Good afternoon, everyone, and welcome back to the afternoon session for Oppenheimer's Annual Healthcare Conference. I'm Jeff Jones, one of the analysts here on the biotechnology team, and I'm delighted to be joined by the leadership team from PMV Pharma, with David Mack, the CEO, and Deepika Jalota, Chief Development Officer. Thank you guys very much for taking the time to join me this afternoon. Thanks, Jeff. It's a pleasure to be here, and I appreciate you making the time for us. I know we've got exciting data coming up later this year, but let's lay the groundwork, if you will. David, maybe take us through a little bit of the backstory here to PMV Pharma and what brings us to this position today. Sure. We actually founded the company in 2013, so we're in our 12th year. I co-founded it with Arnold Levine, who, of course, discovered p53 in 1979. We started the company to develop small molecule restoration drugs for mutant p53s. That was to take a mutant p53 and restore its wild-type activity to induce a very potent program of apoptosis, or cell death. We've achieved that with our lead product, rezatapopt, which we'll hear a lot about today in a Phase 2 registrational trial. We'll be reporting out interim data from that pivotal middle of this year, and we'll hear more about that from Deepika. We started the company with a particular thesis, and that is that looking at the most common mutants of p53, called the hotspot mutants, there's 10 of them, that although they're all mutant p53s, and we asked the same question of all of them, and that is, does a small molecule physically bind the target? Does it structurally correct it to adopt a wild-type-like form? And does that restore p53-mediated transcription and p53-mediated cell death? The challenge with going after the hotspot mutants is that although they are all p53 mutations, they all have a single nucleotide amino acid substitution, which causes that particular protein to be mutant, either as misfolded or disaggregated. Each of those amino acid positions is in a different location in each of those proteins, creating a unique protein structure. That is the challenge here for us, of which we've achieved the proof of concept, of course, both biologically and clinically with rezatapopt. The other nine are challenging in that each of those hotspot mutants is its own screening campaign. It is a platform in that we ask that same question of all of those programs. To be transparent, it has been challenging, although I think we are making strong progress in two areas. One is against hotspot mutants with novel chemical equity. I think traditional small molecules have been challenging, but there has been an emergence of new chemical equity that has promises to address what are challenging targets for decades of biology behind them. We have leveraged this past decade of studying p53, as well as four decades of knowledge around the biology of p53, to better understand some of the upstream players and downstream players of p53. Our pipeline now has evolved not only targeting mutant p53s, but also players that are involved in the p53 pathway that we believe are important in driving tumori genesis. You will hear about one of those towards the end of the first half of this year, which we will nominate and share with you a target and a development candidate that will be entering IND-enabling studies this year, with the promise of being first in human in 2026. We are excited about what is happening with the pipeline. As we sit here today, all eyes are on rezatapopt and its registrational trial, which we are also very excited about. We'll hear details of that from Deepika here today, Jeff. Great. Really appreciate the background, David. Deepika, drilling down on rezatapopt, obviously, I think the original data was announced from the Phase 1 study at ASCO in 2023, to a great presentation and then overview by you guys at the event. Could you refresh us on what you guys have shown to date with that data set from that Phase 1 and as you sort of expanded that study population around the target doses to define your efficacious dose? Absolutely. Just to refresh on the study design, essentially, we were looking in Phase 1 across multiple doses to identify the ideal recommended Phase 2 dose, as well as the MTD. What we identified was that 2,000 mg QD with food resulted in a 38% confirmed ORR. What we saw was preliminary efficacy across six different histologies. That includes ovarian, small cell lung cancer, breast cancer, as well as additional responses in endometrial and head and neck and prostate. That gave us the impetus to move forward into our Phase 2 study, which we are now actively recruiting for, and we are enrolling across approximately 60 sites globally. In terms of the efficacy levels that you demonstrated sort of in the 20%-25% response rates, if I'm recalling my numbers correctly, you saw a lot of responses in the ovarian population. As you guys have designed your Phase 2 study, which is a potentially pivotal Phase 2 study, to be clear, how are you sort of emphasizing enrollment against those different histologies? One of the opportunities here is, given you're really targeting Y220C mutant tumors, is to look at a tumor-agnostic label. How are you guys thinking about specific tumor histologies as well as a tumor-agnostic approach? Thanks for the question, Jeff. With regards to the frequency of the TP53 Y220C mutation, it is mostly seen in ovarian cancer at a frequency of around 3%. When you look across all solid tumors, it's around 1%. That really drove us to the study design we have for PYNNACLE, where we have five separate cohorts, where we're planning to enroll 42 patients in ovarian cancer and 18 patients each across cohorts two through five, which would be in lung cancer, breast cancer, endometrial, and other solid tumors. This enables us to pursue multiple shots on goal, so to speak. That being said, tumor-agnostic is absolutely our best-case scenario to progress with. Our base-case scenario for our initial NDA submission would most likely potentially go forward with an ovarian cancer starting point and building from there to tumor-agnostic based on the study design that we have created. This is supported by our Phase 1 data, where we had a 47% response rate in ovarian cancer, and we had three out of eight responses in breast cancer and additional responses across those histologies that I mentioned earlier. Okay. Jeff, let me just make one point on the tumor-agnostic label. Of the nine approvals that we have seen in the space over these many years, the vast majority of those in the tumor-agnostic space have gotten their first approvals in a tissue-specific manner, so histology-specific, where two to three histologies really drive the majority of the ORR. 50%-70% of the ORR is driven by two to three histologies, leading to a tail that gets you that tumor-agnostic label. Tumor-agnostic is absolutely on the table for us. As Deepika articulated, just given the outsized numbers in ovarian and our incredibly strong ORR there from the Phase 1 data, that is on the table as our first NDA to be submitted at the end of 2026, with the potential to bundle with others. Definitely going with our strongest data set, leading into a tumor-agnostic strategy with the FDA. Got it. No, that makes perfect sense. I guess the one thing that we haven't mentioned is the KRAS wild-type component here that's just worth just raising as it is how you do study design and things like that. Yes. Thanks for the question, Jeff. What we saw in Phase 1 was when we had KRAS-mutated patients, we did not see the same level of durability of response or depth of response compared to those patients that had KRAS wild-type status. When you look at some of the data that is emerging around co-occurring TP53 and KRAS mutations, what has been hypothesized is that when you see both of these mutations on board, there might be a weakened anti-tumor immunity, which causes this immunosuppressive environment. Essentially, when you have these two co-mutations on board, that really supports the data we saw in Phase 1, and that leads us to that potential future opportunity to combine with a pan-KRAS inhibitor to get over that specific immunosuppressive environment that is seen. Got it. As we sort of drill down on the ovarian approach, how should we think about the population there for these ovarian patients, given it's driven by Y220C mutation, not necessarily by other therapies or combinations? How are you defining the ovarian patients for your enrollment? What then does that do as you look at sort of the bar you would think about for approval and labels down the road? With regards to the patients that we're enrolling currently with ovarian cancer, it's platinum-resistant or platinum-refractory that we allow to enroll. From an overall perspective around prior treatments, these patients would have received multiple prior lines of treatment. As a result, when you look at standard of care, the bar for these patients, it's truly a high unmet medical need. It's around 12% as far as that bar. Based on our Phase 1 data, where I mentioned we saw a 47% response rate, essentially, our study is designed to target a 30% ORR overall for the study. Based on the Phase 1 data, we are hopeful that our Phase 2 data would replicate what we're seeing. Okay. In terms of timelines here, you're looking at mid-year sort of for it. Would it be a broad—should we be thinking about a broad update across the trial? Obviously, ovarian is the largest cohort. What should folks be expecting from this update? We would plan to share at least 30 patients' worth of data with at least 18 weeks of follow-up in the middle of this year as part of our interim analysis update. Essentially, we would show the data across the study, not just from our ovarian cancer cohort. We would expect to see at least one-third of the patients coming from that ovarian cancer data set. We expect to see, basically, patients enrolled across all of the different cohorts. You will see that full data set that we have at that point. Got it. In terms of we're just looking at times here, making sure I'm staying on track. In terms of financials, cash runway, and things of that sort, remind us where you stand in terms of what you reported in third quarter runway, what that's going to take you to. Obviously, a big time difference between sort of that end of 2026 NDA filing and data updates that would come along with that versus this near-term update this summer. Yeah. Those are great points, Jeff. As you underscored, our plans are submission of NDA at the end of 2026. We ended last quarter, third quarter, rather, last year with $198 million in the bank. That will get us through the end of 2026. To your point, the end of 2026 will be here before you know it, but it's a ways off from when we announce data in four to five months, that interim look. We will have opportunities, and we're looking at many mechanisms that we can raise capital to get us through that NDA submission. That's ongoing. We think the data will be a nice platform to enter into such discussions. As Deepika has said, we will report across tumor types. Once again, in the Phase 1, we saw activity in six independent histologies. Our hope is that we'll continue to see data to support a broad spectrum of activity. Of course, with a cornerstone of ovarian, given the 3% in ovarian and the unmet medical need. Just a word on the KRAS single nucleotide variants, mutant KRAS versus wild-type, as Deepika shared, we're excited at the prospect of a combination with a pan-RAS inhibitor. Having said that, the effective population, target market population for us, is affected less than 10% by the presence of KRAS mutants. It's mostly pancreatic and colorectal. The other histologies have de minimis KRAS mutations. I think we're still in a very strong place from a potential market access to patients, even in the face of this KRAS wild-type status. We are excited to look at the potential of a combination there as well. All right. Are you doing any work currently in the combination setting, or have you done any in vitro work or, sorry, animal work that would sort of speak to that? We have launched preclinical studies in the space, and I would say the biology is consistent with expectations. Okay. Actually, Deepika, there was one thing I didn't clarify on sort of the bar in ovarian, and that you spoke to overall response rates, but not duration of response. What is the bar for duration of response? Is objective response truly the bar here, or does it need to be something more like PFS? Typically, what we would expect to provide to the FDA is a durable duration of response, which would be a median duration of six months. Based on our Phase 1 data, we had exhibited and observed a seven-month median duration of response. Coupled with the compelling ORR and median duration of response, we're very hopeful for the results for Phase 2 to replicate what we saw in Phase 1. Got it. For the FDA approval, do you think would the endpoint be objective response rate rather than PFS? That's correct, yes. Since it is a single-arm study, that would be the expectation that that would be sufficient for a compelling ORR and DOR, along with a safety profile that's tolerable. Okay. In terms of sort of next steps, and as you talked about a little bit early on in better understanding the p53 pathway and the components of it, how have you guys thought about some of these other targets that may be there and addressable by some of the chemistry work you've been doing? How should we be thinking about announcements you may make and the ability for you guys to expand the portfolio beyond rezatapopt? Yeah. Thanks for that, Jeff. As I touched on, we will be announcing a program that is in development candidate phase. For us, that's a single molecule that we are electing for IND-enabling studies. In our experience, which we've done two in the Y220C space, one of which is rezatapopt, the other of which we put on the shelf as a backup. Both those campaigns took about nine months. I think 9-12 months post-election of that development candidate, which we'll announce likely second quarter and the second quarter, we'll be entering IND-enabling studies. The anticipation is in 2026, a second program against a target that is not p53 but touches p53 that we're excited about. We will be sharing with you not only that target and the characteristics of that development candidate, but also our clinical strategy against that target and the histologies. Definitely news on pipeline this year to complement our movement towards an NDA submission with rezatapopt. There are others behind it, but that is the closest that we will be revealing certainly the first half of this year. Okay. If we think about this data update coming this summer, potentially giving you the opportunity to add to the balance sheet to support some of these preclinical and possibly other studies, as you think about you mentioned some of the combination work and pan-RAS inhibitors and things of that sort, how would you prioritize some of these combination or other approaches leveraging rezatapopt? What would you go after first, and how should we be thinking about expanded opportunities there? Yeah. Lifecycle management is top of mind for us. Deepika, maybe some comments there on current combinations and future combinations. Absolutely. We are looking at opportunities in heme malignancies as well as in solid tumors. We already have discussed publicly around our relapsed refractory AML-MDS study that MD Anderson is currently in the process of initiating, and we plan to have the first patient enrolled in this study in the first quarter of this year. Stay tuned for that. We are excited about that opportunity, given that TP53 mutated heme malignancies do have a very poor and dismal outcome. Physicians are quite excited about the opportunity to test rezatapopt in this patient population. The other elements around combination strategies, we are looking at opportunities in ovarian cancer as well as in breast cancer, looking at potentially with regards to PIK3CA inhibitor combinations for breast cancer, and in ovarian cancer, looking at a potential combination with bevacizumab. These are currently opportunities that we are assessing at the moment. Okay. I guess the other thing, you had done some work looking at pembro combinations that you guys have backed away from. In the learnings from that work, is there something you could take forward or something you could leverage from that work, or should we not be thinking really about checkpoint inhibitors at this point? As you noted, we did evaluate rezatapopt in combination with pembrolizumab. Unfortunately, we did end up stopping enrollment because we had a subtherapeutic maximum tolerated dose, which did not make sense for us to progress further. That being said, it does not preclude us from evaluating rezatapopt with other checkpoint inhibitors. I think there are varying safety profiles and efficacy profiles across different checkpoint inhibitors that we can potentially evaluate in the future. It does not completely close the door. In particular, with pembro, we had overlapping tox. Really, the tox profiles of our checkpoint inhibitor moving forward is an important consideration. Based on our preclinical data and confirmed by clinical that we do activate the immune system by reactivating Y220C, a very similar outcome that a checkpoint inhibitor has. We really think that we overloaded the immune system with pembro to exasperate those co-adverse events. As Deepika says, we can design around that now that we know what we're looking at, to your point, Jeff. Okay. Great. I think I am essentially up on questions. Is there anything else I haven't asked about or you'd like to use the opportunity to touch on? I think you've covered it well. We very much look forward to further interactions with you and Oppenheimer moving forward as we have our public announcement of the interim look into the PYNNACLE trial with rezatapopt. I appreciate your time again here today. I know you have a full schedule. Thank you for that. No, really appreciate the time from both of you and really looking forward to the data this summer. Just in terms of that data, might we be thinking about that at a conference, or do you think that's going to land more as a company event? It will be more as a company event. We will follow it up with additional data at a scientific congress, but our first look will be a webinar by the company. We can take questions from investors, et cetera. Very transparent with the data and the narrative. Okay. Fantastic. Guys, thank you very much for the time this afternoon. Really excited for the summer for you guys. Hey, thanks, Jeff. Appreciate it. Okay. Take care. Take care.