Okay, thanks everyone for joining us. My name is Akash Tewari. I am a pharma and biotech analyst here at Jefferies. We are in the London Healthcare Conference. It's day one, and it's a joy to have you all. I really do appreciate it. Today, we also have the pleasure of hosting the Arvinas Management Team, Andrew Saik, CFO, Noah Berkowitz, Chief Medical Officer, and the Arvinas Team is going to start off with some slides to give some brief introductory remarks, and then we'll get started on one-on-one questions. Okay, thanks, Akash. How do we do the slides? Do we? All right, so thank you, and thanks for having us, Akash. Noah and I are delighted to be here. As many of you know, Noah and I are both relatively new to Arvinas, both having started this year, I think Noah earlier in the year and myself mid-year. Delighted to be with what we think is the most exciting, the innovator in protein degradation, and we think the leader in the space. We're delighted to continue that leadership. We have a really exciting year coming up. Akash, maybe go to the first slide. Yep. We have a robust pipeline with our lead two candidates, both in phase 3. Our lead two candidates have both been partnered with large pharma, so Pfizer with vepdegestrant, and our second one with Novartis. Very excited about both of those, but we're also excited to start exploring protein degradation beyond just oncology. We have five programs in the clinic that spans into immuno-oncology, neuroscience, and immunology. Really excited to see what this technology can do, both in oncology and our two main programs and outside oncology. We have a really exciting year coming up. Why don't you go to the next one? We have our standard. These are the main four. Again, I mentioned our first two programs on the left in oncology, our second one, which are both wholly owned. That's probably an important point to make. Our first two programs are partnered, but the rest of our pipeline is completely independently owned, so including our LRRK2 degrader, which will have data coming out next April, first in human data. Very excited about that and we started a phase two with 393 in BCL6 earlier this year. We're really excited to start generating data on that as well, so maybe go to the next one. This is the standard slide that everybody likes to see. We handed off 766 to Novartis, phase three ready. We're excited to see them develop that. We're transitioning that to Novartis this year, so that's going to be a wholly run program by Novartis. We will get milestones and royalties off of that. We think that we picked a great partner, really working with the Novartis team well, and we're excited for them to continue that development. Maybe go to the next slide because it's the one that investors are most interested in. We have a really data-rich next 12 months coming up. The first set of data in vepdegestrant is going to come out in San Antonio in December, and that'll be our combination data. Really excited to show the combinability of vepdegestrant with CDK4s. We think that the space that we're going into is mainly going to be a combination space, although we're excited to see our data in monotherapy, and we think that it's going to have a nice market share in monotherapy alone. Our vepdegestrant program, so we actually just updated our guidance on vepdegestrant VERITAC-2. We're now signaling Q1. So we had a two-month delay in the PCD date, which is now going to be January. So we're most likely expecting data in February on vepdegestrant. Yeah, I mean, Noah, maybe you just fill in if I missed anything on the slides and we can get into questions. Sure. Thanks, Andrew. So we've summarized how the VERITAC-2 Phase III study will report out in the first quarter of this year. That would be our first registration study. That will be our intention with vepdegestrant in this partnership with Pfizer is to develop it also in a second-line combination setting. That's a study we expect to start next year. We'll start that with Palbo and/or another CDK4/6 inhibitor. And then we're looking for a first-line study where vepdegestrant is combined with either atirmociclib or palbociclib. Atirmociclib is Pfizer's CDK4 inhibitor, which is advancing rapidly in the clinic. That would be something quite competitive in this space, and we think a nice point of differentiation for Arvinas if we can run a first-line study combining with that exciting future leader in the first-line space. So beyond vepdegestrant, in addition to the LRRK2 data that'll report out in April at the Alzheimer's Disease and Parkinson's Disease Conference in Vienna in April, we hope to provide updates for BCL6 and also get started on a first-in-human study with a KRAS G12D degrader, competitive space, but where preclinically we show nice differentiation with our degrader. And with that, I think I'll turn it to you. Thanks so much. So let's start off with the news that just came out. Not surprising. Okay, this is something that you had talked about even on the Q2, Q3 call. There's a range on the primary completion for VERITAC-2. That's your upcoming monotherapy Phase III study. But the way Wall Street works, we always want to read into things. So from a scientifically responsible way, if event rate like A, doesn't sound like this was due to slower enrollment, obviously. It may have been due to slower event rate accrual. But it's also not a massive shift, right? I mean, you're talking about a two-month shift from where you were originally planning. Is it responsible to read into this at all, whether it's like, hey, maybe responses are more durable, we're going to have better efficacy? Or is it more like, look, this is such a small delay from what we initially planned. You really shouldn't be reading into this one way or the other. I wish I could give you some specifics to it. We are blinded to the study results. I'll just say that a study endpoint for an event-driven study is driven by the enrollment curve and the event curve. We had a plan two and a half years ago that was updated when we started to see some maturing data this summer. We said that the primary completion date of the study or the right events would come in by November with further maturation of the study, and as we hit that date yesterday or two days ago, we thought it prudent to update. The intent had not been to update again, but it looks like it was going to end up being more than a month, and so given that it was more than a month later than originally expected this summer, we provided an update. But how to try and untangle whether that's enrollment or events? I don't think would be warranted or to interpret the meaning of a later date. Okay, understood. Now, this will get a little more technical, but one thing that we've been kind of thinking about is how do you enroll different studies and then how do you see ESR1 mutation rates change over time? And I think we've seen some interesting kind of more recent data points, right? Like if you look at the KAT6 data, Pfizer hadn't, it's part of the reason I wasn't particularly impressed with the KAT6 data. Or you look at the postMONARCH data that Lilly generated, you are seeing ESR1 mutation rates for patients who have prior CDK4/6 use higher than I think what we would have expected in the past. I mean, in the postMONARCH study, in the KAT6 study, you're seeing an ESR1 mutation rate of 50% or higher, right? When you think about your study, you're going to have pretty much all prior CDK4/6 treated patients monotherapy. If you were to guess right now, is your ESR1 mutation rate going to be similar to what we've seen with postMONARCH or with that KAT6 data? Or maybe it's going to be more like high 30s, low 40s? What would you guess that ends up being? Right, so we have been guiding in conversations. I don't think if we put anything in print, but guiding to expect in the 40%-50% range for ESR1 mutation rate, which overall is probably consistent with what you see out there. postMONARCH ended up being a little higher. Other studies have been a little lower, but we think that's an accurate number. Understood. And this is kind of the question I think my team and I have been trying to figure out is if you were to guess the median PFS patient in your monotherapy study, is that patient going to be an ESR1 mutated patient or is he going to be a wild type patient? I mean, if you think about it, if let's say that rate gets to over 50%, that might be a median PFS patient might actually have an ESR1 mutation. Is that a discussion that you're having with your team internally? Do you think there's a possibility that you actually have a majority ESR1 mutated subtype in your study? Again, we do think that we'll have less than 40%-50%, so likely less than 50% ESR1 mutant in the study. That means, look, ESR1 mutant breast cancer is a biology that's driven by a ligand-independent endocrine or estrogen receptor signaling. So that's going to be very susceptible to endocrine or estrogen receptor degradation. So we think that we'll have the strongest effect in ESR1 mutant patients. And the study was planned with that assumption. That's one of our co-primary endpoints. Another endpoint to the study is the hazard ratio improvement in ITT, the full population. There, we think that we'll, because that's about 40%-50% ESR1 plus the remainder of 50%-60% wild type, we do expect that will be a little lower. We do expect that we have activity in ESR1 wild type patients. Overall, the ITT population will probably have a median PFS that's a little lower than the ESR1 mutant selected patient population. I think that we'll have a very successful drug if we win in both. How we eventually get approval, that's going to be a regulatory discussion. We've guided in the past, this isn't your question, but while we're bringing it up, we've guided to the fact that there is precedent for a narrow FDA and your EMA restricting a label in the study design to an ESR1 mutant patient population because of the way we're doing the statistics. We're hopeful that if we show a strong enough benefit in non-ESR1 mutant patients and we have a nice safety profile, they could give us a broader label. The restricted label is the base case. Now, it's funny, a lot of people talk about this just in the second-line setting, but in reality, there's not going to be that many people taking a monotherapy degrader in second line. It's probably going to be combo. When you talk to Lilly, they're like, look, part of the reason we're interested if a SERD can show a benefit not only in ESR1, but also in wild type is we're looking at adjuvant, first-line adjuvant, because everything's a really good degrader in first line. But if you can show a benefit in that wild type population, that's where it gets really excited. Is that the way that you guys think about this too? We shouldn't be that like the commercial opportunity is not really about, okay, I'm going to get a broad label as a monotherapy. It's more about if we're showing a signal in wild type, we can pursue a frontline strategy. Yeah, I think that's a great point, Akash. That's really our intention. We degrade estrogen receptor very well, whether it's mutated or it's wild type. Because 50% of patients are mutated in the second-line setting, well, it's easier to demonstrate a benefit there. That's the design of our VERITAC-2 study. But because 30% of patients are treated with monotherapy, we'll get some market share there. We'd rather be able to address the full 40,000 patients who move into second-line endocrine therapy by hitting wild type as well, by having an ITT population as well. And we'll do that either with monotherapy or combining with another drug. And that's why we're going to start a combination study in second-line next year. But when you look at first-line and you look in the adjuvant setting, patients don't really have much mutated ESR1 receptor. They're 95% of patients are wild type. Well, we degrade that exceptionally well, and the goal is to get into first line as soon as possible, probably combining with atirma, maybe with Palbo, and a discussion for next year is to also think about a study that could start the following year in the adjuvant setting, and that's an important decision we'll have to make next year, but we agree with that type of reasoning that you could start in late line in a select patient population, but move more broadly into earlier line even in the adjuvant setting. Understood. Now, this is a question you've got a lot. And I remember I spoke with Jeff post, I think the Q2 or Q3 call, the placebo response, right? So if you looked at postMONARCH, it's like, okay, I've not seen a lot of studies where fulvestrant is showing five, five and a half months on PFS. And the question that I'm sure your team gets a lot is like, you know, is that something we should expect with VERITAC? And I feel like your team's been pretty adamant. No, you're expecting PFS more in that four- to five-month range, not that five- to six-month range. What kind of gives you the confidence that that's where fulvestrant is really going to behave? Right. So we've guided to three- to four-month range, actually. But you're right, so lower. We were a little surprised that in the interim analysis of postMONARCH, they reported four months for fulvestrant in the final analysis for reasons that are not clear because maybe further patient selection. Fulvestrant produced five plus months of median PFS. We designed our study thinking that fulvestrant would do three to four months in this setting. The way our study is differentiated from postMONARCH is postMONARCH was a pure second-line study. 100% of patients were receiving now fulvestrant or abemaciclib plus fulvestrant as their second-line therapy. Ours will be mostly second line, some third-line patients. And so you would expect with more heavy pretreatment, patients don't do quite as well. So it wouldn't be surprising if we do a little less. And I think that our planning a few years ago or my predecessor's planning was spot on. And that's what we expect from fulvestrant in a few months, data on the investigational arm with vepdegestrant. Understood. And maybe to that point, is it an 85-50? In terms of pure second line versus more pretreated, what do you think that split is? Because I mean, you do have that kind of six-month ET requirement. You would think a lot of these patients are going to be more pure second line. So what would be the general breakdown you're expecting in your study between pure second line and then more pretreated? I don't think we've guided to it specifically, but it's definitely more than 50% second line. But I don't think it'll rise to that level of 85%. Got it. Understood. Now, I think another thing your team's been adamant about is like, hey, don't look at the absolute PFS. We're really confident. And you should be. I mean, that's the more important thing, placebo-adjusted delta. Right? Talk to me about why you've been flagging that to investors. Why are you confident that don't look at the absolute PFS, but the delta is really where we're going to shine? What gives you confidence with things? The study design is one that's based on comparing hazard ratio. We want to look at what do we see for the Kaplan-Meier curve on fulvestrant and how much hazard reduction is there when you look at the vepdegestrant arm. It really depends on the hazard will depend on how you do on fulvestrant. How much more attractive or how much better is the vepdegestrant curve in comparison? If we were to have a two-month median PFS for fulvestrant, we could win with a smaller benefit for vepdegestrant than if we have a four-month median PFS for fulvestrant. That's the nature of it. The median PFS is just like a quick snapshot of what the curve might look like, but in reality, you look at the overall shape of the curve. That's what the health authorities are looking at. We have a way to characterize the benefit over the course of all patients, not just that median patient. Understood. Yeah. Yeah. And And Akash, just to follow up on that, I mean, one of the things that we do get concerned about is cross-study comparisons. So we know that our comparison to fulvestrant is going to be a good comparison. When you look at things like EMBER-3 data coming out later this year, good study, but different patients, right? And so if you try to compare the PFS on ours to that study, it's going to be apples and oranges. They're going to need to go in and look and peel back CDK4 exposed patients to get a true comparison to ours. And you can take that and apply it to every study. So really, we just want people to focus on what we can control and not compare patients that are not the same. Understood. You know, it's kind of interesting though with EMBER-3 in a weird way because, right, like Lilly might be enrolling more ex-US patients, they might have more AI use first line. So prior CDK4/6 use might be 70%, maybe yours is 100. There's kind of this interesting dynamic for in a combo setting. That's actually a good thing because CDK4/6 in combo for patients who have never been pretreated with the CDK4/6, those patients are going to do really well. But in monotherapy, I suspect patients who are prior treated with the CDK4/6 are going to do really well on monotherapy, right? And there's this kind of weird dynamic. Can you talk about that? How we should think about expectations for EMBER-3 in combination and then as a monotherapy? Right. So, and I think that Andrew was moving in this direction. So let's say that 30% of patients in EMBER-3 are CDK4/6 naive. So the combination arm of Abemla plus imlunestrant compared to fulvestrant could do exceptionally well because those patients have never seen CDK4/6. The median PFS for any of the CDK4/6 inhibitors plus an AI is 24 months. So it's really an unfair comparison. I mean, that, and we will have to look at the San Antonio breast conference at the presentation to make sure that they separate the naive from the prior CDK4/6 exposed patients. When it comes to monotherapy in those patients that are naive, so they may have been CDK4/6 naive, but they already had endocrine therapy for sure in first line. So it's maybe more like a second line comparison. The benefit of having not received CDK4/6, I don't think is well established in the literature. It's just going to make comparisons to all the other competitors in this space difficult. And I think approval challenging for them. Interesting. Okay. By the way, I will be at San Antonio. Okay. Want to go over. Now, thinking about the data you're going to have at San Antonio with Abemla and vepdegestrant combo, you know, last year at San Antonio where your stock skyrocketed, you showed, I think a lot of people look and I think sometimes I feel all the certs are the same or the degraders are the same, but that combo data that you showed with Ibranz was uniquely good, right? Like I don't think we've seen a combination data set, 11 months, 13 months, wild type or not. I mean, you're showing a benefit that's pretty outstanding in both populations. But the pushback was always, well, they have this drug-drug interaction. It's because of the higher Ibranz exposure. Now, you're going to have a data point with Abemla. Are we going to have enough N? Are we going to have enough follow-up where you can go to investors and say, you guys thought it was because of higher Ibranz expression. Now we're showing it not just with Ibranz, but we're showing it with Abemla. Or is it more we're running the study to show that we have a manageable drug-drug interaction and it's more of a safety de-risking event? So how much of your San Antonio data cut is efficacy versus safety de-risking? Yeah, we'll be reporting on all, right? We'll have PK, we'll have safety, and we'll have efficacy. But at this first presentation of the data set, it'll be fewer than 20 patients, you know, not that many fewer. And so interpreting a PFS there is going to be difficult. So I wouldn't focus on that. Instead, when you have, and in fact, even in last year's presentation at San Antonio Breast Cancer Symposium, I think that interpreting a median PFS in a small study is always fraught. I think what you look at is what does the clinical benefit rate look like? What do the response rates look like? And we'll have data at the San Antonio conference this year. Last year, we saw about a 60% clinical benefit rate for the Palbo-Vepdeg combination, similar across ESR1 mutant and wild type. And we saw a response rate that was up to 40%, a little more in mutant. We saw subsequently a little more in mutant than wild type. And so we'll be looking at those types of numbers this year. I think that's what investors should be looking at. Understood. And I will, you know, I actually took the Pfizer team on the road a couple of weeks ago, and they made a point that I think is really interesting because if you think about clinical design development, SERENA-6 for Astra, beautiful academic study, who the heck's going to run that in the real world measuring ctDNA? I feel like the strength on the Pfizer Arvinas program is when you think about how to stratify patients, it's going to be prior CDK4/6 exposed and not. You're going to have what you've described as an efficacy-based and safety-based decision with CDK4 and vepdegestrant mid next year. And I think you can make an announcement, A, on your first line strategy, but B, I personally believe you're going to run a second line study with CDK4/6 with vepdegestrant. Talk to me about who are, what are the patients in that combination study? How many of them are first line versus second line? And should we not focus on first and second line? And we should really be looking at that prior CDK4/6 dynamic that Pfizer is alluding to. Right. So we're running a few studies now. We're reporting out the Abemla data set. We are running a first line. We're running the VERITAC-3 study safety run-in. That's Palbo plus Vepdeg where we're using two lower doses of Palbo in a safety run-in. That's really a safety-driven evaluation of the combination in first line. Those data are maturing. We're going to use that to inform our first line choice of combination partner for Vepdeg. But we're also combining with the atirmociclib, the CDK4 inhibitor that is a crown jewel in Pfizer's future development portfolio. And we are looking at the future as a company. We're looking if we want to be in first line, what's going to be the most popular drug years from now in first line? It was Palbo, now it's Ribo, but where will it be a few years from now, and we believe it could be atirma. Pfizer certainly believes it, and so we're looking to just establish the safety of that combination, some early signals of efficacy, and then we start a first line study next year. When it comes to the combination for second line, we'll have Palbo data from last year's San Antonio. We have this Abemla. I think between those, we can make a choice if it's going to be Palbo or Palbo plus Abemla or just Abemla, and we'll see where Ribo comes into the mix. Now, from what you just said, wouldn't it be more bullish if the decision is CDK4 plus vepdegestrant in second line as well? I don't want to guide to bullishness, but I'd say that the idea is we're also looking at where drugs are going to be used in the future. Ribo is on its ascendancy for use in the adjuvant setting and the first line setting. Atirmociclib has a predictable future from our point of view in first line, and we'll see, it'll take many more years in the adjuvant setting. We look at combining with it potentially in first line because of dominance it could play there, and it'll be a discussion next year if we also look for it in the adjuvant setting. We're out of time. Oh. Thank you so much. Thank you. Really appreciate it. Okay.