All right, good morning, everybody, and thank you once again for joining us for the 6th Annual Oncology Innovation Summit. I'm Yaron Werber from the TD Cowen Biotech team, and it's a great pleasure to moderate the next fireside chat with PMV Pharmaceuticals. With us today, we have David Mack, CEO; Deepika Jalota, Chief Development Officer; and Tim Smith, SVP and Head of Corporate Development. Tim, thank you for joining us. We appreciate it.
Yaron, thanks for having us. We appreciate being here. Thank you.
This is very timely, just given the upcoming update, which we'll talk about in a second, which I think we're expecting it to be in July or August. For the audience, if you have any questions, feel free to email me directly or put it into the Wall Street Webcasting chat, and I'll ask it anonymously on your behalf. The phase II, this is the pivotal pinnacle trial, 114 patients for the audience. This is in Y220C, p53 mutations of KRAS wild type. You have five different cohorts. You have ovarian, lung, breast, endometrial, and other. I'm going to ask maybe first, you're targeting opening 60 sites, and about 90% of those were open as of March. Can you give us a little bit of an update, kind of where are you now?
Sure, Deepika.
We've progressed quite well with site activation, and we're close to where we need to be from that full site activation. Enrollment progresses to target, and we plan to complete enrollment by the end of this year.
Is it running? Is it on target, or is it maybe even a little bit ahead of target, just given that you've increased the number of patients you'll show us at the interim?
It's running, I would say, on target to what we were expecting.
Okay. Maybe I'll just stay organized, and I'll come back to that in a second. Of the sites that are open, did you sort of prioritize the target ovarian? Because that's obviously one of the key initial cohorts versus the rest of the cohorts. Secondly, where are you on opening lung cancer sites as well?
Basically, our overall strategy from a site selection perspective was to identify those sites that use next-generation sequencing to identify patients. From there, we focused on enrolling or targeting sites that had gyne-onc specialists as well as thoracic specialists, in addition to those medical oncologists that focus in on breast cancer enrollment. We are really focusing in on these three subspecialties when it comes to focusing in on trying to enroll the patients that we need for this trial.
Got it. Okay. And so maybe before I dive into data questions, you're going to get an update this summer. And again, I think you've said mid-year. Is mid-year sort of, can we roll out June? Because that's really Q2. And can we sort of roll out September? Because that's really definitively Q3. Kind of how are you thinking about mid-year?
We've been basically stating externally that it will be mid-year. I think based on what you're saying, it's a logical explanation as far as where we would most likely land.
I think you bookended well.
Yes.
You're right.
It sounds like it's probably between July and August. Make sure everybody on vacation has connectivity. You're now expecting to enroll 50 patients at that interim, up to 18 weeks of minimal follow-up. I believe 40% of those patients are going to be ovarian. That was sort of the initial guidance when you expected to have 30 patients mid-year, and now it's 50. Maybe the first question is, what drove that delta if it wasn't enrollment facet unexpected?
Yeah, it's a great question. Enrollment was definitely a facet. I think we were looking at the timing of when the futility analysis would occur. We want to provide as much data as possible from an external perspective to share what we've gathered so far. That's basically where we landed with the 50 and the timing for the 60.
Is it still 40% is ovarian or 20 women?
Yes, that's correct. It will be approximately 40%.
Okay. And how much follow-up? It sounds like it's going to be minimal of 18 weeks. Do you have any sense? Are we going to be able to start looking at the median DOR and median PFS, et cetera? Or is it going to be too early?
I think we will be sharing swimmer's plot information. You will get an understanding of the durability so far, but it will be a bit immature as far as assessing the median DOR at the same timeframe.
Although, Yaron, we can point to the phase I data, which we did show a median duration of response of seven months. On the backs of that, look through that lens when you look at the swimmer's plots.
That was specifically in ovarian?
That was across histologies.
Across histologies. Okay. Got it. Okay. So seven months.
Just to clarify, so I think that's our goal to, of course, achieve the phase I median duration of response or exceed it. But it might be too early for us to share or.
No, for sure.
For seven months durability.
No, the pivotal data are still evolving to durability of response as Deepika said. The 18 weeks, we stand by that, which is three scans. Scans are every six weeks.
Okay. Q6 weeks. Got it. That is three scans. In the previous data, patients typically, again, I am looking at a little bit on the ovarian side. Specifically, patients typically responded in the first one or two cycles. At least of those eight responses in ovarian, I believe five out of the eight responses were in the first one or two cycles, one or two months. Would you expect something similar in this interim?
We are basically scanning patients every six weeks. We would expect the first response to be seen at least at the first or second scan, so at the 6- or 12-week mark.
Got it. Yeah, that makes sense. Okay. When we looked at the, to give the audience just a refresher, at SGO in 2024, you showed 8 out of 15 PR in ovarian. And that's specifically there too, with seven months MDOR. At San Antonio, you showed some of the updated data in breast cancer, and it was 3 out of 8. Now, this is across the 1150-2500 doses. Can you remind us where were the, in which dose were the responses specifically?
With regards to the breast cancer data or?
Both breast cancer and maybe in ovarian.
It was basically for the breast cancer data, we saw 2000 mg as well as 2500. For ovarian, it was spread across the efficacious dose range. It was 2000, 2500, and 1500 mg b.i.d.
It was okay. But it was 2000, 2500, and then 1500 b.i.d.
That's correct.
That was the 8 out of 15. The pivotal dose here is 2000.
PD, that's correct.
Yeah.
Yes.
How do you feel? I mean, at ASCO, what was it now? ASCO 2022? I can't remember. I think it was ASCO 2022. You showed your initial PK. Just remind us, why did you choose? Because you've done Project Optimus too. How did you come to choose the 2000 mg dose?
This was based on exposure response that we saw from an efficacy and safety perspective, as well as the preliminary efficacy and safety, and looking at the non-clinical modeling as well. All of these components put together really put us at that 2000 mg QD dose level. In addition, we did have healthy volunteer food effect data that helped us understand what the exposure impact would be when administering food to patients. We ended up seeing a 40% increase in exposure as well as a decrease in GI toxicities. As a result, these patients are receiving 2000 mg QD with food as far as the recommended phase II dose.
They have to take food and eat, and you take the pill while you're eating or sort of right afterwards?
You take your food, and then you take the capsule, the tablet, or the four tablets after you eat with water.
Yeah. Okay. Is there a fat effect, or you can eat a regular meal?
Basically, we have minimal food guidance. So essentially a granola bar, 3 grams of fat, 100 calories. But the patient can take it with any type of food. There are no restrictions, but that's just a minimal requirement.
Got it. Okay. So given the biology of p53 and what you know so far, what are you expecting to see in terms of effect across different solid tumors? Do you expect the same effect in each tumor, or are there some tumors that are going to be more sensitive than others?
Essentially, our study. Go ahead, David.
Yeah, I'll just comment on that. When Arnie Levine and I started the company, of course, Arnie discovered p53 in 1979. Not based on any clinical data or even preclinical at that point, we envisioned that there would be certain histologies that would be particularly sensitive to reactivated p53. Now, a priori, which those are, it's hard to predict. Although if you do look at ovarian cancer, basically p53 is 100% mutated in high-grade serious ovarian cancer. That was one where we thought that that particular histology really does not tolerate wild-type p53 activity well, right? We thought that would be particularly sensitive just based on that observation. I think what you'll see from the data is an evolution of activity across histologies as predicted by the mechanism of action.
I think there will be certain histologies particularly sensitive to the p53 pathway given what I just articulated about ovarian cancer. Although, having said that, stepping back, the prediction is that it is a tumor-agnostic mechanism of action. I would argue we demonstrated that in phase I. Now, albeit some small numbers, three out of eight in breast cancer, for example, still we saw activity across six independent histologies in phase I. I would argue that does not happen by accident. It is consistent with the mechanism of action.
It sounds like if we look at the prior data, again, small cell was pretty early. It was one out of two, and the mutual was one out of one. You did not really have any lung cancer patients sort of early. I mean, you had non-small cell, I should say. There was some variability, but to a certain degree, you can argue eight out of 15 is very similar to three out of eight, more or less. Do you expect sort of the same sort of response in each tumor type? Does it depend on what kind of previous therapies they received?
Deepika?
I think we will be seeing our data where essentially we'll be able to highlight the information from a prior line of therapy perspective as well as what we're seeing across the different tumor types. As you can imagine, we have the most robust data in ovarian cancer, given that it is 40% of our 50 patients. We will have enough data across the other cohorts to provide that initial information with regards to the signal that you would be seeing.
Okay. At the interim analysis, would you break out the data by cohorts? Would it be certainly break out ovarian and then lump the rest of the histologies? Is it just going to be one all histologies together?
We will give you the ORR basically across the study in addition to the breakout per cohort as well.
Okay. Each cohort.
That's right.
Specifically, it sounds like it's going to be ovarian, breast. Would you have lung as a cohort or not yet?
Yes, we will have lung as a cohort.
Okay. So it's going to be those.
All five cohorts will be basically provided as far as the data.
That's right. Okay. So ovarian, lung, breast, endo, and other.
Exactly.
Okay.
Yaron, just to be clear on ovarian and why it is consistently outsized in our studies, the phase I as well as I think you gathered from the phase II, one of a couple of reasons. One is that although Y220C is about 1% associated with solid tumors, there is a spectrum of that association. 1% in lung, for example, but 3% in ovarian cancer. Outsized in ovarian. As we have all seen here in the clinic, ovarian cancer is so poorly served therapeutically that we see a lot of ovarian patients. That is one of the driving factors behind the consistent outsized numbers in ovarian. Having said that, with the 60-plus sites, we have gone to great lengths to ensure that we have representation of other histology so that we can build on that phase I observation.
Okay. Great. That's very useful. It sounds like you're planning on filing by the end of next year based on obviously having successful data. Are you thinking about filing for ovarian first, or would you file across all cohorts?
The study is designed for the option to do either/or based on the data as it's evolving. Essentially, enrollment will be driving that decision. As David noted, the frequency of the TP53 Y220C mutation is highest in ovarian cancer. The most likely scenario for that initial NDA submission would be ovarian cancer, but we are also going to be engaging further with the FDA with regards to that viability for the tumor-agnostic optionality for that initial indication.
Perhaps just a little history on the tumor-agnostic label, right? There are nine approvals to date, but six of those nine have gone the way of an anchor indication to get to the tumor-agnostic label, right? In fact, those six of nine, on average, it was two to three histologies that drove 50%-75% of the ORR, with the rest being a tail of other. This approach to take an anchor histology as you march your way towards tumor-agnostic is pretty common and makes sense in that certain other histologies need to catch up in numbers, right, over time. Why wait till the very end? We can get NDAs on the road to the tumor-agnostic label. That is on the table as part of the design, as Deepika said.
Yeah. To file, how much safety data do you need?
Typically, 100 patients would be sufficient from a safety database perspective.
With how much follow-up?
From a safety perspective, usually that entails one dose of rezatapopt being given. The follow-up piece is more from that efficacy and durability of response perspective. The FDA will be looking at ORR as well as durability of response in addition to the safety experience.
Yeah. Is 30% in six months still sort of the bar for FDA?
That's correct. Yes. That's what we would say is the target ORR for our study. What we're trying to exclude from that lower threshold perspective for ovarian cancer is 12% since that is the standard of care ORR.
You could do that with that single-agent design.
That's correct. The single-arm trial design. That's correct.
Got it. And so that's 12% for ovarian. If you're at 20%, is that sort of clinically meaningful, or it really needs to be 30%?
30% is the target that you would expect to see. There are some products that have been approved with less than that, but typically it's 30% and above that you'd want to be at to show that clinically meaningful effect.
Great. As you think about one of the biggest questions we get, I'm going to move now to the commercial element. It's 1% of solid tumors, but we've obviously seen investors are a little concerned if you look at the G12C launches at ROS1. A lot of these markets are sizable on paper, but patients inevitably, even though they're theoretically diagnosed, right, somewhere in the system, they're not really getting therapy or they're not getting that specific TKI. Do you have any sense why is that? As you think about commercialization, what can you do to really entice patients or physicians to use the drug?
Great question. Go for it, Deepika.
Yeah. I think it has to do, there's a bunch of different factors. We think it could be, for example, from a resistance mechanism perspective with the KRAS G12Cs, it's a tolerability element as well as a patient identification. For us, patient identification has not been a concern with regards to the fact even though it's a 1% frequency, TP53 Y220C is present on all of the NGS panels. NGS, as you know, has been becoming more widely adopted over time. If you look back five years ago compared to where we are today, it's transitioned significantly. From a tolerability perspective, when you look at our asset, our GI toxicities are manageable, our lab abnormalities that we're seeing, grade one and grade two in nature, everything that patients experience are monitorable, reversible, and manageable.
As a result, I think we do have a little bit of a different story compared to what you would see in comparison to KRAS G12C, for example.
Yeah. Have you been speaking with EMA about potentially filing based on this data?
We have had some health authority interactions with European national health authorities. We are prioritizing the U.S. at this point in time, but we will continue to engage with Europe as we progress.
Okay. You have not been speaking with EMA?
We've spoken with the national health authority so far, yes, in Europe.
National, yeah.
Yeah. The key ones that would really contribute to the EMA point of view.
Okay. Why not speak with EMA at this point? Because you want to have some of the data first?
That's right. At this point in time, it would be best for us to engage with them once we have the data to have that filing strategy in place with them. That is the most efficient way.
Okay. Are you thinking that this is something you'll take to commercialization yourself, or is that something you'll want to partner? Does it depend on U.S. versus ex-U.S., or how do you think about that?
I think we have many options on the table that we are evaluating currently. We are open to all options, and we're evaluating them significantly.
Would you want to launch this in the U.S., or does it make sense to get a partner into an existing infrastructure?
As mentioned, Yaron, I think we're looking at all options for commercialization.
Okay. Got it. Can you just remind us, cash, how much do you have, and what does that carry you through?
Sure. We closed last quarter with $166 million in the bank. That gets us through 2026, so through the NDA submission with the agency. We're comfortably capitalized, although this is a major catalyst, as you appreciate. We feel pretty comfortable with our cash position.
Okay. At FDA at CDER, how has the interaction been? Are the reviewers been sort of consistent, or have you seen some changes in the review team?
Yes. In the microcosm of rezatapopt, what we have seen is no changes at all. Our clinical team is intact at the FDA as well as the Oncology Center of Excellence. There has not been that much attrition from what we can see. Our division director is still present. As you know, Rick Pazdur has not left, and he has no interest in leaving. I think that in itself will provide the level of stability that we need in the divisions that we're working with.
So that's.
Yeah. To be fair, they've been incredibly responsive these last few months as they have been consistently throughout.
That's your sense, is that you're not hearing anything from kind of bubbling up that at some point, Pazdur is probably going to leave as he's deserved his retirement.
We hope.
It's a pleasure, by the way.
Yeah. I think Rick Pazdur has no interest in leaving from what I can from the grapevine that I've been interacting with, he's here to stay.
Well, that.
He's been there for a long time, so he's seen a lot in his time at the FDA.
Yeah. I think that alone should merit all the stocks going up 10% because I think there's been a lot of fears, unfounded, honestly.
Yeah. A lot of fears.
Life is too short.
Yeah.
Okay. I know we're over time. Maybe I'll ask one final question. Just on the combination with azacitidine, this is the MSK-MD Anderson program, the AML-MDS program, initially in AML, I believe. You're going to enroll 25 patients initially and have an option to enroll 10 more. Any update on that?
MD Anderson has enrolled their first patient in this study, and enrollment continues to progress.
Okay. Has Memorial opened enrollment or not yet?
Not yet. That will happen in the very near future.
Okay. Got it. Okay. And it's going to start with AML, and then you'll add MDS, or it's open to high-risk MDS right away?
It's open to high-risk relapse-refractory AML-MDS patients right away.
Okay. It is going to be 25 initially and then an option for 10 more.
That's correct. Yes.
Okay. What triggers that option?
Basically, it's once we identify the optimal dose for these patients, then we would continue to expand.
Okay. Oh, so that's going to be an expansion cohort.
Yes. That's right.
I see. Got it. Okay. Terrific team. Thank you for the time. We appreciate it. We'll be sure to stay to hover in July or slash early into August as well.
Great. We appreciate your hovering, Yaron. Thank you for your time here today. From PMV, thank you.
Great. Good seeing you. Thanks so much.
Great to see you always.
Thank you.