Arvinas, Inc.

Good day, and thank you for standing by. Welcome to the Arvanas fourth quarter 2024 earnings conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question during the session, you'll need to press star 1 1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1 again. 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, our Venice's Chief Executive Officer, President, and Chairperson, Noah Berkowitz, our Chief Medical Officer, Angela Cacasey, our Chief Scientific Officer, and Andrew Seck, 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 three top line 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 our VINUS, our ProTag discovery platform, and an update on our pipeline. Noah will then provide an overview of our VetDegistrant or VetDeg clinical program, including reviewing the Phase III Vertac II trial, and also provide an update on our first neuroclinical program with ARV102, our LRRK2 degrader. Angela will provide an update from our earlier stage programs, including our BCL6 degrader, ARV393, 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 chimeras, 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. VetDeg is the most advanced program in our pipeline, and in addition to our ongoing phase three monotherapy trial, our current development plan includes two additional phase three combination trials across the first and second line settings in metastatic breast cancer. VetDag is an oral 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 VetDag 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 Vertac II, our first-ever phase three trial. Data from this Phase III clinical trial will be an important milestone for Arvinas, and we look forward to sharing top-line 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. NOAA 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 VERITAC2 during the Q&A portion of our call. Last month, we announced updates to our clinical development plans for VET-DEG 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 three trial with VET-DEG plus Pfizer's novel investigational CDK4 inhibitor, a termocyclic. In the second line, we announced that we plan to initiate a Phase III combination trial evaluating VEPDAG with a CDK4-6 inhibitor, which we also expect to initiate in 2025. Beyond VEPDAG, we have a data-rich year ahead, and we believe there are exciting opportunities for PROTACs across oncology and neuroscience. In April, we plan to present the first in human data from ARV102, 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 ARV393, our BCL6 degrader, in patients with non-Hodgkin lymphomas. And finally, we are in track to file an investigational new drug application for our KRAS G12 de-degrader this year. I'll now turn the call over to Noah for an overview of the VEP-DEG and ARV-102 programs. Noah?

Thanks, John, and good morning, everyone. Last year, together with Pfizer, we made great progress with our VEP-DEG program. As John mentioned, in addition to sharing top-line results from Veritech II later this quarter, We intend to initiate two new phase three combination trials in the first and second line settings later this year. We continue to believe VEPDAG 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 top-line data readout, I won't spend too much time discussing the VERITEC2 trial, which, if successful, could result in a submission of a new drug application and the first-ever regulatory approval of a protact degrader. Recall, the VERITEC2 clinical trial is evaluating the efficacy and safety of VEPDEG compared with Silvestrin 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 VipDegestrant in the VERITEC2 trial. VERITEC2 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 Veritech 2 in a top-line press release in Q1 and to present full results at a medical congress in 2025, where we also intend to host an investor call. In addition to anticipating Veritech 2 results, we are pleased to be progressing our plans to initiate registration trials evaluating DepTag combinations. Later this year, We plan to initiate a first-line phase three trial of VEPTAG in combination with Pfizer's novel investigational CDK4 inhibitor, a termocyclid, pending emerging data and health authority feedback. The decision to prioritize VEPTAG plus a termocyclid in the first-line setting is based on the totality of evidence from the ongoing phase 1b2 TACTIV-K combination trial evaluating VEPDAG plus a termocyclid in the late-line setting and our trials evaluating VEPDAG plus palbocyclid. This evidence, in addition to shifting treatment paradigms for early and advanced breast cancer, gives us the confidence that VEPDAG plus a termocyclid is the best combination to advance as a potential new treatment option in the first-line setting. We in 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 III combination trial of VEPTAG plus a CDK4-6 inhibitor in 2025, pending emerging data and health authority feedback. Compelling efficacy signals have been shared previously for VEPTAG in combination with palbocyclid or with abemacyclid in the second-line plus setting. In December 2024, we presented preliminary data from 16 patients in the Phase 1b combination trial of Depdeg and Abemacyclib 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 was generally consistent with the demonstrated profile of both agents. Importantly, no significant drug-drug interactions were observed, and VEPDAG had no clinically meaningful effect on the bemacycline exposure. The combinability of VEPDAG was also supported by a Phase I pharmacology trial of VEPDAG, which demonstrated that DDI potential is not a concern for the ongoing clinical development of VEPDAG as a backbone ER therapy. We look forward to initiating the second line phase three combination trial later this year, pending emerging data and regulatory feedback. In totality, the data we have generated continue to support our belief that VETDEC 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, ARB102, is a novel oral PROTAC designed to cross the blood-brain barrier and target leucine-rich repeat kinase 2, or LARC2. LARC2 is a large multi-domain scaffolding kinase genetically implicated in progressive supernuclear palsy and Parkinson's disease. Preclinically, we have shown that ARV102 crosses the blood-brain barrier and achieves deep brain region penetration and degradation of LARC2 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 ARV102 in healthy volunteers. This ongoing phase 1 trial was primarily designed to establish the safety of ARV102, but it will also measure LRK2 degradation in the periphery and in the cerebrospinal fluid, or CSF, of patients to establish the ability of ARV102 to cross the blood-brain barrier and degrade LRK2 in humans. And I'm pleased to share that initial data from the single ascending dose cohort of the trial will be presented in an oral session at the Alzheimer's Disease, Parkinson's Disease, or ADPD conference in April. These data confirm that ARV102 is orally bioavailable in brain penetrant with dose-dependent exposure in the CSF. At the ADPD 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 one 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 ARV102 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 one ascending dose trial of ARV102 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 ARV393, our BCL6 degrader, our KRAS G12 D-degrader. Angela?

Thanks, Noah, and good morning, everyone. The preclinical profile of ARV393, 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's lymphomas. ProTAC-mediated degradation has the potential to overcome the historically undruggable nature of BCL6. ARV393 has a differentiated preclinical profile. It potently and rapidly degrades BCL6 protein, which is critical to overcoming BCL6's rapid resynthesis rate and sustaining anti-tumor activity. ARV393 has demonstrated significant anti-tumor activity in numerous preclinical in vivo models of non-Hodgkin lymphoma. We plan on presenting ARV393 preclinical data at the American Association for Cancer Research Conference in April. These data show the promise of ARV393 as a monotherapy in angioimmunoblastic T cell lymphoma patient-derived in vivo models. Additionally, We will show ARV393 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's lymphoma in a phase one clinical trial of ARV393 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. Preclinically, 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 finding event results in the elimination rather than the inhibition of KRAS G12D. In addition, our KRAS degrater 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 end of December 31st, 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 VEPDAG 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 in negative revenue in the fourth quarter of 2023. We recorded $263.4 million in revenue for the year, compared to 78.5 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 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 and external expenses primarily related to the outlicensing of ARV 766. For the year ended December 31st, 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 three top line results expected later this quarter for VeriTAC2. For ARV102, our first grader 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 one 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 one study of our BCL6 degrader, ARV393, in patients with non-Hodgkin's 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 three VERTAC2 trial and advance our promising pipeline of protein degraders. As we prepare for our first phase three data readout, the first ever for a PROTAC, the excitement here at Adventist 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 today 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 Veritech 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. As a reminder, if you would like to ask a question, please press Star 1 on your telephone. We also ask that you please wait for your name and company to be announced before you proceed with your question. One moment while we compile the Q&A roster. Our first question today will come from the line of Derek Archela of Wells Fargo. Your line is open.

Hey, good morning, and thanks for taking the questions. Just one in terms of just the TACW cohorts that you'll be reading out this year. 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, TACTIV-U, as you know, or for everyone's knowledge, is a study that is evaluating DEPDEC in combination with some other agents. So, those agents include a CDK7 inhibitor, ribocyclib, and also abemacyclib. So we've shared data about the abemacyclib 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, you know, as data mature, we can be sharing more. As to the question about whether or not this will determine the choice of CDK4-6 inhibitor that's combined with VEFDAG. We think at this point we've established that VEFDAG combines very nicely with PALBO and combines with abemacyclib. 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 LARC2, just in terms of what you plan to share for the SAD, I guess, you know, 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, you know, many others showing that 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 LRK2 expression levels in the brain, in particular in microglia, that show that there's two-fold elevation in LRK2 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, you know, we believe that we stand the best chance of testing the LRRK2 hypothesis by reducing LRRK2 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. 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 three 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 TIRMO combo at Detective 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, John. So, Overall, you know, as we've shared, we plan to combine Vepdeg with the Termocyclib 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 the Termocyclib from an earlier data set in which we were looking at two different doses of the Termo combined with Vepdeg 200. and are now in the expansion part of that, and also reflecting back on palbocyclib, how we did in our combination there. These were, you know, 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 palbocyclib is being used much, much less And we see a great opportunity for termo in the future. As for what's gating, there is a, 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. It's not, we do not feel that we need 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 Veritech 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 is your commercial prep going and what do you think ramp there needs to be 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 with the team, and we're in good shape.

So thanks very much.

Thank you. One moment for the next question. And our next question will be coming from the line of Lee Wasak 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 Veritech 2, if it has any resale to the two phase three 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, about 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 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, you know, our health authority preparation and discussion and also, you know, 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 for 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.

Thank you. Thank you. One moment for the next question.

And our next question will come from the line of Aakash Tiwari of Jefferies.

Your line is open. Thanks so much. So, I just previously mentioned that the decision to progress the VEBDEC-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 CFS? And if not, what do you think response rate should be for both a first-line and second-line setting for your go-forward dose? And then on Veritech 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, for the

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, it's, you know, 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 one 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, you know, 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 Tazeem 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 the termo, just considering that historically they will have had a lot more experience with the other CDK inhibitors like Rybo 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, you know, 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 medium PFS, you'd want to see something in that range five, 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 G1 to the greater 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 was, you know, 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. You know, 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 binds 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, and I think you touched on it, but this potency becomes an important issue because ultimately the first line, the first generation Acelis compound did demonstrate some T abnormalities in patients that may have created some dose limitation, so we do have the opportunity with ours maybe to

to address efficacy before those come into play.

Great question.

Thank you.

Thank you. One moment for the next question. And the next question will be coming from the line of... The next question will be coming from the line of Deborah Conda of Truce. Your line is open.

Thank you so much for taking my question. My first question is on ARV393. 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, you know, with other targets like BTKs or BCL2? Thank you. And I have a follow-up.

Yes. That's a great question. Thanks, Kripa.

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 are going very nicely, backlog of patients and making nice progress. In terms of how this drug may differentiate itself, well, first of all, it's 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 is a lot of potential combinations that can open up the door to this, you know, orthogonal approach. towards anti-lymphoma activity. One of the things that we're working out is to what degree do you need BCL-6 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, you know, we got some inbounds around, you know, the around the chief commercial officer leaving right before a key readout and potentially in a year or so before a 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, he had to leave, unfortunately, because of personal reasons, which I can't get into. Luckily for us, and 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's progressing really well. So it was unfortunate, but because we had such a great depth in terms of the leadership team there would be able to move on really quite easily.

Thank you so much.

Thank you. One moment for the next question. And our next question will be 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. No, start with you, then we can go to Angela.

Yeah, thanks, G. So... Just to put us on the same page, 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, you know, what PK properties can be tracked in the periphery, but also in the central nervous system, you know, 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, you know, 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 no one 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. You know, 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 toward 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 a top-line 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 Pacino of Stifel. Your line is open.

Hi. Good morning. Listening to the large pharma earnings, we should expect frontline phase 3 oral CERN 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. Obviously, we're going to be very interested in the datasets coming from both those companies. Noah, do you want to say anything about 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 it's not going to have it's not likely to have impact on our ability you know on the operational feasibility of a study in any way so if anything is 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 protacts are very different than SIRTs because of our targeted degradation. So whatever we see, our hope and expectation would be that we can see something stronger from a protact. 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, Logan Nathan of Stevens. Your line is open.

Hi, good morning. And thank you for taking my questions here. And my first one, will be on a tiramisuiclid, you know, in regards to that first-line combination you're playing with, that DEG. You know, I think a tiramisuiclid is uniquely characterized, you know, by, like, a 20-fold and 4-fold increase in selectivity per CDK4 over CDK6, which I believe that probably helps with the neutropenia or any hematologic toxicities that may have showed up with, like, palpaciclib, potentially. But curious to how you view the, you know, glucose metabolism component for CDK4 involvement in that and how that may play out in the safety profile. And just even just your very, you know, broad view on, you know, what makes a TMS cyclib, in your view, better, you know, than a polycycline, rodent cyclib, or any of the other CDK4-6 inhibitors out there. And I can follow up.

Thanks, Sudan.

Sure, thanks. So, Sudan, So, you had mentioned specifically the neutropenia. So, just as a general observation, we don't really view VEFDAG 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. Since then, we've shared data probably enough to give a very strong glimpse of safety for an ebema 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 a termo combined with AI is is already a phase three 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 Atermo 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 ARV393. Could you share your perspective on the potential efficacy and utilization of the PROTAC technology in comparison to Bristol-Myers Squibb's BMS986458, 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 our next question will be coming from the line of Ted Tintoff 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 the like with the SIRDs and the CDK4-6 up front in first line, how are you seeing the second line treatment paradigm changing ahead of VEPDAG monotherapy data and Veritech 2 data? Thanks.

Thanks, Ted. Great question. I'll hand it 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 and more in the first line setting and somewhat now in the adjuvant setting and that's even more than Abema and Palbo's use is fading there. So the question is what happens? Is there 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 VEFTAG, there aren't great data out there for PALBO in the second line setting, so there's 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 three program that's been kicked off for Cat6 in the second line setting. So this is, you know, and that's combined with Fulvestrant. there's a term mode that's combined with fulvestrin so there are a bunch of drugs that are being combined with fulvestrin and we hope to do some practice informing work that will demonstrate how various drugs can be combined with that egg in this setting and And, you know, 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, you know, the data will probably support, 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. 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 VEPDAG, how are you thinking about potential enrichment strategies for patients who might be more responsive to an oral CERD? And your latest thinking on, you know, what the predictors are of which patients might develop an ESR1 mutation. And then I have a follow-up. Thanks.

Thanks, Ellie. I'm sorry. I'll just . Please. So, 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, you know, 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, you know, 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.

You know, 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 is 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 the 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, you know, that was great, John. I just wanted to add some of the learnings that we've had over the past, you know, 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, you know, with the constraints that John just defined, you know, 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 course. you know, we are looking at some of our assets and some immune indications. So, you know, BCL6 may play a role in innate immune disorders like MS and other disorders. So preclinically, 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, you know, and a lot of potential in our pipeline.

Understood. Thanks.

Sure. Thank you. One moment for the next question. And the next question will be coming from the line of Paul Joy of GS. Your line is open.

Hi, thanks, and good morning, and thanks for taking our questions. I had just a couple quick ones on ARV393. Can you maybe just comment on, you know, 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 subpopulations such as the elderly who are traditionally too fragile for standard of care such as RCHOP? And second, Can you just confirm if that initial phase one data will 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 one. In terms of I'm trying to go back. Did you say something about stem cell? Can you just repeat that?

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

Yeah. So these, you know, that gets into what's the, you know, that gets into study design issues and opportunities. We recognize that there are opportunities, there are limitations for RCHOP in large B-cell lymphoma. I'm sorry. We recognize that RCHOP in large B-cell lymphoma may cure 50% of patients up front. And so it's a preferred treatment. You also see polyp being used with CHIP in this population increasingly. So that's become more of a standard of care. yet there are patients 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, 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 I 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, a 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 ARV393 performs in that setting. So I think, you know, more to come.

Okay, great. Thank you.

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

Hey, good morning. I'm sorry.

A couple more on WebDega strand. Are you planning to present any of the Veritech 3 lead-in data with Powerball 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 termocyclib? And then for Veritech 2, As we are trying to contextualize Lilly's EMBR3 data from last December, perhaps relative to the post-Monarch data from ASCO, what is your base case assumption for PFS in the fulvestrant control arm in ITT and DSR1 mutant subset for that study?

Thanks so much. Thanks, Michael. Yeah, I'll reach into our SLI. At some point, we haven't guided. We'll be sharing that data. Clearly, we've moved to the point where Atirama CyClib 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 at Atirama on the entirety of the data we got. through the SLI plus the data we've seen with the Atermo-VepDec combo. So we're very happy with that decision making. But at some point, once we get past this next big data set, we'll be talking about when the next data sets will come out and potentially including that SLI. Again, the question related to Veritac, we're really not answering any questions, as we said at 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 data set, and once that data set 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 24, 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.