Great. Well, thanks for joining us, everybody. I'm Terence Flynn, the U.S. Biopharma analyst here at Morgan Stanley, and I'm very pleased to be hosting Arvinas this afternoon. Before we get started, I have to make some disclosures. Please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. Joining us today from the company, we have Ron Peck, the company's Chief Medical Officer, and Randy Teel, who is Head of Corporate Strategy and Business Development. Thanks so much, both, for joining me. Really appreciate you taking time out of your day to spend it with us today. Maybe I thought we'd start with just a quick overview, kind of the platform, but also the differentiation.
I think this is something that we, you know, we've talked on and off about over the years, but just remind us kind of the key features of the platform that really differentiate you from some of the other degrader companies out there.
Yeah, I can do that, and thanks very much for having us. Appreciate the opportunity. And so Arvinas was founded 10 years ago now, so it's as we get through the 10th year, it's a great place to be. We've got pivotal trials ongoing, which I can set a little bit of stage on as well. I think when it comes to platform, we have continued to try and make sure that our ability to make protein degraders orally bioavailable, even hoping, you know, to cross into the blood-brain barrier by the end of the year with a new IND that we have coming. We've tried to invest to make sure that platform stays ahead, and I think for us, at this point, we're really being judged by the strength of that pipeline.
So as I said, we've got a pivotal trial ongoing right now with ARV-471, or vepdegestrant, which is an ER-targeting therapy for breast cancer that we have in partnership with Pfizer. That trial is ongoing, expected to read out near the end of next year. We have another safety lead-in for a phase III ongoing as well, also with Pfizer on 471, in combination with palbociclib, which we'll certainly talk about over the course of this meeting. And then we also have data coming by the end of the year, on the palbociclib combination with 471, which we shared a little bit of data about earlier in the year, but that'll be a big opportunity to show how we can combine ARV-471 with palbociclib.
On the prostate cancer side, we've got two programs in the clinic, ARV-110, or bavdegalutamide, is poised to start its first pivotal trial by the end of the year. And we'll have data coming up at ESMO here in a couple, well, actually, end of next month. So that's an exciting moment for us. And then ARV-766 is a follow-up AR degrader, has a slightly broader range than bavdegalutamide, the first AR degrader. We just shared some data for that back in June, which I'm sure Ron will be talking about, too. By the end of the year, we expect to have two more programs through IND or CTA. One is BCL6, undruggable target in heme-onc, and then also LRRK2, which is our first neuroscience target. So that's the one I referred to a moment ago.
I think for us, showing that we can not only continue to create PROTACs that can get into people, and have a good profile so far, in the investigational stage is important, but with LRRK2, that first neuroscience program getting in that we hope will show oral and bioavailability and the ability to cross the blood-brain barrier, which it has done in earlier preclinical studies. So a lot going on for us as we close out the year and head into next year with our first pivotal data. But maybe pass to Ron for the rest of the questions.
Sure.
As usually happens.
The harder questions. No, thanks, Randy. Appreciate it. I guess maybe just starting on 471, because again, I can't pronounce the full new name.
You can do it.
But, again, you said, you know, phase III data by year-end 2024 here. Maybe just remind us, Ron, kind of the patient population design here, and then again, you know, as we think about, you know, how you're thinking about, I guess, the, you know, control arm, et cetera, in this study?
The VERITAC-2 study, so that's our ongoing second-line phase III study. It's over 500 patients, so big, robust trial design. The control arm is fulvestrant, which is still as a single agent, the standard of care in later-line breast cancer. So it's a trial that's basically directly comparing 471 versus fulvestrant. There are two primary endpoints. One is focused on this ESR1 mutant population. There's data over the last couple of years that patients who are in this late line setting, who have ESR1 mutation, seem to be more responsive to endocrine therapy. At this point, they've gone through a lot of therapy, there's a lot of resistance. That's kind of a clue that they may still be responsive.
But we also are including patients who have non-mutant disease as well, so it's, it's basically enrolling all comers. The second endpoint would be looking at all, all patients being treated. The intent is that we would have the ability to get labeling, not just for the ESR1 mutant population, but also all comers. And the data that we have from phase II with the single agent gives us the confidence, really gives us a lot of confidence for this trial as a whole, and not just for the ESR1 mutant population, but also the wild type.
As we think about fulvestrant performance here in this population, maybe just what are the kind of recent benchmarks?
Yeah, sure. Yeah, so over the last couple of years, there's a few studies that have been reported out, post-CDK4/6, and unfortunately, the results are pretty abysmal for fulvestrant. If post-CDK4/6, the clinical benefit rate, which is the typical primary endpoint for phase II, is between 10%-14%. And just as a frame of reference, the data that we had from the phase II had, but actually both phase I and phase II, our CBR was consistently somewhere between 37%-40%. Also, when we've looked at PFS, both in the mutant and the non-mutant, that gives us the confidence that this is gonna, you know, again, it's all across other comparisons and whatnot.
Our population was actually even more resistant than some of the trials that, you know, actually, all of the trials that have been used as our benchmarks. More resistant than that, 80% of the patients had gotten fulvestrant. And that's, you know, a pretty extensive amount of that therapy. And then also, nearly half the patients had metastatic chemotherapy, and it's well established that that is associated with the worst outcome. So going back to the population for phase III, it's actually an earlier line population in that, number one, while they're still post CDK4/6, they are fulvestrant naive. That's why fulvestrant is the control arm. And then they're excluded from having prior metastatic chemotherapy.
The intent here was that we wanted to identify a population where 471 could really achieve as a single agent results that could make it an important therapy in this population.
Yeah. What, and then maybe just remind us, ESR1, what's the frequency of that in the broader population here? Again, I know you're obviously going for the all comers label, but in the event that it's only an ESR1 population, just remind us, like, what that represents.
Yeah, it's roughly about half of the patients are ESR1 mutant.
Okay.
So it's a pretty substantial number. We'll have power, certainly for that subset. It's a big trial, it's over 500 patients, but also we'll have sufficient data to isolate what the benefit, or what the effect is in the non-mutants that help for regulatory decisions.
Yeah. Okay. Okay, great. Maybe just moving on to the other study, VERITAC-3, is the other important phase III trial that you guys are conducting here in combo with palbo. Again, similar type questions. I think the design was recently posted on ClinicalTrials.gov. It's just, you know, overview the population, the design, and then had a couple follow-ups.
Yeah. So this is a trial that is ultimately a Phase III study of palbociclib plus 471 versus aromatase inhibitor plus palbociclib. So basically, that would be the standard of care. And the first part of the trial is a lead-in, so it's a seamless design. The aim of the first part of the study, which is the first 50 patients in the trial, is designed to determine what the optimal palbo dose is.
So this goes back to early in the year, where we had data from the ongoing phase Ib combination to tell us that there's a sufficient enough of a exposure for palbo compared to historical data, roughly about a 50% increase in the AUC, to say that we needed to take a different approach for the start of the trial, again, to determine the optimal dose. And just to put this in context, that's, you know, essentially a 0.5-fold increase. If you look at, you know, traditional drug-drug interactions, you'll see, you know, 5-fold, 10-fold increases. So it's, it's not nearly in that degree, but certainly enough to do this lead-in.
And the important thing is that these two doses that are being tested, 100, which is one small step down from the approved dose, and then 75, which is also an existing dosing strength, are, you know, that's part of standard of care. Oftentimes, those reductions are being used roughly in 30% of patients, and we have, you know, high confidence that one of these two doses will be the right dose.
Okay. And is that, maybe just remind us, will we actually see... number one, will we see data from that lead-in portion, or will we just get a, kind of, we're going ahead with this dose into the broader trial? Like, what's the kind of disclosure policy around the lead-in?
Yeah, we haven't ironed that out. I mean, I think at this stage, it's hard to be specific, but since it's an ongoing trial, we don't want to set the expectation that we'll have data, but there will be some sort of way that we're giving some indication of progress of the study. And the other thing, just to be clear, is on ClinicalTrials.gov, you're not gonna get that breakdown. It's more about thinking of this as a seamless design.
Yeah. Understood. And so any guidance in terms of when that first lead-in, I mean, it's a small number of patients, so is that something that's likely in a complete kind of first half of next year, or is that a little bit too aggressive?
Yeah, we haven't really disclosed that. All I can say is that now that this study is... Actually, it has already started, so this is our second phase III study with 471. And basically, you know, this is part of the reason why we have the partnership with Pfizer is to basically as I think we use the term machine. So there's been a tremendous effort to pull out all the stops and make sure that the lead-in is completed as soon as possible so that the remainder of the trial can proceed as planned. And also there's, you know, very aggressive plans for the remainder of the trial, so it's basically being operationalized to plan for success.
Okay. And it would only, the outcome would be just a single dose, right? That's how the trial is set up, is you pick the best one.
Yep.
Okay. Then what are the criteria? Obviously, you're optimizing for the exposure, but is it also, you're gonna look at efficacy, I assume, safety, tolerability. So maybe just remind us of, like-
Yeah
... the criteria that you're gonna use to make that decision about which of the two. I'm assuming it's just very traditional criteria, but anything non-traditional as you-
Yeah. The-
Look at this?
Yeah, I think you alluded to it. It's really gonna be sort of a totality of the evidence piece. There will be PK part of this, safety. And the other thing is that we have, you know, data that will be coming in from the combination phase Ib, that will also be factored in. And one of the fortunate things for us with the Pfizer partnership is that they have extensive modeling that will also be rolled into the decision. So we really feel like we're gonna make a, you know, a clear decision on this. The other thing I might say is that, you know, back when this came out, I think there was, you know, people were trying to get their heads around this.
I mean, the good news is that we quickly, you know, with the FDA, came around and came up with a plan to address this, and started the trial. And the other thing is we're continuing to evaluate, you know, the profile of the drug from a clinical pharmacology. If you have noticed from ClinicalTrials.gov, we have a number of the traditional DDI studies that are done as part of a filing, and of course, we're thinking about the future of submitting this for approval. And that's also helping us understand the profile. We think this is gonna be, you know, a profile that's gonna be, you know, well accepted, and we think that the palbo piece of this is just, you know, regular drug development.
Yep. Maybe one more piece on that as well, because I don't think Ron said this, but that data we have by the end of the year for the combination from the phase Ib, we did let out a little bit of that data in our first-
Right
fourth-quarter earnings release on that.
Yep.
Just at the CBR level, just over 60%. But obviously, the data set coming up will be a lot more robust than that.
Yep
-single number.
Yep. Yeah, and that, it might be right, yeah.
Yeah, that was my segue question. So like, other than the CBR rate, which we already know, I mean, maybe just any-
Yeah.
in terms of, you know, high-level thoughts on what we're gonna see at, at ESMO.
Yeah. So, we'll have,
That's not ESMO. The other one's ESMO, sorry.
Yeah, yeah.
Undetermined conference.
Yeah. So that's, yeah, yeah. So this is an important disclosure for us because it's, you know, our first combination data out there. I mean, other than the early information we gave, as Randy said, we did have an early analysis on efficacy as part of our earnings release, first quarter. We'll have complete data for what is just short of a 50-patient data set, so more patients than was in that evaluation. We were actually quite thrilled, frankly, with the, you know, 60% or roughly CBR that was reported back then in 30 patients. Of course, they're small numbers, but we'll have more data, and, you know, as we will always do, is we'll, you know, look at this and how to get context, looking at benchmark studies.
So we look at studies like PACE, and MAINTAIN. These are recent CDK after CDK trials. Yeah, given that most of these patients are post-CDK, roughly over, you know, 50, 80, 85% or so. And then, you know, I thi`n`k the CAPItello AKT trial. So you can see a CBR that ranges between 30% to 50%. So, you know, if the data holds up, that will make us thrilled. We did not expect anything more than monotherapy activity, since palbo doesn't contribute based on the PACE study. So, we'll have, you know, complete data. You mentioned CBR, we'll have response data as well.
Okay. So no, no PFS, PFS?
No.
Okay. Okay. Understood. Okay. And then the... I guess if the, if the, I forgot my translate on that one. So, oh, the, the benchmark is in 30%-50%. You want to see that 60% kind of maintained, so that's gonna be the big, the big focal point. Okay. What, and just remind us on the tolerability side here, what you've seen so far. Obviously, there's the-
Yep
... you know, the PK issue, but beyond that, anything in terms of overlapping toxicity or tolerability that, again, as you think about these results, that you want to put into context?
Yeah, I think that the main thing is back to neutropenia. I mean, for several weeks, very, very, very happy with the safety profile. No expectation for overlapping toxicity. In fact, for several, as a single agent, you know, it looks, you know, really quite favorable compared to other therapies out there. And it's about neutropenia. Back in the beginning of the year, we said that with this, you know, 50% increase of AUC, and that's above the standard range of variability for palbo, which is ±30%, that grade 3/ 4 neutropenia is about 76% versus 66%, which is historic. But importantly, that did not translate into any increase in infections.
Out of 20 patients that were treated at the 200 dose of 471, which is the dose we use in phase III, that there was only one patient who discontinued. So it was quite well tolerated. You talk to the investigators, and this is business as usual for oncology. The other adverse events, there was nothing of note, you know, relative to what you would expect.
Okay. What I remembered I was gonna ask is that has there ever been an analysis looking at mapping CBR to PFS? So meaning if we, you know, take some of your data, competitor data, look at CBR rates and what they translate to, is there a fairly linear relationship there between those things?
Yeah, I mean, it's not a perfect relationship. It's certainly CBR is always kind of appreciated more than, especially for ER therapies, response rate. Response rate for single-agent endocrine therapies is always single digit. It's a cytostatic effect. It's not a cytotoxic effect. You know, fulvestrant plus palbo has a 10% response rate, for instance, in a pre-CDK population.
Okay, maybe just a couple more on 471 before we transition to bavdegalutamide . So there's also this TACTIVE-N study looking at the adjuvant setting. So maybe just what are you hoping to learn from that trial? And then what would you need to see to, you know, pull the trigger on a phase III adjuvant study?
Yeah. So this is, as you mentioned, this is a trial that is looking... It's actually neoadjuvant, so it's four months of therapy with 471 as a single agent. We do have a reference arm of aromatase inhibitor therapy. It's not powered for any for differences, but we felt that it was important to have a reference arm. So it includes a biomarker, biomarkers as an outcome, for instance, Ki-67, ER degradation, PR effects... and it, and again, it's, you know, it's the intent is really just to look at this as a, you know, some additional piece of data, and then we'll also have safety and efficacy data.
Certainly this is something that piece of data that is, you know, gonna be important for us to understand this in the domain of early breast cancer and thinking about adjuvant. It's also very important for investigators because, you know, to go and start an adjuvant phase III study, it's important for the investigators to feel like they can talk to patients across the way and say, "Look, I'm gonna put you on this thing. You may be getting it for three-five years." So that's a big part. That was also a big part. It's being done by the TRIO group. They came to us. They were so excited by what they heard about the program. We haven't disclosed on when those data will be presented.
Certainly not this year, but we're very pleased with the progress of that study.
Yeah. Ultimately, how large is that trial?
It's roughly about 150 patients.
Okay, got it. And so when you think about, like, potential phase III path, would it be neoadjuvant? Because obviously in adjuvant, it's CDK backbone. So how do you think about those, those two? Or could you pivot into a typical adjuvant study using this data?
Yeah, I think for ER-positive breast cancer, while in sort of a ER-negative disease, HER2 neoadjuvant is a standard of care. For ER-positive, it's certainly there have been trials to look at it. It's not quite a standard of care, so to speak. So I think what we generally think about this is a postoperative approach. And there are a couple of different ways that one can look at this. You know, we know about the competitors and the different approaches that they're taking, and all these things are being considered in the partnership.
Okay. Okay, great. And then maybe the last one, as you talked about starting some phase I, II work with 471 and some of Pfizer's, they have a next gen CDK4 that we saw some data for at ASCO, and then also I think they're- you guys disclosed as Carrick has a CDK7. So maybe just remind us, what's the rationale or strategy behind each of those combinations?
Sure. Yeah, so, so just to step back, I mean, part of the partnership was not just to have these first two metastatic trials getting started, we're thrilled about that, but it's also, you know, basically, thinking about the evolution in the standard of care and keeping 471 as the drug of choice for ER therapy. So that also means looking at what combinations, you know, look exciting and we believe we should be combining with. So that includes Pfizer's own pipeline. It includes other agents. So for instance, we started the trial with ribociclib and a cohort with abemaciclib.
So, you know, while we know that, you know, certainly there's more data about, you know, what's the best CDK, and it's a more complicated decision than just efficacy, it's also safety, but we also want this to be, you know, thought of for combinations with those CDK4/6. In terms of other therapies, you bring up Pfizer's CDK4 and the partnership that they have for their collaboration with CDK7. I'll start with four, which is. You alluded to this, they had, you know, very exciting data at ASCO. And actually, recently, Pfizer's been talking about this, I think, in their last investor presentation. They talked about what they believe is a platform for ER-positive breast cancer.
That's a combination of 471 to tackle ER and what they believe is gonna be the next generation of CDK inhibitors. And so, with that, you can imagine there's lots of conversations between the companies. And so we are planning with Pfizer to initiate an investigation in the clinic of CDK4 and 471 before the end of the year.
What, and again, I saw the CDK4 data, but what does seven bring to the table? Is it the tolerability? Is it efficacy in resistant patients? I would think.
Yeah, I think there's some evidence that CDK7 may be a mechanism for resistance. They have some data that has been looking in combination with fulvestrant. Yeah, it's a single arm, but if you look at it with historical data, there are interesting aspects, including some of the subsets. So, clearly, Pfizer is very interested in this. So, you know, as we've kind of put it through the evaluation, you know, we felt that this was something that we should be studying. There are other things that we've been considering as well, some of which I'm sure everyone could think of, but the whole idea is to kind of keep pace with the evolution of the science.
Okay, great. Maybe we'll move on to bavdegalutamide now. You know, you're gonna have some updated data at ESMO. And again, I, I think there's gonna be PFS data there. So maybe just set the stage for us in terms of what we've seen, and then also, as we think about kind of, you know, competitive benchmarks-
Yeah.
how to think about the upcoming data.
Yes, certainly. So, the last time that we presented data was, it's been a while. So it was ASCO GU. So this was at a time that we had completed our phase I. We had started our phase II. Actually, we're probably about a little bit more than three-quarters of the way through the enrollment, and we presented data for basically the seamless phase I/II, where the majority of data was at the dose that we would anticipate would be the phase III dose of 420. And at that time, and this is the story about where we've identified a... And just to also, before I get into this, is that, you know, set the background, that this is a very, very heavily pretreated population. So there, there's a lot of...
Evolution and the biology of prostate cancer after patients have gone through multiple therapies, and one of the consequences is that AR therapies, no matter how you target AR, just lose their ability to have the effect. So here we were, to be quite honest, not expecting a whole lot because of all the other pathways that are turned on, p53, AKT, all these other pathways. And this is where we identified a population through biomarkers that seem to retain AR dependency and therefore respond much better to bavdegalutamide coming in a very late line. So this is a case where we had, back at ASCO GU, a PSA 50 of about 46% in about 28 patients with two of the more common AR mutations, 878 and 875.
And that was one or both, regardless of what else was present, meaning they could have had other mutations of AR, they could have had other non-AR mutations. But even with all the prior therapy these patients received, and they received a lot of, you know, chemotherapy, multiple NHAs, enzalutamide, apalutamide, oftentimes both, they still had this activity. So fast forward to the ESMO ASCO submission. That, I mean, ESMO abstract submission, is that we will have PFS, we'll have more data because the trial still had some additional patients to enroll, you know, all at the recommended dose. And the focus is gonna be around the precision medicine population again, this 878 and/or 875 AR mutation population. So we'll have more patients there.
We'll have longer follow-up. In terms of what does good look like? Well, the best place to look is four recently completed phase III studies in the post-NHA setting. These are all recent New England Journal publications. CARD is one of the trials, cabazitaxel. Second one is PROfound, which is olaparib. Third one is the VISION study with Pluvicto, and the fourth is the rucaparib confirmatory trial, TRITON-3. That one's a little bit different than the others in terms of populations. They're all post-NHA, just like our plans for a phase III, and also the population we studied in phase II. But that one was an earlier line. That was chemotherapy naive for castrate resistance, so a little bit, you know, better outcomes than...
So if you look at the low end, so that means what does the control arm do in these four studies? And if you look at the control arms included, at least entirely or in the case of TRITON3, a choice of retreatment with NHA. And so if you look at retreatment of NHA in all four studies, it's very tight range. It's 3.5-4.5 months of radiographic PFS. If we have results like that, that would be obviously highly disappointing. On the other end of the scale, if you look at our PFS for those same trials, and focusing on the three that are in the similar population as our phase I/ II, you'll see also a tight range.
It's between 7.5 months and 8.5 months. So that's sort of, And then I think the other thing I will add here is that if you look at, the other therapies, two of them are IV, Pluvicto, chemotherapy. And then from a safety perspective, the, the three of the, the PARPs and the other two agents all share having neutropenia and thrombocytopenia. That has not, to this date, been a, a safety issue for bavdegalutamide. So from a standpoint of what does good look like for an oral once-a-day therapy, we think that if it's somewhere in the, at least in the beginning of that 7 to 7.5-8.5, range, we think that that would be considered good and certainly, promising for going forward.
Yeah. Okay, very, very helpful. And I guess as we think about the, you know, phase III trial that's coming up at the end of the year, any early thoughts on what that could look like? I'm assuming it's the precision medicine biomarker population, obviously. But given some of the data that we just talked through, how you think about the control arm, I guess? It seems like that's kind of the one-
Yeah, that's a big question.
Yeah.
Yeah. Yeah, we can't, we can't at this stage disclose, I mean, it's the us I think in, in, in this particular setting, it's about what's in, in prior therapy, what's in the con you know, versus what's in the control. So certainly as, and we've been, you've been guiding, for starting the trial before the end of the year. So as we, you know, get to that point, we'll certainly, provide those details. But I think you hit the, the main themes, which is, number one, post-NHA, precision medicine. We're very thrilled to have a biomarker that identifies a population this late line. We are very, you know, very enthusiastic about moving earlier.
I think we'll also be talking about 766, and so we can talk about that too, because, you know, really, we believe that the greatest potential of the therapy could be in the earlier setting, where we know that these other markers of resistance that impede the effect of an AR drug are not gonna be an issue.
Yeah. Okay. That would, I guess, be my last question, is just as we think about positioning for ARV-766 versus darolutamide, sounds like your preference is ARV-766 goes earlier.
Yeah, it's... Well, there's one differentiator, is that it covers the one mutation Bav does not cover, which is L702H. But the other thing that we have seen to date is that the Bav safety profile, while we, you know, think it's gonna be a competitive profile in the late line setting, 766 looks particularly good, and particularly well suited for early disease, where patients are on treatment for years, and even drugs like enzalutamide and apalutamide are, you know, have their own challenges. So the profile so far, we've been very happy with.
Okay. Well, I think we're up against time, but thank you so much, gentlemen. Really appreciate it.
Thank you.
Thank you, sir.
Thank you.