiving the combination therapy, with a good proportion of them having a more than 50% reduction. For those of you who follow our story closely, after AACR this year, we showed a molecular response rate for camonsertib and PARP of 66%, versus camonsertib monotherapy of 43%. The response rate you see in today's data is following the same paradigm, in the combination is better than monotherapy. Importantly, we also showed previously, at least for our TRESR study, now published in Nature Medicine yesterday, to be, that the decrease in ctDNA correlated well with clinical outcome and duration of treatment. Our ambition is to possibly change the course of disease for patients, both responses and long stabilization of tumor, stasis, with our therapies, and the reduced ctDNA burden offers a mechanistic explanation, an early preview for what is happening in these patients. On this side, you see the early preview of three case studies that were selected among the other responders, showing that indeed we are observing clinical responses by RECIST confirmed across the variety of tumor, with all the three genetic alterations that we proposed as sensitivity alterations. The first patient has difficult to treat endometrial adenocarcinoma and achieved 56% decrease in the maximum tumor burden while on therapy for seven months. The second patient with cholangiocarcinoma achieved 35% decrease in tumor burden while on therapy for close to seven months. The final patient had a maximum tumor reduction of 43%, and is ongoing on therapy for more than six months. While we won't be showing here today aggregated RECIST response, I can tell you that we are seeing other responses, not only in this combination, but in all ongoing combination with lunresertib of clinical data. I would like Lloyd to please summarize. Thanks, Maria. Before we move to Q&A, just a couple of quick concluding slides and look ahead. Starting on slide 36, based on the work performed thus far, we note that lunresertib is a potent, selective, and well-tolerated first-in-class PKMYT1 inhibitor. We're satisfied that we've established proof of concept in the clinic. Monotherapy lunresertib tolerability differentiated well from WEE1 and CDK2 inhibitors based on data we've seen to date. We recommended a range of RP-6306 lunresertib monotherapy doses and schedules, and we've seen signals of efficacy in both monotherapy and a range of combinations, virtually every combination we have ongoing. Taken as a whole, our growing understanding of PKMYT1 target, the clinical performance of lunresertib, strengthens our understanding of the novel PKMYT1 target and lunresertib performance, with substantial evidence to support continued exploration for multiple combinations enabled by our work to date. We expect to present more, as Maria noted, comprehensively, in the ongoing combination work, for which we've shared, you know, in a small way today, and will do much more so later in 2023. I think everyone took note, of Maria's description of really encouraging early responses across, our gemcitabine, camonsertib and FOLFIRI, combinations. In other words, all combinations, in multiple tumor types and genotypes. We're seeing an early efficacy signal in combination with camonsertib in tumors that would not have been expected to respond to ATR inhibition alone. That's notable, and I hope wasn't missed. Looking ahead, I just want to make sure that you are all clear on what we're guiding to near term, which is to say we're pretty ambitious about what's up ahead of us. We expect to disclose the MYTHIC, the lunresertib with camonsertib initial data in the fourth quarter. As Maria noted, we're aiming for a major medical meeting. Additional combination trials will follow and be disclosed subsequently. MAGNETIC, the gemcitabine combo, the early data from this trial is likely to be disclosed closest to the MYTHIC data. We hope to provide more specificity around timing in due course. MINOTAUR will follow that. That's the FOLFIRI combination. We note here on the slide that PMCC is going to start later this year, and that's focused on carboplatin and Taxol, and we're pretty excited about that in earlier stages of ovarian cancer and possibly other tumors where this combination we believe is active. The Canadian Cancer Trials Group sponsored phase II basket study that's active for patients' enrollment. We've been talking increasingly about the WEE1 combination and evaluating in vitro and in vivo data to assess that combination potential in the clinic. That concludes our prepared remarks. I'd like now to open the floor to the operator and Q&A. Thank you. We will now begin the question and answer session. To ask a question, you may press star then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. Our first question comes from Joe Catanzaro with Piper Sandler. Please go ahead. Hey, guys. Thanks for taking my questions and nice start to the program here. I guess my first question maybe relates to safety. Wondering if you could just elaborate a little bit on the rash that you're observing and maybe better characterize it, of whether it was acneiform or maculopapular. Did the GLP talks predict this? You know, correct me if I'm wrong, rash is maybe not something you frequently observe with DDR or cell cycle pathway inhibitors. Wondering if maybe you could speculate on the mechanism here. Thanks, I have a follow-up on the early combo data. Thank you. I will take this question. In the preclinical studies, we indeed had. As you know, preclinical studies are not very predictive of skin disease in animals. However, we did indeed, at very high doses, see some signs of rash. The rash that we obtained, observed in the clinic, any grade, as Dr. Yap mentioned, in about 36% of patients, so this is not common. We are seeing it that it's related to the exposure or dose. The rash is low, usually low grade, it is reasonably polymorphic because it can be only change in the how the skin looks like. It is like a sandpaper with no itching, no pain, no any symptoms. It's just a change in the in the touch, or it can be similar to chemotherapy-related toxicity, just like we see in chemotherapy. We have actually 22 skin biopsies from the patients with rash. Almost everybody got biopsies. The dermatology consultants are not predicting that it is anything terribly what they didn't see before. What is important, we have very extensive program investigating the reason for the rash. We don't have a full answer yet, and this definitely will be reported when we know. Okay, thanks. Then maybe a quick follow-up on the early lunresertib, camonsertib combo. I guess, what's the dosing strategy here? Are you looking to use sub-monotherapy doses like you did with camonsertib and the PARP inhibitor combo, or are you know, exploring potentially full monotherapy doses of the respective agents? Then maybe at a high level, wondering if you could just speak to the safety you're seeing with that combo. Thanks. Right. As, as you saw, we were very careful about designing the monotherapy doses so that it is suitable for whatever we need, we have the dose. I am not planning to disclose the, how we are dosing, but, we are trying to do what we can to do the right dose. You will see the detailed data when, we are presenting them later in the year. I could just add that preclinically, we had flexibility on either agent with regard to dosing, at or below MTD to drive regressions. It is important, just to add further to Mike, it was very critical that we showed in our preclinical data that you can use the drug, continuously and intermittently without losing any efficacy. This offers the flexibility that we really desire, because combination with chemotherapy obviously requires different dosing than combination with targeted agents. The camonsertib is probably not the only targeted agents that we are going to combine it. This, we are in a very comfortable position with the dosing. Okay, great. Thanks so much for taking both of my questions. Our next question comes from Marc Frahm with TD Cowen. Please go ahead. Thanks for taking my questions. Congrats on the progress. Maybe to start, one of the slides where you showed the kind of the PD changes, looking at CDK1 and γH2AX, I'm wondering if you could speak to maybe the correlation of the effects you're seeing are between patients. You know, so a single patient, if they see the largest effect in CDK1, are they also seeing the largest effect on γH2AX or is the signals kind of a bit too noisy to make that correlation? Yes. I think we can say that there is a good correlation between the two. You know, with a key caveat that fossil endpoints always have some variability that are associated with them in the studies. Where we were able to look at them, there was a good correlation of seeing the fossil CDK1 down in the same cells that you saw the γH2AX coming up as a for instance. Okay, that's helpful. Maybe to follow up on Joe's question, just on the skin rash. Can you maybe walk through what you've tried either to treat it or prophylactic against it? You know, are things like moisturizers working or steroids, just, you know, how is it being dealt with clinically? You know, some rashes, just like the rash that I just told you with the change in the how the skin looks, basically does not require treatment at all. If the patient wishes to be treated, this type of patients, they are just getting moisturizers. What is very, very important, which I didn't add to Joe's question, is that the rash is appearing quickly and going away also quickly. The half-life of the agent is about nine hours. The complete disappearance of the exposure obviously is probably within two days, and this is exactly what we are seeing. There is no specific treatment. Usually what the dermatologist, which we have to advise us, recommend, is just standard treatment with either moisturizing skin set, oral antihistamines if there is itching, which usually there isn't, by the way. The rash is reasonably easy to treat, as you heard. What helps with those patients who have rash, is that we are just moving them to intermittent treatment, and it alleviates it almost completely. Okay, thanks. That's very helpful. Our next question comes from Chris Shibutani with Goldman Sachs. Please go ahead. Hi, everyone. congrats on the data. This is Charlie on for Chris, and thank you for taking our question. I was just wondering if you could comment maybe on any degree of correlation or differences in responses across the three genomic alterations being tested in this study, whether you're seeing any sort of differential characteristics and responses that you're seeing there? I have a quick follow-up. Right. What we believe as of today, not only based on this study that we reported, but looks through the entire program, that there is truly not a obvious alteration that performs better. It is very difficult to really answer the question because, as you know, for example, patients who have CCNE1 amplification usually belong to the gynecological malignancies, either ovarian or endometrial. Patients who have FBXW7 happen to have more colorectal cancer. We have a patient with breast cancer and cholangio and other patients in the trials. But what, if you are asking whether there is any preferential benefit in one of those, the answer is clear no. Okay, great. They are equally valuable to us, I would say. Okay, great. Thank you very much. Then my follow-up was just, I guess, just focusing specifically on CCNE1 amplification. Do you, are you seeing any correlation with degree of responses and the copy number of the amplification? Very good question. We examined it, very carefully with, preclinical studies, where we saw, CCNE amplification between six and, 43. We did not see any, clear relationship between the degree of amplification and the preclinical responses. We do not see any of those in clinical studies neither. They just have to have amplification. Okay, great. Thank you so much. That's very helpful. Take care. Our next question comes from Charles Zhu with Guggenheim. Please go ahead. Hi, good afternoon, everyone, and thanks for taking the questions. My first one, if I could perhaps expand upon one of Catanzaro's initial questions. Given that you've a lot of experience on the ATR/PARP combination front, and perhaps could you also comment upon, you know, how similar or different the development path could look for PKMYT1 plus ATR? Also, again, can you also comment on some of the potential overlapping anemia as well, and, you know, how we should think about ctDNA relative to RECIST? Thank you. Thank you. You know, I would like to avoid talking about the combination because we are trying to present it very intensively with very extensively in the fourth quarter. There is really no overlap in patients. We believe that our specific plan, without telling you what our specific plan is, our specific plan for each of the combination, we did it for purpose. The new combination that we are planning to open imminently, which is the carboplatin combination, is going to be geared towards very specific indication, which we hopefully will reveal later this year. We have also plans for the ATR, specific plans for the ATR, and specific plans for the gemcitabine. Obviously, for FOLFIRI, I don't need to explain to you that this is, this combination is going very well, and is geared towards colorectal cancer. I think just to maybe clarify, make sure that we heard the right thing, but if you were also asking whether the ATR/PARP combo versus the ATR lunresertib combo, those are two totally different. Yeah. patient populations, it would be really an expansion of where RP-3500 could be used in this combination. Distinct genotypes for the sensitivity to each of those different combinations. Maybe, maybe I misunderstood the question. The ATR/PARP combination is in homologous recombination defect, most patients. The combination of PKMYT1 is obviously, PKMYT1 is a proficient homologous recombination proficient patients. We are not planning to test them in the deficient patients. The mechanism, as Mike explained, of the ATR is not related to ATR. It is related to the help that ATR inhibition provides for resistance, or less activity of PKMYT1. Got it. Great. Thanks for taking the question. Our next question comes from Jeff Hung with Morgan Stanley. Please go ahead. Thanks for taking my questions. For the response patient, what were the levels of FBXW7 and PPP2R1A loss? You know, I know it's limited numbers and still early, but anything you can glean from that patient to begin to gauge which patients are more likely to respond? I have a follow-up. Yeah, that patient had both an FBXW7 and PPP2R1A inactivating mutations. They were both hotspot mutations. They were microsatellite stable, didn't have a high tumor mutation burden. That's a unique, we see a small population, as we showed early on, that has that overlap of the two biomarkers, mostly in the endometrial setting. I'd say it's just too early to say whether or not there's any indication, whether that was what was responsible for this or it was a combination of different things. We just need to have additional patients on to be able to understand that more thoroughly. Okay. Then can you talk about the magnitude of PKMYT1 target inhibition at the active doses, and what magnitude of PKMYT1 inhibition correlates to the 2x increase in γH2AX? Thanks. That was all the preclinical work that we had done. We looked across multiple models, both FBXW7 and CCNE1 amplified models that we had to understand, because obviously there's some variability between models and the absolute sensitivity. We found that across all of those models, if we had reached a 50% or greater inhibition of phospho-CDK1 on the threonine phosphorylation site, that correlated with getting the maximal activation of γH2AX and the maximal efficacy in that study. That's specifically using our IHC assay that we use clinically, because we wanted to be able to compare apples to apples in that regard, as different assay types resulted in different numbers. In the study, what was the magnitude of the PKMYT1 target inhibition at the? In the study, across all 17 evaluable biopsies for phospho-threonine, we saw on average a 50% decrease or greater. We saw a greater than 2-fold increase in the 2-fold or greater in the γH2AX across 25 evaluable biopsies for that endpoint. Great. Thank you. Our next question comes from Yusheng Xu with Berenberg. Please go ahead. Hi, good afternoon, and thanks for taking the question. The first one, I want to ask with regard to Dr. Yap's comment on the potential for the drug as a maintenance therapy. Maybe can you explain what that potential is? Yes. As you know, part of our program is chemotherapy combinations, and chemotherapies usually are not given forever. Let's say, if you are treating patients with FOLFIRI, in addition to PKMYT1 inhibitor, you usually would give the patient, you know, six plus, minus courses of the FOLFIRI, and the patient hopefully will have either benefit or no progression. Then, the standard would be to stop the treatment and wait until the patient progresses. In the case of PKMYT1 inhibition, because the monotherapy has a toxicity profile, as Tim described to you, that is extremely benign from a long-term dosing perspective, therefore, it is a very suitable compound to give to the patients because you don't have to even see the patients and check the blood count or any follow-up. The patient, if the patient has an exacerbation of rash, which by the time that the patient finishes chemotherapy, the dose for the rash prevention is already established, you basically can follow the patient very infrequently, because there is no expectation of toxicity that requires physician's attendance to it or laboratory work for that matter. Okay, thank you. Then a quick follow-up on, can you remind us the difference between PKMYT1 and inhibition and CDK2 inhibition? Obviously, we've seen some interesting data at ASCO, just ASCO, on some CDK2 inhibitors. I see you also will conduct some studies on the combination with CDK4/6. I wonder how you think about that opportunity there. Yeah. I guess, the first part, I can just give a quick recap. I think CDK2 is obviously the direct partner with cyclin E, it's directly targeting that cyclin E amplified CDK2 complex, at least as demonstrated by Blueprint and Pfizer, blocking progression in the cell cycle, and resulting in tumor growth in addition to stasis in vivo preclinically. PKMYT1, I think, is taking a different approach, it's really looking at the vulnerability created by the cyclin E1 amplification, i.e., the early entry into S phase and the need of the cell to be able to hold off mitosis until that extended S phase is completed. Which really, I think, gives us a lot of opportunities for combinations that might be distinct through that mechanistic rationale and really amplify that synergy in that setting. Our next question comes from Tim Chang with Capital One. Please go ahead. Oh, thanks. I noticed in your, in your last slide that you talked about a potential combination with a WEE1 inhibitor. I mean, have you decided which WEE1 inhibitor you might use, for a combination study? We have not disclosed our clinical plans in that setting. It just was based on data that we had with collaborators that was presented at AACR and additional internal data, again, showing really nice mechanistic synergy between PKMYT1 and WEE1, and really thinking about how we're going to execute that clinically and hopefully provide information on that in the future. Maybe just one follow-up. On the adverse events, the side effects, I didn't see any diarrhea as listed. I mean, was there just very little diarrhea in the patients that you dosed? I would ask maybe Dr. Yap, because he's treating the patients and seeing this in the context of diarrhea. Tim, would you mind to please comment on it? Yeah. Thanks very much, Maria. No, not really a big issue. You know, diarrhea is something that can be very easily treated overall and well managed, similarly with other GI toxicity, so not been a major challenge. I noticed, just one last question, maybe for Dr. Yap. There was no decreased appetite in the recommended dosing schedule. Is that right? That's correct. Okay, great. Thank you. Our next question comes from Ben Burnett with Stifel. Please go ahead. Hey, thank you very much. Congrats on this data. It looks like you're seeing a much improved safety profile relative to other cell cycle drugs, targeting drugs. When you did see anemia with lunresertib, how was this managed? Did patients get transfusions or was this managed more through, like, dose interruptions or dose reductions? Thanks for the question. It's a very interesting question. Number one, any interpretation of anemia in patients who are in phase I study is a difficult one because, as you heard from Dr. Yap, 42% of patients had more than four previous lines of therapy. Usually these patients in phase I studies have a rather sort of beaten-up marrow, and they are borderline hemoglobin. And the probability that the marrow can very quickly react to any additional impact is small. In addition, all these patients have something that we call anemia of chronic disease because they usually have the cancer for a very long time. Interpretation of anemia in patients in phase I study is very, very difficult. We do see, as you saw on this slide, a very small percentage of grade III anemia. Grade III anemia not always requires transfusion, and usually the patients to start with accommodate to the lower hemoglobin. But to get to the bottom of your question, this is in the hands of the treating physician, whether the patient requires transfusion. We are recommending in our protocol that the transfusions are used as a last resort, and usually the first treatment is either to decrease the dose or to do a little treatment break. Not too many patients. I can check on it next time, how many patients require transfusions, but our overall recommendation is always to try to avoid it. Okay. That's very helpful. Then I just wanted to go back to some of the comments around the CCNE1 amplifications that you were seeing in the study. I guess, I think in the past there was maybe some potential to use, like, an amplification cutoff to sort of define patient population. Do you still think that's gonna be a viable approach, or are you just looking for sort of any... Do you think just any amplification would be sort of sufficient to confer sensitivity to PKMYT1? Yeah. It's a great... I think right now there's just a practicality that most of the NGS assays have a defined cutoff, and they just say it's greater than six copies. We are again going back, and we'll have all the data on what the actual copy number was, the exact copy number, to be able to see whether there's any changes in the cutoff that are necessary. I think so far it looks like the, the calls that are being used now are sufficient, to be able to highlight the patients that are, driving sensitivity, to PKMYT1. This question is related to the question previously, whether there is a relationship between the degree of amplification and this. You know, what we believe is that, as of now, we don't see any relationship. We still need to have, obviously, more patients to rule it completely out or not. However, what is important for the mechanism of this drug is that, it is the amplification that is necessary, for the compound to work. Okay. Okay, understood. That's helpful. Thank you very much. I think we're at the hour, so I just wanted to thank you all for your insightful questions. I'd also like to extend our gratitude to Dr. Yap for his participation today and for his ongoing clinical leadership. I'd also like to thank all the patients, their families and physicians and other caregivers who participated in the studies. Without them, we would not be here today. A special thank you goes to the entire Repare team for their incredibly hard work and diligence in advancing our mission to be a leading precision oncology biotech focused on novel synthetic lethality medicines that meaningfully improve the lives of cancer patients. That concludes our call today. Thanks for taking the time with us. Good evening. The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.