PMV Pharmaceuticals, Inc H.C. Wainwright 28th Annual Global Investment Conference

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 rezafapt.

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, rezafapt, 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.

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.

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.