ARVN - NASDAQ

Hello, and welcome to the Arvinas fourth quarter 2025 earnings call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question and answer session. And if you would like to withdraw your question, press 1 again. Thank you. I will now turn the call over to Jeff Boyle, Head of Investor Relations. Jeff, you may begin. Good morning, everyone, and thank you for joining us.

Earlier today, we issued a press release with our fourth quarter and full year 2025 financial results, which is available in the Investor and Media section of our website at arvinas.com. Joining us on the call today, we have Randy Thiel, our President and CEO; Noah Berkowitz, our Chief Medical Officer; Angela Cacace, our Chief Scientific Officer; and Andrew Saik, our Chief Financial Officer. Before we begin, I will 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. A replay of this call as well as today's press release and an updated corporate deck will be available on the Investor and Media section of our website. I will now turn the call over to Randy Thiel. Randy?

Thanks, Jeff. And thank you all for joining us today. It is an honor and a privilege to lead such a talented and committed team as Arvinas enters a period where we anticipate multiple value-driving milestones at the company. Addition to the team, we have a technology proven in the clinic. An exciting pipeline, and a strong balance sheet, allowing us to continue our work to make a meaningful impact for patients, their families, and our shareholders. 2025 saw meaningful progress across our pipeline and was a transformative year for the company. In addition to submitting our first New Drug Application, setting the stage for potentially the first ever FDA approval of a PROTAC degrader, we redefined our strategy to maximize the opportunities ahead in each of our core areas of focus. With four ongoing clinical trials across oncology and neurology, including our recently begun first-in-human trial of our polyQ AR degrader, ARV-027, we believe we have the potential to bring truly differentiated treatments to millions of underserved patients. We are entering a pivotal period at Arvinas. As we have been previewing for the past six months, 2026 will be defined by multiple data readouts and clinical advancements. We believe these milestones will validate our strategy of developing only treatments that are highly differentiated from other options. I will summarize clinical data expectations for the year and make a few comments on corporate strategy before turning the call over to the team to walk through recent accomplishments and our forward-looking plans in more detail. Beginning with our LRRK2 degrader, ARV-102, I am pleased to announce today that data from our Phase 1 clinical trial in patients with Parkinson's disease was accepted for an oral presentation at the Alzheimer's and Parkinson's Diseases Conference in March. We will assess the ability of ARV-102 to degrade LRRK2 in the CSF and see how it impacts important pathway biomarkers. Rather than inhibit LRRK2's kinase activity intermittently, ARV-102 degrades the entire LRRK2 protein. An important consideration when thinking about its potentially differentiated profile. Turning to ARV-806, our KRAS G12D PROTAC potently and selectively eliminates both the on and off forms of the protein. Based on faster-than-expected enrollment in this trial, by the 2026 we now expect to make our first data disclosure for the program, and we have already submitted data from that trial for presentation at a medical congress in the coming months. This will be an important look at why we believe ARV-806 has the potential to be a clearly differentiated treatment. So stay tuned for more on our disclosure plans. Next, our PROTAC BCL6 degrader, ARV-393, is continuing to progress well in our Phase 1 dose-escalation trial. And we intend to share data from this trial in the 2026. As announced on our last earnings call, we have already seen responses in early cohorts in patients with both B- and T-cell lymphomas, even at exposures below those predicted to be efficacious. We also observed robust BCL6 degradation and the safety profile of ARV-393 supports continued dose escalation. With respect to vepdegestrant, as you know, we are working with Pfizer to select a third party for its commercialization and potential further development. Our goal remains to make sure that if it is approved, vepdegestrant is launch-ready and available as a potentially best-in-class therapeutic option for patients with ER-positive, HER2-negative, advanced breast cancer in the second-line ESR1-mutant setting. Our discussions to date with potential partners have been productive, and we are working to have an agreement in place before the June 5 PDUFA date. Finally, before I turn the call over to the team, I would like to make two comments on corporate strategy. First, last year, we decided to refocus our resources on our Phase 1 clinical programs, which we now have four of. While we believe vepdegestrant has the potential to be a best-in-class therapy for patients, we think the best way for Arvinas to create shareholder value is to focus on ARV-102, ARV-806, ARV-393, and now ARV-027. Second, we recognize the bar is high for all of our programs. We will not settle for “as good as,” and we hope patients do not have to choose between efficacy, safety, and tolerability. We are determined to only develop treatments that are differentiated and will be highly disciplined in moving programs forward. We believe our pipeline is producing potentially transformative treatments for patients, and we look forward to sharing what we believe will be compelling data for each of these programs as we reach milestones in the future. With that, I will turn the call over to Noah. Noah? Thanks, Randy. And good morning, everyone. I will begin with ARV-102, our LRRK2 degrader. As background, ARV-102—

Thanks, Noah, and good morning, everyone. I will start by sharing some additional details about ARV-027, our PROTAC degrader designed to target the polyglutamine-expanded androgen receptor, or polyQ AR, in skeletal muscle. We have deep expertise in developing AR degraders. Our first clinical candidate was an AR degrader, and ARV-766, which we out-licensed to Novartis in 2024, is progressing through multiple Phase 2 trials in hormone-sensitive and castrate-resistant prostate cancer. PolyQ AR is the root cause of disease in spinal and bulbar muscular atrophy, or SBMA, also known as Kennedy's disease. SBMA is a rare, genetically driven neuromuscular disease with no approved treatments available, and consequently significant unmet need. For background, SBMA is an X-linked disease caused by a CAG expansion in the AR gene resulting in polyQ AR accumulation. This toxic accumulation impairs contractility and causes atrophy and ultimately weakness and loss of endurance in muscle. The goal for developing a disease-modifying therapy in SBMA is reducing polyQ AR in muscle. We believe ARV-027 has the profile to become the first ever therapy for patients with SBMA that tackles the protein as the genetic root cause of the disease. ARV-027 is a PROTAC that drives degradation of polyQ AR in skeletal muscle. We presented the first ARV-027 preclinical data last year at the World Muscle Society Conference in October, and we will share data again at the Kennedy's Disease Association Conference later this week. These data show with oral ARV-027 induced degradation of muscle polyQ AR, which resulted in clear functional improvement and extended survival in a rapidly progressing SBMA mouse model. We recently initiated our Phase 1 trial of ARV-027 in healthy volunteers and are excited to be developing ARV-027 for thousands of patients with spinal and bulbar muscular atrophy, a disease with no approved disease-modifying therapies. Rounding out programs that we expect will enter the clinic this year, we have our first immuno-oncology-focused PROTAC degrader for solid tumors, ARV-6723, that targets HPK1. HPK1 acts as a central intracellular brake on the immune system, depressing T-cell receptor signaling and broadly dampening both innate and adaptive antitumor responses. Beyond its kinase activity, HPK1 also serves a scaffolding role that reinforces immune suppression, making it an attractive kinase for degradation rather than inhibition. Preclinically, ARV-6723 has shown deep and sustained HPK1 degradation, eliminating both kinase and scaffolding functions, an effect not achieved with kinase inhibition alone. As a single agent, ARV-6723 demonstrated meaningful and durable tumor growth control across multiple syngeneic models, including both high- and low-immunogenic tumors, and outperformed investigational HPK1 inhibitor and anti–PD-1 therapy in several settings. It also demonstrated strong activity in combination with anti–PD-1. Mechanistically, HPK1 degradation induces a distinct proinflammatory tumor microenvironment with increased activated T cells, NK cells, and monocytes. In addition, ARV-6723 was found to reduce immunosuppressive neutrophils while inducing broader proinflammatory pathway activation than inhibition alone. Last week at the AACR Immuno-Oncology Conference, we presented preclinical data demonstrating ARV-6723's robust single-agent activity and outperformance when compared to the clinical HPK1 inhibitor in efficacy studies with several mouse models representing hot and cold immunological settings and demonstrated efficacy in multiple models of anti–PD-1 resistance. Collectively, these data position ARV-6723 as a potentially differentiated oral immuno-oncology approach designed to drive deeper and more durable antitumor responses. ARV-6723 has potential to address significant unmet need across multiple settings where currently available immunotherapy drugs have failed. Pending regulatory feedback, we are planning to begin first-in-human studies for ARV-6723 later this year and based on preclinical findings, we believe ARV-6723 could change the treatment paradigm in the immuno-oncology treatment landscape. Finally, we are making strong progress in our oral pan-KRAS PROTAC program, a preclinical program that complements our clinical KRAS G12D degrader.

—differentiates from all inhibitors in that our novel oral degrader is designed to target KRAS for elimination. Preclinically, we have demonstrated broad degradation across KRAS alterations, including wild-type amplified KRAS, with selectivity over RAS isoforms and activity in both on and off states. Compared to pan-RAS inhibitors, by degrading and removing the oncoprotein, we have observed stronger antiproliferative and apoptotic effects, greater tumor growth inhibition, and enhanced activity when combined with anti–PD-1 therapy, providing preclinical evidence for a differentiated profile. We will present preclinical data comparing our PROTAC pan-KRAS degrader with pan-RAS inhibitors at the AACR Special Conference on RAS in March, and we will also be presenting data highlighting efficacy in a KRAS syngeneic model and associated immune microenvironment changes at a scientific congress in the first half of this year. With that, I will turn the call over to Andrew to review our quarterly financial information.

Andrew?

Thanks, Angela, and good morning, everyone. I am pleased to provide financial highlights for the fourth quarter and full year ended 12/31/2025. As a reminder, detailed financial results for the fourth quarter and year-end, including a reconciliation of GAAP to non-GAAP financial measures, are included in the press release we issued this morning. As we look forward to our anticipated data readouts later this year, we are in a strong financial position to maintain our guidance of cash into 2028. At the end of the fourth quarter, we had just over $85 million in cash, cash equivalents, and marketable securities on the balance sheet, compared with just over $1 billion at the end of 2024. We believe our strong balance sheet will enable us to advance our programs to meaningful data events, which will help us make important portfolio decisions in the coming months and years. Turning to the fourth quarter and full year 2025 financial highlights, during the quarter, we reported $9.5 million in revenue, compared to $59.2 million in revenue for the same period in 2024. The decrease was primarily due to a decrease of $40.3 million of revenue from the Novartis license agreement. We reported $262.6 million in revenue for the year, compared to $263.4 million for fiscal year 2024. General and administrative expenses were $23 million in the fourth quarter compared to $34.1 million for the same period in 2024. The decrease of $11.1 million was primarily due to a decrease in personnel and infrastructure-related costs of $4.4 million and a decrease in costs related to developing our commercial operations of $3.1 million. G&A expenses were $95.9 million for the year, compared to $165.4 million in the prior year. Fourth quarter non-GAAP G&A expenses were $15.3 million in 2025, compared to $23.7 million in 2024. Research and development expenses were $61.1 million in the fourth quarter compared to $83.3 million in the same period of 2024. The decrease of $22.2 million was primarily driven by a decrease in compensation and related personnel expenses of $14.1 million and a decrease in external expenses of $7.6 million. For the year ended 12/31/2025, R&D expenses were $285.2 million compared to $348.2 million for the prior year. Fourth quarter non-GAAP R&D expenses were $56.5 million in 2025 compared to $74 million in 2024. Total non-GAAP expenses for the fourth quarter and full year were $71.8 million and $323.4 million, respectively. Our reduced spend in Q4 is a direct result of our cost-cutting efforts in 2025, and we will continue to look for efficiencies in our operating model this year. As previously announced, in September, our board authorized the repurchase of up to $100 million of our outstanding common stock. As of year-end, we had bought back approximately 10 million shares at an average price per share of $9.09 for a total of $91.9 million, including commissions and excise tax. This program is now suspended, and we have no further plans to repurchase shares. Details of our stock repurchase program can be found in our 10-Ks, which will be issued later today. As I mentioned, we are maintaining our cash runway guidance into 2028, which allows us to reach important data readouts and continue prioritizing investments in programs that we believe are truly differentiated and that will provide patients with significant benefit. Let me now turn the call back to Randy for closing remarks. Randy?

Thanks, Andrew. I will summarize and then open the call for questions. Over 2026, we anticipate sharing new clinical data from our Phase 1 trials of ARV-102, ARV-806, and ARV-393. We expect that our polyQ AR degrader, which just entered human trials, will be joined in the clinic later this year by our HPK1 degrader. And we expect important new trials to begin for both ARV-102 and ARV-393. I believe we are entering a period of meaningful execution and value creation at Arvinas. Very few Phase 1 companies have such a strong pipeline and the potential to reach important milestones. And even fewer have a platform that has already announced positive Phase 3 clinical trial results. This is what makes me so enthusiastic about our upcoming opportunities to make a meaningful impact for patients and shareholders. With that, I will hand the call to Jeff to start Q&A. Jeff? Thanks, Randy. And as a reminder, we are always available to take questions offline if you cannot join the queue. But for now, I will ask the operator to open the line for Q&A. Operator?

Actually, this is Randy jumping back in with a quick change of plans.

Before we pass back to the operator and open Q&A, we need to do one more section. Especially with the storm coming the past couple of days, we prerecorded the prepared remarks. To ensure we would have no technical difficulties. Obviously, we did, and some of you noticed that Noah's section was almost entirely skipped. So we will have Noah read his section live now and then jump straight to Q&A after that. Noah.

Thanks, Randy. Okay. So we will talk about some of our clinical-stage assets here. As background, ARV-102 is an oral PROTAC LRRK2 degrader intentionally designed to cross the blood-brain barrier and selectively degrade leucine rich repeat kinase 2, or LRRK2. LRRK2 is a multidomain protein with three key functions, of kinase, GTPase, and scaffolding activities. Together, LRRK2's activities regulate endolysosomal trafficking, and when activity is elevated, the lysosome becomes dysfunctional. This leads to obstructions when clearing the aggregated pathological proteins that would typically be degraded through the properly functioning lysosomal pathway. We believe that degrading LRRK2 has the potential to restore endolysosomal homeostasis and to provide therapeutic benefit in disorders characterized by lysosomal dysfunction. Two of those diseases are progressive supranuclear palsy, or PSP, and Parkinson's disease. Several competitors are pursuing LRRK2 as a target in these diseases. Our PROTAC approach is differentiated because we reduce LRRK2 protein while competitors only inhibit LRRK2 kinase function. By degrading the entire LRRK2 protein complex, we disrupt the key functions believed to be linked to neuroinflammation, and 102 offers the potential for deeper and more durable therapeutic benefit versus inhibitors. Our confidence in this program is bolstered by the data we have generated from our Phase 1 clinical trials in healthy volunteers and Parkinson's disease. As previously disclosed, ARV-102 has been well tolerated and demonstrated dose-dependent CSF exposure across both trials, indicating excellent brain penetration. We also reported that ARV-102 reduced LRRK2 in the CSF by more than 50% and reduced downstream proteins driven by LRRK2 variants that are elevated in the CSF of patients with Parkinson's disease and linked to lysosomal stress. Two such proteins, GPNMB and CD68, demonstrate clear and disease-relevant pathway engagement in the central nervous system, even in healthy volunteers where they would not have been expected to be elevated. Altogether, these data provide further evidence that total protein degradation of LRRK2 may have a best-in-class impact on underlying disease compared to inhibition. As Randy mentioned, we were accepted for oral presentation at AD/PD, where we will show pathway biomarker results in patients with Parkinson's disease. We look forward to updating you on these data. Let us turn now to the development plan for ARV-102. As we have previously shared, there is strong evidence that endolysosomal trafficking driven by increased LRRK2 is associated with the clinically meaningful progression, often within one year, of PSP, a progressively debilitating neurodegenerative disease that is typically fatal within five to seven years of diagnosis. We intend to initiate a Phase 1b trial in PSP in the first half of this year, with the potential to initiate a registrational trial in late 2026, pending health authority feedback. If successful, ARV-102 has the potential to become the first and only disease-modifying treatment for this rare, life-threatening neurological disorder that affects approximately 25,000 people every year in the U.S. We expect to provide additional updates on our clinical development plans in the coming months. We can now move to our KRAS G12D degrader, ARV-806, and I will say we completed dose escalation for once-weekly administration in our Phase 1 trial well ahead of plan. We believe that reflects strong clinical investigator interest and high demand for effective KRAS-targeted therapies. ARV-806 targets KRAS G12D for elimination. KRAS G12D is a well-known oncogenic driver associated with poor prognosis and resistance to standard treatments across major tumor types, including pancreatic, colorectal, and non-small cell lung cancer. Importantly, there are no approved targeted therapies on the market for tumors with KRAS G12D mutations. As a reminder, on our last call, we shared preclinical data presented at the Triple Meeting in October that highlighted the clear differentiation of ARV-806 from both KRAS inhibitors and degraders currently in the clinic. These preclinical data show ARV-806 to be more than 25-fold more potent in reducing cancer cell proliferation compared to clinical-stage KRAS G12D inhibitors, the leading clinical-stage—sorry, for seven days, after a single dose with efficacy responses across pancreatic, colorectal, and lung cancer models. We anticipate sharing initial Phase 1 clinical data in the coming months. There is a very high bar for differentiation, and we believe ARV-806 has the potential to transform the field by exceeding that bar. Let us shift to ARV-393, an oral, investigational novel degrader of BCL6 with the potential to become a chemo-free standard of care across non-Hodgkin's lymphoma indications. BCL6 has a rapid resynthesis rate and is known to be difficult to target by inhibitors. ARV-393's iterative, event-driven mechanism of action counters the rapid resynthesis rate of BCL6, resulting in potent, sustained degradation of the protein. As announced on our Q3 earnings call, we have already observed responses in both B- and T-cell lymphomas in the early cohorts of our ongoing Phase 1 monotherapy trial, even at exposures below those predicted to be efficacious. We also observed evidence of robust BCL6 degradation and the safety profile of ARV-393 supports continued dose escalation. In preclinical data presented last year, ARV-393 showed broad, synergistic antitumor activity combined with standard-of-care biologics and investigational small-molecule inhibitors. In December, we presented compelling preclinical data that support ARV-393 in combination with glofitamab, a CD20-directed bispecific antibody, as a chemotherapy-free combination approach in diffuse large B-cell lymphoma, or DLBCL. These data demonstrated tumor growth inhibition of 91% with ARV-393 plus glofitamab dosed sequentially, compared to 36% for glofitamab alone. Additionally, RNA sequencing and biomarker analysis suggested that ARV-393 enhances CD20 expression and genes that promote interferon signaling and antigen presentation but also downregulated proliferation-associated gene sets. Overall, these preclinical data suggest mechanistic synergies between BCL6 degradation with ARV-393 and T-cell engagement. We believe these results bring hope for DLBCL patients left with minimal treatment options when standard-of-care therapies fail. With our encouraging preclinical data in hand, we are on track to initiate our Phase 1 combination trial with glofitamab in the first half of this year. So now I will turn the call over to the operator for Q&A.

Thank you, Noah. We will now begin the question and answer session. If you would like to ask a question at this time, simply press star followed by the number one on your telephone. And our first question comes from the line of Jonathan Miller with Evercore. Jonathan, please go ahead.

Hey, guys. Thanks so much for taking my question. And congrats on all the progress across multiple interesting-looking programs. One thing that I immediately react to in some of your prepared remarks is your assertion that you are only going to develop programs for which you are going to see differentiated activity. You know, multiple of these programs are in competitive areas as you are well aware. So I wanted to ask across the pipeline, at what point are you going to get the killer data that determines to you whether or not a program is differentiated? And, obviously, that is different for different programs, but could you just go through the pipeline and tell us what you think the key experiment is that will let you know if you have got truly differentiated or not?

Yeah, Jonathan, thanks very much for the question. And just as we start the Q&A, I apologize again to all the folks on the call for the confusion there. I hope that was clear as we had to redo Noah's section. Jonathan, that is probably a question we could spend a lot of the day on, right? So to your point, for each program, it is going to be different. And certainly, as we think about a plan where we need to be clearly differentiated against competitors, which I think is actually pretty reasonable, it does not necessarily mean that when you first show data in a very early Phase 1 trial that it has to be, you know, beating a competitor that has expansion data, Phase 3 data, and so on. So I will pass to Noah here in a little bit to talk, you know, maybe program by program for some details that we expect to have this year. Probably the right place to focus. But as we look across—maybe I will highlight a couple of things. For LRRK2, for ARV-102, our LRRK2 degrader, the competition there is inhibitors. It will be really important to show that degradation leads to a different result than inhibition for a target that has not been proven to modify disease overall by drugs that the industry has produced. So that is the key risk. For ARV-806, for KRAS G12D, the target is much more validated, but the competitive space is much more intense in terms of other programs that have been out there ahead of it. For BCL6, similarly, it is a relatively new target, but there are competitors out there that have paved the way a little bit, showing that the target has now become somewhat validated. And maybe we will leave 27 to the side for the moment. But I think for each of those, the Phase 1 data will be of some interest, and as we move forward, we will have to compare over time. Noah, anything else you want to add, you know, maybe specifically some of the near-term data updates?

Sure. Thanks, Randy. Yeah, let us take the example of ARV-102 for starters. So in that case, we have signaled pretty significant conviction. We have said we are starting a trial in PSP this year and, regulatory permitting, we may even be able to move towards a registration-quality trial, you know, before the end of the year. We recognize that there are properties of a LRRK2 inhibitor that can be exceeded with LRRK2 degraders. We have shown already in healthy volunteers that we have more than 50—we can achieve more than 50% LRRK2 degradation in the brain. That has been our target. We have been communicating that clearly. Because we know in general, if you want to just simplify in broader strokes, that patients with Parkinson's disease have twice to three times the level of LRRK2 protein expression in the brain compared to their age-matched controls. So our goal was to achieve that, something that cannot be touched by inhibitors. So that is why we have lots of conviction there, plus pathway data, more to come at AD/PD in April. Now if I shift for a moment to 806, it is a very competitive space. We know that there are many other G12D-targeting drugs ahead of us, mostly inhibitors and, let us say, one degrader. But fundamentally that really makes it easier for us because we know where the bar is. We know that—I am going to speak in broad terms. I am not setting the bogey here because this is an imprecise science. But we know that we have to be better than, let us say, 35% response rates in this space to be differentiated. So we are going to have to generate data that gives us confidence that we are better. We will signal as the year moves on about exactly what level of confidence we have, and as we can share data with folks. But that is clear from the numerous drugs that are in the clinic today, that we have to be better than the large majority of them, which, you know, would put us in that range. And then when it comes to 393, we are kind of at the front right now. There is a competitor that has shared data, and we do see that there is activity with their drug. But this is really early days. Like, we are months or maybe—you know, I do not want to give a specific time frame that we are behind. It is hard to know. But we are basically at the leading edge of this right now. So we are going to look at the data that is shared by our competitor, we will look at the data that we generate, we will share that, and we believe that for all three of these drugs, there will be data this year to demonstrate their differentiation that we should, you know, over the course of the year, be able to share with our investors.

Thanks so much. And your next question comes from the line of Edward Tenthoff with Piper Sandler. Ted, please go ahead.

Great. Thank you very much. Randy, congratulations. And the whole team, I really appreciate the energy you guys are bringing. It is really exciting to have this early-stage program advancing in so many really unique shots on goal here. I wanted to pick back up with what Noah was saying about 102. What really should we be expecting from that data at AD/PD? And would there be an incremental PSP update ahead of the registrational trial initiation? I love the speed with what you are moving here. But I want to understand sort of what the bar is to moving into registrational study. Thank you.

Maybe I will take the second part of that and then pass back for the expectations at AD/PD. Ted, I think the answer to that is no. And just the reason is the timing that we laid out in the prepared remarks just now is that we are anticipating starting a Phase 1b in PSP sooner. And then as we have said, look, all things going our way and pending some further data from AD/PD and regulatory go-ahead, we would hope to start a registrational trial by the end of the year. So I think the data there in between of starting the PSP trial earlier and then getting to a second one later, I think would prevent that. But we think that the data that we will be showing at AD/PD, which are in Parkinson's patients, will be relevant for both moving forward in PD or PSP. Noah, back to you for the AD/PD view.

Sure. So, look, we cannot prerelease results, but I can—we can—I guess I can frame it? We shared data months ago about—or that started last year and culminated in biomarker data some months ago in the healthy volunteer population. So now we will share data in the Parkinson's disease patient population that I think a discerning scientist would be looking for. Are—well, what happens in Parkinson's disease? Is the drug demonstrating continued safety, like was observed in healthy volunteers? Because now patients are older—25 years median age for healthy volunteers, much older for Parkinson's disease patients. There is much more elevated LRRK2 in the CSF at baseline. So it was something that was observed at low levels, now repeated at higher levels, because you have to overcome even more LRRK2 presence in the brain. Obviously, deep portions in the brain, is represented by the CSF levels. And then the biomarker story. Right? The biomarkers that were seen in healthy volunteers—is that like a once—a finding that cannot be replicated, or is it something where the pattern continues or it intensifies when you look at Parkinson's disease patients? That would be the kind of set of questions that I would look at, and we hope that we can answer those questions at the meeting. That is great. Really helpful, and I am looking forward to all the other data and updates in progress this year. Thanks.

Sure. Maybe I will pass to Angela in a moment to talk a bit about that. And as you pointed out, we have a pan-KRAS program that, as we talked about, is moving ahead preclinically behind the KRAS G12D degrader that will have data at some point this year. But Angela, a bit more on the AACR data for pan-RAS?

Sure. Thank you for the question. We will be sharing data, comparing to the inhibitors. So, you know, our goal in the pan-KRAS story is, of course, to remove the oncoprotein. So we differentiate from the on and the off inhibitors in that we are removing the oncoprotein. First and foremost, what is observed as a regulatory mechanism when you treat with an inhibitor is compensatory upregulation of KRAS. So this is something that is seen with the ON inhibitors. And so we will share KRAS-amplified data, so we will be sharing how we compare to the KRAS ON inhibitor in that setting. And then we will also share some of the mutant data as well in terms of the activity that we see on the antitumor activity. So expect to see those data as well. I hope that helps. Thanks so much. And then we will also share some syngeneic model data in the presence of an intact immune system. So I think that is also important with respect to the pan-RAS inhibitors, with respect to our pan-KRAS molecule that is selective for KRAS versus pan-RAS. So we are not hitting NRAS and HRAS. Yep. That affects T-cell activity.

You know, maybe I will try to rephrase. I think the first question around 393 was do we, in broad strokes, expect the need to do any dose modification for 393 with glofitamab? And maybe I will let Noah comment on that in a moment, as we have had some data there late last year. And maybe I can take the second one. Look, we think that the Roche data from late last year validate the hypothesis that an ER therapy will work where ER is driving disease, which is what we have always believed. And so really, no, I do not see a concern there. It certainly validates what we thought would be the case. And we hope that as we are out with our partners at Pfizer looking for a new partner to commercialize, and preferably continue to develop that, it gives somebody the enthusiasm to do that. So no, I do not see that as an issue. But, Noah, back to you on the march and potential for requiring dose modifications based on the data we have shown to date.

We do not really anticipate that we will require dose modifications, although obviously, you know, in an abundance of caution, we will have some dose escalation to evaluate the combination. There is non-overlapping tox, which is to say that the principal tox for glofitamab is going to be things like CRS, and also, there may be some accumulated hematopoietic toxicity for patients from glofitamab. But we, on the other hand, are not really seeing toxicity in those categories at all. So, you know, we will be advancing it cautiously, but do not anticipate dose modifications. Yes. Thank you. Yeah.

Thanks. Yeah, I am going to pass that one pretty quickly over to Angela. I had a few comments on the biomarkers, but Angela, please dig in.

Sure. So in PSP, there have been some recent publications showing that you see the same pathways increased. So you see elevated endolysosomal pathway engagement uniformly in progressive supranuclear palsy, and LRRK2 elevation in that population. And so, you know, we expect within that population that we will see efficacy there. So within that population, when you subset that population and look specifically at LRRK2 elevation, you do see accelerated progression and clinically meaningful progression. If you do look specifically at the elevated population, you do see acceleration by a year and it is, you know, clinically meaningful, upwards around 20 to 30 points of the rating scale. So Ed Jabari and his colleagues at University College London have shown that. So those data point to within that genetically defined population that that is the case. So, you know, anytime you see an increase in elevated expression, you know, for a PROTAC, that is the place you want to go. So PSP is a place where we can prove a concept within a year. So we are encouraged by that and remain very committed to this therapeutic hypothesis in PSP.

Not further than what we put in the remarks this morning. On track. We feel good about that process that we are pursuing alongside Pfizer, but all is on track and we hope to have a partner in place by the PDUFA date in early June.

Yeah. That will certainly be an important part of the readout, although as you have talked about, it is still a relatively short duration. Noah, any other comments to make on safety?

Sure. So, overall, with the Parkinson's disease patient study that we will be sharing, patients have had 28 days of treatment. We should keep it—so, you know, we are doing standard observations of patients to assure safety and assure that there are no findings. I am not going to provide the data here on the call, but that is something to look at at the meeting. I think it is important to recognize that there is an on-target activity that you have identified in the lung of patients that requires tracking, and that is why anyone in this space will do things like PFTs, pulmonary function tests, and they could be following that up with high-resolution CT scans of the lung if there is anything suspicious. And the goal will be to demonstrate in the end that you have the right benefit-risk for a drug, and we anticipate that that should be fine. I will point out that—it is so standard—that there is something called the LIGHT initiative, which is a recommendation from experts about anyone who is dealing with LRRK2-targeting agents should be thinking about pulmonary function monitoring. So it is something we have incorporated into our study, and we will provide updates at an appropriate time.

So we think it is very related. Let us look at what both diseases share here. They both have a toxic gain-of-function mutation that is associated with the disease or disease severity. Right? And we understand how there is a pathway that is activated—for, you know, and this is the endolysosomal trafficking pathway of which LRRK2 plays a central role. So our goal, as was stated earlier, is to degrade LRRK2 to at least 50%. We know that that could be achieved in both of these diseases. You know, we have reason to believe that that can direct benefit. We have done, and we have shared earlier on different calls, or publications that we have, that we have been able to do seeding experiments in PSP, that show that LRRK2 degradation can interfere with the propagation of—or tau polymerization. And overall, we are going into this disease where no doubt LRRK2's central role—for tau is the pathological tau species that is almost pathognomonic for the disease, right? I mean, it is found in all patients with PSP on autopsy, and we know that we should be able to degrade this tau or and prevent its accumulation.

Yeah. I will let Noah comment, but you are right to rehighlight that late last year we said that even at doses that were below what we would have expected to prove some efficacious range of exposure, we did see some responses in patients with both B- or T-cell lymphomas. And had seen good degradation of BCL6. But for the data later in the year, Noah?

I do not think that we could guide specifically to those findings other than to say that if you are in the business of drug development, and you have a new mechanism of action, and you see a drug that can achieve a complete metabolic response in patients that otherwise have a deadly disease, you remain very committed and enthusiastic about the future for that product.

Okay. Yeah. We will do 027—let Noah and Angela—and then come back.

Yes. I am going to start, like, almost at the end and then turn it back to Angela because it will have to do with clinical strategies. Which is to say it is really early, so I cannot answer the question in great detail there. But I will give you a range of possibilities. Right? We already know that patients with SBMA show a pattern of muscle atrophy and fat infiltration that can be picked up clearly with the right sequencing on MRI. So that is a setup for a surrogate marker for the disease. But surrogacy requires significant engagement with health authorities and a review of the data that is out there existing and possibly new, and negotiations. So we are at the very beginning of a process, but knowing that that is potentially something that we could look at in the future. Beyond that, we know that if you are not going to rely on surrogacy, you are going to look at things like a six-minute walk test or other functional measures of patients' strength and their ability to not deteriorate, right? Because ultimately, these patients become bedbound, they develop bulbar symptoms, it does happen over the course of many years, but it is progressive, and it is trackable. So that is the strategy. I think those are things we are looking at in that range. And I will turn it to Angela.

Great. Sure. Okay. So, you know, preclinically, we have—degrading the root cause of spinal and bulbar muscular atrophy, which is the polyglutamine repeat–expanded androgen receptor in muscle is the goal of the program. And so we have been able to do that with 27. And in the preclinical models, we see very robust reduction in muscle and this leads to, you know, improvement in muscle atrophy. We see increased grip strength. We see improved endurance. And all of these things lead to improved muscle energetics, and we can measure these things in terms of muscle biopsy. Right? So the goal of the preclinical program and turning into a translational program is to measure the reductions that we see in our healthy volunteer, and then ultimately in the Phase 1 trial, is to include SBMA patients also and measure muscle biopsy for reduction of AR and then polyQ AR. And then, ultimately, as Noah was saying, relate that to measures of, you know, muscle atrophy, which can be then measured as muscle integrity measures, which are muscle MRI. So fat infiltration, muscle fat volume, things like muscle volume, etcetera. And then function.

So clinical trial—I do not think we are going to share where the program is, but we—other than to say that it has moved faster than expected, which I think we just mentioned on the call. And beyond that, that we have already submitted for a conference. So we will see how this plays out.

So lots of things—interest.

Yeah, it is a good question, right? So G12D very specifically targets G12D whereas the pan-KRAS is intended to target all the mutants for sure. In terms of how they can coexist, you know, maybe I will make a high-level comment and then pass to Noah. But in general, we have seen them as independent programs. Right? There is certainly argument to say that a specific G12D degrader could have a profile that better allows for combination with other therapies. That is theoretical for sure. A pan-KRAS degrader that had a great tolerability profile could be quite combinable as well. So we have seen them as independent programs. Noah, anything else you would like to add on how they could move forward?

Yeah. I think that that is the key point. We have highlighted before that one of the key mechanisms that differentiates degraders from inhibitors is our ability to continue to degrade in the presence of amplification or overexpression. So that is something that—the 35%, 40% of pancreatic cancer patients have G12D. But that leaves the other 55% or 60% of patients that have other variants. Just in pancreatic cancer alone, there is a larger opportunity for a pan-KRAS than a G12D. Differentiation—you know, we like the idea potentially of using them together, and we like the idea of being able to really overcome resistance pathways. So that is it. And that same pattern, though to smaller percentages, is true in non-small cell lung cancer, in colorectal cancer, and in other—potentially in other GI tumors as well.

And your next question comes from the line of Terence Flynn with Morgan Stanley. Terence, please go ahead.

Great. Thanks for taking the question. Randy, you talked a lot about the opportunity set this year from a lot of the early-stage programs in terms of data. How are you thinking about potential partnerships for these programs? I know historically you have kept some, you have partnered others. So how are you thinking about partnering versus retaining rights on each of these? Thank you.

Yeah, it is a great question, Terence. Thanks. And I think, you know, stepping up a little bit, right? What we have done here is we have got a platform and a team that has produced some really high-quality clinical candidates that we think could be differentiated. You know, we have got—we was about to say three in the clinic but as we announced this morning four now just very recently with 027 going in, and 6723 for HPK1 entering the clinic later in the year. So that is five. Right? That is a lot for a small biotech to take on. And so that is helping the strategy shift from talking about this fantastic platform that we have to adding on the need for each program to be, you know, independently valued and differentiated from its competition. And I think that as we move those programs forward this year and beyond—not necessarily this year, right, but going forward—we may reach places where we decide that it makes sense for us to resource programs and where it might make sense for others to. You alluded to our history. Right? We did a deal with Pfizer for vepdegestrant back in 2021. I mentioned the ARV-766 deal from Novartis in 2024. And so partnering certainly has been an important part of our strategy in the past and will be going forward in the future. You know, as far as program by program, you know, we try to make sure that pharma companies are apprised of our progress across the pipeline so that we know if and when it comes time for us to look for a partner, we know who that might be. So I will probably save any more specific comments for the future, but it is certainly on our mind to think about how we can best move forward each program.

Sure. Why do I not take the first one because it is easy and I will pass to the team for the second one. With respect to the timeline, we have said we just started in clinic just now. So a bit early to guide on when we will see our first data, so I would not expect that in the very near future. But as that study gets up and running, we will look to provide some guidance on that. We have spoken a bit about the data coming from 027, but—Noah, please jump in on what we associate from the healthy volunteers.

Healthy volunteer study, but it has a component that we will follow up in the end with some SBMA patients. So think of it as your initial—establishing the dose range, right, in a dose-escalating single-ascending dose treatment of patients that drives then to multiple-ascending dose cohorts. We will be looking at PK. There is a PD component here that is very strong that we do not have in many other studies. The PD here is we are targeting AR degradation in muscle, and we can biopsy those muscles, and we will. And that will help us choose the right dose range to move forward into later trials. We are not guiding yet to—and by the way, so that is both for the healthy volunteers in the SAD and MAD, but then in, like, this confirmatory small cohort of SBMA patients at the end, we will also be doing those biopsies. We just are—I do not think we can guide right now to when we will have those results, but we will, since we just recently dosed our first patients, keep you updated.

Yeah, we have not talked yet about the exact timing for the clinic for pan-KRAS. So I will not give that guidance quite yet. But although, as you can see, we are continuing to put out data at multiple conferences there. So it is moving ahead well. In terms of the opportunity for pan-KRAS, you are right that there are other programs in this space for sure. Going back to the questions from—especially from Jonathan at the start, it is a place where we are certainly going to have to be differentiated. But we think that space is one where having multiple programs across G12D and pan will be helpful. Combinations with those and other agents will be important as we move forward. Anything else, Noah, that you would like to add? I think we have said what we can on the pan-KRAS opportunity for now. Got it. Thank you.

And your next question comes from the line of Sudan Loganathan with Stephens Inc. Sudan, please go ahead.

Hi. Thank you. First, wanted to say congrats to Randy for his continuing on Arvinas, but with this new role. Looking forward to working with you and the team as Arvinas kinda takes on this plethora of exciting new projects. My first question is, you know, as you move towards initiating the Phase 1b in PSP, what specific regulatory feedback are you seeking from the agency? Separately, is there any risk that regulatory feedback in PSP alters the development strategy or timeline for the PD program? And then finally, can you outline how you are thinking about the trial design evolution in both PSP and PD—endpoints, enrichment strategy, duration, and what constitutes registrational or credible data set in each indication.

Right. Okay. Thanks for the multiple questions there, and thanks for the comments. Look, to get the Phase 1b started, it is your fairly typical moving it through the regulatory authorities. With our guidance of starting that in the first half of the year, you can presume we are moving forward there, and all is on track. With respect to, you know, data for PD versus PSP, Noah, I will ask you to comment there in terms of, you know, the development could affect each program.

Right. So—in terms of the question was—there are two questions there, right? What is the—how can the regulatory feedback impact both programs? And then there were questions about enrichment strategy and things like that. So there is no—we are just outside of the U.S., filing the IND. Right? So even though we did all this work, we have not interacted with the FDA. And so there is an opportunity here, and I think it is more opportunity rather than risk, right, to speak to the FDA about these plans. So think of our IND as mapping out what we expect to do with our development, you know, with the first trial, and opening up this dialogue because the FDA knows a lot about PSP and PD, and we are hoping to get really good feedback. There are—the risk-benefit of drugs developed in PSP and Parkinson's disease are different. So we are going to start off with PSP. You know, the intent is to eventually have a conversation about Parkinson's disease also. I do not think that we are going to go into details on a call here about the Parkinson's development strategy, because we have only guided towards what we are doing in PSP today. But suffice it to say, once we clear these discussions with PSP, then the idea would be to start moving into conversation around Parkinson's disease. You raised the question about what could enrichment strategy look like. So in PSP, it is not going to be a biomarker or a biomarker enrichment, but there is going to be a patient focus. So we will be looking at patients that have PSPRS, you know, the more severe and symptomatic form, and aggressive form of the disease—I do not remember exactly, but I think they probably represent about 40% of patients with PSP. That would be our focus for enrollment in this study. And we are going to develop a strategy, and we will guide eventually towards how this gets expanded into the broader population or even if that is not necessary. In terms of Parkinson's disease, I think what folks can start anticipating is that we are doing a lot of work trying to understand what are the biomarkers that predict outcome in Parkinson's disease using existing sources that have had major investments and a lot of publications, such as the PPMI—so the Michael J. Fox Foundation–funded Parkinson's Progression Markers Initiative. And we are using that to help identify markers. Think of it—we can start now tying that in to the biomarker changes that we see in our healthy volunteer study and that we are seeing in our Parkinson's disease study. So we are at a unique competitive advantage, having the only degrader being developed in this space, and having already shared, at least in healthy volunteers, that we have biomarker movement that we could start correlating to prognosis in Parkinson's disease. And think of this as moving ahead into—you know, we will do that with our Parkinson's disease patients. And eventually this may lead to some patient selection strategies or analyses we can do in our studies. So cannot offer more guidance than that, but gives you a sense of where we could be headed.

Maybe I will take the second one on vepdegestrant and then pass back to Noah for PSP. Look, as I have said, we are moving ahead well on the partnership plans alongside our partners at Pfizer. And if that becomes an issue, certainly, we are well situated with Pfizer to address that question. As the process is moving along, it is less of a concern, but certainly something we have on the radar if needed. Noah, back to you on the PSP questions.

Yeah. I think the gold standard in PSP where there have been attempts to develop symptom-modifying drugs but not necessarily disease-modifying drugs, is the PSP Rating Scale. So we would intend to use that in our regulatory—I am sorry, our, you know, submission-quality study down the road. It is obviously going to be used in the Phase 1b, which is not going to be powered to evaluate that fully, but look for—can identify trends between what is going on with biomarkers and that tool. And something else we include in all of our studies in these neurodegenerative diseases—we did it in our Parkinson's disease, and we will be doing similar type of work in the PSP studies, even the Phase 1b—is looking at things like eye movements or other type of, you know, indicators or surrogacy for function. Right? It is a rapidly evolving space where there are some markers—you know, markers of activity, of movement in the eyes, or of muscle movement—that may be predictive of clinical outcomes. These are not accepted as registration-quality tools yet. But they are things that we are incorporating into our studies because we think they could be very revealing.

I think that concludes our question and answer session. I will now turn the call back over to Randy Thiel for closing remarks. Randy?

Thank you very much, operator, and thanks to all on the call for all the good questions. I will close by just saying that now that we have positioned ourselves as a Phase 1 company, the priorities are clearly to move the trials along, produce some good data, and make decisions. Right? So as we do that over the coming months, we will look forward to keeping you all updated. Thank you all very much for joining the call.