Good morning, ladies and gentlemen, and welcome to the Arvinas and Pfizer conference call. At this time, all participants are in a listen-only mode. Following the formal remarks, we'll open the call up for your questions. I would now like to turn the call over to Jeff Boyle, Vice President Investor Relations at Arvinas. Please proceed. Thank you, operator. Good morning, everyone, and thank you for joining us to discuss the ARV-471 dose escalation clinical trial results presented this morning at San Antonio Breast Cancer Symposium. Earlier this morning, we issued a press release highlighting these data, which can be accessed in the investor section of our website at arvinas.com. With me today are Arvinas President and Chief Executive Officer John Houston, Arvinas Chief Medical Officer Ron Peck, and Pfizer Oncology Chief Development Officer Chris Boshoff. Ian Taylor, our Chief Scientific Officer, will join for the Q&A portion of the call. Before we begin the call, I'd like to remind you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined on Page 2 of our presentation in today's press release and in the company's recent filings with the Securities and Exchange Commission, which we urge you to read. Our actual results may differ materially from what is discussed on today's call. Now I'll turn the call over to our CEO, John Houston. John? Thanks, Jeff. Good morning, everyone, and thank you for joining us today. We're very happy to provide this exciting update from our ARV-471 program. I'll begin with a brief introduction before handing the call over to Ron and Chris for a detailed review of the data presented at the San Antonio Breast Cancer Symposium this morning. We'll then open up the call to your questions. If you could turn to slide four. At Arvinas, we've developed our PROTACfinity PROTAC discovery platform to engineer proteolysis targeting chimeras or PROTAC targeted protein degraders that are designed to harness the body's own natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. ARV-471 is a PROTAC targeted protein degrader that induces degradation of the estrogen receptor, or ER, a well-known driver of breast cancer. You may recall last December, we presented interim data from this phase I dose escalation trial, and the poster presented this morning now includes data from nearly 3x as many patients. We are pursuing a robust development plan for ARV-471, and I believe these completed phase I results reinforce our decision to move this program forward expeditiously. As you may know, we initiated the ongoing VERITAC phase II expansion trial in locally advanced or metastatic ER-positive, HER2-negative breast cancer earlier this year. We also have an ongoing phase I-B trial in combination with Pfizer's IBRANCE, which is a dose escalation study intended to identify the right dose of 471 for combination in later trials. In 2022, we look forward to beginning two phase III pivotal studies of ARV-471 in metastatic breast cancer. If successful, the clinical program is designed to position 471 as a best-in-class endocrine backbone therapy across the breast cancer treatment paradigm from the adjuvant setting through late-line metastatic disease. Despite advancements in oncology in recent years, there remains a considerable unmet medical need for the treatment of breast cancer. Breast cancer is the second most prevalent cancer in women, and one in every eight women will be diagnosed with breast cancer at some point in their lifetime. The combination of targeted therapies with existing endocrine treatments have become commonplace in the management of advanced ER-positive breast cancer, but success is still limited. This is particularly notable for CDK4/6 inhibitors, which have become firmly established as a standard of care for the initial treatment of advanced ER-positive, HER2-negative breast cancer. Despite these advances, breast cancer remains a major public health issue due to the shortcomings of current therapies that we believe can be addressed by more effective targeting of the estrogen receptor. We believe ARV-471 is fundamentally different from any other therapeutic in development and has the opportunity to become a future standard of care in ER-positive breast cancer, first for patients with metastatic disease and ultimately for patients with early-stage breast cancer. Now, moving to Slide 5. If you recall, in December of 2020, we reported a clinical benefit rate of 42% in 12 eligible patients. Today, we're reporting an equally compelling clinical benefit rate of 40% in 47 eligible patients. This is in a patient population expected to be resistant to ER-targeted therapies, which Ron will talk about in just a few moments. As a reminder, CBR is the standard primary efficacy endpoint in phase II studies evaluating new therapies in patients with previously treated ER+, HER2- breast cancer. In order to qualify as a clinical benefit responder, patients must either have achieved a confirmed RECIST response or durable stable disease, defined as disease stabilization of at least 24 weeks duration. This study enrolled the most heavily pre-treated patients of any trial of an ER targeting therapy, with all patients required to receive prior treatment with CDK4/6 inhibitors. Despite the advanced stage of disease and heavy pretreatment, the data we presented today reflect a high clinical benefit rate and deep ER degradation with a favorable safety and tolerability profile. While ARV-471 has not been studied against fulvestrant or any clinical-stage SERD, we believe today's data position it strongly among these current and potential future options. Now, before I turn it over to Ron, I want to reflect back to last December when we first shared what we believed was quite remarkable interim data with 471. We told you that we believed 471 was tracking to have the best-in-class profile, including safety, efficacy, and ER degradation for any ER-targeting therapy. Now, nearly one year later, I couldn't be happier to reiterate that the data continue to support this potential position. ARV-471 continues to demonstrate a compelling clinical profile, and I'm more confident than ever that we have an opportunity to provide a significant advance in treatment options for patients with ER+, HER2- breast cancer. Now, with that, I'll turn the call over to Ron, who'll take a deeper dive into these compelling data. Ron? Thanks, John, and good morning, everyone. Before I take you through the really exciting data on ARV-471, I'll briefly describe the design of the first-in-human trial as shown on Slide 6. We employed a traditional 3+3 dose escalation design, and the primary endpoints and secondary endpoints are typical for oncology phase I trials. We began with a starting dose of 30 mg administered orally once a day, and dose escalation continued up to a maximum administered dose of 700 mg. A maximum tolerated dose was not reached. The inclusion criteria for the trial are shown on Slide 7. Importantly, all patients must have received at least one prior CDK4/6 inhibitor agent. We believe this requirement is unique to our phase I trial as compared to those for the various SERDs currently in development. This is a critical point because we now know that patients who progress on or after a CDK4/6 inhibitor display a particularly high level of ER-independent resistance and have aggressive disease that progresses rapidly. More specifically, recent molecular profiling studies show that 66% of patients treated with these agents develop mutations across multiple pathways that are associated with unresponsiveness to ER-directed treatment. Not surprisingly, these patients do poorly with current treatment options, including the standard of care agent fulvestrant. At this year's ASCO meeting, the results of the VERONICA trial demonstrated that fulvestrant had a clinical benefit rate of just 14% in patients who were previously treated with a CDK4/6 inhibitor. As shown on Slide 8, patients in the trial received extensive prior therapy. The median number of prior therapies was four. 80% of patients received fulvestrant, and 78% received prior chemotherapy. Most notably, 55% of all patients in this trial had been treated with chemotherapy in a metastatic setting, which is well-known to be associated with poor outcomes in this patient population. To our knowledge, the percent of patients who received both fulvestrant and metastatic chemotherapy are among the highest reported in the first-in-human trials of novel ER-directed therapies. Together with the 100% prior CDK4/6 inhibitor use, we believe that this is the most treatment-resistant patient population across the competitive landscape. This makes the efficacy we are seeing with 471 even more exciting. Slide 9 outlines the safety profile observed in this study. ARV-471 was well-tolerated across all dose levels, up to 700 mg, and no dose-limiting toxicities were reported among the 60 patients we are reporting on today. Adverse events were primarily Grade 1 and 2, and only four patients experienced a Grade 3 adverse event that was deemed potentially related to ARV-471. Of these individual Grade 3 adverse events, none were indicative of a true safety signal based on the data to date. Importantly, only 1 out of 60 patients discontinued due to an adverse event, and only 1 out of 60 required dose reduction. Based on these results, ARV-471 continues to demonstrate a highly favorable safety profile that we believe is well-suited for patients with ER+ breast cancer across all lines, including the postoperative or adjuvant setting, where patients tend to remain on treatment for five years or even longer. The key efficacy endpoint, CBR, defined as the rate of confirmed complete or partial response plus durable stable disease lasting 24 weeks or longer, is presented on Slide 10. Among 47 evaluable patients, ARV-471 achieved a clinical benefit rate of 40%. Approximately 30% of these patients are still on treatment, two of whom have received ARV-471 for more than 1.5 years. Importantly, clinical benefit rate was seen in patients with both ESR1 mutant and wild type tumors. This CBR result is favorable relative to the rates reported in phase I trials of the various SERDs now in development and is particularly notable in the context of the extensive prior therapy these patients received. The 40% CBR rate is also encouraging given that 14% was seen with fulvestrant achieved in the CDK4/6 inhibitor treatment patient population in the VERONICA trial that I mentioned earlier. As shown on Slide 11, ARV-471 also demonstrated promising tumor regression in these late line patients with measurable disease at baseline. Three patients achieved a confirmed partial response and one notable response to talk about here, just to give you a picture of what this looked like, was in a patient who entered the trial with extensive liver metastases after progressing through multiple standard agents, including multiple therapies that are targeting the ER receptor, multiple targeted agents, and chemotherapy in the metastatic setting. Patients with large hepatic lesions often do not respond to endocrine therapy and are therefore commonly treated instead with chemotherapy. This patient had a substantial reduction in her lesions, as demonstrated in the CT scans included in the poster and met criteria for a confirmed partial response. Moving to Slide 12, ARV-471 degraded ER up to 89% through the 500 mg dose level with a median reduction in tumor expression by 67% and a mean reduction of 64%. This level of ER degradation exceeds the mean of 40%-50% reported in published data with fulvestrant administered at the optimal dose of 500 mg. Importantly, degradation was consistent across both wild type ER and ESR1 mutant protein. With that, I'll now turn the call over to Chris. Thanks, Ron. Turning to Slide 13, to summarize, in this phase I trial with a heavily pre-treated patient population, including 100% of patients previously treated with a CDK4/6 inhibitor, 80% with prior fulvestrant, and 78% previously exposed to chemotherapy, ARV-471 demonstrated early clinical benefit and is well-tolerated. A robust efficacy signal was observed in this population, which we believe is the most heavily pre-treated compared to other recent studies with ER targeted degraders or modulators. In this setting, only approximately 34% of tumors would be expected to be driven solely by estrogen receptor signaling. Even in this very advanced stage patient population, we saw clinical benefit rate of 40%, which included three confirmed partial responses, and we demonstrated impressive ER degradation. As a reminder, only 1 out of 60 patients discontinued due to an adverse event, demonstrating a favorable benefit risk profile and supporting the further development of ARV-471 as a monotherapy or as a suitable combination partner to test in early lines of treatment. Turning to Slide 14, which outlines our clinical development plan. In partnership with Arvinas, we will jointly develop ARV-471 through a broad clinical program designed to generate data that, if positive, could position ARV-471 as a best-in-class endocrine backbone therapy across the ER positive breast cancer treatment paradigm from the adjuvant setting through to late line metastatic disease. ARV-471 is currently in two ongoing clinical trials for ER+, HER2- metastatic breast cancer, a phase I-B combination study with IBRANCE or palbociclib, and the VERITAC phase II monotherapy dose expansion study, which I'm pleased to announce is now fully enrolled. In 2022, we expect to share data from the VERITAC monotherapy phase II study as well as data from the phase I-B trial in combination with IBRANCE. We also intend to initiate phase III studies next year across multiple lines of therapy in both monotherapy and in combination, as well as expand an umbrella study with other targeted medicines, including our next generation highly selected CDK2 inhibitor, our CDK4 inhibitor, and our specific KAT6A inhibitor. With that, I turn it back over to John. Thanks, Chris. If you all turn to Slide 15, I hope you share in our excitement for the data we presented today at the San Antonio Breast Cancer Symposium with a strong efficacy signal, compelling ER degradation, and a well-tolerated safety profile. These data further demonstrate that ARV-471 has a consistent, potentially best in class profile and is well positioned to become the future go-to choice for ER targeting therapies. As Chris outlined, we have a clear development path for ARV-471 with a data rich 2022 ahead. We look forward to reporting data from multiple studies, both monotherapy and in combination, and to initiating two phase III studies in the upcoming months. Now before we open the call for questions, I want to thank our employees for their continued dedication and importantly, the patients, their caregivers, and physicians who participated in this trial. Thank you again for joining us this morning. Operator, we're ready to open the call for questions. Ladies and gentlemen, if you have a question or a comment at this time, please press the Star then the one key on your touch-tone telephone. If your question has been answered and you wish to remove yourself from the queue, please press the Pound key. Our first question comes from Ellie Merle with UBS. Hey guys, thanks so much for taking the question. Just in terms of safety, could you elaborate a bit on the QTc prolongation seen in one patient as well as sort of the liver elevation seen in one patient that were Grade 3? Just in terms of the planning for the phase III, could you talk a little bit about how you're looking at the AMEERA- 3 data as well as the data from RADIUS and any implications in terms of your trial planning? Thanks. Thanks, Ellie. Some nice questions there. Yeah, we're very pleased with the safety profile we're seeing at this stage of the phase I and moving into phase II last year. Let me hand over to Ron, who can take you through those examples you mentioned. Thanks, John. Yeah. I'll start with the QT. This is an isolated event. This is a grade three event. The point about that is, based on the thorough evaluation of the data, we don't believe this represents a signal. This is not unusual to pick up in a phase I trial. We don't see this as a signal. There were, for this particular patient, the patient was on a couple of medicines that could be associated with QT prolongation. The other point I'd like to make here is that preclinically, we have not seen a preclinical signal that around QT prolongation, either in the hERG assay nor in the dog studies. We don't see this as a signal. With regard to, I think you mentioned liver, but I just have to make a correction. You probably are referring to amylase lipase. We haven't had any grade three liver events. The amylase lipase is similarly an isolated event. This is a patient who had elevation in one lab test. A subsequent lab test was unremarkable. Both cases for the QT and the amylase lipase, these were asymptomatic findings. This is another case where we don't see this as a signal based on the data that we have today. Ron, do you want to talk to the second half of Ellie's question related to plans for phase III as it relates to RADIUS? I mean, generally, we are actually pleased to see other companies with SERDs showing positive data. I think that bodes well for our compound because the profile of our compound at a similar stage of development in the phase I would clearly look very, very good. So, we're pleased to see that. Ron, do you have anything about any change of plans? I don't think we have a change of plan, but thoughts about the overall planning for phase III. Yeah. Certainly no. We don't have any. This doesn't affect our plans. I mean, for us, you know, we're thrilled that we have activity both in ESR1 mutant and ESR1 wild type. Also, I mean, just as we have been talking about, you know, we're very excited by the efficacy data, especially in the context of extreme prior therapy that these patients received. You know, we feel that this is something that makes perfect sense for us to move into the second line, and our strategy doesn't change as a result of these results. Thanks. Great. Thanks so much, and congrats again. Our next question comes from Joon Lee with Truist Securities. Hi. Thanks for taking our questions, and congrats on the very impressive data. You know, in the swimmer plot data, there are five patients with stable disease past six months who are no longer on 471. What's their disposition? I have a follow-up. Ron, do you wanna take that? Yeah. Can you restate your question, please? Sure. There's 5 patients in the swimmer plot that had stable disease. What's their disposition? In the swimmers plot, when patients are still on therapy, they'll have an arrow. If they don't have an arrow, that means that they've stopped, usually for progressive disease. I think one thing that is, you know, with regard to, I guess, stepping back overall, the thing that we're excited by is that we have approximately 30% of patients who are still on therapy, including some patients who've been out for a pretty long time. Got it. The other question is, you know, post CDK4/6 is expected to drive high rates of ER-independent resistance mechanism, yet a lot of people, and it's 100% of the patients who are on CDK4/6, yet you have high rates of response. So what's the mechanism by which ER is having an impact in these presumably resistant patients? Well, just again, Ron can talk to that, but you know, overall, we know, we believe in these patient populations, this late-stage patient population, over 65% of the patients probably have tumors that are ER-resistant. That does leave a significant number that still potentially could respond, and that's why we're so excited by our data. To have a 40% CBR in a highly resistant patient population is really significant. Ron, do you wanna talk in relation to the ESR1 mutant versus wild type? One thing just to, we talked about the activity there in the mutant and the wild type. The clinical benefit rate in the mutant population is actually 50%, which is pretty remarkable, especially with all the treatments that these patients have gotten. In the ESR wild type patients, remember that this seems to be a signature for lack of responsiveness or underresponsiveness to estrogen directed therapy, we still have a clinical benefit rate of 30%. You know, just to put that into context, if you look again back at the VERONICA trial, which had a 14% clinical benefit rate, we're still seeing double the clinical benefit rate that would be expected in this population with the current standard of care. Thank you. Our next question comes from Ted Tenthoff with Piper Sandler. Great. Thank you very much, and congrats. My congrats on the data too. It's really cool to see how far the technology is coming, and I really love the broad development plans. I wanted to focus in on the phase III trials and get a sense. It seems like this is gonna be building on this experience in later stage women. Can you give us any idea of patient population, maybe even size of a potential phase III trial? I appreciate you guys answering the question. Thanks. Thanks, Ted. Of course, we are very excited to have a great partner now for ARV-471 with Pfizer. Chris Boshoff's on this call. Maybe Chris, I could turn to you and talk about our early thinking on phase III plans. Thanks very much. Good question. So overall, we are working very closely with Arvinas to design the phase III study, and we will provide additional information or further information in 2022 regarding our strategies. We believe the RADIATE data as referred to earlier provides proof of concept and confidence in the next generation class of ER-targeted medicines. We also believe, of course, that ARV-471 could be potentially a best in class molecule. We will incorporate any lessons from their studies, obviously into our trial designs, both in the later and earlier lines in combination with CDK4/6, but also for the adjuvant setting. Thank you. Good stuff. Thanks, Chris. Thank you. Our next question comes from Alethia Young with Cantor Fitzgerald. Hi, good morning and congratulations on the data. This is Naynaad for Alethia. Why did you decide to design your trial with 100% of patients requiring prior CDK4/6 treatment while other trials have not? How do you believe that your levels of prior chemo and fulvestrant treatment compares to other trials? Thanks. Thanks. Thanks, Alethia. I mean, I'll hand over to Ron for a broader answer, but that was a requirement from the FDA in terms of the 100% CDK4/6. So that's why we know that we're in one of the latest patient populations, not only 100% post CDK4/6, 80% post fulvestrant and 78% that had prior chemotherapy, so an incredibly late stage population. Ron, do anything you want to add into that? Yeah, I think maybe just to add to the point that we assume that the FDA put that requirement to us because we're coming in with a new modality. The only other thing that I would say is we've of course to understand our data, we also have to put it in context with the others. You know, as we've looked through this very carefully, we do see a difference. You know, also, when you look at the literature in the ER-positive, HER2- setting, you will see that prior chemotherapy, fulvestrant but also chemotherapy in the metastatic setting clearly is a predictor for a much worse outcome. Thank you. Our next question comes from Michael Schmidt with Guggenheim. Hey, guys. Thanks for taking my questions and congrats on the data as well. Just wondering if you could provide some additional comments around the dose response and your rationale to select two doses for phase II, the 200 mg and the 500 mg once a day, and how you will select the phase III dose based on that? Thanks, Michael. Great question, and I'll hand over to Ron to talk about dose response and our initial thinking about phase III dose. Certainly. With regard to, I'll start with the phase II doses. Michael, you brought up that at 200 mg and 500 mg we had selected for the phase II. 200 mg was selected initially based on the exciting data that we had around the time that we had last year's disclosure. 200 mg in particular from an exposure perspective was giving us a comfortable margin above the preclinical threshold. Of course, we you know certainly had safety and efficacy and ER degradation at that level. We felt very comfortable moving forward with the phase II. We selected 500 mg subsequent to that based on the continued phase I dose escalation. 500 mg essentially gives us a bookend to investigate whether there could be a dose-response relationship as we get up higher in dose. 500 mg is safe. 500 mg is the highest exposure that we've achieved. We're seeing activity across the board. What I would say is that this is a phase I trial of course so with small numbers at each of the doses. This is not the trial where you can really discern a dose-response relationship. In terms of us picking a dose for phase III, it's really gonna be dependent on additional data that will come from the VERITAC trial, this dose-ranging study. That will position us to make a very well-informed selection of our optimal dose for phase III. Great. Thanks so much. Our next question comes from Matthew Luchini with BMO. Hi. Good morning. Thank you so much for taking the questions and for providing a nice update this morning. I guess first for me, as it relates to the combo, the phase I-B combo study you're gonna be starting next year, I was just, you know, curious if you have any sense as to, I guess, first, when we might expect some initial results from that study, but I guess more generally, you know, you've talked about maybe looking at CDK2, CDK4/6, if there's any of these mechanisms that you think might be particularly synergistic with 471. On the data presented today, was just hoping you might be able to provide or remind us with some additional color as it relates to both the two patients who have had, you know, I think it's now north of 18 months of treatment, as well as the patient that achieved the partial response with the, despite having liver mets, since that certainly is an interesting result given the patient population. Thank you. Thanks. We can split these components of the questions between Ron and Chris. Ron, do you wanna start off with the palbo combo, and then you can maybe talk about the patients, then Chris, maybe talk about the potential combinations as we move into phase III. Ron? Yeah, certainly, yeah. The palbo combination is ongoing. That will of course inform our selection of the combination dose. Just one word about that trial is it's not designed for efficacy. We allow prior CDK therapy. Our goal here is very simply to look at safety, ensure that the drugs are combinable without any unexpected findings and evaluate PK. With regard to the questions around, I think there was a question around the patient with liver metastases, the one that I had described. Just a reminder, there's a vignette in the poster about this with CAT scan pictures. Yeah, this patient had pretty remarkable response. As you can see in that slide, a patient had excessive prior therapy. This patient actually had received an investigational SERD that is now, you know, in late stage development and never responded to that prior to going on 471 and actually progressed on that. I think your question was what happened with that patient. That patient actually came off without having response. The patient did not have toxicity either that drove her to come off. It was more around a patient who was being treated distantly from her home, was referred into the trial and opted to go back to her referring oncologist. I think the other question that you had was there anything in particular with regard to the patients who are on therapy longer? Yeah, you could see, I mean, across the board, these patients are pretty heavily pretreated. I think it's hard to really discern more specifics, but you know, we are seeing this pattern across the board in terms of the clinical benefit rate. Chris, do you wanna talk to the potential excitement around 471 plus other mechanisms? Thank you. That's a good question. We are working very closely with our colleagues at Arvinas to design the strategies for the combination studies, including an umbrella trial. As you will recall, three years ago now, or four years actually, with our collaborators at the Institute of Cancer Research, Nicholas Turner, we showed that CDK2 is a potential mechanism of resistance to CDK4/6 inhibitor s. That was in our VERITAC studies. We therefore designed and conceptualized, developed this highly selective CDK2 inhibitor, which is currently in phase I, and we will share data in 2022 with the CDK2 inhibitor. Of course, that provides optionality to also combine the CDK2 inhibitor with palbociclib, and such a study is also ongoing. We are also presenting data at San Antonio Breast Cancer with a CDK 2/4/6 inhibitor, and early encouraging data will be shared at San Antonio. Separately, we have a CDK 4 specific inhibitor that's currently in phase I, and again, we'll share data in 2022. The CDK 4 inhibitor is particularly designed because we believe that CDK 6 plays a more important role in the hematological toxicity seen with CDK 4/6 inhibitors. Overall, I think this partnership provides us with significant options and advances over competitors in terms of what we can do to combine to really transform the standard of care for patients with ER-positive breast cancer. It's a good question. Thank you. Thank you very much for all the color. Our next question comes from Zegbeh Jallah with Roth Capital Partners. Good morning, guys. Great results, and thanks for taking my question. As highlighted, we've seen encouraging efficacy observed in a heavily pretreated patient population. If I can have you speculate just a little bit. Based on what you're seeing here, can you comment on what you think the resistance mechanisms could be and what your thoughts are regarding the level of efficacy and the durability we could see in early adjuvant setting relative to fulvestrant, for example, particularly given the reported efficacy in ESR1 mutant patients? I have a quick follow-up. Thank you. Great question. Maybe I could ask our CSO, Ian Taylor, to talk about what's known about potential resistance mechanisms, then we could hand back to Ron for that second part of the question around efficacy. Sure. Thanks, John. Yeah, right now I don't have any data from the clinic that would point to any resistance mechanisms, but what we've modeled pre-clinically is that most of the resistance mechanisms continue to be non-ER dependent, not related to the ubiquitin proteasome system or the mechanism of the PROTAC per se, but more other pathways, other mechanisms beyond ER coming up. Which of course is what we're seeing a lot in our patients currently post CDK4/6. Seems consistent with that, currently. Ron? Yeah, certainly, yeah. I think your question was around efficacy in earlier lines. Yeah, I mean, we're especially excited about how this is gonna work in earlier lines. You know, we firmly believe that degradation is the most important mechanism with fulvestrant as the most active therapy in the market today, and it is a sort of a more indirect degrader, just gives us that confidence. Fulvestrant's experience has also shown that having greater degradation matters. You know, when they moved from the 250 mg original approved dose to the higher optimal dose of 500 mg, which was associated with greater degradation and greater efficacy. You know, we're thrilled with where we are right now. We have a safe drug. We have a drug that has really robust activity in the most heavily pretreated population that we're aware of in these studies of new therapies targeting ER. We really do, we're very excited, I think, probably speak on behalf of Chris, that we're very excited about moving this into earlier lines and adjuvant. As I mentioned, the safety for 471 is especially suited for long treatment, including the longer durations in the adjuvant setting. Thanks. Just a quick follow-up. I know this is a difficult one. I think we've been attempting to answer this question on the call, but just curious on your thoughts regarding whether the efficacy seen in supposedly non-ER-driven tumors could be something unique about how 471 binds to the receptor. Or could it be something unique to the ER effect of degraders and their ability to kind of be effective under low substrate conditions? Maybe more broadly, beyond that, you could talk about how this data perhaps even coupled with data from ARV-110 influences your conviction in the rest of your pipeline efforts, which is expected to probably become more of a focus during 2022. Thank you. Yeah, yeah, obviously we're extremely excited about the potential of 471, and you mentioned ARV-110, which is also progressing really well. I'm not sure between Ian and Ron, do you wanna try and talk about that, what we think is driving efficacy in the ER-resistant? 'Cause we are seeing significant CBR rates in these wild-type patients. Ian or Ron? It sounds like an Ian question. Yeah. Yeah, sure. I can go. Yeah, I think the key point to remember about these resistance mechanisms is always put it in the context of tumor heterogeneity, right? These tumors are not homogeneous at all in terms of their molecular profile. We see that when we're doing the circulating tumor DNA profiling. We see a lot of different mutations. In some clones of the tumor may be ER dependent, and we can see responses there, but other clone parts of that tumor might have other driver resistance mechanisms like Aurora kinase or PI3K. It's kind of hard to tease apart in any one tumor, you know, all the things that are going on and which part of the tumor might be driving the response and which part might be driving the resistance. Clearly, because we're seeing responses and significant clinical benefit rate, you know, in most of these patients, there's certainly regions of the tumor that are responsive to ER and that are responding to ARV-471. We think that's really linked to the degradation mechanism. That does flow over into ARV-110 as well, and the rest of our pipeline. I think we're seeing that if a tumor can respond, if it's even in a resistant setting, it's being driven by ER, the degradation can drive that benefit to the patients. Perfect. Thanks, guys, and thanks again for taking my questions. Thank you. Our next question comes from Brad Canino with Stifel. Thank you. I appreciate the data update this morning. Just so we have the specific details, can you tell us what number of the, I think it was 47 CBR evaluable patients, had a documented ESR1 mutation? And then what was the CBR in both patients with mutated and wild-type ESR1? Ron, do you want me to go through that? Yes. What I can tell you and I don't have the numbers in front of me right now, but what I can say is that the CBR rate in the patients with ESR1 mutants was 50% and for patients with ESR1 wild type was actually 29%, so about 30%. Unfortunately, I don't have the numbers here, but we can certainly get those. Okay. Thank you. On your phase II, you mentioned it was fully enrolled. Can you tell us the N, the sample size there that we will be getting? Ron? I'm sorry. Can you restate the question, please? We've just announced that we'd finished the enrollment of phase II, and I think the total number of patients in there will be 60. Is that correct, Ron? Yeah. Approximately 30 patients for the 230 patients for 500 milligrams. Yeah. Okay. Thanks so much. Congrats on the progress. Thank you. Our next question comes from Mark Breidenbach with Oppenheimer. Hey, good morning, guys. Thanks for taking the question, and very glad to see the CBR rate holding up in the larger data set. Just very simple question from me. Since you mentioned VERITAC's completed enrollment, I'm just wondering if you can give us any granularity on when in 2022 we can expect to see initial data from VERITAC as well as the phase I-B evaluating 471 in combination with IBRANCE. Thanks, thanks for taking the question. Yeah. So far what we've announced is that next year we will have the VERITAC phase II data discussed and released, and we'll have the safety data from the phase I IBRANCE combination study. What we haven't said yet is where and exactly when. There'll be more on that in the new year. Yes, we're committed to having those results coming out next year. Okay. Thanks so much. Our next question comes from Jonathan Miller with Evercore. Great. Thanks for taking the question. I actually just had a couple of quick clarifications. The first one is, aside from the grade three QTc event that you guys flagged, I just wanted to double check that there weren't any Grade 1 or 2 QTc prolongation or bradycardia type events. Then on the two additional confirmed PRs from the prior cut, from what I can tell, I think one of those was a previously unconfirmed patient as of the December 2020 cutoff, and then one is a new patient, but just wanted to clarify that that's correct as well. Thank you. Thanks for the question. Ron, do you want to take this? Yeah, certainly. Yeah, for QT, we had two other patients that had Grade 1 or 2, but these patients had other explanations. One patient had, you know, elevated QT at baseline. The other patient was on therapies that are well known to prolong QT, and these were also very transient observations. The QT would go down to baseline, so it was not, in our assessment, anything that would support a signal here. As I mentioned before, preclinically, 471 did not have a signal either through hERG testing or dog studies. The question was around the unconfirmed response from before that is now a confirmed response. Yeah, so this is, you know, as you know, this is an ongoing trial. The database is, you know, not gonna be final until the study report. This is a case where what was in the database a year ago led to a determination of an unconfirmed response, but with additional querying to the site, the site ended up putting in a correction in the database, and that resulted in the confirmed response. Thank you. Our next question comes from Yigal Nochomovitz with Citigroup. Hi. Great. Thank you very much for taking the questions. I had two efficacy-related questions. The first one is, are we going to see PFS data at some point, or is CBR really the critical metric? And if we do get PFS data, what do you think you need to show there? And then secondly, with regard to ER degradation correlating with clinical benefit, I appreciate that the numbers are too small with the current data to draw any conclusions on correlation of degradation with clinical response. But I'm just wondering, once you do have more data, would it be your expectation that you'd start to see the magnitude of ER degradation start to correlate with clinical benefit? Thanks. Thanks, Yigal. Certainly, I'll have Ian talk about ER degradation. You're right, the numbers so far are relatively small, and of course, even if we're doing 100% degradation in some of these tumors where it's completely ER-resistant, you wouldn't see any benefit. So again, that's the confounder at this very late stage patient population. As we go into earlier lines where the more of the disease is driven by ER, these high levels of degradation are probably gonna have a more significant impact in efficacy. I'll let Ian talk about that in more detail. Ron, do you want to talk about PFS and CBR? Sure. What's the best measure and when we start talking about PFS? Yeah, yeah. PFS is something that we'll likely wait until the VERITAC study. Remember that, well, first of all, of course, this is a phase I study. The other thing is that, you know, so we have doses, we have treating across multiple doses. It's also, as we've already made the case, is that there's a particularly heavily pretreated typical phase I population. We actually allow up to three prior chemotherapy regimens. Phase II is where we're gonna present the PFS data. Yeah, we look forward to having those data available. Ian, anything you want to add to the ER degradation question from Yigal? Not really, John. You covered it pretty well. I mean, it's really driven by the biology. Post CDK4/6, we have so much non-ER dependence that, you know, you can degrade the ER all you want and those tumors won't respond because they're being driven by something else. In this setting, it's gonna be really hard to show that relationship. In other settings earlier, as John mentioned, where there's more ER dependence, then that's where it would show up. Thank you. Our next question comes from Tyler Van Buren with Cowen. Guys, good morning. Thanks very much for taking the questions. I guess, the first one is, what do you view to be the most significant safety and tolerability benefit relative to Sanofi's amcenestrant as we think about you both eventually competing in the market, and then just secondarily related to the EMERALD data, can you discuss why you think the PFS, and CBR rates were higher in mutant patients versus wild type? Sure. I'll hand this over to Ron, but just again, to be fair to Ron, just to position, we're discussing our end of phase I data, and these other companies are discussing data from a later stage of development. We're very comfortable that when we get to compare our data end of phase II, we'll be in a good position to compare. Having said that, Ron, anything you wanna say about safety benefit compared with Sanofi and the EMERALD data, with a- Yeah. I mean, I think. Focus on our drugs. Yeah. I think the message is that we're very confident. You know, the way that we look at this is, you know, this is the most resistant, most aggressive tumor or patient population that's been studied with a novel ER therapy. We think that the safety really is really good all the way up to 700 mg. I mean, this is pretty remarkable with no dose-limiting toxicities. You know, only one discontinuation, only one dose reduction out of the 60 patients. So we think the safety is really quite conducive to long-term therapy. Then the benefit, you know, we we're very excited by a clinical benefit rate of 40 in the most resistant population. You know, we feel like we're in a really good place as we move into phase III. Thank you. Our next question comes from Christopher Liu with SVB Leerink. Hey, guys. Thanks for the question. I just had two. With the first one, I was just thinking about, you know, your go-forward doses with 200 mg and 500 mg. When I look at the CBRs here for 200 mg and 500mg, it looks like, you know, albeit in small patient numbers, but it looks like 500 milligrams has a, you know, meaningfully higher CBR rate. Just wondering if you thought, you know, that could mean something, if, you know, that kind of leans you towards going towards the 500 mg. Well, again, this is our phase I data, so it's dose escalation, where we're very excited to see responses and clinical benefit rate as we went up the doses. Very pleased to see significant degradation through all doses. As Ron mentioned earlier, we chose 200 mg and 500 mg because we thought that would be a nice bookend in terms of exposure and efficacy. Absolutely, we'll see what happens at the end of phase II. At the end of phase II, I think we're gonna have a great, rich data set on 200 mg and 500 mg. But right now, we're just pleased that going through to the end of phase I, the choices that we made early in the year were correct. These were the right choices to pick 200 mg and 500 mg. We'll see how that pans out and what position it puts us in to select which dose for phase III next year. As Ron said, we're this is in a very good position. Got it. For my second question, I was just hoping to get additional color on the Grade 3 AEs that you saw in the 500 mg cohort as well as the, you know, 180/200 mg cohort. Yeah, sure. I'll hand back to Ron to go over again the Grade 3 events. Yeah. What I'm gonna just say is that, you know, just remember that there's only four patients out of 60 who've had Grade 3 related adverse events, and each of these were different. There's not a consistent pattern. As I mentioned in the presentation, none of these individual events represents a particular safety signal based on the data that we have. The other thing that's interesting is that, you know, going from 30 mg- 300 mg all the way up to 700, you know, there's not an obvious dose relationship for adverse events, which again, I think just reinforces the safety of this compound. I think back to what John was saying from the standpoint of picking a dose, the VERITAC study will also give us more information about safety at the two doses, 200 mg and 500 mg. We have to wait for that. Okay. Is there anything you could tell us specifically on what the Grade 3 AE was in the 200 mg cohort and then the 2 in the 500 mg cohort? I actually, I'm not sure I have that information right in front of me. We can certainly provide that. Well, Ron, you already talked about the grade 3 events earlier. Just go through those again. Across the study with 60 patients, we had one Grade three related QT event, which I mentioned, does not in our assessment indicate a signal. We had one isolated case of pancreatic amylase, lipase elevation, also asymptomatic and also not indicative of a signal. We had a third patient who had a thrombotic event. Thrombotic event's very common in oncology, in metastatic breast cancer in particular, and this patient also had another risk factor for clotting so that there's no, you know, no concern about that one as well. We don't think that's related to this treatment. We had one Grade 3 nausea. It's the only Grade 3 nausea that we had. the GI profile looks very good. We're really not concerned about these events. Got it. Thank you. I'm not showing any further questions at this time. I'd like to turn the call back over to John for any closing remarks. Yes. Thank you very much. Thank you again to all of you for joining us this morning and for your continued interest and great questions. Thank you and have a great day. Ladies and gentlemen, this concludes today's presentation. You may now disconnect and have a wonderful day.