Great. I'm Yigal Nochomovitz. I'm one of the Biotech Analysts here at Citi. Sean Cassidy, CFO. Welcome. Hello. Nice to see you. Ron Peck, Chief Medical Officer. Hello. Nice to see both of you. Protein degradation is obviously a super interesting platform. You're one of the pioneers. There are other companies in this space too. Maybe just to level set, you know, give us a sense for what the mission is at Arvinas. How are you differentiated in terms of how you're approaching the protein degradation drug development question? Heck of a question. First, thanks for having us here. Let me kind of go back to the beginning, right? The company was founded back in 2013 based on the work by Dr. Craig Crews at Yale University, where he had this pretty cool technology to degrade proteins using these hetero bifunctional small molecules called PROTACs or proteolysis targeting chimeras. A lot of scientific breakthroughs that we had at the company in the earlier days. You know, taking a look at these larger than average small molecules, we've been able to make them orally bioavailable, a scientific breakthrough. We've actually taken a look at certain PROTACs and been able to design that they actually cross the blood-brain barrier, another nice key breakthrough. If you look at our clinical stage programs, which we entered into in 2019, our bavdegalutamide program, which is targeting and degrading the androgen receptor for metastatic castration-resistant prostate cancer. Also, our ARV-471 program, which is targeting and degrading the estrogen receptor for ER-positive breast cancer. Those compounds hit the clinic in 2019, and we're very happy to say that both of those compounds are on the cusp of going into phase III trials. It's a fantastic way to show how much we're actually in the lead in terms of some of the other companies that are out there. If you look at our ARV-471 program, which is in partnership with Pfizer, we have two phase III trials planned later on this year to kick off later on this year. The first is a monotherapy in the second line, and the second phase III trial that we'll kick off later on this year is in combination in the first line with palbociclib. Our bavdegalutamide is also progressing towards phase III. Again, that's in metastatic castration-resistant prostate cancer. That's progressing to phase III in the second half of next year. As you look at that, how do we sit there and say, how are we the leaders? We've demonstrated that by bringing compounds into the clinic and actually having a lot of the early successes around protein degradation that actually is, quite frankly, found in this field. I think you just answered one of my questions. One of the phase III combos is with IBRANCE. That's correct. That's been determined. That's correct. Okay. One of the important questions around trial design there is how are you thinking about patient selection, specifically the ESR1 mutant population? Can you comment, what can you say about that in terms of how you're designing the trial and what do we know about ARV-471 in terms of its ability to bind the ESR1 mutant variant? Sure. With regard to the trial design, I can't really get into specifics. I think one thing that I can say is that you could be sure that with the reporting of now 3 phase III studies in the second line setting with novel ERs SERD compounds that you know we're very observant of what we're seeing here, starting with the EMERALD study, which was in our mind a proof of concept for a novel ER therapy versus standard of care. It was a positive study designed to look at a primary endpoint in the ESR1 mutant and then the wild type, and then the two recent trials that we can talk about more later that used a different design and didn't hit their endpoint, but at least per an abstract, certainly the Roche seems to have a signal there, and they've commented on that before. With regard to ARV-471's activity in this setting, what we said at San Antonio when we had our phase I data presented with a total of 60 patients, we had a CBR of 40% in all comers, and this is specifically a 100% post-CDK setting, where you have about 33% patients still with ER-dependent disease, so we were very happy with the 40%, and ER dependency still intact in that 33%. In the ESR1 wild type, similar to other drugs, it looks like it's better because we know the ESR1 mutations seem to be a signature of greater ER dependency, so 50%. Even in a wild type, we still see a level of benefit based on CBR that is better than we would expect in this population when you look at the VERONICA trial, which was a fulvestrant trial of about 100 patients in the post-CDK4 setting where overall there's about a 11%-14% CBR. Then also looking at this EMERALD study, where both the investigational arm and the other arm are showing lower CBR. Still, even in the wild type, we think that there's probably still enough ER dependency that this therapy could still offer benefit in those patients as well. One of the other big questions we're getting is, you know, with regard to some of the recent news in the SERD space, from Roche and Sanofi, wanna give you guys a chance to you know, answer the question as to how you're different mechanistically and why that shouldn't be a read-through for what you're doing for 471, 'cause there are very significant differences, and I think people get confused that don't fully understand the biophysics, which gets very subtle. I mean, I think I already know the answer, but I'd like to p eople out there don't know the answer, so. Yeah, no. I mean, look, the platform and this whole PROTAC mechanism is the reason why I joined before there was any clinical data. I was so excited to work at a company like this. What, you know, I looked at before I chose the decision to come there was just amazingly good preclinical data for the ARV-471 molecule, a very potent degrader. Mechanistically, unlike SERDs, which are basically follow-ons to the fulvestrant, which was approved about 20 years ago, it's, you know, it binds ER. The ER degradation is considered the conventional wisdom is that that is the driving mechanism, but it's a very indirect degradation. It's a consequence of the conformational change with the receptor. You have, you know, on average about 40%-50% ER degradation in patient samples. Whereas with the PROTAC, you see that what happens is you're directly hijacking the ubiquitin proteasome system, which means you're facilitating protein-protein interaction that puts the ubiquitin chains on there, and that signals to the proteasome, take this one out. So it directly engages it, and it translates into a high level of potency and in so preclinical high-level degradation, a very, you know, superior preclinical activity versus fulvestrant, both single agent, combination. That also translates into the clinic, where, as I mentioned, post CDK4/6, we're seeing a 40%. You know, again, a population where probably no more than a third of patients still have ER-dependent disease. Very different. You've got some of that ER degradation data. Obviously, you've done all that work in your labs. I was asking Harold Burstein in the prior session about that question. Have you actually shared that data with us? 'Cause it would be very interesting for everyone to see that degradation data just to make that point crystal clear. Yeah. Oh, yeah, Oh, yeah, we had we've included it. The last time was at San Antonio, just you know just last December. We had paired biopsy data in 14 patients, where we saw degradation in all patients. We saw a median of about or a mean about 65%. Now that compares to 40%-50% with fulvestrant. Okay. Also we have about a third of patients who have degradation that's somewhere north of 85%. Then the other thing I should just mention is that we actually have planned one of the studies that we're starting. The big program with Pfizer is that we're starting a neoadjuvant study before the end of the year. One of the things that that can do is in a much more controlled setting, they allow us to look even, you know, in a cleaner population for ER degradation and other markers as we begin, you know, to test this drug in the early breast cancer setting, which is one of the greatest opportunities we see for this therapy. How much do we know about, you know, if there's any kinda like a threshold effect with degradation? You're saying you were going from 40 to potentially 80%-85%, which is a 2x boost. Yeah. Just to be clear, it's about a third of patients are in that sort of. Third of them. Okay. Some lower, but some higher. Yeah. Is it fairly well understood that if you can get to that level of degradation, that's gonna translate to a clinical benefit? Yeah. I mean, what I would say is first of all, the clinical data, you can't really answer that question, right? In terms of what our, you know, ours show, because it's a setting where there's a disconnect between ER degradation and what happens to the tumor because of all the, so the high level of ER-independent resistance. You can hit the target perfectly. Just because of the bad disease. That's just to point that out. However, the data with fulvestrant over a long period of time, they've shown that more degradation translates into better efficacy. It's a drug where it's one of the few cases where the optimal dose came out after the original approved dose. It was 250. They did a trial that actually showed 500 versus 250 showed greater ER degradation. That prompted AstraZeneca to do a randomized study of dose A versus dose B. I believe, at least to my knowledge, it's one of the only trials that has shown higher dose is better than a lower dose for progression-free survival and a very interesting survival benefit seen as well. That means, you know, based on that experience, it's at least a good level of evidence that more is better. The question I think people ask is, well, how much more? I don't think we know that. When we look at our data and we look at the magnitude of degradation we have versus what's been reported for fulvestrant, we think that, you know, this could be a situation where this could translate. Just going back to the phase III strategy. You said you're starting the combo with IBRANCE. There's also a phase I-B safety trial for 471 plus palbo, which I understand isn't reading out till a little bit into 2023. I guess I was just wondering, you know, what's happening there in terms of waiting to see that safety trial versus being confident in starting the phase III with the combo now? I mean, is it putting the cart before the horse or not? Because you already know the combo is safe. Yeah. Well, number one, our messaging is the same now as it was back in July last year when we announced that we said end of this year, number one. Number two is, that's an indication that things are very much the same. Number two is, I mean, the decisions on when we disclose data. We've already, even separate from the partnership. Now that we're a more mature company, we're trying to get away from these interim updates. Mm-hmm. I think the other thing is that, you know, really this is, we don't know what the questions are going to be for this trial from a development side. It's not a go, no-go. This is just more about confirming the dose, and that gets around safety and PK. On the safety side, we don't expect any overlap in toxicity. ARV-471, you know, we're very thrilled with the safety profile. We think it's, you know, as good as any of the other competitors there. You know, the neutropenia is the main toxicity for palbociclib. We don't expect that. From a DDI perspective, now this also brings up, because we always are asked about Sanofi. This is, you know, one sort of new event recently is that they stopped the development of their drug after an interim futility analysis on their combination trial. The Sanofi drug had liabilities that 471 doesn't have. Specifically, it induces the metabolism of palbociclib. This was something that was presented at ASCO 2021. It's a 3A4 inducer, so it revs up the metabolism of the main pathway. For palbociclib. That translates into, I think it's roughly about a 20-20+% reduction in exposure. That's, in other words, a bit of a handicap, unfortunately, because of that specific drug, specific liability. The other thing is, I forgot what the dose was in their second line. They actually cut the dose in half for their frontline study because the DDI was dose dependent. They figured, we're assuming that they were trying to avoid more of a DDI there. What we can say for us is that, our combination trial is going well. The only other thing I would say is that, we're not going to have the same DDI issue. This is not a CYP3A4 inducer. I can at least say that we're not seeing any reductions. You know, 'cause I just, it's important for us to put in context. This is a drug-specific thing. As you think about what the bar would be in phase III for an IBRANCE plus ARV-471 combo, what is, can you say what you would want to see there on a PFS or an OS endpoint? I mean, what I would say is it's a setting where because the base—I mean, fortunately, CDK in palbociclib as the starting point was a great addition to the standard of care, but it's still not a curable disease and patients still progress, but they do well for a while. Because the median progression-free survival is so long, a hazard ratio risk reduction in progression-free survival, you know, that may be 0.8 or whatever, that may be small in more aggressive diseases. That can translate into several months benefit. You know, in our sense is progression-free survival is still a relevant endpoint there. It's less complicated by all subsequent therapy. If we can show, you know, a several-month improvement in progression-free survival, I think that would be considered a win, especially with the safety profile, you know, that you know is you know quite good. I think you've also mentioned in some of your corporate updates that only looking at IBRANCE, there are other, potentially other CDK4s. Yeah. What other ones would you consider and why would you consider a different one? I mean, obviously, IBRANCE is one of the leading drugs that is going to go generic relatively soon. I don't know if that's a factor in how you're thinking about this. Yeah. I mean, I'll start with the whole premise and frankly, the way that we were thinking about it and helped us make a decision about, you know, this is one to partner, is that first of all, breast cancer is a big area. You know, all the way thinking even with adjuvant, which is an opportunity we're very interested in. You and number two is that with the profile that we have, and we're very confident on it, we want this to be the drug of choice, the ER therapy of choice in breast cancer. That means that we have to do that right, then we want this to be, you know, not just the initial phase II's, but we always want to be positioning ourselves to be the standard of care, you know, through the life cycle. That means combining with the therapies that make most sense for where the field is going. Back to CDKs, it was very important to us, and it was a big part of our conversation with Pfizer at the time of the partnership, is that, you know, look, there's some differences in these compounds. There's still, I know, a lot of debate. We have an umbrella trial, which will be starting before the end of the year. This is, for lack of a better term, an incubator for multiple combinations that could support a life cycle program. We have said that we would start with the CDK program. We haven't been specific on which. Of course, Pfizer has its own CDK pipeline, and you know, we're also open to that as well. If the idea is to have this addressed to be able to answer questions about how does this fit into the larger treatment paradigm. That's a great demonstration of just how broad the collaboration is with Pfizer and how receptive that they have been in terms of trying to give 471 the best chance of success and to be in the most different settings. It's been just a fantastic collaboration with them. What about? We didn't talk about neoadjuvant yet. Do you have a study there? Yeah, we have a neoadjuvant study. Yeah. We'll start before the end of the year. We expect it'll be in ClinicalTrials.gov some point in the near future. Yeah, I mean, the simple thing is we wanna get into early breast cancer. There's, you know, value in beginning to study this in a small neoadjuvant study. This study is not, you know, meant to be thought of as a kinda go-no-go, but it's to start to generate data there. You know, we have some, you know, biology questions that we wanna answer there, ER degradation in this clean population where you have a little bit more precision around looking at the ER degradation, look at other downstream markers, and then also treat patients to confirm the profile in the early breast cancer setting that we've already shown in the metastatic setting. That, even at the very minimum, will help with the investigators getting interested in doing a large pivotal adjuvant setting. It wasn't clear. Is that monotherapy or with a combo? We haven't disclosed, but it will once it comes in ClinicalTrials.gov, we can. All right, well, let's move to the other end of the spectrum. You have a post CDK4/6 trial, which I believe is reading out some phase II data soon. Is that correct? Well, we had the phase II expansion, which is. The VERITAC. I'm talking about the VERITAC trial. VERITAC trial. Yeah. Yeah. You haven't yet shown us the PFS there. Is that correct? Or No, no. Just, I can give you a bit of background. Okay. maybe talk about expectations for San Antonio. Is that this is the purpose of this expansion from a development side was to inform optimal dose. Okay. We tested two doses, 200, 500. What I've said is that we'll be happy with either one because they're both in range that we would, you know, expect real good activity. It's more about optimal. Got it. Addressing some of the questions FDA may have. It's the same population. It's 100% post CDK, which is important. We always make that point because it's highly resistant. There's good molecular profiling data to describe that it's a very poor outcome population, right? It's to put that into context. We will not have PFS data at San Antonio because it requires a certain level of maturity. Okay. What we will have is CBR data, we'll have safety data, and really when people say, "What does success look like?" It's really more of the same. It's looking at CBR rates that would show that it's working in the proportion of patients that still have ER dependent disease. You know, we always talk about this Wander publication in molecular profiling, which is about a third of patients with that. Safety, that there's you know no surprises on the safety side. Okay. I actually just asked Noah Berkowitz this question about that population. His answer was he wanted to see at least four months PFS for a monotherapy, not just a PROTAC, but just for any mechanism. In a post-CDK population, so. Yeah. For what it's worth, take it or leave it. Yeah. I mean, I think, you know, well, with the EMERALD study, there's been, you know, that kinda I think while it was a positive study, people are saying, "But does that mean anything? Let's put it this way. We're thinking, you know, similar, but- Okay. Yeah. Okay, let's keep going down the spectrum. Later, how late-line metastatic breast would you take ARV-471? Would you third-line, fourth-line? I don't think I've seen those later-line trials from you yet. No, no. I mean, yeah. Big part of that is what the design of the phase III study is in later line, so we haven't- That is still to be worked on. No, it's not being worked on. It's not being worked on. No. I mean, well, in order to, let's see, it's September. There's still a lot of work on that. Yeah. To be crystal clear. Okay. You know, we just haven't talked about it. Just haven't talked, yeah. We haven't talked about it, I see. Not ready for prime time. Not ready for prime time. We have a big partner that we wanna have a consistent message. When I saw the Pfizer press release last summer, right? Mm-hmm. First thing I thought was they're gonna test ARV-471 from neoadjuvant all the way to, like, fifth line meta, like everything. Yeah. Assuming that was the plan. Yeah. What I get so specifically about the phase III design, and Sean and I have said this, is that, you know, we are still messaging that these studies are gonna start before the end of the year, so it hasn't changed. Okay. Since the partnership. Well, you know, once, you know, we're at a point with a partner that we can disclose the design, we'll certainly do that. Okay. I think the other thing just to bring up is that, you know, we talked about combinations. I mentioned the everolimus combination, because, you know, of course, targeted therapy will also be a consideration, in this setting, and it will be the right thing for the right patient. We also wanna be making sure that we're, you know, having this be the backbone for targeted therapies as well. Okay. Are you working on a next gen four-seven-one or is that not really a focus right now? You're happy with what you have? Pretty happy with what we have. Okay. All right. Fair enough. Yeah. All right. Let's move. We couldn't be happier with what we have. Okay. Let me rephrase that question a little bit. All right. Let's move on to prostate cancer a little bit. You just talk about the recent regulatory news in terms of the decision to go for the full randomized phase III versus an accelerated approval. We'll just go through that. Yeah, what we, you know, had said before the FDA meeting is that we felt that we had a, you know, really strong case for accelerated approval. We referred to the rucaparib precedent for a single-arm approval. We went to the agency for advice. This is in the backdrop of sort of a macro situation for the FDA and their messaging about single-arm studies, which is, you know, based on a couple of recent ODACs talking about accelerated approvals, that they're trying to sort of calibrate in terms of their thinking about single-arm studies, which is to say it's not a no-go for the right situation, but it comes with risk, right? That there's certain requirements, as always are the case. You know, we got advice. You know, as often is the case, it's not a black and white thing. But also just understand, when we went in there, we also went in with a confirmatory phase III concept, right? That's part of the accelerated approval. You get approval on a surrogate endpoint, and then you come in with confirmatories. You have to present them as a package. They gave us, you know, really quite extensive advice in terms of helping us think through this. After getting the advice back and looking at our options and, you know, already knowing that we were planning a phase III confirmatory trial, you know, we ultimately made a business decision that we thought that just going, instead of doing a two-step thing and just starting with the phase III, would be the most efficient way to get the drug to patients and provide data that will be, frankly, probably more compelling in terms of the value of the therapy. Because you have a control arm, it addresses some of the limitations of single-arm approvals. Then the upside is that this allows us to get into other markets that usually turn their nose on single-arm trials. This was thought to be the best and the right decision to get it to patients. I've got a lot of specific questions here about how you might design the phase III. What can you tell us at this point in terms of patient population, comparator arm, other design considerations? Yeah. Yeah. Of course, you know, at this stage, we can't get into specifics, but I would say that, you know, certainly the biomarker selected population, clearly the science points there. I mean, we're very. By that you mean T878X- Yep. And H875. 878, 875. Probably need to clarify something. This is not, it's kinda like the ESR1 story for breast, which is these mutations are more, sort of, a signal of what the biology of the tumor is. We're in a very late line setting where other mechanisms creep up that prevent drugs that hit the AR from having any effect. The question is, which are the tumors that still have androgen dependency? The mutations seem to be telling us which ones still are responsive to an AR therapy, in this case, a degrader. Science points us to this population. We're following the science. We of course talk about how do we get into earlier settings where a mutation probably not required because you get into less resistant. We're following the science in the population. From the standpoint of control arms, I mean, we can't get into specifics, but, you know, it's sort of, you know, we're in a setting where there's already very limited options for patients. Mm-hmm. That's where you choose what your control arm is. The other important thing is that we know that this drug is active in the half of the patients or so who had chemotherapy before. That's important to know that it retains its activity after chemo, which gives us, you know, more confidence if we need to go after chemotherapy and that sort of thing to get the right trial design. It's the same as, you know, in the case of the breast cancer phase III studies. Once we're, you know, at a point where we're ready to disclose that, we will do that. Okay. Can you talk a little bit about where you, because I think you mentioned in a press release earlier in the year that you had some good data in the patient population beyond the T878X and the H875Y. You'd shown some data there showing some good PSA declines and tumor regression. How is that a focus? Would you consider doing work there in that area? Yeah. I mean, to be specific, really the best activity in the post-enzalutamide/abiraterone population are in those mutations. We did see some activities. Some activity, we saw PSA reductions in other populations, but it was a very late-line setting, and so we weren't, you know. There's other biology that is interfering. We actually had this in our presentation where there's p53, very prevalent, PTEN, other mutations that kind of cut the knees off of the androgen axis. The question that we have and everyone else has is, how do these drugs work in the early setting where you're not encumbered by the, what's called a bad biology. Where you have patients who are more responsive to AR therapies, and we're very interested in this space. You know, one sort of approach that we've thought about is the combination with abiraterone. You know, this could be a setting where now that these drugs are in the frontline setting, what if you combine, you know, you hit the AR axis with a couple of things in addition to chemical castration? Would that be enough to, you know, add value and create, you know, making patients, you know, exist progression-free longer? That's one possibility. The other thing I should bring up here is that we have another AR drug. I was about to ask, but yeah, go ahead. Okay. I mean, yeah, tell us about ARV-766, and would that one, to go into your other point, would that potentially be a better choice to combine with some of the hormonal therapies earlier? Yeah. I mean, yeah, I might step back and then come back to that question. We have a second ARV which is an important enough program that and we hope that we generate a lot of molecules well before my time. You know, this has one important differentiator, is that it hits the one mutation that ARV-110 does not cover, and that's this L702H mutation. It's prevalent in about, let's say, the mid- to high single-digit frequency in castration-resistant prostate cancer. So that's the one. That's one clear differentiator, but we're looking at AR more as a franchise. It's not just prostate cancer. There's also multiple, as you were pointing out, there's different indications. There's early, there's late, other opportunities, but there's other tumors. Triple-negative is one that always comes up. There's definitely a potential for an AR therapy in this setting, and ARV-766 is a good choice to test there. T here's also, you know, a group of very serious benign diseases that are driven by AR. There's a bigger kind of chess game for AR. You know, we have started phase I more than a year ago. We've said that we would disclose data before the end of the year. We said that we'd also start phase II expansion there. You know, because we have already a lot of internal knowledge, of course, about one ten, it gives us a good sort of framework for understanding what seven six six could do. You know, it, you know, certainly among the various scenarios that we've been looking at is, you know, could these play in, you know, different settings within prostate cancer? That's one possibility, but there's others that I mentioned. Just more of a really technical question, I guess, on the 878 and the 875. Are those generally co-occur, those two mutations? Or are they kind of separate populations? It's a Venn diagram. A Venn diagram. It's sort of. Okay. There's a bit of overlap and a bit of non-overlap. Okay. I mean, the data that we have indicates that, you know, if there's just one present, it still, you know, looks like it predicts for response. It doesn't. It's not like a recessive gene, if you will. Okay. Now you also have this ARDENT trial, the phase II, I believe. Yeah. We are expecting some more data there soon. Is that correct? Yeah, we haven't disclosed when we would update that trial. We presented back at ASCO GU in February. We had about close to 200 patients from the seamless phase I/II. A lot of data at 420, this is where we showed the 46% PSA50 rate in the mutation subset. There will be a point where we'll update that, and we haven't disclosed when, but that will be something that we'll announce at a future point. Is that the bar that you said the 46% PSA50, is that what you're angling for this update? Is that a fair benchmark? No. I mean, I think. Again, we haven't disclosed. I mean, I think that will get into questions about it. It's gonna be, you know, things like a longer-term follow-up. Okay. Other things from an efficacy and safety perspective. Well, we really stayed at ASCO GU, that trial was pretty well on its way. I mean, there wasn't much left, really, 'cause that was pretty close to it. Okay. Maybe it's more. I should de-emphasize that data point a little bit. Okay. Yeah. Yeah. I mean, there were so many patients that we had when we did the ASCO GU disclosure. Yeah. I mean, it's gonna be, as Ron Peck said, it's gonna be longer follow-up stuff, but it's not like this could be a lot of new patients come on that trial and whatnot. Yeah. We already had a decent number of patients with 878, 875 by that point to get a, you know, I think a good, let's say, phase II data set in that small population. Let's just spend a few minutes on the preclinical. You have quite an interesting effort there in multiple areas. How much, just broad picture, how much of the R&D budget is going to that work? Can you just kinda talk about, you know, rank order some of these programs in terms of priority or probability of success? I mean, you have solid tumors, hematologic, you have the neurology franchise, so there's quite a lot going on preclinically. Sean, you wanna start with the first. Yeah, the capital allocation. Our research group is getting a tremendous amount of funding. I mean, if you look at it, I mean, we publish some of this stuff and some work using case, right? I mean, it's equal to the clinical stage programs at this point. Okay. Oh, wow. Obviously, the clinical stage programs are gonna start surpassing that as they go into phase III trials, you know, into next year, but it's getting a lot of resources. We have a, you know, I don't know, we've directionally upwards of 20-ish plus programs that are being worked on on a consistent basis at the company. In terms of going back to your original question about, you know, trying to force rank some of those, which one's next, we're not at a place to do that. What we have said and what we're excited to talk about in the future is four INDs by the end of next year, of which one is gonna be a neuroscience asset. It gives you a little bit of confidence that our neuroscience portfolio is absolutely real. If you look at the allocation between our oncology and neuroscience research, it's about 75% directionally in oncology, and about 25% in neuroscience. We have substantial efforts all going there. that brings up an important question in terms of molecular design to not only make it a PROTAC, but now make it a CNS penetrant PROTAC. How hard was that to do? Was that- Really hard. Really hard? Yeah. Okay. It's a lot of know-how that we developed, right? It's one of those things that you get the benefit of when you're first, right? We have chemists that have been at the organization for since some of them since 2014, right? That's all they do is PROTACs. Is it hard? Yeah, it's pretty hard, but we've been able to crack that nut and be able to design compounds across the blood-brain barrier. That, quite frankly, was the genesis of us putting a neuroscience group together. We've got lots of capabilities in neuroscience right now. We have all the capabilities to get something into the clinic and Ron Peck, one of his recent, not recent hires, probably about 1.5 years, about 1 year ago now, Juan Chavez. We're bullish on what we have there. You've talked about the targets, Tau, Alpha-synuclein. Yeah. others, but you haven't talked about indications yet, right? That's right. You should also look at when you see our pipeline of targets, that's not all that we're working on, right? We have a bunch of undisclosed ones as well, too. One of the detriments of being first is everybody tries to follow you. We're not being as, you know, transparent about exactly every target that we're working on. We've only disclosed a select few. Okay. I guess I have one admittedly geeky question, but I do get the question from investors. Just to help us answer, the difference between a PROTAC and molecular glue. I know that's probably not a two-minute answer, but just try your best. Well, I'm gonna let the Chief Financial Officer. Oh, come on. He's been in the company since the beginning. Yeah, you know what, Ian Taylor is not gonna really appreciate this explanation, but obviously a PROTAC is a heterobifunctional small molecule with two ends that are specifically designed to recruit an E3 ligase, and the other end is specifically designed for target protein, and there's just a little linker in the middle there. Right. Right? The molecular glues is usually just one particular one more of one structure without the two different barbell type thing, and it binds to a particular E3 ligase. You try and look at it and see, does it serendipitously bind potentially to other proteins, right? Ours is a more targeted approach, right? We know exactly what protein that we're going after. Right. The molecular glue development profile really is, I know something binds with E3 ligase, and let's see what else it potentially binds to. If it does, then we'll try and do some med chem around that to make that better. It's more passive versus active. Yeah. I mean, it's Yes. Yes, I would characterize it that way. It keeps the focus on the target, and then you can, you know, then you basically find a warhead and then construct versus the glue, which is, Sean used the word serendipitous, which is a little bit of reverse engineering kind of thing. What, you know, this gives us a little bit more latitude and more confidence around the selectivity. Oh, Andrew. Oh, I thought you had a question. No. If I keep going on molecular glues versus PROTACs, our Chief Scientific Officer will not be happy with me. [audio distortion] Yeah. Yeah, no. I mean, honestly, we were, let's say, forecasting this and, you know, we were Arvinas has been answering this question since before the partnership, which is, what if this happens or what does that happen? Our answer has been very simple, which is, you know, in the case of the ER PROTAC, if they have a positive study, then that's great for patients, of course. We're excited because we think we have a better mechanism, a better drug. If they're negative, then we'll say, "Well, that doesn't read through to us because we have a different mechanism, a different drug." In all reality it's a mixed picture from that field because there are three studies. I think the recent attention has been on Sanofi and Roche, but there is a proof of concept. I'll call it a proof of concept for a novel ER therapy, which is the Radius compound, which is actually not a degrader. This has been published by the University of Michigan group. In our own hands, we actually, you know, will synthesize the molecules, of course, and see what. Excuse me. That was using a different design than the Roche trial, Sanofi trial. Proof of concept, novel ER, not a degrader. We and many others believe that degradation is the best way to tackle the target. Fulvestrant is a good proof of that. We have data that, you know, tells us that we believe that this should be better than Fulvestrant. I think the trial design for the other Roche and the Sanofi is gonna be one question. Roche appears to have a signal. The CEO mentioned that when they had the press release. Number two is the abstract for ESMO that talks about a hazard ratio of 0.6 versus 0.8 in the mutation group. There is something there and that may, you know, help make you think about the trial design. The last thing I will say is, you know, the other important piece is that Sanofi stopped their development, and that was triggered by a futility analysis that led to a DMC to stop the trial. There's a drug-specific liability with the Sanofi compound in combination with Palbo, and that is that there is a drug-drug interaction issue that is not an ARV-471 thing, which is that it is a CYP3A4 inducer. Palbo is metabolized through CYP3A4. They've shown at ASCO 2021 that exposure to Palbo is impacted by their drug. The other interesting thing is that their phase III, the Sanofi, was with a dose that was half of the dose that they were using in the monotherapy trial. It seems to us that they were trying to avoid more DDIs. They had, like, the potential of two liabilities in that investigational R versus the combination. For us, it doesn't read through to us. We also have a different mechanism. Our clinical data bear out the difference in terms of the efficacy we're seeing in a post-CDK setting, the paired biopsy results that we had for ER degradation. I'll give you a very long answer. Going back to your original question, our timelines have not changed, nor has Pfizer's excitement for this compound, nor has Arvinas's. I can assure you that. Yeah, because I will give the very long scientific answer, and Sean won't give you the punchline that you're looking for. Yeah. We have benefits from other trial designs and how we can design better trials, right? To make sure that they're successful, but it also doesn't change the patient population of which we think this is gonna be applicable for. Just to be crystal clear. Okay. Thank you both very, very much. Appreciate it. Thanks, Yigal. Thanks for having us at the conference. Thank you.