Welcome the Arvinas team to the next Fireside Chat here. My name is Michael Schmidt, Biotech Analyst with Guggenheim, and it's my great pleasure to welcome, Randy Teel, who's the Head of Corporate and Business Development, as well as Ron Peck, Chief Medical Officer. Welcome, guys. Thanks for joining us. So I think, I think Randy wanted to make some, quick opening remarks, and then we'll go to Q&A. Randy? Yeah, thanks, Michael. These are quick fireside, so I won't take a lot of time, but just to make sure we have the overview and stage setting clear. So, Arvinas, you know, I won't give you the full background, founded just over 10 years ago. So we were founded out of Yale. Protein degradation is absolutely the core of what we're doing, PROTAC technology. I'll give the quick overview of where we are in pipeline and development, which is that our lead program is vepdegestrant, an ER degrader. I'm sure we'll talk a lot about that in the next few minutes. We're expecting top-line data from its first pivotal trial by the end of the year. That's the VERITAC-2 trial. We'll also talk a bit this morning, I'm sure, about the data we just showed at San Antonio in December, which was combination data with palbociclib, which we were very excited about. The next program behind that is ARV-766, an AR degrader. We shared information on that last at ESMO, where we pivoted to 766, really, as the lead AR degrader over the very first PROTAC in the clinic, which was bavdegalutamide, so we'll talk about that as well. We'll also start two more clinical trials in the first half of this year. The first is BCL-6, which had its IND cleared late last year to start in NHL, well, to start in its first escalation trial. LRRK2 is our first neuroscience target heading into the clinic, and that will head in in the first half of the year as well, which will be really exciting if we can show, which we hope to do, that we can deliver an oral PROTAC degrader, have it cross the blood-brain barrier, and degrade the target protein of interest. So behind that, we've got a number of other programs a bit further back down the pike, including KRAS G12D, pan- KRAS degrader as well. But, it's been an exciting start to the year, and as our first year with top-line data, obviously a lot to come. So I didn't want to get too far and only talk about the first two programs before we talk about everything. So it's been very nice- Thanks for having us, Michael. Thank you. It's good to be here. All right. Well, thanks, Randy, and, yeah, Ron, maybe just jumping right into vepdegestrant. As Randy mentioned, the VERITAC-2 phase III trial is set, you know, set to read out top-line data later this year. You've presented phase II data so far. Perhaps just remind us how phase II data and also the overall clinical experience in this sort of space in general has informed the design of your VERITAC-2 study. There were some setbacks from other companies. phase II data obviously looks very compelling, but, you know, how did that feed into designing VERITAC-2? Yeah. So, let's make sure you can hear me. Well, just going back to it, and you mentioned this, we started in a good position, which is we were very happy with phase II monotherapy data, had CBR between 37% and 40%, shown both in phase I, phase II. We're able to easily identify an optimal dose, all this in as heavily pretreated a population as possible, so known to be very highly ER-independent resistant. And so for our phase III design, what was important for us is we wanted to design a trial that would give what we believe is the best novel ER therapy, its best shot for showing benefit and showing the differentiation that we believe is there. We wanted to do a straight head-to-head with fulvestrant. This is the thesis for how this program came in as our first, you know, furthest along PROTAC. Number two is designed in a population that is, in essence, the opposite of our phase II population. So these are patients who have gotten no prior metastatic chemotherapy and no prior fulvestrant. So again, a population that we believe that this is going to show its best potential post-CDK. And then the other point is, you know, it's this observation that ESR1 mutations just biologically are predicting which patients most benefit. So we have both endpoints as a primary endpoint. Yeah. Considering, you know, those differences, essentially less heavily pretreated patients in VERITAC-2, I guess, you know, what is your expectation, how that might affect the performance of your drug and then also fulvestrant, the control arm? Yeah, there's so with regard to fulvestrant, the control arm. It's if you look at, you know, various trials, you look at the EMERALD trial, you look at some of the older datasets out there. Fulvestrant in the post-CDK4 is pretty predictable. It's, you know, PFS of two months, maybe three months or so. VERONICA is a phase II from about two-three years ago that probably is closest to the population that we're studying, which is no prior chemo, no prior fulvestrant. It still had about a 2-month PFS. So that's fulvestrant. With regard to vepdegestrant, well, you know, we have a small cohort of patients in the Phase II that actually matches the population. See, these are a total of eight patients, and we had two out of seven patients who were evaluable for response, having objective responses, which is better than you expect for any novel ER therapy. We had a 63% CBR in this population. The PFS is somewhere in the double digits. I will want to be very cautious about that. It's a very small data- Right ... set for events, but at least directionally, we know that it supports what we expect. Right. Great. And, you know, one debate has been also perhaps since the EMERALD data disclosure, has been whether, you know, those drugs would be active in a ITT population, including ESR1 wild type, or whether the monotherapy activity would be limited to the ESR1 mutant patients. You know, what is the expectation here for vep-deg? ... Yeah, so, again, this is, you know, we're not going to expect to see the same exact efficacy in the wild type. That's, it's a biology thing, it's not a drug thing. But, you know, we believe because of, you know, all the data we have and the potency of the drug against ER, that we're going to have as good a shot at and show benefit in this population. We even had, you know, I mentioned responses are unusual or not typical for ER-targeted therapy. We have actually a confirmed response in a wild type patient, even with all that prior therapy. So, the next question is, will we get labeling for a broad population? Well, that's something that is not a drug thing, that's a regulatory thing. Mm-hmm. The FDA has clearly set a higher bar. They've been making points about educating the community that they need to see a real strong signal in that population. So we hope that we can get the broad labeling. The other thing is, and this is maybe a segue into the combinations, is that the combination data that we had at San Antonio, the combination with palbociclib, which really had exceptional results in a very heavily pretreated population. The one of the many interesting things and exciting things is the activity was really independent of the ESR1 status. Yeah. So that's a, that's sort of like a backup, if needed. Gotcha. Maybe just one more on VERITAC-2. Are you stratifying the ESR1 wild-type mutant ratio, and/or is there the possibility that you might get more wild-type patients since the Radius drug is on the market now treating mutant patients? Yeah. So we have, first of all, it's stratified by ESR1 status, so there's going to be balance. Right. Number two, we do have some safeguards in the trial that allow us to sort of regulate in some way to make sure that there's that it reflects what we see in the literature, which is roughly about 50%. Right. Then maybe just one last one. Have you disclosed a statistical design of VERITAC-2? What is the minimum PFS benefit or hazard ratio that you can technically detect? Yeah, we haven't disclosed it- Okay. but it's a highly powered study. Right. So it's a bigger trial than EMERALD. And actually, one of the important things was we wanted to have it powered for survival, which is supports the larger size. Great. Okay, super. Then perhaps switching gears to the combo. You know, as you mentioned, you had some very interesting data recently presented at San Antonio in December for the combination with palbociclib in previously treated patients, though. You know, remind us how the data could potentially de-risk the ongoing VERITAC-3 trial in a first-line setting. Yeah, yeah. You know, just a word about it. I mean, we were thrilled with the results. I mean, from what I'll call an expert investigator perspective, they had—I mean, folks were not expecting that kind of PFS. PFS was amazing, but the response rates and seeing that you could shrink tumors in 42% of patients and having 10 months duration was not something—I mean, essentially, it was something the community sees more for ADCs now in this population, right? Right. So, exceptional data, and yeah, I mean, this to us is a de-risking for frontline. I mean, it's, I mean, the activity is really in patients who have AR-driven disease. And so the frontline is a setting where these patients are essentially all going to be having AR driven disease. Mm-hmm. That de-risks that. It also is a very nice premise for combining with the Pfizer CDK4 drug. Right. And so, you know, one, one question we've been getting is obviously that the VERITAC-3 trial will evaluate lower palbociclib doses than what you had in your phase Ib. You know, based on that, I guess, what is your confidence level that to that level of efficacy is maintained potentially at these lower combination doses? Yeah, we're highly confident. Why is that? Well, number one, the increase in exposure was not a massive increase; it was 1.5-fold. More importantly, there hasn't been any convincing relationship between exposure and efficacy for palbo. Also, for the amount of time that patients are at this higher dose, it's really quite short, it's quite fleeting. So patients get dose or get palbo interrupted once they get into grade three. Neutropenia is an early event for palbo, so you have a nadir, the lowest point is around 14 days for neutropenia. So patients are really basically interrupting therapy after 1 or 2 weeks, and CDK therapies don't work like that. Mm-hmm. They're, you need to have sustained exposure. So here, if you look at the benefit, we have patients who have a median PFS of 11 months, yet that two weeks of intervention, it's just that there's no conceivable way that that could be driving this. So we're very confident in the lower and optimal dose delivering the same efficacy we had in our presentation, also breaking down efficacy by whether they stayed on 125 or they were dose reduced, and the efficacy looks just as fantastic, if not better, if in fact, the lower dose. Okay. Yeah, helpful. And then, so you are in this phase II, dose selection portion of the study at this point. You know, could you just update us on how that, how that's enrolling? When might you be in a position to select the phase III dose? And will you actually disclose the outcomes of that phase II lead-in before randomizing the phase III? Yeah, progress has been great. The study started mid-year, at the beginning. And, we haven't disclosed in any formal way when we would have the data. I think we're saying sort of unofficially, expected some time before the end of the year. As to whether we disclose the data, we cannot commit to that. This is an ongoing Phase III study. We're obviously have a partner, who will, you know, also with us, make sure that we're doing the right thing for the trial. Hmm, okay. The most important, you know, output of that is we're taking it forward, a dose forward into the randomized portion. Right. Right. We don't need to share a lot of data to get that across, which is the most important piece. Right. And then, you know, as you mentioned, Ron, you're obviously planning now the combination with Pfizer CDK4 selective inhibitor as well. You know, does it even make sense at this point to pursue the palbo combo? What-- You know, is there... Or, you know, talk about the opportunity for the CDK4 selective inhibitor combination and how that might fit into the sort of landscape. Well, I think the way that we describe this is, this is a good problem to have. You know, we have this fantastic data at San Antonio, which, back to your earlier point, we believe de-risks the front line with palbo. But at the same time, you know, having Pfizer as a partner gives us the fortuitous situation of having this selective drug, which is getting a lot of attention in the community. And so our job really simply is to, you know, because things move very quickly, is to try to do our best to position this to start a phase III for the CDK4. We said that we would have health authority engagement later this year with that intent of getting an alignment on trial designs and whatever else we can, you know, focus on. And we've initiated, at the end of last year, a combination with the CDK vep-deg. Are we gonna have two parallel trials in the front line at, you know, going in both? That doesn't, you know, that's hard to think of for lots of reasons, even just practically. But we're not in a position now where we can decide that, set that direction. Most important thing is get it in motion. Hmm. We'll have data from the lead-in and other factors that will allow the partnership to make the right decisions. Right. And then I know you're enrolling this TACTIVE-U multi-cohort combination study. Sort of the decision to move forward with the CDK4 selective inhibitor, has that been driven by data that you may already have been generating in TACTIVE-U? And you know, how should investors think about data disclosures from some of these other combinations this year? Yeah, and this is independent of that. Those trials are proceeding per plan. We haven't given any formal guidance. These are trials that are executed by Pfizer, so this is put it more in the negotiation category. But we're expecting that we may be able to share data later this year. And it also informs, as we mentioned, the new plan for a phase III with CDK4 in the second line, that we announced at San Antonio. And we also said that certainly palbo would be part of that, but it may be including another CDK4/6, and this data set's important for- Right ... informing. Yeah. Okay, and then I know you want to obviously focus on your own data, but there are, you know, other registration studies ongoing in the sort of space, especially two big studies from AstraZeneca and Roche, which I think will probably read out in 2025. And just sort of last question on this topic, how do you see the breast cancer space evolving longer term, you know, for vep-deg relative to some of these other? Yeah ... agents that are still in development? Yeah, I mean, I, I'll be a CMO talking about the market, but so bear with me. I mean, it's a big market. Translating from my world, it's, it's a lot of patients. And, you know, good drugs, you know, that are worthy of being prescribed will find their way in such a big market. We, you know, are of the mindset, based on the data, that we think that we could have a best-in-class, or best, I'll say, novel era therapy. Number two is, we don't often talk about the safety because we're often talking about efficacy, but we really have potentially a class-leading safety profile as well. And then, you know, having the opportunity to have the CDK4, also having a launch that is not just a single-agent monotherapy in late line, but also coming in potentially with a combination, that sets us up for a really robust launch. Great. All right, super. So maybe switching over to ARV-766, which is your AR PROTAC for prostate cancer. And so as Randy mentioned, you've selected 766 as your sort of candidate to move forward. Yeah, you know, there's you know, different opportunities in prostate cancer. Just remind us just of the areas of opportunity for 766? Yeah, I mean, just to step back, I mean, this, we're really excited by this. This is, I mean, it's highly active, you know, in this ligand binding domain mutation population. This is a population that, in a late line, are the patients who still seem to have AR-dependent disease. And we're, you know, the first data we showed was around 40%. That's an ongoing trial, so we'll have more updated data later. We expect that it's gonna be, you know, in this, certainly as active as vep-deg in the population, where vep-deg, you know, was the selected population that it can work in. And the safety profile is better than bavdegalutamide, but bavdegalutamide had a better and a competitive safety profile versus other drugs. So we think this is a really strong program. Really, our intent is to position this to start a phase III. We've disclosed that we'd be having health authority engagement, initiating that in the second quarter, which is just next quarter. We believe that we're going to have the data to justify a dose. You know, we did a randomization between two doses that we're equally happy with. So we're all, you know, well-positioned for this in the castrate-resistant. Then the next question is: how do we get this into the earlier setting where we can potentially, you know, get to meet a need in castrate-sensitive, especially in patients where existing therapy is just not good enough? Right. So, there was some competitive data recently announced from Bristol Myers Squibb on their own internal developed AR degrader program that, you know, they're talking about also seeing activity in AR wild-type patients. So for your program seven six six, you know, is there opportunity in AR wild type, or will this be limited to the LBD mutation subset, which is about 25% of the patients, I think you said? Yeah. I mean, we're—I mean, just a couple of things about the competitive data. It's the appropriate question to come up to us, which is... I mean, this is—we've been waiting for the BMS data for a while. And the interesting things for us is that they had the dose very high. That makes us feel good that we made the right choice in the molecule to move forward. You know, we believe that this is going to have the optimal pharmaceutical properties, and then, more importantly, I've mentioned safety. They seem to have an off-target effect. It's a curiosity to us, the scientists in the company, as to why that could be, 'cause we don't have that. In terms of activity in wild type, we have activity in wild type. We had patients been staying on therapy for a while. You know, it, it, and, you know, when we have, you know, data later this year, we might have, you know, to be able to cover that. And, so, you know, my sense is that the activity is going to be quite, you know, just say, similar, but the therapeutic index is going to be the important thing. And then the question actually for BMS is, when they determine what their optimal dose is, will they be able to have the same level of activity that they're seeing in the dose that is causing the QT prolongation and bradycardia? Right. And so you said you're right now evaluating two doses for 766, and you have this FDA meeting coming up in 2Q. So, yeah, what are some of the key considerations here, and what, what should investors expect from that update or on media? What, what are the, the missing data points at this point? Yeah, I mean, the question that comes up is, what would our phase III strategy look like? I mean, we haven't disclosed any details, of course, but yeah, similar to when we were having bav positioned, think of this as post-NHA castration-resistant. It's becoming more of an issue because patients get their NHAs earlier. And it would be like LBD mutations, that's 25% of castration-resistant, which is a much bigger population than for bav. You know, the questions that we'll get is: Is it going to be pre-docetaxel, post-docetaxel? What we want to do is to design this. I'll say, think about it as one shot, and we want to get this to the broadest population possible. And we think that we have the profile that deserves such an approach. Right. I was very vague there, but Will you, will you have a mature PFS at the media update, and is that an important factor? We'll have PFS later this year. Will it be part of the first disclosure? I mean, we want to get the data out there. We have not had a conference presentation. Right. It may be perhaps two different disclosures. And then maybe just one more. I know it's still up in the air, and... But how should investors think about a possible control arm in mCRPC in general? There's been some debates on whether a second NHA is appropriate or not. How do you think about that? Yeah, it's a good question. I can't get into specifics, but, I'll put it this way, working with a lot of the same experts who have a lot of the same opinions about retreatment as the control versus including a choice of chemotherapy. So those are very much... Let's put it this way: We're taking a lot of things to heart. We want to have a trial that we can execute properly and that could inform the regulators, but also physicians on, you know, how they should be treating their patients. Okay, great. And then, yeah, maybe last question on your two newly announced INDs. You know, how did you select BCL6 and LRRK2, and, you know, can you talk about the initial development plans there for either? Yeah, I think the simple answer is it's the speed of science. I will just say a word about BCL6 to say it's a very exciting target. It's totally non-druggable. The validation of this as a target is BMS. They happen to pick BCL6 too. And I will tell you that despite a lot of good new therapies coming to this space, they all tend to congregate around CD19, CD20. So there's a lot of enthusiasm about this. It could be a good combination partner, too, based on the science and the downstream effects on apoptosis. And our trial will be first, a dose escalation across different subsets of lymphoma. We're very interested in getting the combinations. And then LRRK2 is speed of science, and it's also incredibly exciting. Not fully non-druggable, but definitely a good story for differential biology. Right. Maybe just one more for Randy. I know you, you obviously have that big Pfizer collaboration around vep-deg. You know, how do you think about different partnering opportunities for the rest of the pipeline, especially CNS, Parkinson's could be big studies. You know, how do you think about that, and what's the right time for it? Do you- Yeah, we think about that a lot, and we've been very consistent, especially on the neuroscience front, to say you're not going to see us moving into, you phase II Parkinson's, Alzheimer's trials on our own. So, Ron just mentioned that, you know, for BCL6, that's going to be one also where combinations will be very relevant, very fast. So we think a lot about how we do that. You know, we're sitting in a pretty good position capital-wise. We just did a PIPE at the end of last year, which gives us runway into 2027. But given the pipeline that we have coming into the clinic, we will—you know, don't expect us to rest on that. So we think a lot about that. For seven six six, for example, that early space in CSPC, also very big, very long trial. There are a number of places where partnerships could make sense for us as we think about how to progress the pipeline. Right. Great. Well, thank you, Randy and Ron. With that, we'll wrap up. Really appreciate it. Thanks. Thank you very much, Michael.