Charles Zhu, one of the senior biotech analysts here at Guggenheim Securities. For our next session, we have Repare Therapeutics, specifically Lloyd, Maria, and Mike joining us from Repare. Guys, thank you very much for your participation today. We really appreciate your coming down for our conference. Perhaps just to kick us off, could you provide us with a high-level overview of your company platform and pipeline, please? Great, thanks, Charles, for inviting us here. We really enjoy this conference. It's nice to be back with human beings live. Repare is very explicitly focused on developing novel oncology medicines based on synthetic lethality and maybe more generally genomic instability, all derived from our own soup to nuts platform for drug development that we call SNIPRx. SNIPRx does two things for us. It's a CRISPR-enabled large-scale platform that allows us to find novel targets in synthetic lethality, which is since PARP, what I think the field and most of all patients are kinda screaming for. Beyond that, we use that same platform to understand other genetic alterations that can allow us to enrich populations that are predisposed to respond to the drugs that we're developing against those targets. We have been fairly successful since our founding in 2016 in building that pipeline of synthetic lethal drugs, starting with our ATR inhibitor, camonsertib, which last year at AACR showed some great results in ovarian cancer, and we subsequently partnered with Roche in a phenomenal partnership that we announced last May or June. RP-6306, which is in the clinic today, it's an inhibitor of PKMYT1, which is synthetically lethal with cyclin E1 amplification, FBXW7 and one other genetic alteration that we've more recently discussed. We have guided to a Pol θ compound entering the clinic this year and another unnamed compound next year, which means if you take it all together, in the short span we've existed, we've been quite prolific and successful at developing world-class oncology small molecule compounds. Great. Perhaps for your lead and fully in-house, asset, RP-6306, your PKMYT1 compound, could you provide us with a quick overview of, the mechanistic rationale and the synthetic lethality mechanism underlying this asset? Mike? Yeah. Absolutely. I think as was highlighted, we focused on genomic instability, and one of the key genetic alterations we identified early on that's driving genomic instability is cyclin E1 amplification, which really creates an environment where the cell is pushed into S phase prior to actually being able to duplicate the DNA, which creates a lot of stress and expands out the S phase. We thought that was a great vulnerability to look for a novel target. We did our SNIPRx screen and identified a target called PKMYT1, which is a kinase of the WEE1 family, involved in the S phase through regulation of CDK1, and really allowing the cell to sense when it's time to undergo mitosis. Basically, the mechanism that we've been able to elucidate is that because of this highly extended S phase, the cell is under extreme stress and needs to actually have an activated PKMYT1 to keep CDK1 at bay, so the cells don't prematurely undergo mitosis. When we block that with an inhibitor, the cells, while they're still in the midst of duplicating the DNA, transit into mitosis, which obviously is impossible because they're still transcribing, they're still being duplicated, and then the cells undergo cell death. We also had done a step 2 screen, which is the way we use our SNIPRx screen to look for synthetic lethal networks, so other genes that might be synthetic lethal with PKMYT1. We found FBXW7 as another major lesion in that space that we're executing clinically. It was linked, and we were retrospectively brilliant in figuring out that it regulates the levels of cyclin E1 through protein degradation. When mutated in cancer, it basically now means that cyclin E1 in many of those cells can be elevated, and we saw many of the same phenotypes that we saw with cyclin E1 amplification itself. Great. Given that this asset is in the clinic and heading towards initial clinical data later this half, Maria, how would you characterize your ongoing status and progress in this trial, and then how are you setting expectations for that clinical readout? Right. It is a new target, first in human study, and most important out of those two is that it is new target. There is a lot of learning that we are coming for with the phase one study, and we are using our expectations from the preclinical studies. What is very important in developing a new target is that you first need to prove that the target matters for the cancer. There are tools to do that, such as establishing the proof of mechanism, and we know that the PKMYT1 direct target is CDK1 phosphorylation. We are looking for impaired tumor biopsies to decrease the phosphorylation of CDK1, which is proving that the drug inhibits the target that it is designed against. We need to prove that inhibiting the target indeed does something to the tumor, preferably that the tumor dies or that the DNA damage in the tumor that we are creating is sufficient. To do that, which is usually named proof of principle, we are showing that the γ-H2AX, which is the measure of DNA damage, is increased. We are looking at multiplying the cells with discoverable DNA damage, again in paired biopsies. We need to say, "Okay, we have proof of mechanism, we have activity in the tumor, but does it do anything to the patient?" How we are looking at it is looking at this something that is called anti-tumor activity or eventually proof of concept, where we are looking at, for example, ctDNA, which decreases during the multiplicity of evaluations, or we are looking at tumor shrinkage, or we are looking at stabilization of disease, which is only evaluable in later randomized studies. How we are thinking about it, we know that there's a cell cycle inhibitor, and there is a lot of history with cell cycle inhibitors such as, CDK4/6, and those cell cycle inhibitors rarely have tumor shrinkage. As you know, CDK4/6 inhibitors cause response rate in the range of 4%-6%, and despite that, are extremely successful and marketed. The other drugs that do not have single agent tumor shrinkage but are extremely successful is Herceptin, Avastin, PI3K inhibitors, and many others. What we've shown in preclinical studies is that we do see tumor growth inhibition, as expected with inhibition of the target. However, we do not see massive tumor shrinkage. However, we do see very significant tumor shrinkage as expected with cell cycle inhibitors in combination with other agents such as gemcitabine or carboplatin or irinotecan. Therefore, we started already three different combinations, and we are progressing those along with the monotherapy. Because the monotherapy started early, we are expecting in the second half of this year, to present the proof of mechanism, proof of principle, as I discussed, possibly the ctDNA decreases, and most importantly, we need to show that the drug is doing it in a safe style, that there is no toxicity. We are going to have sufficient patient to give you or give us the view on the tolerability profile. Great. Regarding tolerability, what sort of on target PKMYT1-related toxicities would one expect? Given it sounds like that you'll be really advancing combinations longer term, how should we think about the potential for overlapping toxicities? Right ...with the partner? We did not reveal, and usually nobody does, preclinical toxicology data in animals. However, what we did say is that it is not a toxicity expected with the same pattern of inhibitors like WEE1. And the proof in the pudding is that we are doing multiplicity of chemotherapy combinations, including carboplatin combination, which we are starting, gemcitabine combination and FOLFIRI, and all those are pretty significantly myelotoxic. The fact that we are starting many of those possibly suggests that myelotoxicity is not the dominant toxicity. Mm-hmm. But- We think this first data drop should give a sense of that differentiation from WEE1 kinase. Got it. Great. Also, given that you have, not only the single agent but the combinations that were started after the initiation of your single agent, you how would you characterize ongoing progress in dose finding across those cohorts? Perhaps also, when can we expect to see data from those cohorts? The data from the monotherapy, as you know, are expected in the first half, but this will be only monotherapy data. We are intensely evaluating the combinations, and we are planning to show you the data as soon as possible, but I don't think that we said exactly when. It will not be long wait. The K, we're gonna do our best to get some richer guidance into the K. Yeah. Which is this month. Okay, great. One specific combination I also wanna touch upon before we get into gemcitabine and FOLFIRI is the combo with camonsertib. It's now we're kinda touching into your Roche deal, but there are two really interesting parts to that. One, which we'll get into later, but the other one being you specifically retained rights to combine it with your PKMYT1. I guess for one, why? For two, what is some of the underlying key mechanistic rationale of combining PKMYT1 with ATR? Yeah. Hopefully the rationale will be considered why is the two together. As you highlight, PKMYT1 directly phosphorylates threonine 14 on CDK1. ATR, when activated, activates CHEK1, which normally inhibits CDC25, a phosphatase that removes that phosphorylation site. When ATR is inhibited and PKMYT1 is inhibited, you're no longer phosphorylating it, but now you've activated CDC25 and you're actively dephosphorylating it. That results in mechanistic synergy in the backgrounds of cyclin E1 amplification and FBXW7 loss. We saw some very exciting combination synergy at doses of both drugs that are below their MTD in preclinical models. It was a really exciting synergy at levels that we think are highly achievable in man. Great. Also regarding some of your other combinations, whether it's FOLFIRI or gemcitabine and maybe and carbo-taxol as well. Can you perhaps provide us some color as to what sorts of patients you are enrolling? Would it be reasonable to, I guess, you know, enroll primarily patients who would go on gemcitabine or FOLFIRI? You know, how would you describe their treatment history? For the FOLFIRI combination, we are obviously targeting colorectal cancer. Those are patients who are possibly receiving FOLFIRI after FOLFOX plus minus Avastin. The reason for colorectal cancer is that FBXW7 is lost or altered in about 12%-15% of colorectal cancer. That is a significant percentage of a large tumor. We are using FOLFIRI because it is a reasonably early proposition for these patients in the line of therapy. The idea is that if the combination shows synergy in a phase 1 type dose finding study, we can then go to first or second line immediately to colorectal cancer in the selected patients. For gemcitabine, we are targeting patients who are with CCNE amplification in ovarian cancer because gemcitabine is used in ovarian cancer, not necessarily registered as single agent, but definitely is a common agent used in ovarian cancer. carbo-taxol, the purpose of it is that once we confirmed the significant synergy, we are obviously planning to go to very early ovarian cancer where carbo-taxol is a first line therapy. Great. Maybe just to dig a little bit more deeply into some of that. I think you noted, you know, the FOLFIRI combo in colorectal could be used after FOLFOX. FOLFIRI is, I think, believe used after FOLFOX already. Could you go directly after FOLFOX in a re-intake analysis? Yes, definitely. Definitely. The design would be FOLFIRI versus FOLFIRI plus PKMYT1 and make it a new standard of care for second line. Got it. Great. I guess same question for ovarian given gemcitabine is used off label. Correct. Got it. Okay. All righty. Okay, great. I guess, you know, shifting gears a little bit now over to camonsertib. It now seems to be fully in Roche's hands. For the most part, you guys still have the option. Could you talk about, you know, at least what line of sight at least you could provide us for potential updates on that program? Yeah, it's a great question. Thanks. You know, obviously, Roche, who have, you know, made the comment that their goal is to win in ATR inhibition with our partnered compound, are very sensitive to informing Bayer, AZ, Merck Serono, all of whom are competing with their own ATR inhibitors. I think you should expect, and we've guided for that, they're going to be quite silent about their CDP going forward. We are wrapping up our TRESR and our ATTACC work. The monotherapy that we've conducted since 2020 and the combinations, including the three-part combinations in gemcitabine, that'll be this year. Spend will come down materially for us. We're hoping to be able to present some of those results at conferences this year. Roche has the final call, but we're optimistic, just given the commitment that they share with us to our investigator partners and our patients, that we'll be able to share more. Steve and I have pretty regularly shared with the street that the best way to track progress is watch the milestones and their material. We guided to $55 million in milestones in the third quarter this year, and they're tied to meaningful clinical progress, which is, I think, again, a good way to take note because that we have to disclose. Great. Also as part of that deal, the other thing that I previously mentioned was very interesting was your retention of an option to enter into a 50-50 U.S. commercialization. What was your rationale underlying retaining that option, and under what circumstances might you exercise it? Yeah. You know, we saw having an equal share of the U.S. market upside as being a very significant value creator for our shareholders. We insisted on hanging on to it. It was one of the foundational elements of the deal for us. We haven't disclosed the specifics of what will trigger the opt-in for us option. What we can say is we'll have more data and understanding of where presumably a registration-oriented trial will go and an understanding of what the upside and market is and so on. For us, it's then just a straightforward economic and balance sheet decision as to whether it's something that makes sense for Repare. Great. Cool. Moving on perhaps now to some of your earlier pipeline agents, the next one that sounds like it's about to enter the clinic is Pol θ. Perhaps could you talk a little bit about Pol θ as a potentially interesting target as well as how you're tracking towards for first in patient? From the target side, I think Pol θ was one of the originating targets in the inception of Repare, discovered to have a synthetic lethal interaction with loss of homologous recombination genes in cancer by Alan Ashworth as well as several others. We've been working on what is a very challenging target over time. We've highlighted that we've developed inhibitors to both the polymerase and the helicase domain. We haven't said which one that we're progressing forward, but we looked at both of those, and we really wanted to encompass both what was the most compelling biology and what was the most drug-like molecule, obviously, in the end, to pick the one that we're bringing forward into the clinic. I think, in general, it looks like it's a very exciting and particular combination agent with things like PARP inhibitors in this HRD background. One of the, I think, really exciting findings over the last probably 1.5 years-2 years is the recognition that Pol θ is one of the major drivers of the resistance that's being formed through these reversions that occur in BRCA1 and BRCA2. You're able to see the scars of basically Pol θ activity in those reversions, saying that anywhere between 50%-70% of all those reversions are driven by that. Again, thinking about can you move this into an early phase of disease where you may be able to change that evolutionary life cycle in that combination, as well as see synergy, and hopefully extend patients' lives and drive a even greater durability than those original agents. I think the last part is from a safety perspective, it's expected to be a very safe entity to inhibit. When you knock it out in a mouse, there's no real phenotype, which is very unique for a cancer target, to be fair, almost unheard of. I think that was one of the other appeals is we think this will be a very appealing mechanism to combine, especially if you think about moving into earlier lines of therapy, where you wanna have the most tolerable regimen possible. Great. How are you tracking towards a potential IND filing and clinical entry? Our guidance was summer IND of this year. We also guided to an additional unnamed target, unnamed compound and synthetic lethal pair for a DC in the first half of next year and, normal gap to an IND after that one. T his is a fairly prolific pipeline. We're excited about what's beyond. Okay. Okay, great. Perhaps maybe just one more quick one on Pol θ. I would ask you about hints on the unnamed, but I think you said it already. Regarding Pol θ, this question admittedly probably will not be answered until we see clinical data, but polymerase versus helicase, what's your view there? I think, as we progress towards the clinic and we start to talk about our molecule, I think we'll try to provide information on that. Right now, we haven't revealed anything additional in that sense. Yeah. The field doesn't agree on what the right enzyme is to target to effectively drug Pol θ. The one company that that was first into the clinic was a polymerase that's a private company called Artios. They've also made clear in their public statements that they've got a helicase inhibitor that's following it. It's an open question in the field. Great. Perhaps, to close out, could you remind us of your cash balance, expected burn rate, as well as expected runway? Yeah. It's my favorite thing to do. In our peer group, we're probably among the strongest balance sheets of anyone, partly because we were well-funded from the get-go, and I think the Roche collaboration helped out. We finished last quarter with $370 million in cash, and we have guided that, and that excludes the $55 million we're guiding to or any other milestones that could be due. We've guided that takes us into 2026. I think the most important thing we like to convey is that gives us a lot of shots on goal in multiple programs across our portfolio. Perfect. With that, I think we'll wrap up. But I want to thank Lloyd, Maria, and Mike, for joining us here again today. W e don't have much of the conference left, but I hope you enjoy the rest of the conference. Thank you. Thank you. I just found out we're stuck here, not because of Guggenheim, but because of air weather issues. We're gonna enjoy the night in New York City. Thanks to Guggenheim.