Terrific. Good afternoon, everybody, and thanks once again for joining us for the 45th Annual TD Cowen Healthcare Conference. I'm Yaron Werber with the Biotech team here, and it's a great pleasure to introduce PMV Pharma. With us today, David Mack, Co-founder, President and CEO, and Deepika Jalota, Chief Development Officer. Ladies and gentlemen, thanks for coming. We're going to do a presentation, and then we'll take Q&A. Deepika and David, great to see you.
Excellent.
Yaron, thank you for that and for the invitation to present today. It's always great to see you and always great to be at the Cowen Conference, so thank you again. We're excited today to give you an update on progress at PMV Pharmaceuticals with an emphasis on rezatapopt, our clinical candidate in a Phase II pivotal trial. Just to remind the group, rezatapopt is a first-in-class p53 reactivator of the Y220C hotspot mutant. It's a structural corrector, so it engages the mutant p53 protein and converts it to a wild-type structure, which induces p53-mediated transcription and p53-mediated cell death. We achieved a clinical proof of concept in our Phase I, which demonstrated a preliminary efficacy at the recommended Phase II dose of 2,000 mg q.d., so once-a-day dosing, with a 38% ORR, and it was very well tolerated.
We will go through that data today with our Chief Development Officer, Deepika Jalota. What Deepika will expand on is our single-arm registrational trial, and an interim analysis is planned for the middle of this year. That will include a minimum of 30 patients and a minimum of 18 weeks of follow-up. We plan on submitting the NDA for rezatapopt at the end of 2026, and we ended last year with $183 million in the bank, which is sufficient funds to get us through the end of 2026.
Just a quick word about Y220C, which is in about 1% of solid tumors, but there was a spectrum of association of that hotspot mutant with specific histologies ranging from, you know, about 1% in lung all the way to 3% in ovarian cancer, which is not surprising to hear as high-grade serous ovarian cancer is associated with about 100% mutant p53. You will see these histologies reflected in our Phase I, and you can expect to see the same in our Phase II pivotal. With that, I will hand it over to Deepika, who will update us, remind us of the Phase I and the design and updates on the Phase II pivotal. Deepika?
Thank you, David. The PYNNACLE study is a Phase I/II seamless study design. Here you can see the Phase I study design, which was an mTPI design where we enrolled patients that were at least 12 years of age with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. Our primary objective was to determine the MTD as well as to select the recommended Phase II dose and evaluate the safety and tolerability of our product. In addition, our secondary objectives included pharmacokinetics as well as preliminary efficacy. When you look at our study design, we enrolled patients across multiple dose levels ranging from 150 mg q.d. all the way up to 1,500 mg b.i.d. In blue, you can see the efficacious dose range that was identified, which was 1,150 mg q.d. to 1,500 mg b.i.d.
In green, you can see our recommended Phase II dose, which was 2,000 mg q.d. This was basically identified through Project Optimus, and we did this in line with FDA alignment. We enrolled 77 patients in total, and when you look at the efficacious dose range, we enrolled 67 patients in that specific dose range. This is a data cut that we'll be walking through from September 5th, 2023. Here you can see the patient demographics and the disease characteristics across the efficacious dose range. We essentially enrolled, if you look at the right-hand side, the majority of our patients were in the ovarian cancer population, which was around 33%. We also included patients that had pancreatic cancer, breast cancer, as well as colon and prostate. In addition, we had small cell lung cancer and endometrial cancer patients enrolled.
These patients had a median age of 63 years of age, and the majority of our patients were female, as you can see based on the tumor types that we enrolled. As far as the race, the majority of our patients were white, and 67% of our patients were ECOG status 1. When you look at our prior lines of systemic therapy, there was a median of three prior lines with a range of one to nine prior lines of therapy. We, in addition, enrolled germline patients. We had one that was positive, and from a safety perspective, it was consistent with what you would expect from a somatic mutation point of view. From a KRAS status perspective, we had wild-type as well as KRAS mutated patients.
When you look at the KRAS wild-type, it was 75% of our patients that were enrolled, and the KRAS single nucleotide variant patients were about 25%. When you look at this specific subgroup of patients with the KRAS single nucleotide variant, we essentially saw that there was not the same depth or durability of response compared to our patients that had KRAS wild-type status, which, as you'll see in a few slides, drove us to a KRAS wild-type and TP53 Y220C patient population. When you look at the impact of that, essentially, KRAS mutated patients only resulted in a 10% decrease with regards to the eligible patient population. Really, 90% of the patients that have TP53 Y220C mutations are KRAS wild-type. Here you can see the patient filter with regards to the efficacy evaluable population.
When you walk through from a full analysis set to the efficacy evaluable, where we landed on TP53 Y220C and KRAS wild-type patients with at least one post-baseline assessment, you essentially have 38 patients from our Phase I dataset that we'll be walking through in just a moment. As you can see, it's a compelling waterfall plot where we do see responses across multiple tumor types. Here you can see in teal, it represents the ovarian cancer partial responses that we saw. In addition, we have responses in breast cancer, small cell lung cancer, prostate cancer, as well as endometrial. In addition, beyond this dataset, we did have a head and neck responder as well. That is a total of six histologies of which we saw responses. When you look across the waterfall plot, you have a tumor shrinkage that's observed in 87% of patients.
Here is our data broken out per tumor type as well as from the recommended Phase II dose of 2,000 mg q.d. and the efficacious dose range. When you look at the confirmed ORR at the RP2D, it is 38%. We also had a seven-month durability of response. When you look at the right-hand side, you can see that 7 out of 15 ovarian cancer patients across the efficacious dose range had a response. In addition, in breast cancer, we had 3 out of 8 responders. When you look at small cell lung cancer, endometrial, prostate cancer, and then beyond this dataset, we had a head and neck responder. That total response enables us to have six histologies of which we did see responses. Here is the swimmers plot where you can see the median time to response was 1.5 months.
Patients are scanned every six weeks, and essentially, we tend to see patients respond either at the first or second scan. In addition, rezatapopt has demonstrated a favorable safety profile across the efficacious dose range you can see here. Most of the treatment-related adverse events were Grade I and II in nature, and most frequently, we were seeing nausea and vomiting, which basically improved with food. The dual benefit of administering with food is that you also see a 40% increase in exposure as well as the decrease in treatment-related adverse events related to GI toxicities. We had a low rate of drug discontinuations at 3% due to treatment-related adverse events. Beyond the GI toxicities, essentially, you do see blood creatinine increase as well as ALT and AST increase, primarily Grade I and II in nature. With that, we'll transition to the Phase II study design.
Taking all the learnings we had from Phase I, we designed this Phase II study in patients that have locally advanced or metastatic solid tumors, excluding primary CNS tumors, primarily because of the low blood-brain barrier penetration. In addition, these patients should have documented TP53 Y220C mutation as well as being KRAS wild-type status. This is based on the learnings we had from the Phase I study. Also, these patients would have received prior standard of care or would be ineligible for appropriate standard of care. This is a basket study of 114 patients where we have five cohorts in total. Cohort I has 42 patients in ovarian cancer. Cohorts II through V have 18 patients each in lung cancer, breast cancer, endometrial cancer, and other solid tumors.
As you can see, this enables us to pursue multiple opportunities, define registration paths in ovarian as well as tumor-agnostic patient populations. We have received alignment on the recommended Phase II dose as well as the patient population and the pivotal single-arm Phase II study design. This enables us to pursue an accelerated approval strategy from an NDA submission perspective, which we are targeting for the end of 2026. As mentioned earlier, approximately 90% of the TP53 Y220C patients are KRAS wild-type. As you can see here, KRAS wild-type status for pancreatic cancer is quite low at 6%. These pancreatic cancer patients are primarily KRAS mutated. In addition, in CRC, it is about 50% of these patients that have KRAS mutations. The impact for our addressable market population is quite low with regards to exclusion of these KRAS single nucleotide variant patients.
As you can see here, rezatapopt has the potential to benefit over 14,000 patients in the U.S. When you look at the standard of care overall response rate, for example, looking at SCLC second line, it's a very dire ORR that we're looking at at 7%. It ranges from 7%-15% in all solid tumors. In ovarian cancer specifically, it's a standard of care overall response rate of 12% in the platinum-resistant population. This truly demonstrates that TP53 mutated tumors really have a correlation with poor overall clinical survival and outcomes across multiple tumor types. This is truly a high unmet medical need population. Our study will enable us to generate additional patient data across multiple tumor types and ultimately to support a tumor-agnostic approach.
With that, essentially, we are executing on our Phase II study, and we are on a path to NDA submission in 2026, at the end of 2026 specifically. We look forward to that interim analysis data coming out in the middle of this year for this study as well. Also, beyond our monotherapy program, we are evaluating rezatapopt in combination with azacitidine in collaboration with MD Anderson and MSK in an investigator-initiated trial. This is a very highly unmet medical need, with these patients having a dismal outcome as far as their overall survival. Physicians have been waiting for a long time for a TP53 targeted agent in this patient population. This study has started enrollment, and we look forward to sharing additional information as the study progresses.
In addition, in the middle of this year, we plan to provide additional information around our undisclosed target that we are currently developing and is in the lead optimization stage. In summary, our key upcoming milestones include for our monotherapy program, interim analysis in the middle of this year, our planned NDA submission at the end of 2026. As noted, we did initiate Phase I enrollment with MD Anderson this past quarter. Essentially, what we're left with from a cash balance perspective as of the end of 2024 is $183 million. That concludes our presentation.
The interim analysis mid-year, you said 30 patients. Do you have any sense? Is it going to be enriched for ovarian? Is it sort of all comers just based on how they're coming in? Secondly, it's going to be a minimum of 18 weeks follow-up, right? As you think about the go, no go to continue to enroll, what are those sort of criteria?
We do anticipate that about a third of our patients will have ovarian cancer, and it will be a heterogeneous patient population from an enrollment perspective across all of our different cohorts. I think from a go, no go perspective, it's a matter of looking at our data and assessing what will be the initial indication that we will pursue. We do plan to have health authority interaction in the coming months, essentially to align on that path forward based on that data for the interim analysis.
Based on that, is the thought to then decide whether you hyper-enroll cohort X, Y, Z as opposed to all five cohorts, or whether you then engage with regulatory authorities to see if you can do accelerated approval for other types of cancer? Kind of how are you thinking about it?
Yeah, I think there are multiple options on the table. I think when we discuss with the health authority, it's really to focus in on what will that initial indication look like. For example, a base case option could be to pursue ovarian cancer to basically expedite getting that initial NDA across the finish line and then continuing to enroll and to build from there. When you look at tumor-agnostic approvals, there have been nine to date so far. Three of those essentially were in the NTRK gene fusion space. Those were the only ones that really had an initial approval with a tumor-agnostic indication. The other six really built from their initial indications and built towards that tumor-agnostic approval.
There is optionality built in based on our study design where we can essentially, based on our ovarian cancer pre-specified primary analysis population, pursue that specific indication as a start.
It sounds like about a third, so it's about 10 patients or so. Do you have a sense based on who's coming in so far and which sites open quickly? Kind of who are the other next ones? Like in the past, you've showed responses in breast, endometrial. You have not had a lot of patients in lung historically, but you've showed responses in the other three, obviously including ovarian as well.
I think what we'll see is a very diverse group of patients across those five cohorts in total. You will see more experience beyond what we saw in Phase I as far as the diversity of tumor types.
At this point, how many sites are open already?
We have 90% of our 60 targeted sites that have been opened so far.
Where are they located, just geographically?
Yeah, they're located in the U.S., U.K., Europe, as well as Asia-Pacific.
Do they, in terms of, do they require NGS screening at baseline or you can look at historical surgical samples to detect p53 status?
We enroll patients based on local historical NGS testing. We assess whether or not the assay is robust and is considered to be a sponsor-approved test. Based on that historical testing, we can enroll patients in that pre-screening stage and then they enter into screening and then they will be assessed for other inclusion/exclusion criteria.
Are those screens validated screens that are available pretty much around the globe, or is there in some sites it's kind of a local test?
There is commercial testing as well as at these academic sites, they have their own locally developed tests. We assess the viability of all of these tests and whether or not they're robust enough to identify that TP53 Y220C mutation. This includes Foundation Medicine, Caris, Tempus, all of the big commercial players.
The local sites that you've opened, you know that you can rely on their tests and the FDA is going to accept those tests.
That's correct.
In your discussions with FDA, sort of even to get an accelerated approval for ovarian, is it sort of the magical 30% is the cutoff response rate in six months or how are they six months could be long in ovarian as a monotherapy? How are they thinking about it and how are you thinking about it?
Yeah, we have designed the study to enable us to target that 30% overall response rate while excluding the 12% lower bound of that 95% confidence interval threshold. We believe that 30% will be compelling from an FDA perspective as well as a median durability of response of six months in addition to having favorable safety profiles. These are the three components that would be evaluated from the FDA perspective.
It sounds like you're expecting to enroll the remaining 82 patients or so, 84, right? Thirty initially and then 84 by the end of the year. Is it just based on timing of how you open the sites? You're on sort of the hockey stick curve?
That's exactly right. There is this startup period with regards to site activation that enables us to now be at this peak enrollment level per month to enable us to achieve that.
The cohort two, three, four, I mean, these are 18 patients per cohort. I imagine you'll ultimately, based on that data, you'll probably want to fill them fuller to then expand the label. Am I kind of thinking about it correctly?
Yes, I think this will, if ovarian cancer ends up being our base case, there will be the optionality, for example, to potentially have multiple tumor types in that initial NDA or tumor-agnostic. We'll let the data drive that initial NDA strategy.
Okay. Essentially, let's say we have about 10 patients in ovarian, we're looking at 30-40% response rate. Because the other ones are going to be almost, again, if it's going to be sort of equal, 20 patients, so it's almost like five patients per cohort roughly in the initial interim.
It's basically based on enrollment. It could be some cohorts may have a little bit more versus a little bit less.
Okay. In terms of you're in this quarter, you're going to start a combination study in AML with MD Anderson. What's the reason to pick AML?
Yeah, it's actually already started. First patient has been enrolled. It's been huge. There's been a huge interest from the external community to find a product that can target these TP53 mutations. Based on the experience we've had with MD Anderson in the solid tumor space, they were very much interested in initiating this study in the hematologic malignancy space. As mentioned, these patients really have a dismal outcome from an overall survival perspective when they have TP53 mutations on board. There's been a lot of incoming interest with regards to hematologic malignancies.
How big is that initial IST expected to be?
We are doing a Phase Ib study design. It is around 25 patients, and then we have the option to expand to 10 additional more patients.
It's going to be in one site, so it's going to be in two sites?
It's going to be in two sites. MD Anderson has kicked it off, and MSK should be up and running within the next few months.
Okay. Terrific. Maybe as you think about cash usage through the end of next year, the $183 million, so that's going to get you through data and through filing at that point.
Correct. We expect that to last us to the end of 2026 to get us to that NDA submission timeframe.
With this data, do you think you can file in Europe too, or it's really mostly FDA enabling?
We think there is definitely optionality from a global perspective. We will be engaging with European health authorities once we have further discussions with the FDA.
Have you engaged with EMA already about the trial design, or it's mostly been a little bit more FDA-centric?
We've engaged with multiple health authorities in Europe so far.
Okay. Is this something you might want to partner ex-U.S.? And what about in the U.S.?
We are looking strategically at multiple options. There is that potential to partner in Asia-Pacific, for example, or globally. I think we're opportunistic with regards to our strategic options.
Okay. It sounds like in mid-year you might give an update on your next development candidate that's in lead optimization right now. Can you give us maybe a little bit of a hint which mutations you're looking at and what we might hear?
It is orthogonally connected to p53. It is not a p53 hotspot mutant that we're going to be targeting. There will definitely be more information to come.
That's in lead ops. That's probably IND filing late 2026, potential timeline?
We plan to have a development candidate announcement in that mid-2025 timeframe that enables us to have an IND submission in the first half of 2026.
Okay. Is that going to be, is it covalent or non-covalent?
It is a non-covalent.
I imagine oral.
That's correct.
Okay. For solid tumors or liquid tumors?
It's for solid tumors.
I can start naming all the solid tumors. All the mutations. I have a list here. Okay. So that development candidate, so it sounds like you're pretty late in lead up already if you're going to have a dev candidate in three months from now.
That's right.
Okay. All right. Terrific. Team, thank you so much for coming. Great to see you. Really appreciate it.
Thank you for your time.
Thank you.