Everyone, we'll get started here with the session. My name is Li Watsek, a biotech analyst at Cantor, and we have Arvinas joining us for the discussion, and we're thrilled to have Noah and Andrew join us from the management team, so welcome. I guess for our audience, maybe we can start with an overview and then what's coming up. I know it's gonna be a pretty big year for you guys. Okay, Thank you. Yeah, so I'll kick it off as Noah will take us through most of the science. So first off, yeah, nice to meet everybody. Really exciting time to be at Arvinas. We have multiple events coming up over the next 12 months. The nearest term is our vepdegestrant readout on our phase III study, so potentially the first approval for a protein degrader in the space, which is really exciting for everybody. That data we've signaled will come out late Q4, early Q1. We're very excited about it. We're also excited because a lot of the studies that we've been doing, the smaller studies, to prove combinability will be, the data will be available later this year and early next year. So we're really looking forward to getting our second-line and first-line combination studies in the clinic with Pfizer. We think that this is critical to the program. Really important to the company to have multiple launches in breast cancer over the next five years. As many as three, we're hopeful. So really exciting times, and I think providing some certainty on those studies for investors is going to be really important. Because I think at this point it's been aspirational, but as those get into the clinic, it'll provide, again, much more certainty for our investors. We also have the next generation of programs coming online. BCL6 is very exciting. That's in the clinic. We're starting to get patients in. LRRK2 is another target that we're working on, that we've started the SAD/MAD on, and we're hopeful to progress that and get proof of concept as soon as we can in the next year or so. Really, really exciting times. Noah, let me know if I missed anything at a high level. No, I think that captured it. You know, I just wanna echo the general enthusiasm to look at these results from vepdegestrant, start to share more information about combinability, and then be able to share more information over the course of the next year about the other programs that we have, that you've just outlined. And particularly exciting, too, to be able to move, you know, share data for our first neuroscience program. So that's the LRRK2 degrader, which will. You know, I'm sure at some point we can talk much more about. Okay, great. So maybe let's dive into vepdegestrant a little bit. Obviously, Lilly's EMBER-3 sounds like it's a positive trial, but we haven't seen the details yet. So I want to get your view on that trial and what will be the read-through to your VERITAC-2. Sure. So we've only heard that Ember-3 was declared positive in interim a few weeks ago. We don't know any of the details, so we're somewhat limited in what we can even venture to say about it. It's an important study because it's looking at patients who are in the second line or maybe even patients who are earlier with metastatic breast cancer, right? Because it seems to be a study that enrolled patients who had previously been treated with a CDK4/6 inhibitor, but may have even enrolled patients who were never exposed to a CDK4/6 inhibitor. And they either received fulvestrant as monotherapy, or they received abemaciclib, a CDK4/6 inhibitor, combined with imlunestrant, a SERD, or they received imlunestrant alone. So I think you're asking about it, Li, because it has in it some components that are comparable to ours. There's this monotherapy. And there are a lot of the patients will have had second line, will be receiving second-line, endocrine therapy. And it would be the second readout of a comparison between some form of the degrader, in this case a SERD, with, with fulvestrant in that setting. So we know a few years ago that EMERALD read out, and that showed that, that elacestrant can, add a little less than two months of median PFS to what patients could expect from fulvestrant if they have, the ESR1 mutation. In their estrogen receptor. And now we'd be looking to see whether we're seeing similar results, a little better. Is there some activity in the wild-type, which was not recognized by the FDA in the EMERALD study, you know, and limited the label for elacestrant? So will that read out positively for imlunestrant or not? We believe that we have a best-in-class drug here with our PROTAC. We're very confident from our phase I program that showed great activity in monotherapy, and we're on the verge of reading out our study, where we think we can see, you know, a few months of improved median PFS for patients who have, ESR1 mutant or all comers, all patients that are enrolled in the study. So we're excited to share those results when we know about them, and we're guiding towards a Q4 or Q1, top-line results. I guess in terms of the expectations for VERITAC-2, I wonder if you can just dive into the details a little bit. Obviously, everyone is interested in the control arm fulvestrant, and I guess because you enroll sort of earlier stage, I guess, patients, so what would be your expectation be for the control arm? And then, to your point, I mean, there's a huge debate in terms of, you know, what this is gonna show in ESR1 mutant versus, you know, wild type. So maybe just set the stage for us. Sure. So, so there I just alluded to two studies or highlighted two studies that have. Well, I referenced one study that is read out already, and that is the EMERALD study, which showed a 1.9-month PFS for fulvestrant in patients, many of whom had prior chemotherapy, prior fulvestrant. And so overall, they, you could look at them as being second, third, or later line in the metastatic breast cancer setting with hormone receptor-positive breast cancer. That we think is like the baseline for what you could see in that type of setting. At ASCO a few months ago, the postMONARCH study read out, in which a pure second-line study was reported. There, fulvestrant provided four months of median PFS in the patients, in the interim analysis that was reported, so we believe that in our study, based on our selection criteria for patients that we excluded patients that had prior chemotherapy, patients that had prior fulvestrant, but we enriched for patients that had more than six months exposure to prior endocrine therapy, so we think that we'll do somewhere on the fulvestrant arm between two and four months of median PFS. And the goal is to have, you know, two or three months of improved median PFS in the treatment arm of the study. We saw results in both ESR1 mutant and in wild type, spectacular results in the phase I for the ESR1 mutant patients who were in later line. We saw even a 30% clinical benefit response rate for the patients that were ESR1 wild type in our phase I experience. And so we expect that as we're in this earlier line, we're gonna see these results for ESR1 mutants and the full population, which would include some wild types, and we look forward to sharing those results with you at the appropriate time. Okay, great. So this may be more of a regulatory question, but we are trying to understand, you know, from your VERITAC-2, what do you need to show, right, in the non-ESR1 mutant population for the FDA to give you a broader label? Maybe just talk a little bit about your thoughts in terms of the benefit. Right. So we're using a similar study design to the one that was applied in EMERALD, and that means that we have co-primary endpoints of an improvement in hazard, meaning an improvement in the progression-free survival for patients that have ESR1 mutation, and those will be about 40%-50% of the patients in our study, and for the overall population. The overall population obviously includes that 40%-50%, and it includes another 50%-60% of patients who are gonna be described as wild type. So that study design will allow us to look at those two endpoints. When our competitor went to the FDA with their results, which was, as I said, less than a two-month median PFS improvement in the best population, the ESR1 mutant population, the FDA, as you could see in the meeting minutes from the advisory meeting, the ODAC evaluated in the end as being positive for ESR1 mutant, but not convincing enough in the overall population, 'cause they weren't sure how much of the benefit overall was coming from. ESR1 mutant alone. And then with the toxicity that was seen with the drug, which was increased nausea, vomiting, and hyperlipidemia, the FDA said that the balance of benefit-risk could not be established for non-ESR1 mutant patients, and that's why the label is limited. We believe we're running a similar study design, but we could... if depending on our results, we may be able to have a broader label because there was a pathway there that the FDA articulated. "If you can convince us that there is a benefit, or that the benefit-risk is positive in the non-ESR1 mutant population, you could potentially get a broader label." So that's not our base case.... right? We're thinking about the ESR1 mutant as the base case right now. But if we have a pristine safety profile, like we demonstrated in phase one, and we're demonstrating a strong trend in the efficacy, you know, a positive result in the overall population that does not appear to be driven only by the ESR1 mutant population, then the benefit risk could be argued as positive, and we would make that argument if, if the data support it. I wanted to talk a little bit about the second-line commercial opportunity. Obviously, we're looking at some players here, and then, you're also doing some combinations, and then Arvinas may move into earlier line as well. So how do you guys sort of size up the opportunity for the mono? I know you're also doing combinations while we just touch on the second-line market. Okay. So we've been guiding towards a multi-year plan to go into three indications that we've described so far, and a subsequent indication that we can talk more about next year. The three right now are monotherapy in second line, combination therapy in second line in a study that we'd start next year, and would involve a combination with palbo and/or another CDK4/6 inhibitor, possibly. And then a first-line study that could start next year, too, and would report out a little after that, and that would be a combination of vepdegestrant with atirmociclib, the exciting drug that's that Pfizer is developing to be used as the, you know, become the leading drug in first line in adjuvant. Or maybe palbo, depending on some results that we'll evaluate over the next many months. So that's our, like, three-step plan. Right now, in second line, which you've- Li, you're suggesting that I focus on the range of possibilities for patients are to take monotherapy or combinations that seem to deliver somewhere between about two months of monotherapy fulvestrant, 3.8 months in the ESR1 mutants for monotherapy elacestrant, you know, up to about six months, let's say, for everolimus plus exemestane, abemaciclib plus fulvestrant. That's not a lot of progression-free survival benefit for patients, whether you're talking monotherapy or combination therapy. So we think, and then there's also, of course, some subset of patients that have PI3K pathway mutations, and they may get something like eight months of benefit from a very targeted drug there, especially the newer generations ones. But, so you're talking three up to eight months in the most selected patients. Well, we'll know, you know, by the first quarter of next year, whether or not our monotherapy is solving that problem on its own, or if we even can do better, and we believe we probably can, right? We're expecting, you know g ood, good results that will bring us, you know, near the top of that, what I've just described in terms of monotherapy, in terms of second-line treatment benefit for patients. We think we can get that from monotherapy. And then, if you start combining it with another agent, like a CDK4/6 inhibitor, maybe you can start driving that up towards eight to 10 months or so. So that's the ambition, but a lot will depend on what are the results of VERITAC-2, for me to start predicting where we can go from there, right? But certainly after that, we move into first line. Just a closing point on second line. It's a highly fragmented space, so there are more than 12 different regimens that are commonly used there. If we establish that our PROTAC delivers a quality result, right, as monotherapy, we think there can be consolidation in that space around it. And then following a few years later with a combination that allows for a very tolerable, impactful combination, that can even drive not just consolidation, but growth in the treatment opportunity for patients. So in terms of the timing of the top-line readout, so it's either gonna be Q4 this year or Q1 next year. So what are the swing factors here? And then second is: What is going to be included in the top-line data? Okay. So, we've been guiding for a long time that the results would be in the second half of 2024. When the data started to become more mature a few months ago, we were able to do an evaluation of this event-driven trial and start predicting a little more accurately when it might read out. There's still variability. So we have a, you know, a date in mind that's in the fourth quarter, and, you know, it could end up being a little before, it could be a little after. And so a readout in the fourth quarter is possible. It is the end of the year. It could swing into next year because of holidays and so on. So we've updated our guidance to say a Q4, Q1, top-line results. The results are not agreed to, you know, exactly what is in that top-line result report with our partner has not been agreed to yet between the companies. There's no disagreement. We literally h aven't gone through the process. But I think typically, we would share some results about the primary endpoints of the study and comments about safety. And, and the primary endpoints, as I said, are how are we doing in the ESR1 mutant population and what we call the ITT, the overall population. So that would be. I think you can look for those types of answers. Now, in terms of the combo data that you guys are gonna share later this year with abema, maybe just tell us a little bit about what should we expect, and, should we expect PFS data there? Thanks for asking about it. We guided at the end of the quarter to sharing data at the end of the year about a combination with abema. It's. As you know, we have something called the TACTIVE-U study, which allows us to combine vepdegestrant with a few different drugs. Some of the drugs that are being evaluated in TACTIVE-U include abemaciclib, ribociclib, and a CDK7 inhibitor. We have previously reported out combination with palbo. We're doing some work with another drug as well. The key is, well, these studies are designed to demonstrate what happens to the PK of the drugs, and what type of safety and efficacy trends are you seeing? These are not definitive studies. One of the questions that was being asked last year is: we saw that you increased palbo exposure by dosing vepdegestrant. Is that gonna happen with all drugs? We're seeing that the answer is no. I'm not gonna go into the results for the abema, but I, you know, you can look forward to that at the end of the year and see our ability to dose safely with abema, and you'll start to see, you know, a reasonable cohort to start getting an estimate of efficacy and a pretty good, and a very good estimation of the safety. We hope that we can give you results next year about ribo. We hope we can share results for you at some point about a midazolam study we did to demonstrate the mild CYP3A4 inhibition that is associated with the drug, so you know, that's in contrast, let's say, to a drug like ribo that has a significant CYP3A4 inhibition, meaning in this class, this happens sometimes. But mild CYP3A4 inhibition can drive up the exposure of CYP3A4 substrates a little bit. In a drug like palbo, that caused neutropenia 'cause there's a narrow therapeutic index, and it's very sensitive to exposure. Other drugs like ribociclib, abemaciclib, everolimus, you know, maybe some other PI3K inhibitors, these are not likely, and in our hands, not having really any, a meaningful change in exposure or safety. Okay, great. Maybe just talk a little bit about front-line combination. Obviously, you guys are still trying to figure out whether you're gonna go forward with palbo or CDK4, for that matter. So I guess talk a little bit about, you know, what needs to be done for you and for your partner, Pfizer, to make that decision. At the beginning of this year, you know, or the very last days of last year, we started a combination of vepdegestrant and atirmociclib. And so that required some type of... You know, it's a phase I, so you look at cohorts of patients and then expand, and so that's going very well. That will inform what we do in phase I. Pfizer is also developing atirmociclib to replace CDK4/6 inhibitors and is running studies that are informing them and will inform us about our conviction about how great a drug that can be. And we wanna be with the best-in-class drug because we're the best-in-class estrogen receptor degrader. We will accumulate the data to demonstrate that we can safely dose with the atirmociclib. They will accumulate data about the safety and efficacy of atirmociclib, which is, in a way, behind vepdegestrant right now, right? So they're not reporting out a phase III registrational study by the end of the year. That's something we're doing. So we have to wait to collect a little more data, and then next year, if things look good, we're probably gonna go ahead with that. So that's, you know, I hope to give you updates as we collect more data and as Pfizer and we, you know, do the evaluation we need to do. We've been running a larger set of cohorts of patients with a palbo combination at lower doses, and that's something that is more mature. But we're really waiting to see what's going on with atirmociclib because palbo's use in first line is much diminished over the past two years. And atirmociclib's potential use in first line could be quite significant, and that would be an exciting program to move into. Guess we can switch to your neural pipeline, and LRRK2 is a very interesting target. So talk a little bit about why you think a degrader approach may be better than an inhibitor approach? Sure. Thanks, Li. We are really excited about moving into neurology. Neurology was one of the first areas of interest for Arvinas, but sometimes you can have great ambition, but science is a process of discovery, not pure engineering, and it takes time to develop all the tools you need, and over the past few years, we really got there in neurology, and that's why it's very exciting to be dosing patients with a LRRK2 degrader right now, and, you know, we're looking forward to sharing results with you next year. In general, the company decides whether we should use degradation a s a tool, you know, and we only go forward with that when we know that it can beat inhibition. So inhibition, you need what we'd say, like a stoichiometric similarity. Like, you need enough drug there to be binding the target of interest, and so you keep that binding on, you keep that inhibition on, and then the protein isn't signaling. But in the case of degradation, you can use sub-stoichiometric doses. So much, much less drug has to be available, because each time your degrader engages the target, it degrades it, and then another target another one of the targets comes over. It degrades it, so one molecule of our PROTAC can degrade so much of that protein, and that can be promising in certain diseases. And we think that that's very promising in the case of Parkinson's disease and progressive supranuclear palsy, diseases that we think are driven by LRRK2. LRRK2 is a validated target in Parkinson's disease. There are patients that have founder mutations with it. So there's, you know, 15% of patients have inherited Parkinson's or familial Parkinson's disease, and many of those can be coming from a LRRK2 mutation. And then there are sporadic mutations in LRRK2 that can cause it. So overall, that's why other companies have tried to develop inhibitors for it or antisense. But the inhibitors, they have the limitations I was alluding to earlier. Antisense, you have to inject it into the intrathecal space, and it's uncomfortable for patients, and it doesn't distribute broadly in the brain. But with our degrader, we can take this validated target, degrade LRRK2, and therefore eliminate the kinase activity, the GTPase activity, the scaffolding activity, all of which contributes to the lysosomal dysfunction caused by LRRK2, and we think is important in Parkinson's disease. And in our study, we're gonna be able to demonstrate the PK/PD of our drug very soon. Sorry to give you the lengthy answer here. But in non-human primates, we demonstrated that we can give this orally bioavailable, brain-penetrant drug to monkeys. You can degrade in the periphery, you can degrade in the brain, as we saw in pathology, and you can track that by degradation products seen in the CSF. We were able to model all that, and now we're dosing human beings, and we're looking at how that PK/PD relationship works in humans. What is the right dosing we have to give to get it in the brain, to see it in the CSF, degrade, see degradation in the CSF, and now power us to run a registrational study pretty soon? That's our enthusiasm. Great. Looks like, that's all the time we have today. Oh! Sorry. Thank you so much for a terrific, discussion. Thank you. Thanks. Appreciate the questions.