Welcome to our next session. I'm Robert Burns, Managing Director and Senior Biotech Analyst at H.C. Wainwright, and I'm joined today by David Mack, the CEO of PMV, Deepika Jalota, the Chief Development Officer at PMV, and Phil Herman, the Chief Commercial Officer at PMV. Gentlemen and lady, thank you for joining us today. Why don't we just dive in? For those who may be unfamiliar with PMV, can you provide a brief overview of the company and its pipeline? Yeah, absolutely. First of all, Rob, I want to thank you for the invitation to participate today and H.C. Wainwright for the invite to be here. So thank you for that. At PMV Pharma, we're focused on the biology of p53 and targeting mutant p53s for the treatment of cancer. Just a bit about p53. It's the most frequently mutated protein in all of human cancer, with over half of all human tumors having a mutant p53, and it was discovered in 1979 by my co-founder, Arnie Levine. It's been many decades in the making of being targeted by a small molecule, and our lead product candidate is rezatapopt. It is a small molecule that is targeting one of the 10 hotspot mutants of p53, so these are the most frequently seen mutations in the p53 gene, resulting in a mutant protein that has lost the wild-type function of p53. And p53's job is to be the guardian of the genome. So it's to survey the health of a cell, and when it senses a lesion in DNA, or some type of external insult, it pauses the cell cycle to see if that can be repaired. And if it can't, this is its job. It tells the cell to kill itself. So it is in charge of cell suicide. It is the most potent protein that induces programmed cell death or apoptosis. So it's the first thing that a cancer cell wants to get out of the picture, hence the frequency of its mutation in human tumors. Y220C is a hotspot mutant. The nomenclature is that. First of all, p53 is a transcription factor, and so it turns on a transcriptional program of apoptosis cell death. So that is lost in a mutant setting. And so the nomenclature is the wild-type protein, Y220C, has a tyrosine at position 220 in the DNA binding domain of p53. That is mutated to a cysteine. Okay? That single amino acid substitution from tyrosine to cysteine at position 220 results in a misfolded mutant p53 protein at physiological temperature, which has lost its wild-type function. And so, rezatapopt, our job with that small molecule, was to address this mutation. That cysteine causes a cleft or a pocket in that mutant p53, where a water molecule can embed itself and destabilize it. We designed rezatapopt to very selectively and specifically fit into that crevice, that pocket, and stabilize that Y220C protein into a wild-type form. That is what we accomplished and demonstrated in preclinical studies, that in fact, rezatapopt is very selective and specific for Y220C, converts it to a wild-type structure, resulting in restoration of that wild-type transcriptional control resulting in p53 mediated cell death. It is important to appreciate that rezatapopt was designed, again, to be very specific for Y220C. So it interacts exclusively with that mutant protein and spares wild-type cells as it does not interact with a wild-type p53. So the promise of rezatapopt in the clinic was that it would be very well-tolerated and a very potent inducer of apoptosis in a tumor. In fact, when we talk very shortly about the clinical data, you will see that has been borne out extensively in clinical trials. We are on the road to submitting our first NDA Q1 of next year in ovarian cancer, so in the PROC setting, you will hear a lot about that today, with an anticipated approval by the end of next year and a commercial launch. You will hear about our commercial efforts to build a fit-for-purpose sales force and infrastructure for the end of this year. With that, I will leave it to these guys to get into some very specific data regarding rezatapopt in the clinic and our commercial model. Awesome. Thank you so much. Thanks, Rob. Before we get into the rezatapopt data, which you just put out maybe a week ago, maybe level set us on the current treatment paradigm in PROC on how does the typical treatment evolve over the course of lines of therapy, and where do you see the greatest remaining unmet need? Yep. Thank you so much for the question. Patients start out with getting surgery, and then ultimately they have carboplatin paclitaxel with or without bevacizumab in the platinum sensitive setting. Unfortunately, what ends up happening is that after multiple cycles of chemotherapy, many patients, and the majority of patients, transitions to the platinum resistance setting. In that platinum resistance setting, for a long time, the standard of care was single agent chemotherapy, and that is given with or without bevacizumab. Now you also have some biomarker selected patient populations that are benefiting from recently approved therapies such as HER2 positive, PD-L1, as well as folate receptor alpha targeted therapies. What you see is that the standard of care in platinum-resistant ovarian cancer is very much loaded with ADCs as well as chemo backbones. Where rezatapopt differentiates ourselves from what's available in standard of care is that it's monotherapy, it's a chemo alternative, and it is biomarker selected from the point of targeting that point mutation of TP53 Y220C. It really truly addresses a high unmet medical need because these patients have cumulative toxicities that are attributed to chemotherapy. With ADCs coming on board, you see ocular tox, ILD, as well as just cumulative toxicity that is occurring because of multiple cycles of chemo. Okay. No, thank you for that insight there. That leads me to my next question. Obviously, we saw data from GSK's B7-H4 ADC was a 62% objective response rate. I want to get your thoughts as to how you see the efficacy profiles of these ADCs and potential deployment in the PROC setting relative to rezatapopt. Yeah, thanks for that question. I think when you see the ADCs coming into play, they are targeting different antibodies, right? There's a bystander effect. So in the end, they are chemos that have this antibody that's associated with them. That being said, ADCs, most of them have a Topo1 payload. So what ends up happening is that there's this issue of sequential resistance, and it limits the ability of a patient to receive sequential ADCs because it's the same payload in the end that is creating this efficacy. That being said, rezatapopt would be available to patients either before ADCs or after. It's very unique in that the mechanism of action is unique, as David outlined. We are a structural reactivator. We do not have a chemo backbone. As a result, even if other ADCs do come into the fold, we will be essentially being used for those patients that are TP53 Y220C mutated. Perfect. Now let's get into the data set. It was September 1st you released updated data here. Talk to me a little bit about those results, and as the data set has matured, how has the objective response rate and mDOR evolved over time? Yeah. That's great. Yeah. What has been great to see is that the overall response rate has remained consistent across the different analysis sets that we have shared publicly. Currently, it is 46%, and we are looking at 76 evaluable patients as part of that. That includes four complete responses, 29 partial responses, and two unconfirmed partial responses. This is quite compelling that that ORR has just been consistent over time. Yeah. What we are seeing is the median duration of response increasing over time. Currently, as of the mid-May data cut, it is 10 months, and this is still considered an interim data cut. We are planning to have a primary analysis set available at the end of this year. The fact that we are seeing four complete responses, and that is from demonstrating that deepening of efficacy over time, because these patients started out having partial responses, as well as this median duration of response increasing over time, it is truly demonstrating that benefit for patients that is being observed. Obviously with all precision oncology targeted drugs, resistance mechanisms tend to crop up. Have you done any analysis to evaluate what sort of resistance mechanisms are appearing as due to rezatapopt therapy? Yeah, it is interesting. We have been looking at this from a ctDNA perspective, and from a resistance point of view, we are not seeing a clear trend. Right? We tend to see, for example, in about 10%-15% of patients, a second site TP53 mutation that forms, but that is to be expected. That does not necessarily preclude a patient from maintaining a response or having a response. Okay. We are really not seeing a clear resistance mechanism that is appearing. Although one would, and we did anticipate that second site inactivating mutations would be the mechanism of resistance as often seen in a targeted therapy like this, right? Pre-clinically, we were able to recapitulate that. Hence we thought we would see it in the clinic, and as Deepika said, we are not. We are seeing second site mutations, but they are not inactivating. Yeah, that is interesting. It is interesting. When a patient breaks out and we have looked at multiple other markers and drivers in addition to Y220C, there is no obvious candidate of why a patient progresses on rezatapopt. Having said that, the ORR is about 50%, so half the patients respond. It is important to note that it is a small molecule, so it is the only ovarian cancer therapy that is at home. All the others are IV based, whether it is an ADC or a therapy in combination with chemo. When I think about the Y220C targeted reactivator landscape, obviously I have three molecules come to mind: FMC-220, GenSci128 Yeah. And NTS-071. Sure. We have seen preclinical data for pretty much all of them. They are either in the clinic or advancing into the clinic. Based on the data you have seen to date for those competitor molecules, how are you thinking about those agents from a competition standpoint? Yeah. Where do you believe rezatapopt is differentiated relative to them? I'll take that. There's probably about 12 programs out there, Y220C, all of which are basically single atom knockoffs of rezatapopt. Frontier Medicines might be its own beast because it's a covalent binder. We can go into that. The one on mainland. The others. Other ones. Yeah. Forget about it. Okay. Yeah. Okay. So that one, just smart guys. We know them, and we like them. It's an interesting molecule, but rezatapopt came out of a screening campaign of covalent binders and non-covalent binders. We ran those in parallel, and what we found, and so just for the group here, tyrosine to a cysteine. A cysteine is a natural target for a warhead. You have the opportunity to create a covalent binder. To be clear, rezatapopt is reversible, but it has a very fast kon and a super slow koff. Its resonance time is for a good amount. The problem with the covalent binder, so one is empirically, they were inferior to the non-covalent binders in our hands. Second of all, when you take p53 biology into account, and I would argue that, so we've been at this for 13 years, right? The guy who discovered it is at the company every week. We are heavily steeped in p53 biology and adherent to that. An important dynamic of p53, is one of its immediate downstream transcriptional targets, and it's a protein called MDM2, which is an E3 ligase that physically binds p53, the protein, ubiquitinates it, and targets it for degradation. The reason is, if p53 went unchecked, and it's in every one of our cells, we would all melt. What happens is p53 is kept at really low concentrations in a normal cell. What happens is it gradually increases its expression, induces MDM2 goes up, binds wild type p53, degrades it, p53 goes down, MDM2 goes down. There's this oscillation. One of the consequences of restoring wild type p53 and Y220C is that it does turn on MDM2 because it is in its wild type pathway. Bearing that in mind, we dose every 24 hours with rezatapopt. What that does is you quickly restore wild type activity. We see responses by the first scan, vast majority of the time, six weeks. This was anticipated that rezatapopt's mechanism of action would have a very quick onset. What happens is we restore that wild type activity. MDM2 starts going up as other apoptotic target genes, starts degrading p53. We start cannibalizing our own target. We reset that clock every 24 hours. If you chronically induce wild type p53 activity, you chronically induce MDM2, and you are battling yourself. You are degrading the target that you are restoring chronically. We also, from just the biology of p53, thought that the covalent approaches would be inferior. We shall see in the clinic, good luck to them. Also we are looking at approval next year, and they will be lucky to find a patient in North America. We wish the best for them. We do not think it is going to compete with rezatapopt. Plus, we are in the market next year. Following your recent interaction with the FDA on that topic, looking more towards you now. You are targeting the NDA submission for accelerated approval in 1Q of next year. Outside of locking in the final clinical data from the completed ovarian cohort from the primary analysis, what operational or CMC requirements need to still be met over the next few quarters in order to ensure a successful submission? You can take it, but we are done. Okay. Yeah. We're very well positioned from a CMC perspective. Our API has been manufactured. It's been completely validated, and now it's just a matter of executing on the drug product batches, and that should be very straightforward. At least help frame for investors why you're so confident in this potential accelerated approval. Can you give us some historical context in terms of the PROC, in terms of the PROC indication, and why those precedents give you confidence in your accelerated approval pathway? The precedence that gives us confidence is more in the precision oncology area across the different tumor types where this has been utilized as when you have a rare biomarker selected patient population, utilizing a single arm study via an accelerated approval pathway will enable us to get there. Of course, what you need is a compelling ORR and a DOR that is also compelling. What you also need to exclude is standard of care. When you look at the AURELIA data and the composite of the chemotherapies, it was a 12% ORR. But when you look at the strongest agent that was performing, it was single agent paclitaxel at 30%. We are clearly exceeding that bar from a standard of care perspective if you're looking specifically at paclitaxel, and our 95% confidence interval is very compelling, as well as our point estimate. This is what gives us that confidence. Our median DOR currently is at 10 months, and we do hope that that will continue to improve over time for the primary analysis. So obviously under an accelerated approval pathway, the FDA often places a significant emphasis on the design of the confirmatory phase III and where it is in the timing. Maybe outline the plan, the trial design, key endpoints, comparator strategy here, anticipated enrollment and initiation timelines for that study to support full approval. Given the rarity of the mutation, essentially the agency has confirmed that we can continue to enroll in a single-arm fashion to provide that confirmatory evidence. So we plan to complete the enrollment of the PYNNACLE phase II study, specifically for ovarian, by the end of this year on approximately 120 patients, and that should be sufficient to essentially support that confirmatory evidence. So with the NDA filed, now I'm coming to you, Phil. With the NDA filing for rezatapopt in 1Q, and given your recent appointment here at the company, how are you preparing for the U.S. commercial launch of rezatapopt? And maybe talk to me a little bit about how you see biomarker testing in the field currently for PROC. All to you. Yeah, no, I really appreciate the question. In terms of launch preparations, it's actively underway, really anchored around three key priorities. The first being people and staffing, so we're actively recruiting for and looking to build out the commercial leadership team. Second is the infrastructure, so as you think about making a transition from being a clinical stage company to a commercial organization, making sure that we have the systems in place to enable the launch of rezatapopt. And then third is around strategic planning. So, we're actively developing and refining the launch plans that will enable us to really have a rapid trajectory. But I would say the net takeaway here is that we do believe that a lean, fit-for-purpose commercial model will enable us to unlock a meaningful value and really get rezatapopt to the patients who need it the most. And then, to your question around biomarker testing, patient identification is really important for rezatapopt. I think for us, if anything, it's a point of strength and not necessarily a weakness here, in that when you think about the landscape today, TP53 Y220C mutation is actively being identified today across NGS panels. So what does that mean for us at launch? What that means is that at time of approval for rezatapopt, many patients will already know if they're TP53 Y220C positive or not, and now with the approval of rezatapopt, and something that's actionable, we think that it'll really set up for a nice accelerated approval at launch. Yeah. When I think about the PROC side, it seems like the folate receptor alpha ADCs sort of did a lot of the work for you in terms of NGS testing here, right? Because the office had to identify which patients were folate receptor alpha positive, and since it's included in these NGS panels now with Y220C, it seems like there would be a relatively high percentage of patients that are already tested in that PROC setting. What sort of percentage are actually receiving that test? Yeah. Our early estimates, based upon some of our early work in preparation for launch, is that upwards of 80% of patients are being tested prior to their first-line treatment in ovarian cancer. Then as they progress along their patient journey, if they haven't been tested in that first-line setting, they continue to be tested in second and third line. Okay. So that being said, we are confident that there is going to be really a high bar of patients that are already tested. Yeah. And pre-identified on rezatapopt. All right. Well, good luck to you, Phil. Thank you. Obviously, no pressure. Yeah, no pressure, dude. Not feeling it. Beyond ovarian cancer, David, obviously we've seen a few data sets in other indications. Where do you see the most compelling additional opportunities here? Which ones are the highest priorities for you moving forward? Right. Well, obviously, PROC to start with, and expanding there in combination and further upline, even to PSOC. But in addition to rezatapopt in ovarian cancer, as you appreciate, we had a basket trial of which we designed ovarian cancer to break out to be our first NDA, very likely to be followed by endometrial cancer. So that cohort is still being actively enrolled, but as we track those patients, and we've been public about this, the ORR is incredibly strong, around 50%. So, it's tracking like ovarian cancer in terms of activity and tolerability. So endometrial will be the next NDA. And then we see a strong signal in lung cancer as well. And we feel to really tackle lung properly, that stratification is probably the approach for rezatapopt. Okay. We're going to maybe look at triple-negative breast cancer as a standout. Okay. So there are numerous strategies for expanding rezatapopt in more of a tumor-agnostic setting. Okay. Last question from me before I toss it over to the audience. When we think about the next 12-18 months, obviously we have the potential launch of rezatapopt. When do we think we might see this primary analysis actually be done here? Can you remind us of your cash position, what that operational runway actually looks like? Yep. Primary analysis data is planned to be available by the end of this year. As you noted, we have that first quarter NDA submission, as well as that potential launch at the end of next year. I think in parallel, what we are looking to do is also initiate other clinical studies, for example, in combination with bevacizumab in the maintenance setting in PSOC, also looking at the relapse refractory AML/MDS population. There is an ongoing study by MD Anderson that is currently in dose escalation. Makes sense in that indication. Absolutely. As you know, these patients are poorly served. Yeah. By current standard of care when they're TP53 mutated, and there hasn't been a drug available to target— Right. TP53 in recent times. We're very excited from a clinical perspective, and I'll hand it over to David to talk about the capital. Yeah. I will be brief here. We ended the last quarter with $79.4 million. We just raised $50 million in a public offering a couple of weeks ago. In addition to that $50 million, there is another $25 million that the company can call at acceptance of the rezatapopt NDA in PROC. That will get us through the second quarter of 2028. We are going to launch at the end of this year. I think we feel pretty confident about our capital situation and well-funded through launch and beyond. Awesome. Well, I really appreciate you guys talking.