Good day, and thank you for standing by. Welcome to the Arvinas Fourth Quarter 2024 Earnings Conference Call. At this time, all participants are in a listen-only mode. After this speaker’s presentation, there will be a question-and-answer session. Please be advised that today’s conference is being recorded. I would now like to turn the conference over to your speaker for today, Jeff Boyle. Please go ahead.

Good morning, everyone, and thank you for joining us. Earlier today, we issued a press release with our fourth quarter and full year 2024 financial results, which is available in the Investors and media section of the website at arvinas.com. Joining the call today are John Houston, Arvinas’ Chief Executive Officer, President, and Chairperson; Noah Berkowitz, our Chief Medical Officer; Angela Cacace, our Chief Scientific Officer; and Andrew Saik, our Chief Financial Officer. Before we begin the call, I’ll remind you that today’s discussion contains forward-looking statements that involve risks, uncertainties, and assumptions. These risks and uncertainties are outlined in today’s press release and in the company’s recent filings with the Securities and Exchange Commission, which I urge you to read. Our actual results may differ materially from what is discussed on today’s call. And now, I’ll turn the call over to John Houston, our CEO, President, and Chairperson. John?

Thanks, Jeff. Good morning, everyone, and thank you for joining us this morning. It’s a very exciting time for us here at Arvinas, as we’re on the cusp of some major accomplishments that include our first Phase 3 topline data results expected later this quarter and first-in-human data from our first PROTAC targeting neurodegenerative disease. We continue progressing a robust portfolio of exciting development programs that have the potential to transform the treatment landscape across a broad range of cancers and neurodegenerative diseases. Our novel approach to discovering, developing, and commercializing a new class of medicines has always been the backbone of our company, and we’re pleased to provide an update this morning at such an important time for the organization. Today, I’ll begin with a brief overview of Arvinas, our PROTAC Discovery platform, and an update on our pipeline. Noah will then provide an overview of our vepdegestrant, or vepdeg clinical program, including reviewing the Phase 3 VERITAC-2 trial, and also provide an update on our first neuro-clinical program with ARV-102, our LRRK2 degrader. Angela will provide an update from our earlier stage programs, including our BCL-6 degrader, ARV-393, and our KRAS G12D degrader. And finally, Andrew will provide an overview of our fourth quarter and full year 2024 financials before we open up the call for your questions. Over the course of the last year, we have made significant progress on our mission to improve the lives of patients with debilitating and life-threatening diseases. Our pipeline of PROteolysis Targeting Chimera or PROTAC protein degraders have been designed to harness the body’s natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. Our innovative PROTAC platform has enabled us to create a deep pipeline, while making significant breakthroughs in targeted protein degradation. These breakthroughs include designing degraders with drug-like properties that are orally bioavailable and when needed able to cross the blood-brain barrier. Vepdeg is the most advanced program in our pipeline and, in addition, to our ongoing Phase 3 monotherapy trial, our current development plan includes two additional Phase 3 combination trials across the first- and second-line settings in metastatic breast cancer. Vepdeg is an oral PROTAC protein degrader, specifically designed to target and degrade the estrogen receptor for the treatment of patients with ER-positive/HER2-negative breast cancer. Together with Pfizer, we are developing vepdeg with a goal of becoming the best-in-class ER targeting backbone therapy, first as a monotherapy, then with multiple combination strategies, and soon we expect to have data in hand from VERITAC-2, our first-ever Phase 3 trial. Data from this Phase 3 clinical trial will be an important milestone for Arvinas and we look forward to sharing topline results later this quarter. If positive, these results will support our first new drug application and mark our potential transition to a commercial stage company. Noah will provide an overview of the trial later in the call. Now, given how close we are to this disclosure, we will not be answering questions about trial progress or offering additional guidance on expectations for VERITAC-2 during the Q&A portion of our call. Last month, we announced updates to our clinical development plans for vepdeg combination trials in the first- and second-line settings, pending emerging data and health authority feedback. In the first-line, we announced that in 2025, we intend to initiate a Phase 3 trial with vepdeg plus Pfizer’s novel investigational CDK4 inhibitor atirmociclib. In the second line, we announced that we plan to initiate a Phase 3 combination trial evaluating vepdeg with a CDK4/6 inhibitor, which we also expect to initiate in 2025. Beyond vepdeg, we have a data-rich year ahead, and we believe there are exciting opportunities for PROTAC across oncology and neuroscience. In April, we plan to present the first-in-human data from ARV-102, a LRRK2 degrader, which we believe will highlight the potential value our PROTAC degraders can offer to patients with neurodegenerative diseases. Additionally, in 2025, we plan to share preliminary data from our Phase 1 trial with ARV-393, our BCL6 degrader, in patients with non-Hodgkin lymphomas. And, finally, we are on track to file an investigational new drug application for our KRAS G12D degrader this year. I’ll now turn the call over to Noah for an overview of the vepdeg and ARV-102 programs. Noah?

Thanks, John, and good morning, everyone. Last year, together with Pfizer, we made great progress with our vepdeg program. As John mentioned, in addition to sharing topline results from VERITAC-2 later this quarter, we intend to initiate two new Phase 3 combination trials in the first- and second-line settings later this year. We continue to believe vepdeg has the potential to demonstrate superior efficacy and tolerability and become a best-in-class ER targeting backbone therapy preferred by physicians and their patients. Given the proximity to the upcoming topline data readout, I won’t spend too much time discussing the VERITAC-2 trial, which, if successful, could result in a submission of the new drug application and the first-ever regulatory approval of a PROTAC degrader. Recall, the VERITAC-2 clinical trial is evaluating the efficacy and safety of vepdeg compared with fulvestrant in patients with ER-positive/HER2-negative advanced breast cancer, who have previously received and progressed on a combination of CDK4/6 inhibitors and endocrine therapy. Important progress has been made in the treatment of patients with metastatic breast cancer, who have progressed after receiving prior treatment with the CDK4/6 inhibitor, yet there is an ongoing need for improvement in treatment. An oral agent approved a few years ago for patients with ESR1 mutations only managed to extend median PFS a few months to 3.8 months. This highlights the unmet medical need among patients with advanced metastatic breast cancer and the potential opportunity for vepdegestrant in the VERITAC-2 trial. VERITAC-2 has two primary endpoints, PFS in the ITT or intention-to-treat population and PFS in the ESR1 mutation subpopulation. The study also has secondary outcome measures that include overall survival, anti-tumor activity, including objective response duration of response and clinical benefit rate, and of course, there are safety and quality of life assessments. It is worth noting that events determining PFS will be assessed by blinded independent central review. We expect to announce the outcome of VERITAC-2 in a topline press release in Q1 and to present full results in the medical congress in 2025, where we also intend to host an Investor Call. In addition to anticipating VERITAC-2 results, we are pleased to be progressing our plans to initiate registration trials evaluating vepdeg combinations. Later this year, we plan to initiate a first-line Phase 3 trial of vepdeg in combination with Pfizer’s novel investigational CDK4 inhibitor atirmociclib, pending emerging data and health authority feedback. The decision to prioritize vepdeg plus atirmociclib in the first-line setting is based on the totality of evidence from the ongoing Phase 1b/2 TACTIVE-K combination trial evaluating vepdeg plus atirmociclib in the late-line setting and our trials evaluating vepdeg plus palbociclib. This evidence, in addition to shifting treatment paradigms for early and advanced breast cancer, gives us the confidence that vepdeg plus atirmociclib is the best combination to advance as a potential new treatment option in the first-line setting. We and Pfizer are excited by the potential this combination represents for a new treatment option in this setting. Our plans also include initiating a second-line Phase 3 combination trial of vepdeg plus a CDK4/6 inhibitor in 2025, pending emerging data and health authority feedback. Compelling efficacy signals have been shared previously for vepdeg in combination with palbociclib or with abemaciclib in the second-line plus setting. In December 2024, we presented preliminary data from 16 patients in the Phase 1b combination trial of vepdeg and abemaciclib at the San Antonio Breast Cancer Symposium. This combination demonstrated encouraging clinical activity with a clinical benefit rate of more than 60% and an overall response rate of nearly 30% in patients previously treated with the CDK4/6 inhibitor. Safety and tolerability of the combination were generally consistent with the demonstrated profile of both agents. Importantly, no significant drug-drug interactions were observed and vepdeg had no clinically meaningful effect on abemaciclib exposure. The combined ability of vepdeg was also supported by a Phase 1 pharmacology trial of vepdeg, which demonstrated that DDI potential is not a concern for the ongoing clinical development of vepdeg as a backbone ER therapy. We look forward to initiating the second-line Phase 3 combination trial later this year, pending emerging data and regulatory feedback. In totality, the data we have generated continue to support our belief that vepdeg has the potential to provide superior efficacy and tolerability, both as a monotherapy and in combination for patients with metastatic breast cancer who need new treatment options. I’m now going to turn to our neuroscience clinical program. Our most advanced neuroscience PROTAC, ARV-102, is a novel oral PROTAC designed to cross the blood-brain barrier and target Leucine-rich repeat kinase 2 or LRRK2. LRRK2 is a large multi-domain scaffolding kinase genetically implicated in progressive supranuclear palsy and Parkinson’s disease. Pre-clinically, we have shown that ARV-102 crosses the blood-brain barrier and achieves deep brain region penetration and degradation of LRRK2 in non-human primates. We’ve also observed differentiation from inhibitors by showing improved effects on lysosomal dysfunction and movement of disease-relevant biomarkers in the central nervous system in preclinical studies. In 2024, we initiated dosing in a first-in-human Phase 1 clinical trial of ARV-102 in healthy volunteers. This ongoing Phase 1 trial was primarily designed to establish the safety of ARV-102, but it will also measure LRRK2 degradation in the periphery and in the cerebrospinal fluid or CSF of patients to establish the ability of ARV-102 to cross the blood-brain barrier and degrade LRRK2 in humans. And I’m pleased to share that initial data from the single offending dose cohort of the trial will be presented in an oral session at the Alzheimer’s Disease/Parkinson’s Disease or AD/PD conference in April. These data confirm that ARV-102 is orally bioavailable in brain penetrant with dose dependent exposure in the CSF. At the AD/PD conference, we will disclose degradation data from the peripheral blood and CSF of healthy volunteers. An exciting milestone that we look forward to sharing. The learning from this Phase 1 trial will be valuable as we strive to address the incredibly high unmet medical need in neurodegenerative diseases. We intend to explore the potential of ARV-102 in two severe neurodegenerative disorders that are linked to LRRK2 dysregulation. The first is progressive supranuclear palsy in which LRRK2 mutations are strongly linked with faster progressing disease. And the second is Parkinson’s disease in which LRRK2 has been shown to contribute to disease pathology. We recently initiated a Phase 1 ascending dose trial of ARV-102 in patients with Parkinson’s disease and expect to complete enrollment and present the initial data from this study later this year. It should be noted that we also plan to initiate a multiple ascending dose cohort in patients with Parkinson’s disease later this year. Now, I’m going to turn it over to Angela, who will talk about ARV-393, our BCL6 degrader, and our KRAS G12 degrader. Angela?

Thanks, Noah, and good morning, everyone. The preclinical profile of ARV-393, our oral PROTAC designed to degrade B-cell lymphoma 6 protein, or BCL6, has been highly positive. For background, BCL6 is a transcriptional repressor and a major driver of B-cell lymphomas. The BCL6 protein facilitates B-cell tolerance of rapid proliferation and somatic gene recombination through the repression of cell cycle checkpoints, terminal differentiation, apoptosis, and the DNA damage response, which becomes dysregulated in several types of non-Hodgkin lymphomas. PROTAC mediated degradation has the potential to overcome the historically undruggable nature of BCL6. ARV-393 has a differentiated preclinical profile. It potently and rapidly degrades BCL6 protein, which is critical to overcoming BCL6’s rapid re-synthesis rate and sustaining anti-tumor activity. ARV-393 has demonstrated significant anti-tumor activity in numerous preclinical in vivo models of non-Hodgkin lymphoma. We plan on presenting ARV-393 preclinical data at the American Association for Cancer Research Conference in April. These data show the promise of ARV-393 as a monotherapy in angioimmunoblastic T-cell lymphoma patient-derived in vivo models. Additionally, we will show ARV-393 in combination with standard of care biologic agents and small molecule inhibitors in high grade and aggressive DLBCL in vivo models. We have made significant progress in enrolling patients with non-Hodgkin lymphoma in a Phase 1 clinical trial of ARV-393 and look forward to sharing initial data this year. As a final note, we remain on track to file an investigational new drug application this year for our KRAS G12D degrader. KRAS is a driver oncogene in several major tumor types and is associated with poor prognosis and resistance to standards of care. Pre-clinically, our degrader is a highly selective and potent molecule that demonstrates dose-responsive degradation of KRAS G12D leading to robust anti-tumor activity in KRAS G12D mutated cancers, including pancreatic and colorectal cancers. Our degrader forms a ternary complex with both the active and inactive states of KRAS G12D. This PROTAC induced binding event results in the elimination rather than the inhibition of KRAS G12D. In addition, our KRAS degrader is at least 30-fold more potent in vitro than an inhibitor currently in the clinic. I look forward to updating you on our progress with KRAS G12D and other promising degraders that are in discovery at Arvinas in the coming months. With that, I’ll turn the call over to Andrew. Andrew?

Thanks, Angela, and good morning, everyone. I’m pleased to share financial highlights for the fourth quarter and full year ended December 31, 2024. As a reminder, detailed financial results for the fourth quarter and year end are included in the press release we issued this morning. As we move into 2025, we are in a strong financial position with cash on hand sufficient to support operations into 2027. At the end of the fourth quarter, we had just over $1 billion in cash, cash equivalents, and marketable securities on the balance sheet, compared with $1.3 billion at the end of 2023. Our strong balance sheet will allow us to advance all of our key strategic objectives, which include progressing the vepdeg clinical program, preparing for our first commercial launch, and developing our promising portfolio of earlier-stage PROTAC degraders. Let me now turn to the fourth quarter and full year 2024 financial highlights. During the quarter, we recorded $59.2 million in revenue, compared to a negative $43.1 million in revenue for the same period of 2023. The increase of $102.3 million was primarily due to adjustments made in 2023 to revenue from changes in contract estimates, which resulted negative revenue in the fourth quarter of 2023. We recorded $263.4 million in revenue for the year, compared to $78.5 million in the prior year. General and administrative expenses were $34.1 million in the fourth quarter, compared to $27 million for the same period of 2023. The increase of $7.1 million was primarily due to developing our commercial operations of $2.6 million, personnel and infrastructure related costs of $2.2 million, and professional fees of $1.8 million. G&A expenses were $165.4 million for the year, compared to $100.3 million in the prior year. Research and development expenses were $83.3 million in the fourth quarter, compared to $95.2 million for the same period of 2023. The decrease of $11.9 million was driven by a net decrease of $9.9 million in external expenses, primarily related to the out-licensing of ARV-766. For the year ended December 31, 2024, R&D expenses were $348.2 million, compared to $379.7 million for the prior year. We are well capitalized as we move into 2025, with the potential for an exciting milestone-rich year, beginning with our first Phase 3 topline results expected later this quarter for VERITAC-2. For ARV-102, our first degrader targeting neurological disease, the presentation of first-in-human data in April is another important milestone for the company. Later this year, we expect to share data from the single ascending dose portion of our Phase 1 trial in patients with Parkinson’s disease and initiate the multiple ascending dose cohort in the same study. We also look forward to sharing data from the Phase 1 study of our BCL6 degrader, ARV-393, in patients with non-Hodgkin lymphoma and submitting an IND application for our KRAS G12D degrader. With that, I’ll turn the call back over to John for closing remarks. John?

Thanks, Andrew. We expect to have a data-rich year ahead of us as we prepare for a key clinical trial readout from our Phase 3 VERITAC-2 trial and advance our promising pipeline of protein degraders. As we prepare for our first Phase 3 data readout, the first ever for a PROTAC, the excitement here at Arvinas is palpable. I want to thank our dedicated team for working tirelessly and enthusiastically to bring this potential new medicine to patients, but none of it would be possible without the patients and physicians who are participating in our clinical trials. I want to express my sincere gratitude to them as we could not have achieved our success to date without their collective efforts. I also want to thank our shareholders for your continued support and encouragement as we work together to bring the promise of protein degraders to benefit patients across multiple life-threatening diseases. With that, I’ll now turn the call over to Jeff to begin the Q&A portion of our call. Jeff?

Thanks, John. Before I turn the call over to the operator, I’ll remind you we will not be answering questions related to the progress or status of the VERITAC-2 trial or providing additional guidance on our expectations for data at this time. So with that, operator, will you please open up the queue?

Thank you. Our first question today will come from the line of Derek Archila of Wells Fargo. Your line is open.

Hey, good morning, and thanks for taking the questions. Just one, in terms of the TACTIVE-U cohorts that you’ll be reading out this year, if you think about the cadence of that data across different medical meetings, and ultimately, are you waiting for that data to really decide on the second-line CDK4/6 combo? Thanks.

Thanks, Derek. I’ll hand over directly to Noah, and he can answer that.

Hey, thanks, Derek. So TACTIVE-U, as you know, or for everyone’s knowledge, is a study that is evaluating vepdeg in combination with some other agents. So those agents include a CDK7 inhibitor, ribociclib, and also abemaciclib. So, we’ve shared data about the abemaciclib combination. Those data continue to mature. We haven’t shared information for the other two yet. We haven’t offered guidance about when we will share the specific updates of these. But the hope is that, as data mature, we can be sharing more. As to the question about whether or not this will determine the choice of the CDK4/6 inhibitor that’s combined with vepdeg. We think at this point, we’ve established that vepdeg combines very nicely with palbo and combines with abemaciclib. So, overall, the likely determinant of what we combine with is what will be the best drug to combine in the second-line setting. So, I don’t want to go into more detail on that right now, but we hope that we can give updates in the next few months.

Understood. And if I can squeeze one more on LRRK2, just in terms of what you plan to share for the SAD, I guess, what level of degradation do you find to be therapeutic in kind of the preclinical setting and how will that translate to the human setting? Thanks.

Yeah, Angela, do you want to answer that question?

Certainly. Thanks for the question, Derek. So, based on preclinical data that’s been published by many others, showing that a 50% reduction of the protein is disease modifying in certain contexts, including in the context of alpha-synucleinopathies as well as tauopathies. So, those data are published. In addition, human genetics guide us, more recently, omics studies that relate to single-cell LRRK2 expression levels in the brain, in particular in microglia, that show that there’s a two-fold elevation in LRRK2 expression in microglia. And this has been confirmed in iPSC-derived cells from Parkinson’s disease patients, where there’s overexpression of LRRK2 in idiopathic Parkinson’s disease. So, we believe that we stand the best chance of testing the LRRK2 hypothesis by reducing LRRK2 by 50% in the brain, and that’s what we aim to show in the central compartment.

Excellent. Thanks again. Congrats on the progress.

Thank you. One moment for the next question, please. And our next question will be coming from the line of Jonathan Miller of Evercore. Your line is open.

Hi, guys. Thanks so much for taking my question. I guess since we just had a question on the Phase 3 and the second-line gating factors, I’ll ask on the first-line. Obviously, you’ve already chosen the CDK combo here with the CDK4. What’s the gating factor to getting that study started? How much data do you need in the atirmo combo at TACTIVE-K before you can make those trial design assumptions? Do you need six-month data to go to the FDA with a trial design for Phase 3?

Yeah, great question. Noah?

Thanks, John. So, thanks for the question, Jon. So, overall, as we’ve shared – we plan to combine vepdeg with atirmociclib in the first-line, and this is based on the totality of evidence that we have in which we’ve assessed what we could do with atirmociclib. From an earlier data set in which we were looking at two different doses of atirmo combined with vepdeg 200 and are now in the expansion part of that and also reflecting back on palbociclib, how we did in our combination there. These were – where we’re looking in later line settings, but also in the first-line setting. And, overall, recognizing how there’s a shift in the use of CDK4/6s in first-line and palbociclib is being used much, much less and we see a great opportunity first terminal in the future. As for what’s gating, there is as we’ve shared, we need to have some health authority discussion and we have to continue to look at data. The good news is that the data continue to mature nicely. We do not feel that we needed at least six months of data to have this conversation with the health authorities.

Great. And maybe if I can squeeze one more. I know you’re not answering questions about VERITAC-2, but could you talk to commercial preparations beyond what we assume is going to be a wonderful readout in a couple of weeks? How does your commercial prep going and what do you think ramp there needs to be ready for a launch?

Yeah, clearly, we’ve been focused on building the initial runway for a commercial organization. We have that in place. All the other aspects of the different components for a launch are getting in place as well. As you know, we’ll be launching with Pfizer and we’ll be the U.S. lead. So a significant amount of planning related to that. So, yeah, I’m very pleased with the progress getting made by the team and we’re in good shape.

Thanks very much.

Thank you. One moment for the next question. And our next question will be coming from the line of Li Watsek of Cantor. Your line is open.

Hey, good morning, team, and thanks for taking our questions. I wonder if you can maybe just comment on VERITAC-2 if it has any ratio to the two Phase 3 trials that you plan to initiate this year. Any elements of the trial design might be impacted by the results?

Noah, do you want to at least talk about that part of the potential influence?

I guess the read-through, if anything, would be more in the second-line setting, understanding the scope of the activity we see for the monotherapy in the second-line. We don’t see it having any read-through to first-line. I probably can’t go into more details like that. We’re in the process of going through our health authority preparation and discussion, and also just continuing to evaluate maturity of data in the second-line setting.

I understood. And, I guess, just from a pipeline perspective, you’ve got three additional programs that you’re moving forward into the clinic. So, I guess, what level of investment that you guys are looking to make, especially for the larger indications like Parkinson’s disease?

Yeah, great question. Yeah, we’re very pleased with the progress the portfolio has made through the last year. Clearly, very excited about seeing our first neuroscience, neurodegenerative program moving forward. And PSP and Parkinson’s disease, very interesting areas for us to move that compound into. And we are well placed to take LRRK2 degrader to a significant stage of development. We’ll see in the future how the progress of the compound is, whether or not there’s an ideal situation where we find a strategic partner, that’s all ahead of us. Right now, we’re very focused on moving that program forward internally and getting it to a significant milestone.

Okay.

Thank you. One moment for the next question. And our next question will be coming from the line of Akash Tewari of Jefferies. Your line is open.

Thanks so much. So Pfizer has previously mentioned that the decision to progress the vepdeg CDK4 combo would be in part an efficacy-based decision. We know we’re going to a first-line right now. With that in mind, can you frame expectations on that upcoming combo data? Will we have enough follow-up to give an early take on PFS? And if not, what do you think response rate should be for both the first-line and second-line setting for your go-forward dose? And then, on VERITAC-2, this isn’t a timing question, but how concerned are you that a six-month prior ET requirement is not sufficient to remove ET fast progressors? And what percent of fast progressors do you expect in your study versus what we saw with Lilly? Thank you.

So, the second half of that question, again, as we said at the beginning, we won’t be answering any questions related to VERITAC-2. First half of the question?

In terms of how much efficacy and safety data we’ll be looking at, decisions about going into first-line are mostly safety driven. We’ll be looking at efficacy as well, but safety is the dominant deciding factor. And you also just want to know the overall activity of your drug, which I think we’ve established already in the second-line plus setting from the Phase 1 programs that we’ve run. So mostly now it’s just discussing whether or not the dose that we recommend is going to be acceptable with health authorities and continue to as we have those discussions to just look at the maturity of the data to see if anything unfolds.

Thank you. One moment for the next question. The next question will be coming from the line of Tazeen Ahmad of Bank of America. Your line is open.

Okay. I think that’s me. So maybe I have a couple of questions. The first one is on metastatic breast cancer. So what data do you think you’ll need to show to give confidence to KOLs on the profile of that and atirmo, just considering that historically they will have had a lot more experience with the other CDK inhibitors like ribo and palbo, for example? And then I have a follow-up.

Noah?

Thanks. Yeah, thank you for the question. We have – so, I think if the question is focused on first-line, what we expect to see, we’re not prepared to go into the exact study design, the hazard ratio that’s being targeted, or other features of the statistical plan. But in general terms, all the feedback we get is that investigators would want to see more than five months, six months of improvement in median PFS to know that they have something that’s substantially different, even if we’re up against generic competition a few years from today when palbo is generic. And so, if you view the first line CDK4/6 plus AI combination as delivering somewhere between 24 and 28 months of median PFS, you’d want to see something in that range - five to six months better to know that you have something special.

Okay. Got it. And then if I could ask a question on your KRAS degrader, can you talk about how you think it might be differentiated given that this G12 degrader space is pretty competitive? You’ve got other companies like Astellas in the clinic and what would you want to see in order to move it forward?

Yeah, we’re very excited about our KRAS program and Angela do you want to answer that?

Yeah, sure. So based on the details that are public, we’ve compared to the Astellas molecule. We know we’re 40-fold more potent than that Astellas degrader. It is encouraging that the Astellas degrader did show some efficacy at the higher doses, but I think discontinued for issues due to safety. We feel that we’re very competitive with respect to the in vitro profile and in vivo profiles based on the data that we’ve generated. We do believe that in terms of the inhibitors in the G12D space that we’re very competitive. We have a catalytic mechanism of action. We know that we bind to both the inactivated and activated states in terms of our ternary complex, so very different than an inhibitor. The degrader finds both. And we know that we’re more potent in inhibiting cell proliferation and inducing cell death. We also disrupt the scaffolding functions that are known for G12D KRAS and we have the potential for distinct and non-overlapping resistance mechanisms that we can impact with G12D. And beyond that, we have some very compelling data in terms of some of the neoantigen profiles that we’re producing that we know inhibitors do not.

And just to add to that point, Angela, I think you touched on it, but this potency becomes an important issue, because ultimately the first-line – the first generation Astellas compound did demonstrate some abnormalities in patients that may have created some dose limitation. So, we do have the opportunity with ours maybe to address efficacy before those come into play.

Thank you. One moment for the next question. And the next question will be coming from the line of Devarakonda of Truist. Your line is open.

Guys, thank you so much for taking my question. My first question is on ARV-393. Can you talk a little bit about enrollment status for this program and whether there’s any focus on a particular subset of NHL patients? And given the profile of the target, where do you think this might fit into the landscape with other targets like BTKs or BCL2? Thank you. And I have a follow-up.

Yes. That’s a great question. Thanks, Kripa. Noah?

Thank you, John. Yeah, Kripa, great question. We’re pretty excited about this compound and let’s break it down into a few different areas. In terms of enrollment so far, the study started its enrollment last year. It was a little later than we initially expected, but things going very nicely, backlog of patients and making nice progress. In terms of how this drug may differentiate itself. Well, first of all, differentiated in the sense that there are no BCL6 inhibitors that are in the clinic really or approved. There is another degrader that’s in development out there and it’s probably at a similar stage of development, not much has been shared. We are very satisfied with combination data, some of which we’ve shared, more of which is coming and we want you to direct your attention to AACR where there’s going to be an opportunity for an update. We view what you would see there as a lot of potential combinations that can open up the door to this orthogonal approach towards anti-lymphoma activity. One of the things that we’re working out is to what degree do you need BCL6 expression or how much expression is necessary for this pathway to be targeted effectively with this agent. The combinability, the fact that the drug hasn’t really demonstrated pre-clinically and in our top studies, evidence of real hematopoietic toxicity suggests that there are opportunities for us to combine nicely with any of these agents that you mentioned, whether we’re talking about BTKi inhibitor, anti-CD20 therapy, whether it’s an antibody therapy or if it’s bispecifics. So, lots of paths we can follow, and the first step obviously is generating data about a maximum tolerated dose and then moving on to combinability.

Great. We’ll keep an eye out for AACR. Just a follow-up question. We got some inbounds around the Chief Commercial Officer leaving right before a key readout and potentially a year or so before potential commercial rollout. Can you talk a little bit about it and help alleviate investor concerns about this? Thank you.

Yeah, absolutely. Yes, our Chief Commercial Officer, John Northcott, had to leave unfortunately because of personal reasons, which I can’t get into. Luckily for us and that was also through great planning, we had a second in line highly experienced executive, Alex Santini, who has been able to step into the breach as our interim Chief Commercial Officer, and he’s absolutely superb. So, I can honestly say we haven’t missed a beat. Alex has continued the game plan that was laid out by John and the team is progressing really well. So it was unfortunate, but because we had such great depth in terms of leadership team there, we’d be able to move on really quite easily.

Thank you so much.

Thank you. One moment for the next question. And our next question is coming from the line of Jeet Mukherjee of BTIG. Your line is open.

Great. Thank you for taking the question. I was hoping you could elaborate a bit more on what we can expect from the Parkinson’s patients update for ARV-102 later this year? And are there any biomarkers you’d be looking for that would translate to functional improvements in these patients? And I have a follow-up. Thank you.

Thank you. Noah, start with you, and then go to Angela.

Yeah, thanks, Jeet. So just to put us on the same page, the immediately like the first step is to demonstrate or to share what we’ve demonstrated in healthy volunteers. And so this involves our understanding of PK/PD, so understanding how dosing leads to what PK properties can be tracked in the periphery, but also in the central nervous system by virtue of what we see of drug in the CSF. And then, of course, there’s PD. So what’s happening to LRRK2, again, in the periphery and more importantly in the CSF. And so, we expect the first glimpse of those data at the Alzheimer’s disease, Parkinson’s disease conference in Vienna in early April. But as we’ve also shared, we have begun dosing on Parkinson’s disease patients. Unfortunately, we can’t offer guidance at this point about exactly when those data will be shared, but recognize that we started off and this is for regulatory reasons with SAD patients, so a single ascending dose. And then, we would next move to MAD dosing, so multiple ascending dose in Parkinson’s disease patients. And depending on the progress of this and it’s going very nicely right now, we would hope we can – and conference schedule, we hope we can share some update that would be at least SAD, but we’ll have to see how much data we can accumulate by the appropriate conference later in the year.

And just to continue with respect to what Noah was saying, at least in non-clinical primate studies, we’ve been able to conduct a discovery effort around biomarkers that we think are LRRK2 driven based on published Parkinson’s disease progression initiative from the Michael J. Fox Foundation. So, we’re encouraged by our non-clinical data that suggests that we can move neuroinflammation endpoints as well as lysosome function endpoints. So it’s promising and so we await getting towards the MAD portion of Parkinson’s disease studies to assess this.

Understood. That’s helpful. And maybe a VERITAC-2 question, if you just wouldn’t mind. You said you’d present full results at a medical conference. Would any abstract embargo rules potentially limit what you could say as part of the topline press release? Thanks.

Yes, I think there would be. So, we’ll get more information on that as we get past that next stage.

Thank you. One moment for the next question. And our next question will be coming from the line of Brad Canino of Stifel. Your line is open.

Hi, good morning. Listening to the large pharma earnings, we should expect frontline Phase 3 oral SERD trials in combination with the CDK4/6 inhibitors from Roche and AstraZeneca this year. That’s right around the time you and Pfizer will be kicking off the frontline vep CDK4. How will Arvinas think about these results of the studies as they pertain to your frontline plan? Thank you.

Yeah. Thanks, Brad. Yeah, obviously, we’re going to be very interested in the datasets coming from both those companies. Noah, do you want to say anything about it, add additional to that?

Sure. So, thanks, Brad. I guess the question can be will this impact standard of care? And the feeling is that with the study that’s going to launch this year and take less than a couple of years to enroll, it’s not likely to have impact on the operational feasibility of a study in any way. So if anything, it kind of just creates some excitement in this area if there are some positive results. We also recognize at the end of the day that PROTACs are very different than SERDs, because of our targeted degradation. So whatever we see, our hope and expectation would be that we can see something stronger from a PROTAC. So, we’re looking with anticipation, but recognize that it just creates opportunity.

Thank you. One moment for the next question. And our next question will be coming from the line of Sudan Loganathan of Stephens. Your line is open.

Hi, good morning, and thank you for taking my questions here. And my first one will be on atirmociclib in regards to that first-line combination you’re playing with vepdeg. I think atirmociclib is uniquely characterized by like a 20-fold and four-fold increase in productivity for CDK4 over CDK6, which I believe that probably helps with the neutropenia or any hematologic toxicities that may have showed up with like palbociclib potentially. But here’s to how you view the glucose metabolism component for CDK4 involvement in that and how that may play out in the safety profile. And just even just your very broad view on what makes atirmociclib in your view better than palbociclib, ribociclib or any of the other CDK4/6 inhibitors out there? And I have a follow-up.

Thanks, Sudan. Noah?

Sure. Thanks. So, Sudan, you had mentioned specifically the neutropenia. So, just as a general observation, we don’t really view, we don’t view vepdeg as having a neutropenia liability. There was some neutropenia or increased neutropenia, which is really a palbo liability that was observed in combination with palbo. And since then, we’ve shared data probably enough to give a very strong glimpse of safety for an abemaciclib combination and there was no signal of anything like this. So, when it comes to DDIs, that whole concept is fading away and that may have been particular to palbo’s toxicity. In terms of what to expect in first-line, well, we should note that atirmo combined with AIs is already a Phase 3 study that Pfizer has announced. So you can see that listed on ClinicalTrials.gov. That means that it’s been presumably that it’s been reviewed by health authorities and there’s a willingness to let that trial go forward. So the safety profile of that and tolerability profile of the dose that was chosen was acceptable to health authorities. So in our case, we’ve now been dosing patients with vepdeg and atirmo in collaboration with Pfizer. We’ve been seeing a really attractive safety and early glimpse of efficacy look fine. So we’re just planning to have those health authority discussions. Hyperglycemia is not a significant concern of ours right now, and we’ll keep you updated. But as we’ve shared, the hurdles for us are just to reach agreement with health authorities about dose and schedule, which we don’t think is a high bar. And then, of course, we’ll just update you on the trial design.

Great. No, I appreciate the insight there. And my second one is in regards to the BCL6 degrader, ARV-393. Could you share your perspective on the potential efficacy and utilization of the PROTAC technology in comparison to Bristol Myers Squibb’s BMS-986458, I believe, which employs the ligand-directed degradation for B-cell malignancies? And if your strategy has evolved or changed in response to any preliminary data that BMS has provided up to this point with their degrader?

Yeah, nice question. Yeah, we’re obviously aware of the BMS degrader. We haven’t seen much in the way of data from that company. Our belief is our degrader is designed using our technology, our insights. So, we have a belief that our technology and our program will be significantly better. We have to see how that looks going forward, but difficult to mention anything about the BMS degrader, because we haven’t seen much in the way of data there. So, we’re very focused on our own program and moving that forward and taking that to the next stage.

Thank you. One moment for the next question. And the next question will be coming from the line of Ted Tenthoff of Piper Sandler. Your line is open.

Great. Thanks for taking the question everyone. I’m excited for all the data this year. Similar question to those asked earlier about kind of how the frontline treatment paradigm is changing? But to the second-line with – how are you guys seeing sort of a like with the surge in the CDK4/6 upfront in first-line? How are you seeing the second-line treatment paradigm changing ahead of vepdeg monotherapy data and VERITAC-2 data? Thanks.

Thanks, Ted. Great question. I’ll hand straight over to Noah.

Okay. Hi, Ted. So, thanks for the question. So, certainly, there are changes in the treatment landscape and the bigger trend is that ribo is being used more in the first-line setting and somewhat now in the adjuvant setting, and that’s even more than abema, so and palbo is used as fading there. So the question is what happens is their use of CDK4/6 after CDK4/6. There’s some, it’s still limited, but in the second-line setting, you would think that there would be much less use of ribo and the data outside of our experience with combining palbo and vepdeg, there aren’t great data out there for palbo in the second line setting. So, there is probably some limit on the part of physicians about their interest in using that combination or using palbo after other CDK4/6 inhibitors. But what we do recognize in addition to those general trends is that there are accumulating data for the use of drugs targeting the PI3K pathway, and that’s having some impact. You’ve obviously seen some exciting data and we know there are Phase 3 programs that have been kicked off for KAT6 in the second-line setting. So that’s combined with fulvestrant. There’s atirmo that’s combined with fulvestrant. So there are a bunch of drugs that are being combined with fulvestrant and we hope to do some practice informing work that will demonstrate how various drugs can be combined with vepdeg in this setting. And, it’ll be up to physicians in the end whether they want to be using fulvestrant or they’d be wanting to use an oral agent in those types of settings and the data will just in the end have to support whatever decision they make.

Okay. Great. That’s really helpful. I appreciate that color and looking for data from the rest of the pipeline too.

Thanks, Ted.

Thank you. One moment for the next question. And the next question will be coming from the line of Ellie Merle of UBS. Your line is open.

Hey, guys, thanks for squeezing me in. Just in terms of the frontline setting for vepdeg, how are you thinking about potential enrichment strategies for patients who might be more responsive to an oral SERD? And your latest thinking on what the predictors are of which patients might develop an ESR1 mutation? And then I have a follow-up. Thanks.

Thanks, Ellie. Sorry, I’ll just…

Yeah, go ahead, please.

Yes. So Ellie, in the first-line, we are not likely to be taking all comers in our study. So, there are obviously some patients that have progressed rapidly in the adjuvant setting when they’ve been exposed to AIs. And standard of care now in these patients would be a CDK4/6 inhibitor plus fulvestrant. So those are not likely to be included in our study design. As for other enrichment strategies, we have a drug here that we believe degrades ESR1 wild type as well as ESR1 mutant. And so, therefore, should work very well in a broad population, 95% of patients in first-line, something in that range may have ESR1 wild type, so there’s no thought of molecular enrichment there. One of the reasons that the first-line study may work even better is because maybe we can prevent the evolution of ESR1 mutant clones by effectively suppressing any clone that would develop, because we degrade that as well. So, I don’t think ESR1 mutant selection in any way is going to play into the study design. Beyond that, not much to add clinically. We’re happy to discuss that offline with you some more if you have some good ideas.

Thanks. And then just a follow-up, maybe just a broader strategic question. There’s been a lot of focus on STAT6 as a target for degraders, but obviously there aren’t so many companies that have expertise in making degraders. What’s your perspective on whether you might expand your focus to targets or say a target in the immunology space? And just from like a platform perspective, what’s the latest on how long it would take from say selecting a target protein to making a PROTAC development candidate?

Yeah. Clearly, our focus over the last several years, Ellie, as you know, has been oncology and neuroscience. There’s been elements of immuno-oncology that has brought in elements of immunology as well. So, we’re always aware of potential targets that we believe a degrader could drive differentiation. So, we’re not blind to that and we do look at things like that, but our major focus has been neuro and oncology, and it will continue to be that for the foreseeable future. In terms of our approach to moving a target forward, it’s very dependent on what the starting points are. Clearly, we have abilities to move the PROTAC design forward fairly rapidly. To get to that point though, you need good starting points in terms of ligands against the target. So that is one of the big determinants of speed. Do you have a high quality or a good quality ligand that binds to the target of interest? And when you have that, we can move a program forward relatively fast, because of our insight and know how to apply the technology. So, it’s a fairly generic answer, but ligand discovery is an important piece to this early on. Angela, anything you want to add to that?

Yeah, I just wanted to add – that’s great, John. I just wanted to add some of the learnings that we’ve had over the past 13 years that have been built into our platform technologies, where we iteratively learn from some of the pharmacokinetic, pharmacodynamic properties that we have in our molecules that lead to more rapid designs and accelerated movement through our pipeline. So, with the constraints that John just defined, of course, building out our ligand capabilities is core to where we’re focused now to tackle some of these under drugged targets. And then just a point about the immunology indications, of course, we are looking at some of our assets in some immune indications. So BCL6 may play a role in innate immune disorders like MS and other disorders. So, pre-clinically, we’re evaluating and so we’re keeping an eye open there as well as LRRK2 and its role in irritable bowel disease and Parkinson’s disease that may be extended based on some of the biomarkers that we’re seeing move at least in preclinical studies. So, I think there’s a lot of opportunity and a lot of potential in our pipeline.

Understood. Thanks.

Thank you. One moment for the next question. And the next question is coming from the line of Paul Choi of GS. Your line is open.

Hi, thanks, and good morning, and thanks for taking our questions. I had just a couple of quick ones on ARV-393. Can you maybe just comment on what you’d like to see from your initial clinical data in patients that’s coming up later this year to think about potential expansion into the post-stem cell population or maybe other sub-populations such as elderly who are traditionally too fragile for standard of care such as R-CHOP? And, second, can you just confirm if that initial Phase I data will be either be at EHA or ASH? Any clarity there would be great. Thank you.

Okay. Thanks, Paul. Noah here. So we – well, we’re not giving guidance as to when we’re presenting this. It’s a bit far off still and, obviously, we’re also still enrolling patients in this Phase 1. In terms of trying to go back, did you say something about stem cell? Can you just repeat that question?

Yeah. Post-transplant populations, yeah, or elderly populations who are traditionally too fragile for R-CHOP.

Yeah. So, that gets into what’s the – that gets into study design issues and opportunities. So, we recognize that there are opportunities, there are limitations for R-CHOP in large B-cell lymphoma – I’m sorry, we recognize that R-CHOP in large B-cell lymphoma may cure 50% of patients upfront. And so it’s a preferred treatment, you also see Polivy being used with just in this population increasingly. So that’s become more of a standard of care. Yet there are patients with that can’t be addressed with those treatment options. And so, your question I guess is can we make inroads in that population? And we think of it, it’s possible. We’re showing good preclinical data for a combination with anti-CD20 therapy. That would be a thought of how to bring this forward. But, overall, we’d be looking at and then you referred to the post-transplant patients. So, I guess, you’re talking whether it’s an autologous transplant or if it’s with bispecifics or with CAR-T. And, I think, it’s premature to comment on those populations on one hand. That’s no doubt that’s where there’s the most significant unmet medical need, but those patients also have very severe disease or rapid progressors and are a challenging population to look at as your first indication. So it depends on the data that we continue to accumulate in our Phase 1 study. But, I think there’s some inevitability to combinability or to combining our 393 with other agents, whether it’s an anti-CD20 therapy bispecific or other agents in these advanced late line settings as a start and then obviously moving to combinations in second line-and even hopefully first-line.

And then if I could just add to that, there are key opinion leaders who have collected post-CAR-T refractory lines that we are taking a look at pre-clinically just to assess how ARV-393 performs in that setting specifically. So I think more to come.

Thank you. One moment for the next question. And the next question is coming from the line of Michael Schmidt of Guggenheim. Your line is open.

Hi, good morning. I’m sorry. A couple more on vepdegestrant, are you planning to present any of the VERITAC-3 lead in data with palbo this year? And are there any learnings in terms of efficacy from that experience that can perhaps be applied to the design of the planned Phase 3 study with atirmociclib? And then for VERITAC-2, as we are trying to contextualize Lilly’s EMBER-3 data from last December, perhaps relative to the postMONARCH data from ASCO, what is your base case assumption for PFS in the fulvestrant control arm in ITT and the the ESR1 mutant subset for that study? Thanks so much.

Thanks, Michael. Yeah, in regard to our SLI, at some point, we haven’t guided, we’ll be sharing that data. Clearly, we’ve moved to the point where atirmociclib is the combination partner of choice in our first-line setting. So, in terms of having informed that decision, it was probably lower ranking in terms of the decision making. Clearly, we made the decision in terms of the entirety of the data we’ve got through the SLI plus the data we’ve seen with the atirmo/vepdeg combo. So, we’re very happy with that decision making. But at some point, once we get past this next big dataset, we’ll be talking about when the next datasets will come out and potentially including that SLI. Again, the question related to VERITAC, we’re really not answering any questions as we said in the beginning related to VERITAC. And I know that’s a very frustrating scenario for people on this call. We understand we’re so close to the dataset. And once that dataset comes out, all questions will be answered.

Thank you. This does conclude the Q&A session for today. I would now like to turn the call back over to John Houston for closing remarks. Please go ahead.

Well, thank you, operator, and thanks to everyone for joining us and all the great questions. As you can expect, we’re really pleased with our execution and progress in 2024, and we look forward to a very exciting 2025. So, thank you for your time this morning and have a great day.

Thank you all for joining today’s conference call. You may now disconnect.