All righty. Good morning, everyone. Day three of our Jefferies Healthcare Conference. My name is Akash Tewari. I cover pharma and biotech companies here at Jefferies. I have the pleasure of hosting the Arvinas Management Team. John and Noah are here today. Arvinas is one of the names we really like in oncology. Because the way I kind of think about it is, it's hard to find companies where time is your friend. And especially oncology, where it's such a competitive space. But I think when we look at your degrader, and I think we can also talk about your AR degrader, I think your team is well positioned with competitive regimens, not just in this decade. But I think really the question I have is really, what happens in 2030 and beyond, especially in the HR-positive space? John, maybe I'll hand it off to you. I think we both may have come back from ASCO and had to deal with that flight back from O'Hare. Talk to me about what you saw at ASCO. Obviously, DB06 data, we saw some of the MonarchE data from Lilly. How did you see the HR space evolve? And where does Arvinas kind of fit in that paradigm? Yeah, thank you. It's a great question. And clearly, I'll let Noah talk about that in depth. But when we looked at ASCO, in terms of the data that may be presented, we're really looking forward to seeing the postMONARCH data with abemaciclib. We're looking forward to seeing the DESTINY data. And both those data sets came out. And it was clear that in the abemaciclib trial, that they had some nice data. It clearly worked. But it allows us a lot of opportunity still in that space. I think in our setting with palbociclib, we got really significant PFS, over 11 months PFS. I think in combinations with drugs like palbo, abemaciclib, or ribo, I think we'll be in a very good position to see significant activity. So we're actually pretty pleased with that set of data. But the DESTINY data, again, I thought that was good data. But it's clear from the KOL settings that endocrine therapy will be used first and exhausted before I think that people move on to more chemotherapy-like treatments, unless that is a very kind of a severe setting. So overall, I thought ASCO, even though we weren't actually presenting much there in terms of significant data, was actually a very positive meeting. Would you add any more to that? Not much to add. The highlights for us were these two different data points. Because the abemaciclib, the postMONARCH study looking at abemaciclib in combination with fulvestrant informs our second line study design and plan. So to have cleared up any uncertainty around that is helpful with our planning. And to confirm with investigators and eventual prescribers how enthused they are about vepdegestrant was a great opportunity for us. OK, so really helpful. Actually, let's start. I wanted to start on maybe MonarchE, and then we'll hit on even SERENA-6. MonarchE is kind of interesting. Because the feedback I got from clients is, oh, it's kind of surprising to see that fulvestrant did five months there. I think what I think people are missing is, if you look at the way that Monarch was designed, it was juicing for what would be a response to anastrozole or a degrader, in terms of 100% of those patients were post-CDK4. And they were often on post-CDK4 for 12 months and beyond. And I think that, if anything, is enriching for a response. And you see, in terms of the ESR1 rate, it's very high. I think it was 50% plus. For investors who might ask you, hey, are you worried that fulvestrant is showing five months in that population? If you can step back and look at your drug as a monotherapy, what do you think it would have been able to show if it was one of the arms in that study? So thanks, Akash. Overall, we've designed our VERITAC-2 study to look at patients in an earlier line setting, much more similar to what was observed in this study than what has been reported out recently, let's say, with elacestrant's comparator arm, which is in a later line setting. So our whole premise is that while in later lines, we were doing four-six months of median PFS as monotherapy, as we move to earlier lines, we're going to be doing better. And this is a standard accepted assumption for anyone developing drugs in the endocrine space. So we were pretty excited to see that, in fact, in line with our protocols design and our hazard ratio anticipation, looking at patients that were principally second line in this post-MonarchE study, we observed in the fulvestrant arm somewhere between 3.9-5.3 months of median PFS, depending if you rely on the interim analysis, which was the primary statistical analysis of the study, or the analysis presented at ASCO, which was a post-hoc nominal p-value presentation of the final analysis in the study. Understood. I think maybe to that point, a question that we posed this to Lilly when we were there. I still think they probably regret removing that 6-month ET cutoff. I think if you looked at their earlier studies, they had that. They removed that when it came to EMBER-3. So I wanted to kind of pose, and we'll talk about Lilly in a bit, but you haven't designed, you haven't really revealed the design of your combo with CDK4 at this point. In your upcoming VERITAC-3 trial, you have a requirement of 6-month therapy on ET prior. That's A, removing some of these fast progressors that should also enrich for an ESR1 mutation. I think a question I think our team is chewing over is, when you do the combo, is the cutoff six months, or is the cutoff 12 months? Would you consider maybe tweaking to a 12-month requirement on being on a CDK4/6? Are you speaking about the second line study? Yeah, so the second-line study that you haven't necessarily announced the full design on the CDK4/6 combo with your degrader. So there are a few things, a few steps before we finalize that. We are planning over the course of the next several months to meet with health authorities to discuss that study design. We're digesting the results of the postMONARCH study to look at how it influences our design and whether we want to have ABEMA in the study or not. And obviously, we're also going to look at the fullness of data that have now been presented over the past few years, looking at whether or not this enhancement or enrichment of patients who are not fast progressors, how much that helps. So I think it's still on the table. We haven't announced anything. There isn't really an update that I can provide. OK, understood. Now, going to Lilly, and we've done a lot of work on the upcoming EMBER study. As a reminder for the investors, this is kind of one of the biggest data sets we have with a SERD, both in combination with the CDK4/6, but then also as a monotherapy. I think it does have at least somewhat of a read across to your trial. The question I get a lot from investors is, hey, is Arvinas confident that you can get both a wild type and then a mutant label? You listen to Lilly. It certainly seems like what they're betting on is, from a risk-benefit profile, why take an injectable therapy and subject patients to that? As long as safety is good, an oral therapy that has equivalent PFS to fulvestrant and wild type as a monotherapy should be good enough in order to get a broad label. And then in the ESR1 patients, we're confident that we're going to show that kind of benefit. When you think about the same story for Arvinas, is the confidence on getting a broad label on the risk-benefit of the drug, or is it actually maybe degrading the receptor or the differentiation you've seen maybe in some of your clinical data that drives your confidence on being able to get a broad label as a monotherapy? So our Phase III study in the current VERITAC-2 study is, just to remind everyone, a comparison of our vepdegestrant monotherapy versus fulvestrant monotherapy. Fulvestrant is a SERD that's given as an IM injection. And our vepdegestrant is the only PROTAC, and it's given as an oral drug. So that already puts us at an incredible advantage. And I think it is in line with what you were describing as some of Lilly's thinking. In terms of the study design, we're looking at a study that has an ITT population, so a mixture of wild type and mutant type patients, and an analysis of just the, I'm sorry, of just the ESR1 mutant subset. So we have co-primary endpoints, and we can win on either one of them. In that way, it's similar to what elacestrant did. Right. They're doing, right? Now, elacestrant was challenged when they did their ITT analysis because the health authority said, well, how do I know that most of that benefit is not driven by the ESR1 mutants? And you're incurring obvious additional toxicity. There's more nausea. There's more vomiting. And there's more hyperlipidemia. So the overall benefit risk is not clear. And in the end, decided that they're going to give them a mutant ESR1 label. So in our case, we believe that with some precedent, we'll have to overcome that type of precedent and that we're probably going to get a mutant ESR1 label. But it's possible to make the argument that if we win with ITT, as we expect to, that with the pristine safety profile of the drug, the overall benefit risk would be more attractive. And the health authority may be willing to give us approval in that setting. So I think in line what you're, you know, when you look at Lilly's combination, imlunestrant is a great SERD. There's no question about it. But it's also a SERD that has overlapping toxicity with abemaciclib. So the patients have a significant amount of GI toxicity that was observed in Phase I in that combination. So we'll have to see the results of the benefit risk in that population. But overall, where we can differentiate ourselves is by having a CDK4/6 PROTAC combination that has the very promising, the very notable benefit or efficacy, but with a very tolerable safety profile. In terms of if we can't get the wild type approval based on our monotherapy study, we think that that combination study in the second line will bring us the broader approval in a few years. So we're excited about starting that study in early 2025. And that will be kind of additional uses for Vepdegestrant in the second and later line setting. Understood. And that's really helpful. And maybe just to highlight on that point, we've talked about this in a lot of our own research. There is that significant difference, at least in my mind, between the EMBER design and then what your design is as a monotherapy that's reading out at the end of the year. And again, it is this requirement that patients are on a prior therapy for at least six months. And again, the two benefits in my mind are you are removing these ET fast progressors. And then number two, you're enriching for ESR1. So I'd hand it off to you. Number one, by making that inclusion, how many ET fast progressors do you anticipate kind of weeding out? I think we've seen in studies somewhere between 10%-30%. Then number two, if you were to make a guess of what percentage of your patients will be having an ESR1 mutation, I think we can look at MonarchE and some of these other studies as kind of an example, the Serena-6 study too. Where would you guess ESR1 mutation rates will end up being for your trial at the end of the year? So for the VERITAC-2 study, our monotherapy study reading out at the end of the year, we think that we're going to read out somewhere in the 40%-50% range of ESR1 mutants. In terms of what happens in the subsequent study that we'll run, the second line study, which would again be all comers, it might be slightly lower ESR1 mutation population because obviously patients have been treated earlier. We have the dynamics that you just spoke about with patient selection. And on top of which, they're going to be, at least in the U.S. and maybe by then Europe while we're running the study, some patients that are going to go to an ESR1 mutant approved drug. And so they may not be as available to us. Or the numbers may go down a bit. But I think that's OK. We have to keep in mind that Vepdegestrant has been shown to work in patients who have mutant ESR1 and wild type. So it works in both, maybe better, not surprisingly, in ESR1 mutants. But we're going to get benefit in the wild type population as well, no doubt. Understood. Now, this is something that I think we're still trying to understand as well, which is I think you're right. There is, I think, an investor attention on the monotherapy study. But at the end of the day, I think most of these patients, as long as they can handle a CDK4/6, you're going to be taking a degrader or CDK4/6 combo in second line, especially if you're getting, let's say, 11-13 months, both wild type and mutant. What is going on from a synergistic perspective that allows, I think, you have very similar response rates in this kind of second line population in combination with the CDK4/6? And I think maybe the difference we've seen with other SERDs, at least in a monotherapy setting, is maybe a little different than that. Like the gap seems to tighten up when you do the combo. Is that a dynamic of you enriching these really second line ER-driven patients? Or is that more of a dynamic of some type of synergy that you see in combination with the CDK4/6? I'll start to answer the question. I may turn it back to John if he has some reflection on the underlying biology. But overall, look, we're the only company that has been able to demonstrate, at least so far in our Phase I palbo-vepdegestrant combination, that 11-13 months of median PFS, which there just isn't an expectation based on anything we've seen with any other combinations for a double-digit median PFS, right? So even in the postMONARCH study that just reported out, which was principally second-line, those patients had six months median PFS for the abema-fulvestrant combination. This is something very desirable for investigators. And we think that's why the study will enroll fast when we open it because of the promise demonstrated in our Phase I. In terms of the synergy, beyond selecting a little more in a slightly earlier setting for ESR1 sensitive patients, I'll turn to John. But I think that we haven't really identified an answer yet to that in terms of pathway. Yeah, like I said, there's well-known interactions between the CDK4/6 pathway, the endocrine pathway. Pre-clinically, we saw the synergy. Our CSO, Ian Taylor, was not surprised to see it in the clinic. He was pleased with the scale of it. But he believed profound degradation of the estrogen receptor plus the combination of CDK4/6 results in a synergistic effect. And that's what we're seeing in the clinic. And we saw it pre-clinically as well. Understood. Now, maybe hitting on another data set that came out at ASCO, which was KAT6. And again, I think maybe I had a different read of that data than the market did. I looked at, again, a population that was juiced for exactly where I think a degrader combination with the CDK4/6 would do well. Again, almost all of those patients were prior CDK4/6. And I think the vast majority were also on a CDK4/6 for at least a year. When you think about KAT6 and the data that came out from Pfizer, and you think about in that second-line HR-positive setting, is KAT6 something that will be competing head-to-head against your regimen? Or is it something where it's going to be more used after a degrader such as yours? Yeah, I don't think that there's any perception that it's going to invade the endocrine therapy space. It will be used as a combination. And right now, we're thinking about whether or not we can get started soon on a CDK6 combination study. We do have a study that's open and ongoing in our partnership with Pfizer that allows us to bring in various combinations. So we're studying in the TACTIVE-U study an abemaciclib combination, ribociclib, and also CDK7. So all of those arms are currently enrolling. And we have some open arms there for additional promising drugs. And based on the data that were presented at ASCO, it certainly is a top of mind for us about whether we should include a CDK6 combination. Understood. Now, maybe stepping back and talking about your partnership with Pfizer, I think a question that we sometimes get from investors is, hey, what is going to be Pfizer's approach in first line? And your team has guided to a data-driven decision on the combination of your drug with their next-gen CDK4, which is clearly a huge bet for the company. Look, I'll give you my take, and I'd love yours as well. When I look at AstraZeneca in the Serena-6 study, it's a beautifully designed study, completely commercially unviable. But they're going to have outstanding data. But they're in combination with palbociclib. And when I think about the regimen that's best positioned as we go into the next decade, I feel like a CDK4 combo with your drug is more attractive than a palbociclib combo with your drug in first line. That's my personal bias, even if it might have a delay in terms of just trial initiation. How does your team kind of think about this and the competitive landscape? And really, which drug do you think is best positioned for you guys long term? I was just going to say that we are aiming towards a data-driven decision there. Clearly, we've got a safety leading study with palbociclib and vepdegestrant ongoing. We'll have that data the second half of the year. That will allow us to choose 100 or 75 mg dose to go forward both in second line and in first line. Simultaneous to that, we have the ongoing CDK4/vepdegestrant study that starts at the beginning of the year. So by the end of this year, the beginning of the next year, we'll have all of the SLI data. We'll hopefully have the dose that's selected. But we'll also start to have then CDK4 combo data, certainly from a kind of a safety combination point of view and maybe some indications of activity. It's clear, and you should ask Pfizer, but I think Pfizer would like the idea of putting forward a CDK4/VEP combination. For them, that's the most exciting. We're equally excited about that scenario. But both parties want to make sure that we've got as much data as possible to allow us to say, yes, that's why we should do it because here's the data that supports it. And I think we'll have that towards the end of this year or the beginning of next year. So the first line study should be in a position where it could start in 2025. But yes, I mean, you want to be able to see where the trends are going, where the puck's going to be. And I think CDK4 is one of the ones that's going to be there as a viable alternative to some of the other CDK4/6s. Understood. OK. In terms of what data you'd be able to generate to make that kind of data-driven decision, it seems like it's not just simply a safety question, but it also might be an efficacy question. But then the thing I always think about is, well, will we have enough durability with that update to really make that answer? So A, I think we saw the data at ASCO with the CDK4 in combination with fulvestrant, where grade 3 neutropenia was kind of in the 15%-ish. Really exciting. I'm assuming that with your drug, it's probably in the low 20s. I mean, it's still going to be markedly lower than, let's say, ribo or the palbo combos. Is that A, the bar that we should be thinking about from a safety perspective? Number two, if there's an efficacy component with that update as well, what should we be looking at that will justify moving forward with that combination? I think the decision's going to be driven more by efficacy. We'll have more data in that setting. We already know that combining with CDK4/6 is adding efficacy based on our palbo combination. There's no reason to think that we shouldn't be seeing the same pattern with CDK4. You have at least as much CDK4 inhibitory activity. Just you don't have the CDK6 inhibitory toxicity when we look at atirmociclib. We're interested in that combination on the basis of safety and a little bit of efficacy that we'll have. We'll have less. Is there a bar that you're looking for? We don't have a specific bar. Any sense on the duration of treatment that you'll be having there? We'll want to see enough patients that have had at least six months of treatment. Six months. OK, understood. Now, just maybe lastly on drug-drug interactions. And I think this is a question that comes up with investors. And I think as the understanding on the DDI has evolved, I think it seems more CYP-related than, let's say, systemic, like maybe it was initially thought. And I think the question is, OK, there could be overlapping metabolism with ribo, with palbo, and then even theoretically the CDK4. But I think there's also a nuance of a non-clinically meaningful DDI where there's no adjustment needed and then one where there's a modest adjustment needed, like let's say with palbo. When you look at those three agents and the ability to combine with your drug, how would you characterize any theoretical DDIs? Meaningful in the sense that there's a dose modification or not meaningful in the sense that there's really nothing that you're going to have to do? So we know that we have to find a different dose with palbo. And that's why we're doing the safety run-in that we alluded to earlier, where we're looking instead of at the 125-milligram monotherapy palbo dose, we're looking at 175. And we believe, based on all the modeling we've done, that we're likely to come out at 100. And that should be fine. We'll probably get the same or a little more exposure than one gets at 125. And the expectation would be we will have dialed out the neutropenia. When it comes to some other drugs in this space, there's no data right now that anyone should be looking at that would suggest that we're going to have a DDI with them. We're currently evaluating whether there is at most a mild CYP3A4 interaction, which may have contributed to the palbo increased exposure. That may affect some other drugs but would be likely to be very mild. Understood. The issue with palbo overall is it's a drug with a very narrow therapeutic index. And so therefore, a mild increase in exposure, which is what we experienced in that study, had some impact on neutropenia. Drugs like abema, the new CDK, atirmociclib, the new CDK4 inhibitor, or ribociclib, these drugs have a much better therapeutic index. And any mild impact on exposure is unlikely to have any impact on the dosing. Understood. And maybe just, John, for you, last question. In terms of the obviously limited, you can speak for Pfizer. But in terms of your partnership with the company, the excitement internally within Pfizer about your drug and its long-term strategic plans in breast cancer, any general comments you can kind of make? Yeah, I mean, the partnership with Pfizer has just been going fabulously well. They push us with a lot of different mechanisms. They've deployed some of the best people to move the Phase IIIs forward. They're very excited about positioning Vepdegestrant as the endocrine therapy of choice. They've got 50% of the pie. They want to make sure that pie is as large as possible with the different combinations. And yeah, no, we're very pleased with the teams and the interactions. And their enthusiasm for Vepdegestrant has been absolutely excellent. Awesome. Thank you so much for everyone for joining us. Thanks so much for you guys.