Arvinas, Inc. Aktie

Good day, and thank you for standing by. Welcome to the Arvinas First Quarter 2026 Earnings Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your first speaker today, Jeff Boyle, Head of Investor Relations. Please go ahead.

Good morning, everyone, and thank you for joining us. Earlier today, we issued a press release with our first quarter 2026 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 Teel, our President and CEO; Noah Berkowitz, our Chief Medical Officer; Angela Cacase, our Chief Scientific Officer; and Andrew Saik, our Chief Financial Officer.

Before we begin, 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. A replay of the 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.

And now I'll turn the call over to Randy Teel. Randy?

Thanks, Jeff, and thank you all for joining us today. Since stepping into the role as CEO earlier this year, my appreciation for the strength of the Arvinas platform, the talent and execution capability of our team, and our deep and differentiated pipeline has only grown.

As the first PROTAC degrader company, we believe we've built unmatched translational expertise in the protein degrader space. I believe we're in a great position for a highly productive and value-generating 2026.

Several months ago, after filing the new drug application for vepdegestrant, we announced our intention to identify a third party with the capability to maximize its commercial opportunity. During this time, we remain confident that vepdegestrant has the potential to become a meaningful treatment option for patients with metastatic breast cancer.

Our optimism was validated by the recent FDA approval of vepdeg, now known as VEPPANU. And yesterday afternoon, we were pleased to announce that we and Pfizer have entered into a global licensing agreement with Rigel Pharmaceuticals for the commercialization, development and manufacturing of VEPPANU.

I'll begin with the FDA's approval of VEPPANU for the treatment of ESR1-mutant, ER+/HER2- advanced breast cancer. This is an important milestone for patients and physicians, and demonstrates the potential of targeted protein degradation to treat disease. There have been minimal second-line treatment options for these patients. And as the lead investigator in our Phase 3 trial set, the approval of VEPPANU brings renewed hope to patients who need additional options.

The approval of VEPPANU was the first ever approval of a heterobifunctional PROTAC degrader. In our industry, few biotechs are successful in bringing a molecule from discovery through approval. Fewer companies still make it on to the very short list of companies, big or small, that have ever been the first to bring a new therapeutic modality from inception to approval.

We believe this achievement fully validates our innovative targeted degrader platform, which Arvinas pioneered more than 10 years ago. It also strengthens our confidence in the breadth and versatility of our exciting Phase 1 pipeline across oncology, neurodegenerative disorders and neuromuscular diseases.

I am deeply grateful to the team that has worked tirelessly on VEPPANU with the unfaltering belief that it can bring renewed hope to patients who need new treatment options. We are committed to making sure VEPPANU is available for patients as soon as possible.

Rigel has a fully established oncology sales team and the infrastructure needed to ensure VEPPANU is available soon. They are committed to unlocking the full value of VEPPANU, and we are confident that they are the right partner to bring this important treatment to the patients that need it.

At the same time, this agreement allows Arvinas to invest in the next wave of innovation across our pipeline while maintaining a strong and disciplined approach to capital allocation. Indeed, this was the rationale for seeking a new partner for VEPPANU so that patients could receive VEPPANU while Arvinas could dedicate itself to our next generation of degraders.

I am fortunate to lead an organization advancing an industry-leading portfolio of degraders. Guided by patient genetics and by identifying the central drivers of disease, we deliberately select targets where protein degradation can deliver transformative impact.

To date, we have dosed more than 2,000 patients and healthy volunteers using our PROTAC technology, and our team has had remarkable success in advancing promising compounds from preclinical studies to clinical programs. As we look ahead, our ambition is clear. We are not simply advancing molecules to the clinic. We are relentlessly focused on creating differentiated therapies that raise the bar for patients on safety, tolerability and efficacy.

We're not looking for incremental improvements, but rather working towards fundamentally changing what's possible for patients and clinicians. And we are doing it from a position of strength. With a healthy balance sheet and a deeply committed team, we are well positioned to deliver long-term value for patients, their families and our shareholders.

We are in the promising position of having 4 Phase 1 clinical programs ongoing with the capital needed to reach important inflection points for each of the programs that will inform our investment priorities and ongoing development strategies

Now I'll turn the call over to Noah and the team. Noah?

Thanks, Randy. Good morning, everyone, and thank you for joining us today. We have an exciting year ahead at Arvinas, beginning with the recently presented Phase 1 data for our lead program, ARV-102 at AD/PD. These results represent a key milestone and provide strong validation of our approach in neurodegenerative diseases.

ARV-102 is an orally administered PROTAC designed to cross the blood-brain barrier and potently and selectively degrade LRRK2, a multi-domain protein that regulates neuroinflammation, lysosomal and synaptic function. Elevated LRRK2 levels are implicated in disorders, including progressive supranuclear palsy, or PSP, and Parkinson's disease.

By degrading the full LRRK2 protein complex, including its scaffolding, GTPase and kinase functions, ARV-102 addresses multiple disease-relevant pathways in contrast to kinase inhibitors, which target only a single function. We have shown that ARV-102 penetrates the CNS, produces dose-dependent reductions of LRRK2 and cerebrospinal fluid, and modulates downstream disease-associated proteins.

At AD/PD, Phase 1 data in patients with Parkinson's disease demonstrated approximately 50% or greater reductions in CSF LRRK2 by day 14 across dose levels sustained through day 28, consistent with our goal of normalizing the approximately twofold LRRK2 elevation observed in Parkinson's disease. Importantly, LRRK2 degradation led to dose-dependent reductions in biomarkers of neuroinflammation and lysosomal stress, including CD68 and GPNMB.

To our knowledge, this degree of biomarker modulation has not been observed with LRRK2 inhibitors. ARV-102 was also generally well tolerated with no serious adverse events through 28 days of dosing. These findings support advancements into PSP, our immediate clinical focus. PSP is a rapidly progressive tauopathy driven by 4-hour tau accumulation with a typical survival of 5 to 7 years and no disease-modifying therapies. In patients with PSP, elevated LRRK2 expression is associated with accelerated and clinically meaningful progression within one year.

Preclinically, we have shown that ARV-102 impacts neuroinflammation, enhances endolysosomal function and most importantly, reduces tau pathology in multiple relevant disease models, aligning with our clinical observations of improved endolysosomal function and reduced neuroinflammation. Together, these data reinforce our view that LRRK2 degradation offers a differentiated disease-modifying approach to the treatment of PSP, a devastating fatal disease without available therapy, which affects 25,000 patients in the U.S.

I also want to provide an update on the timeline for initiating our Phase 1b clinical trial with ARV-102 in patients with progressive supranuclear palsy. We submitted an IND earlier this year with the intention of initiating the trial in the U.S. during the first half of the year. Following the 30-day review period, the FDA requested final data from our chronic tox studies in nonhuman primates prior to authorizing the initiation of the Phase 1b in the U.S. in patients with PSP. Given this requirement, while no patients in the U.S. have been treated, the planned trial is on clinical hold and will not begin until we provide these data, which we expect will be available in mid-2026.

We anticipate the U.S. trial will begin by the end of 2026. We do not anticipate this will impact our plans for trials in the EU. So there's no change in our guidance on the start of the Phase 2 study, which we are planning as a global study.

Turning now to oncology. I'll begin with ARV-806, our KRAS G12D degrader. KRAS G12D is a well-characterized oncogenic driver associated with poor outcomes and resistance to standard therapies across multiple tumor types, including pancreatic, colorectal and non-small cell lung cancers. ARV-806 is designed to potently and selectively eliminate both ON and OFF forms of KRAS G12D, a key differentiator for a challenging target in solid tumors.

Our confidence in ARV-806 is supported by compelling preclinical results, which demonstrated approximately 25 to 40-fold greater potency than clinical stage KRAS G12D inhibitors and degraders. These data also showed durable degradation greater than 90% for 7 days after a single dose with efficacy responses across pancreatic, colorectal and lung cancer models.

As we shared on our prior call, we completed enrollments of the dose escalation for once-weekly administration in our ongoing Phase 1 trial well ahead of schedule. We view this rapid enrollment as a strong indicator of investigator enthusiasm and unmet medical need in KRAS-driven cancers. We believe the initial data we show later this year will be the first step in showcasing ARB-806's potential as a differentiated and clinically meaningful treatment option for patients with KRAS-driven cancers.

Finally, turning to ARD-393, our PROTAC BCL6 degrader. We continue progressing through the Phase 1 monotherapy dose escalation trial for patients with both B-cell and T-cell lymphomas who have received multiple prior therapies. We are particularly encouraged by early responses observed across both populations, including responses at exposure levels below what we predicted to be efficacious.

We have also observed robust BCL6 degradation, a notable finding given that BCL6 is rapidly resynthesized. We look forward to sharing additional clinical data from our ongoing Phase 1 monotherapy trial in patients with relapsed or refractory non-Hodgkin's lymphoma later this year.

In parallel to enrolling the monotherapy cohort, we've initiated a combination trial with glofitamab in patients with diffuse large B-cell lymphoma, an important next step as we look to expand the potential opportunity with ARV-393.

With that, I'll now turn the call over to Angela. Angela?

Thanks, Noah, and good morning, everyone. I'll begin by talking about the patients with spinal and bulbar muscular atrophy, also known as SBMA or Kennedy's disease. These patients are living with a progressive neuromuscular disorder that steadily robs them of muscle strength and endurance.

It's an X-linked disease caused by a CAG repeat expansion in the androgen receptor gene, which leads to the buildup of a toxic form of the protein, polyglutamine expanded AR or polyQ-AR in skeletal muscle. That accumulation disrupts normal muscle function, drives atrophy and over time significantly impacts the quality of life. In other words, polyQ-AR is the root cause of the disease, and there are currently no approved disease-modifying therapies for these patients.

With ARV-027, we've designed a PROTAC degrader specifically to eliminate the toxic polyQ-AR protein from muscle cells. By removing the driver of pathology rather than just managing symptoms, we aim to preserve muscle function and alter the course of the disease. We've now enrolled the first 3 cohorts in our Phase 1 single-ascending dose study in healthy volunteers, which is an important step forward for the program. Given our extensive experience with AR degraders, we feel confident in our ability to translate this approach into clinical benefit.

Earlier this year, at the Kennedy's Disease Association Conference, we shared preclinical data in an aggressive SBMA mouse model showing that our oral ARV-027 degraded polyQ-AR in muscle led to meaningful functional improvements and extended survival. As a reminder, we have a terrific track record in developing AR degraders. Our first clinical candidate was an AR degrader and luxdegalutamide, which we out-licensed to Novartis in 2024, is progressing through multiple Phase 2 trials in hormone-sensitive and castration-resistant prostate cancer. We are excited about the potential of ARV-027 to become the first disease-modifying therapy for patients with SBMA.

Now let me turn to the discovery pipeline as we move closer to the clinic. First, ARV-6723, our oral immuno-oncology PROTAC degrader for solid tumors. The target is HPK1, which acts as a break on the immune system. It dampens T-cell signaling and suppresses both innate and adaptive antitumor responses.

What makes the HPK1 target especially challenging is that it works in 2 ways: not just through its kinase activity, but also as a signaling scaffold. So inhibition alone doesn't fully shut it down, degradation does. And that's exactly what we see with ARV-6723: deep, sustained removal of the protein and both of its functions.

In preclinical models, the data are very compelling. We see strong single-agent antitumor activity across multiple tumor types, including both high and low immunogenic settings. In fact, ARV-6723 showed greater tumor growth inhibition, outperforming both an HPK1 inhibitor and anti-PD-1.

Even more importantly, in 7 checkpoint-resistant models, ARV-6723 showed activity as a single agent while the inhibitor and anti-PD-1 were inactive. And mechanistically, this isn't just about T-cells. We're seeing reversal of the immunosuppressive tumor microenvironment as we just showed at the American Association for Cancer Research Conference. ARV-6723 induces a meaningful impact on the myeloid compartment, which you typically don't see with standard checkpoint therapies.

So stepping back, we believe this program has the potential to really change the treatment paradigm in immuno-oncology landscape, and we're on track to enter the clinic later this year.

Finally, let me touch on our oral pan-KRAS PROTAC program. Three key points to frame it. First, we're seeing broad degradation of KRAS across multiple alterations, including wild-type amplified KRAS with selectivity over other RAS isoforms. Importantly, this works on both the ON and the OFF signaling states.

Second, what matters biologically by degrading the protein and removing the oncoprotein rather than just inhibiting it, we are seeing stronger anti-proliferative and pro-apoptotic effects, along with greater tumor growth inhibition.

Third, in preclinical models, this approach shows enhanced activity, especially in combination with anti-PD-1 compared to the investigational pan-RAS (ON) inhibitor. That gives us confidence in a differentiated pan-KRAS degradation strategy that also complements our KRAS G12D program. We'll be sharing more updates later this year.

With that, I'll turn the call over to Andrew to review our quarterly financial results. Andrew?

Thanks, Angela, and good morning, everyone. I'm pleased to provide financial highlights for the first quarter and full year ended March 31, 2026. As a reminder, detailed financial results for the first quarter are included in the press release we just issued this morning. Reiterating the team's sentiment, we have much to look forward to later this year and are pleased with our strong financial position that will allow us to continue to advance our pipeline into the second half of 2028.

At the end of the first quarter, we had $614.9 million in cash, cash equivalents and marketable securities on the balance sheet compared with $685.4 million at the end of 2025. With our healthy balance sheet and focus on our early pipeline, we are well positioned to continue to develop our promising oncology and neurology programs.

Turning to our first quarter 2026 financial highlights. Revenue for the 3 months ended March 31, 2026, totaled $15.6 million compared to $188.8 million in revenue for the same period in 2025. The decrease of $173.2 million was due to decreased revenue recognized from the vepdegestrant collaborative agreement with Pfizer, driven by changes to the estimated remaining program costs.

General and administrative expenses were $19.1 million for the first quarter compared to $26.6 million for the same period of 2025. The decrease of $7.5 million was primarily due to a decrease in professional fees of $5.3 million.

Research and development expenses were $60.3 million in the first quarter compared to $90.8 million for the same period of 2025. The decrease of $30.5 million was primarily driven by a decrease in compensation and related personnel expenses of $15.6 million and a decrease in program-specific expenses of $9.5 million. Our cost reduction programs initiated last year and finishing up midyear 2026 continue to materially reduce our expenses.

Non-GAAP R&D was down $25 million compared to the same period last year, representing a reduction of 32%. Non-GAAP G&A came down by $10.1 million or 44% compared to prior year. Total non-GAAP expenses of $67.3 million is down $35.1 million from the same period last year and is representative of our new cost structure for 2026.

We continue to maintain our cash runway guidance into the second half of 2028. And in doing so, we will be able to fund operations through key data milestones over the coming months and continue to support our differentiated programs that have the potential to meaningfully improve patients' lives.

Additionally, our cash position will benefit from an approval milestone related to the approval of VEPPANU, which we expect to receive later in the year, and the upfront and near-term milestones from our out-licensing agreement with Rigel.

With that, I'll turn the call over to Randy for closing remarks. Randy?

Over the past 10 years, Arvinas has proven itself a leader in making potent, selective, orally bioavailable and brain-penetrant PROTACs with differentiated profiles. We've now successfully developed the first PROTAC to receive FDA approval, an accomplishment we believe further validates our technology and promising pipeline. Out-licensing VEPPANU to Rigel Pharmaceuticals allows us to focus on our Phase 1 clinical programs, each of which were advanced based on very differentiated preclinical data.

We believe these programs have the potential to transform treatment paradigms across oncology and neurology. We are positioned to deliver multiple clinical updates across our portfolio, including both ARV-806 and ARV-393 later this year, and we expect to bring our HPK1 degrader, ARV-6723 into the clinic in the coming months.

For ARV-102, we are working diligently to provide additional data needed to enable the initiation of the Phase 1b trial in patients with PSP. We anticipate beginning this trial and potentially a registrational trial in the second half of the year.

This is a defining year for Arvinas. It is a year of focused execution, clinical progress and the multiple shots on goal, all powered by a healthy balance sheet and a team deeply committed to advancing differentiated first-in-class therapies. We believe the work we're doing has the potential to fundamentally change treatment paradigms and deliver meaningful impact for patients with serious unmet needs.

With that, I'll turn the call back to Jeff to begin the Q&A. Jeff?

Thanks, Randy. And as a reminder for everyone, we're available to take questions offline if you aren't able to join the queue. But for now, I'm going to ask the operator to open up the line for Q&A. Operator?

Our first question comes from the line of Srikripa Devarakonda of Truist Securities.

This is [ Ana ] on for Kripa. Just 2 quick questions on the Rigel partnership. Congrats on that. Could you talk a little bit about the economics associated with Rigel sublicensing the drug outside of the U.S., and kind of how Arvinas and Pfizer may split the percentage of the sublicensing revenue? And remind us what the ongoing development activities are that Rigel is expected to contribute that $40 million towards?

Thank you very much for the question. And yes, I just want to start by saying how happy we are to get that done, right? So it's been really important to us to make sure that VEPPANU gets to patients as quickly as possible, now that it's approved as the first ever PROTAC degrader to get approved. We really chose Rigel as a partner because we were confident in their ability to really maximize the value of the drug and get it to patients quickly and efficiently. It's been a great process with them and we're grateful to them for that.

In terms of the economics around it, maybe I'll turn it over to Andrew to talk about that.

Yes. Thanks, Randy, and thanks for the question. Yes, the way to think about our out-license and our deal with Pfizer, Pfizer and us both have a 50-50 interest. So when you read things like milestones and royalties, think about Pfizer and us splitting those right down the middle for the duration of the out-license, okay?

The economics that we put in the press release this morning largely pertain to the U.S. That's where we have our current approval. Rigel has global rights. As you may know, Rigel is mainly focused in the U.S. So they would need to find partners to launch it internationally. There would also be a royalty coming back to Pfizer and us, but we did not disclose that number in the press release as we only have a U.S. approval at this time.

Our next question comes from the line of Etzer Darout of Barclays.

This is [ Luke ] on for Etzer. For the -- for 806 and KRAS G12D, can you talk about the scope of the data that we did later this year around like the number of patients, follow-up time, et cetera? And what you're viewing as the bar of success for advancement in the future development?

And then for 027, how translatable is the mouse model into humans? And what are the relevant biomarkers that we can look for from the healthy volunteer study? Or is this really just going to be a safety assessment?

Great. Thanks for the questions. And we can take them maybe in turn, and I'll look for Noah and Angela to jump in here too.

On 806, those data will be coming out this year. As you know, we're in a Phase 1 dose escalation, which has been going on since last year. Obviously, that's a space that's been evolving pretty rapidly over the past few months and the space that we're pretty excited about having a PROTAC degrader for G12D.

We've said the data will be coming in 2026. We haven't been exactly specific on where and when. We will be sharing safety, PK/PD and some initial response rate data. Clearly, the later in the year that we get that -- those data out, the more durability data we'll look to have, which is obviously what we think is going to be some of the most important information for comparison. So that's the story for 806.

Maybe for 027, Angela, the question on translatability of models.

Sure. So for ARV-027, we know that we're targeting the polyglutamine repeat androgen receptor. This is the only form of androgen receptor that's expressed in FDA-EMA. It's the root cause of the disease and that's exactly what we're going after, right? We have a lot of experience with androgen receptor degraders. We've put many of them into the clinic. And we know that we degrade the androgen receptor clinically.

So what we're hoping to achieve clinically is just that in muscle, right? We've designed this androgen receptor degrader to degrade the polyglutamine repeat androgen receptor in muscle. We've proven that in this aggressive mouse model where we've shown not only very nice dose-dependent degradation of the polyglutamine repeat androgen receptor in muscle, we've also shown that we've rescued 2 endophenotypes that are very important for the disease: endurance and strength, right?

So our goal is to translate that ultimately into the disease. But first, we need to show pharmacodynamically that we impact the target in muscle, and that's our goal with the Phase 1 trial in healthy volunteers.

Our next question comes from the line of Yigal Nochomovitz of Citigroup.

This is [ Caroline ] on for Yigal. Can you tell us what are the average levels of LRRK2 in PSP patients? And would the 50% knockdown seen in Parkinson's be enough to bring PSP patients back into normal physiologic range?

Yes, that is exactly our thinking. But in terms of patients with Parkinson's and other neurodegenerative diseases where LRRK2 is playing a role, it's generally double. So that is the thinking there.

Anything else you'd like to add, Noah?

Sure. So we can speak towards the levels that we see with the assay that we have. I think it's important to recognize that LRRK2 is an evolving area and different folks in clinical trials and in just general kind of Phase 0 studies just doing assessments of CSF have different measurements. But we recognize that healthy volunteers -- think of it roughly as healthy volunteers having a little below 10 picograms per ml as their median LRRK2 level and patients with Parkinson's disease having about twice that. And as you said, I think you hit it spot on. Our goal would be to reduce the Parkinson's disease patient levels towards that what's seen in healthy comparators.

And the good news there is that that's exactly what we have seen in our studies to date, right? So in the studies that we showed at AD/PD in our Phase 1, if you compare the healthy volunteers to the patients with PD, we do, in fact, see that the patients have somewhere on the order of double the LRRK2. And in addition to that, we're able to show that after treatment with ARB-102 that we then knock down and reduce that level of LRRK2 by at least 50%, depending on the dose that we get. So we feel like we certainly have a path to get there.

And just to add to that, in postmortem brain, we know from published results that there's twofold elevation in microglia in the brain as well. And that by normalizing that, we feel that we will normalize neuroinflammation as well and the biomarkers that Noah and his team have shown. We move -- we hope will alter the course of the disease.

Great. And just to clarify, do you expect the same for PSP patients, as the Parkinson's patients?

Could you say that again, ask the question?

You just seem to respond in terms of Parkinson's patients and I was just clarifying that you expect the same 50% knockdown in PSP patients.

Right. So we also expect that there's -- well, we have shared -- well, there are data that have been published by others, demonstrating an association of LRRK2 with PSP. We understand that it's -- in general, in these neurodegenerative diseases, when the LRRK2 protein is mutated, but also when it's expressed at higher levels, it's leading to endolysosomal dysfunction, which can drive the accumulation of pathological proteins.

PSP fits into that perfectly. It has the genetic association with LRRK2. There is accumulation of pathological tau. And our expectation is that we will see reductions of LRRK2 in the PSP patients, which would lead to an improvement in the tau deposition or reduction in it.

And to add to what Noah said, there's elevated LRRK2 and peripheral monocytes. So biomarkers are elevated. So LRRK2 is elevated in PSP, and this is correlated with more rapid progression clinically within a year in that already progressive disease. So that indicates to us that reducing LRRK2 could move the needle in that disease. That's PSP.

Our next question comes from the line of Sudan Loganathan of Stephens.

Congrats on the VEEPANU approval and the Rigel deal. The first question I wanted to have was on vepdeg program. For any future clinical trial developments or any ongoing trial developments, how is that going to be structured in the way that you or Rigel or Pfizer will be managing it?

And then secondly, I wanted to ask if there's any combinations with the ARV-806 for the KRAS G12D degrader, if there's any combination options when you -- as you're looking at the different solid tumor indications you're going after?

Yes. Thanks for the questions. On VEEPANU, the ongoing trials, as you know, are being run by us and Pfizer. As we talked about this morning in the releases, Rigel will provide some cost offsets for some of those ongoing development plans.

For future development work, the economics then would fall to Rigel. However, it will make sense to wait a little bit for us to get through the appropriate reviews and get that transaction fully closed before talking about that. And really, the questions on development will go to Rigel.

We're pretty excited with where we are right now in terms of what we've created for a development plan for VEEP and getting that to patients.

In terms of 806 combos, Noah, would you like to join in?

Sure. So we have shared some data previously and are continuing to share about combinations of 806 -- you can look at upcoming congresses to see what happens, for example, when you combine with chemotherapy. We're obviously doing work to look at other combinations internally. Right now, our guidance is simply towards sharing the results of our dose escalation. And...

And just to add that we know that we are combinable from a degrader perspective with anti-PD-1. This is something that we've shared and it looks different than daraxonrasib. We've also shown functionally that we don't inhibit T-cell receptor function, which is different than daraxon. So we feel that we have opportunities there as well.

Our next question comes from the line of Michael Schmidt of Guggenheim.

Maybe one on the BCL6 program. Could you comment on potential for differentiation from the Bristol Myers Squibb program? And just help us understand what you're doing in the Phase 1 study, the monotherapy study. Is that in all comers? Are patients selected in any way? And how should we think about the efficacy bar in B and T-cell lymphomas?

Yes. Thanks for the question, Michael. Right. So ARV-393, our BCL6 degrader, it's a program in our Phase 1 dose escalation as of now. And that's a program that when we began it really was considered an undruggable. So we've been gratified to see some of that early data from BMS around response rates in B-cell tumors. And as we reminded folks this morning, while that Phase 1 is ongoing for us, we mentioned last fall that we have seen some early responses in both the B and T-cell lymphomas.

In terms of the potential for differentiation, Noah, would you like to speak?

Sure. I just want to clarify though. The question was differentiating us from -- you said the CELMoD. Should we...

[Indiscernible], yes.

I believe [indiscernible] or there be BCL6. I just wanted to be clear in my response.

The BCL6, I'm sorry.

The BCL6. Okay. So the BCL6 degrader that they've published on demonstrates activity in follicular and large B-cell lymphomas. So we're obviously looking at that a way that we've differentiated our dose escalation study, is that we've queued in on AITL as well. This is a -- this population, angioimmunoblastic T-cell lymphoma, represents about 3% of all NHLs. There is tremendous unmet medical need because after first-line shock where patients will progress pretty rapidly on average in about a year or less, there really isn't a good standard of care. And we've described that we've enrolled such patients in our study. We've seen responses. It becomes an important area of differentiation in terms of the development plan for us.

You -- in terms of efficacy bars, so there becomes a difference between efficacy bars in T-cell malignancies and B-cell malignancies. I described AITL to you. If we shift to B-cell malignancies and look at the 2 major ones, follicular, there's diminishing unmet medical need because patients have very long progression-free survivals with current first, second and third-line therapies.

In large B-cell lymphoma, which we've hinted at or not even, I guess, we've stated that that's an area of more interest to us, there is also diminishing medical need, but still a significant enough one, in second and third line where even though you have drugs like CAR T that can be curative and you have tremendous responses with bispecifics, fundamentally patients are still progressing. And we envision a future where we'll be combining with bispecifics and impacting large B-cell lymphoma.

So we already shared today that we started dosing patients in a large B-cell lymphoma dose escalation where we combine with glofitamab. So that becomes an important part of our program.

Our next question comes from the line of Ananda Ghosh of H.C. Wainwright Co.

I have 2 questions, one on KRAS and one on the LRRK2 degraders. Maybe start with the KRAS. AACR 2026 had a pretty good disclosure reach data on how the competitive landscape for KRAS inhibitors, such degraders, look like. So my question is, what were the learnings from the AACR data reads with respect to tolerability, efficacy, the efficacy bar and resistance aspect of the KRAS problem?

Thanks for the question. Yes. Look, on KRAS in general, and I'll pass to Noah here in a moment, I think you're absolutely right to point out the space is evolving quickly. We are pleased to see the RevMed data come out, both earlier a month or so ago and then the recent publication, which helps clarify even some of the sort of different levels of data and efficacy that we see in different populations. So it's certainly a space that we're watching very carefully, both as we move the programs forward and plan our own data disclosures.

And I would say that's true for both our G12D program, which is in the clinic, now as well as our pan-KRAS program, which is still preclinical. Like other companies, we think that it's going to be quite helpful to have multiple assets in this space, both the more specific mutant degrader and then as well as the pan.

Noah, please chime in on this space.

Thanks, Randy. So yes, there definitely have been great learnings over both at scientific conferences and obviously with RevMed's announcements. So this is an area of active development, intense development because of the potential impact for patients. So I think we recognize the transformative -- all of us recognize the transformative nature of the first pan-RAS inhibitor. And at least by what's been presented for the impact as monotherapy in second-line PDAC.

What we also recognize is that with that tremendous efficacy doubling overall survival, there's also toxicity burdens, right? So it's an amazing drug, but patients also are experiencing a lot of toxicity, and maybe this is because of the broad targeting of beyond KRAS of NRAS and HRAS as well. So this opens the door for folks that are looking at more targeted therapy, whether that means looking at G12D, which represents about 40% of that patient population in PDAC and also about 10% to 15% in CRC and several percent in non-small cell lung cancer or if you're looking at a pan-KRAS. And that's why we've chosen to develop -- discover and develop drugs in this direction.

Now beyond the -- there's an opportunity for differentiation by more targeting, but also if you can reduce the toxicity that's seen, particularly the skin tox that's seen with the pan-RAS, then that also creates the opportunity for broader combinability. So we recognize that there may be opportunities to combine a pan-KRAS or a G12D targeting agent that doesn't have much skin toxicity with EGFR receptors, which can move you in the CRC direction. And there are opportunities potentially to combine with chemotherapy and use higher doses than our -- than a pan-RAS can use.

So we recognize that. We recognize the intense competition in the G12D space. And that's why we're just keeping our heads down, charging forward and look forward to sharing data later this year on our G12D program.

Great. Maybe if I have time, can I ask one question on the LRRK2 program?

Please.

Given the data, which you disclosed at the AD/PD, it would be interesting -- it would be important to know kind of the factors which drove the decision to look at the PSP trial from whether it is a mechanistic point of view, whether it is from the biomarker point of view, whether it is from the indication point of view, which might lead to a faster registrational trial. So just wanted to understand what were the thoughts -- the strategic thoughts that went inside the decision?

Yes, absolutely. I'll pass to Noah on the design and thinking about PSP as an indication. On those AD/PD data, just to reiterate that, and we talked about it in the prepared remarks. But I really think that what we're doing there is pretty unique, right? What we've been able to show there in terms of both reduction of LRRK2 and also the downstream disease-relevant biomarkers, we think really stands apart from what others have shown both preclinically and in the clinic, right?

So we're moving downstream biomarkers that we know are important for neuroinflammation and driving the disease in a way that we think is you need a degrader to get to all the functions of LRRK2, which could ultimately be relevant in PSP as well as other diseases.

But on PSP specific, please, Noah?

Thanks for the question. Thanks, Randy. So I think all -- for all the reasons you highlighted or all the general areas, indication, mechanism, biomarkers, all of that supports the focus on PSP. And let me be very clear, there's no pivot here. We did a study in Parkinson's disease because those patients are readily available because it is a disease of interest to us, and we could see a long-term opportunity to develop the drug in that space as well. But we chose that initially because it was the most -- it was the most informative next step after a healthy volunteer study to prove some of the biomarker points that are applicable to PSP.

So the PSP program has been long in planning. It's a disease of incredible unmet medical need that's rapidly progressive and allows you to identify a more homogeneous population of patients that have rapid progression, significant changes in the PSP rating scale on an annual basis, which is -- means that you can run a study with fewer patients and see the effect of your drug.

So from an indication point of view, less unmet medical need, less competition, more homogeneous and quite a significant indication in its own right because as we said, it's a rare disease. And -- but at the same time, there are 30,000 patients in the U.S. You can make similar estimates for Europe, obviously, and Asia. So that's the indication side.

Mechanistically, same fundamental issue. You have endolysosomal dysfunction, you have degeneration of synapses and circuits in the brain that underlie the disease. And in this particular disease, it's a tau pathology that rather than something like alpha-synuclein, where I think there's more heterogeneity there, less certainty in the community about how that works to drive disease. There's understanding that the 4R tau in PSP is a driver of this disease. So it's something that we're going to be able to measure as well.

And then from a biomarker point of view, we've done the lifting so far now in PD and that's transferable. So we know that the drug can degrade LRRK2 in the brain in a predictable way. We know that we can drive decrease in biomarkers that are associated with that and the lysosomal dysfunction that I described earlier that's driving the 4R tau accumulation. And so that allowed us to choose a dose range that we can bring forward for our Phase 1b and our registrational Phase 2 program.

Our next question comes from the line of Jon Miller of Evercore.

Congrats on all the progress. I'd like to focus on the RAS programs as well. You're moving into the expansion cohorts -- Phase 2 expansion cohorts. I noticed for the G12D, it seems to be specifically in pancreatic. And I was curious what led to that decision. Obviously, PDAC is arguably the most competitive of the KRAS relevant spaces, and I know you know that the landscape is evolving rapidly there. So what drove you into PDAC specifically? Have you considered doing expansion cohorts in other RAS-relevant indications? And when could we hear more about some of those combo approaches that you mentioned in previous answers?

And then on the pan-KRAS side, I was really interested to hear and to see the recent publication of the improved synergy with the anti-PD-1. And I was curious what your thoughts on the mechanism there was why the pan-KRAS would have a better or a degrader would have a better synergy with PD-1 than pan-RAS agents.

Jon, thanks for the question. We'll do that in 3 parts. I'll start and then pass Noah for PDAC and then Angela can probably speak best to the pan and the PD-1.

And look, I think it bears repeating, right? So as this space evolves, we're clearly looking at what's changing. What hasn't changed is our preclinical data, right? So our preclinical data gave us reason to believe based on the data in our hands that we could be more potent in terms of tumor growth inhibition versus the clinical stage inhibitors and degraders. So that's what we're relying on to think that we could be better. Now that better could result in durability, preventing resistance. There's also opportunities, as Noah spoke about before, around combinability and tolerability. So I think we'll be looking at all of those things.

The other thing that I would say before Noah, I pass to you on pancreatic, is that when you have a program come along like RevMed has and it's going to change the space, it isn't only going to be about can you win head-to-head. There are going to be new opportunities that are created in that space as the whole treatment paradigm changes in the years to come.

But maybe Noah, on PDAC and combos and Angela on pan.

Yes. Thank you, Jon, for the question. So let's -- so building on Randy's point about the potency, which we saw preclinically. So that -- now that we look at the data from other competitors in the space, we recognize that that potency could be a big deal. We know that Astellas' degrader wasn't able to achieve its originally intended maximal dosing because of DLTs in their Phase 1 study. We know that when daraxonrasib combined with Gem-Abraxane for their first-line PDAC study, they had to do a dose reduction, right?

So all of those types of signals suggest that if you have a drug that can be more potent, you might be able to achieve the target engagement and avoid some of the toxicities that one accumulates when you have to use really high doses. So with that said, we're doing the practical thing. We did our dose escalation. One needs for project optimist to choose a recommended Phase 2 or Phase 3 dose, however you want to describe it. So that requires some expansion. And when you do that -- and PDAC makes the most sense because it's a monotherapy space. The patients are accessible. The need is there and I think that's been borne out by the pace of our study so far.

We -- I don't want to -- those are the steps that we've guided to. So I don't want to go beyond that and start talking about other combinations and other indications. But the focus now is to understand what's the best dose as monotherapy. And then from there, we could get into a discussion. Once we've disclosed that, we can get into a discussion about other directions we can go.

I'll turn it to Angela for the KRAS piece.

Sure. Thanks, Jon. And thanks for highlighting our oral pan-KRAS poster at AACR. So we did show that we had differential impact versus daraxon in terms of the tumor microenvironment, where we saw daraxon was inhibiting the T-cell function by 3 different measures, right, functionally. But in the T-cell microenvironment, we know that not only are we recruiting T-cells, but we're recruiting other cells to the tumor. And so we are seeing greater complete responses because of that alteration that we're seeing in the microenvironment.

We did show that we were inducing MHC. So we are inducing antigenicity of the tumor and stay tuned for more mechanistic information on what's going on in the tumor microenvironment. It's an exciting time for the degrader.

But Angela, just to clarify, it sounded like what you were suggesting is that this is pan-KRAS effect where sparing some of the broader activity of daraxon might be the key here rather than a degrader effect. I'm just curious if it's possible to tease those 2 things out at this point.

So just so I understand the question and clarifying. So right. So we believe that through degradation, right, through both G12D with 806 or through pan-KRAS mechanism that the degrader has a differential effect relative to the KRAS (ON) inhibitor in the tumor microenvironment. And that's exactly what we showed in our mechanistic study. Looking at the tumors themselves in terms of seeing that we're actually recruiting more of a T-cell signal, but we're also seeing that we are inducing the antigenicity of the tumor, recruiting more immune cells to the environment -- to the tumor microenvironment, and we are seeing greater complete responses.

In addition, we also showed the difference between the impact of our molecule in a dose response, a degrader -- our degrader in a dose response relative to the KRAS (ON) clinical inhibitor in 3 different T-cell functional assays. So we're not inhibiting the T-cell function, whereas daraxon is.

Our next question comes from the line of Paul Choi of Goldman Sachs.

Congrats on all the progress. I want to turn back for a moment to 027 and the spinal and bulbar Kennedy's disease program. And just curious if you could maybe provide some context on how it compares to the 766 program for prostate cancer since both degrade androgen receptors and just sort of its potency and sort of what level of effect may be necessary to get to a clinically meaningful benefit here in your opinion? That's my first question.

And my second question is on VEPPANU and just what the latest status or plans are for European and other global filings, and just thinking about how we should model that on the forward here given it's now partnered to Rigel.

Great. Thanks. And for 027 for SBMA, that program began earlier in the year. And you're right to remind of the luxdegalutamide deal we did with Novartis a few years ago for prostate cancer. The key difference between the molecules is that while both degrade AR, 027 was specifically selected for its ability to degrade AR in muscle. So it really gets into muscle well, which is really important as that's the site where we'd like it to be active for the neuromuscular disease of SBMA, not the case for 766 or luxdegalutamide, the one that's for prostate cancer with Novartis.

In terms of depth and going forward, obviously, we have the U.S. approval. Further regulatory work will be done by Rigel, the new partner. Certainly we've got an ASR period to get through. After that point, it probably makes sense to connect with Rigel on all questions regarding the future development. We're certainly excited for them to take it over for both commercialization and the potential further development of that.

Our next question comes from the line of Derek Archila of Wells Fargo.

This is [ Jacob ] on for Derek. I just wanted to clarify, did you say the ARV-102 is on hold in the U.S., but still going ahead ex U.S.?

Effectively, that's -- yes, that's correct. So for 102, right, as Noah said, after filing that IND, we get to the 30-day period where the FDA essentially have 2 options, either to move forward or to put it on hold. So while that trial has not yet begun in the U.S., we have not dosed any patients in the U.S.; technically, yes, it's on hold. The trials that have been going on outside the U.S. are not affected. And the thinking is that as we move forward, speaking with both the FDA and ex U.S. regulatory authorities, we'll consider down both paths in parallel.

I see. And what are the gating factors there for starting in the U.S. versus ex U.S.

Why don't you take it, Noah?

Yes, Randy. So essentially a couple of years ago, before we started this program, we met with the FDA, and we described or we asked them what would be necessary to start in the U.S. At the time, we had already made a strategic decision to run the healthy volunteer and eventually do the Parkinson's disease study in Europe to get the program started, very common in neuro drug development.

They had outlined for us that for chronic treatment, you need to provide the following information. We provided that information, and now they were asking for more than had originally been requested. So we have to get it in order. We'll share it with them, but the conversation will continue.

Our next question comes from the line of Jeet Mukherjee of BTIG.

Just coming back to PSP as an indication, can you remind us how these patients are diagnosed and where they're frequently treated? Are they concentrated at certain centers of excellence? And any view so far on what a potential pivotal study could look like in terms of length and primary endpoints?

Thanks for the question, Jeet. Noah, please.

Sure. Yes. Thanks, Jeet. So the patients are typically diagnosed after having been mistakenly diagnosed with Parkinson's disease, right? Because you have someone that's coming in with tremor, stiffness, instability. These are common presentations for Parkinson's disease and are also present in PSP. There's kind of a clinical differentiating feature, which is that they have a vertical gaze problem that leads to falls.

And there's a clinical management indicator that also drives you in the direction of PSP, which is that patients with Parkinson's disease will be treated with L-dopa of some kind, and they will show some improvement typically. But when you have a PSP patient, they do not respond to that. So think of it as an initial commonly misdiagnosis unless they present with falls when it would be more obvious. And then they have this diagnosis. And unfortunately, it's a rapidly progressive disease and differentiates from Parkinson's disease in that way.

And as we said, time from diagnosis to death is 5 to 7 years or so. So that is -- now you asked where are the patients treated. There definitely are at some centers of excellence, but it's something that is seen broadly -- most -- all neurologists will see PSP patients at some point. There are centers that see quite a lot of them. There is a history of running clinical trials at various centers in the U.S. Right now, the only other Phase 3 program that is going to be concurrent with this, it looks like, is Novartis' study because they've announced an ASO targeting tau that's moving into Phase 3, and that involves quarterly injections, intrathecal injections of an ASO.

We believe that we'll be able to recruit our patients successfully because there's a long track record of global recruitment for the PSP trials. And we think there may even be a preference for this type of study that we're running. And in terms of endpoints and knowing the size of that study, we've said in broad strokes before, it's a few hundred patients. It will be 2 dose of -- presumably 2 dose levels versus placebo and require a year of treatment.

Our next question comes from the line of Tyler Van Buren of TD Cowen.

This is [ Nick ] on for Tyler. Moving back to the LRRK2 program. While you are prioritizing PSP for the reasons that you mentioned before, is there anything that you could see in your PSP data at some point that would affect your decision to move forward in Parkinson's disease? Or could the Denali LRRK2 inhibitor Phase 2 data later this year support advancement into Parkinson's disease?

I mean I think the short answer is no in the way that I wouldn't expect -- we think that the data we've generated so far in both healthy volunteers and patients with Parkinson's can be translated to both patients with Parkinson's and PSP. So I guess from that perspective, there's certainly we could do in PSP and data that we could see that would give us more confidence in our ability to do what we've already started to show, which is have 102 be an orally available brain penetrant drug that reduces LRRK2 right where we wanted to degrade it in deep brain regions.

When it comes to the Biogen readout, certainly something we're looking at. As a reminder, we're talking about 102 as a degrader here focused on all 3 aspects of LRRK2's function, which we think is important for the reasons that we've already outlined on this call. And so for that reason, we are certainly hopeful that the trial is positive for patients. And we think that if it is, we think we can show a benefit beyond that with the technology that we have. And if it's not, we think that the differentiation that we've already shown both in the clinic with biomarkers as well as preclinically with things like endolysosomal function, the ability to reduce tau, we think there's a lot of data we've already shared that shows how different we are from that program. So we'll be moving ahead.

Our next question comes from the line of Akash Tewari of Jefferies.

This is Manoj on for Akash. Just one from our end on ARV-806. It seems like you are going with 2 dose levels randomized in the Phase 2 trial of ARV-806 rather than like just one dose selected from the escalation portion. Just trying to understand the rationale of those 2 dose levels going randomized into the Phase 2. And also what endpoints will kind of finally decide the final dose selection like ORR or KRAS degradation [indiscernible] like just trying to understand the rationale there.

Yes, you're right. As we head into the dose expansion, we are planning to explore 2 doses, which I think is fairly typical in oncology.

Noah, anything to add on that?

Yes. All of those factors will go into it, meaning when you do a dose expansion and you're trying to optimize the dose, satisfying for yourself that you have the right dose, but also satisfying the FDA, let's be frank. It's very important for them. You look at all these factors. We'll look at the overall response. We'll look at as much degradation data as we can collect. You're looking at the safety and other indicators of efficacy. So it all goes in there. But I think we're looking at a pretty typical expansion here.

Our next question comes from the line of Li Watsek of Cantor.

This is Daniel Bronder on for Li. How do you view the patient population in the future for your KRAS program? I noticed on the KRAS G12D degrader you have so far based on clinicaltrials.gov, excluded any pretreatment with KRAS-targeted agents. Do you think you will be developing it in the same phase? Do you think you'll be going after pan-RAS or pan-KRAS or even targeted KRAS G12D drugs in the future?

Yes. I think you're highlighting the answer, right, which is that there's a lot of options here. The most important thing to do first is show that our drug works, right? We need to show that in the Phase 1, we're able to be competitive, and that's what we're looking to do with both the escalation and the expansion. Beyond that, as your question and others have alluded to, there's options in different indications. There's options for monotherapy versus combination. You mentioned KRAS pretreatment as other programs come on to the market and get used. Certainly, that's going to create a new opportunity to follow that in other therapies, and we'll have to figure out a way to play in that space.

One thing that I've been pretty consistent in saying since taking over the CEO role a few months ago is that we're not interested in producing incremental, I mean 2 sorts of programs. So it's important for us, especially as a company that has 4 programs in Phase 1 right now, with a fifth entering in the second half of the year. It's really important that we focus Arvinas on where we can play to win and where we can be differentiated. And we need to show that we can be. And as we create that development plan, we'll move forward if we are.

So again, it sort of goes back to saying that we look forward to sharing those data this year, and that will be the point to share a bit more on the development plans beyond the initial stages of monotherapy expansion and escalation.

Thank you. This concludes the question-and-answer session. I'll now turn it back to Randy Teel for closing remarks.

Well, thank you very much, everybody, for joining. I probably can't say this enough, but I really couldn't be prouder of the team and where we are. Just in the past few -- in past 10 days, 11 days, we've had both the approval of BEP, which is the first ever heterobifunctional degrader PROTAC to get to the market. As I said earlier, it's a very short list of companies that get to take a program -- take a technology all the way from inception to its first approval. I couldn't be prouder of that.

Working with Pfizer to get the program VEPPANU licensed to Rigel for them to launch, also a huge accomplishment. And as I reiterated a moment ago, we've got 4 programs in the clinic. We've shared some data for one already this year, have a couple more coming with some trial starts. So a lot to look forward to and we look forward to keeping you updated along the way.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

Great. Hello again, everyone. I'm Etzer Darout, Senior biotech analyst at Barclays. It's my pleasure to have Arvinas with us for our next session. I have Randy Teel, Chief Executive Officer; and Angela Cacace, Chief Scientific Officer at Arvinas.

Thank you guys for joining us today. Randy, maybe just give us an overview of Arvinas where you are today, and then we'll jump into Q&A.

Well. Thank you very much, and thank you to Barclays for having us down here. Yes. So Arvinas, as we start 2026, has 4 programs in Phase 1, which is a pretty exciting pivot for us. Over the past year, we've taken steps to really reposition ourselves as a Phase 1 company. And so that's where we are with 4 programs. We have a LRRK2 degrader, which is relevant for neurodegenerative disorders. We have a KRAS G12D degrader relevant for solid tumors.

We have a BCL6 degrader for hematology. And just in the past month, we began a clinical trial of a program for AR, polyglutamine repeat AR, which will be relevant for patients with Kennedy's disease. And we've done all of this at this point with a pretty strong foundation for our formerly lead program Vepdegestrant, which was an ER degrader, is an ER degrader.

We had positive pivotal data last year, and that program is now -- has an IND -- sorry, an NDA filed with the FDA, which has a PDUFA date in early June of this year. So the platform that we have created over the last 12 to 13 years really now has pivotal validation.

In addition to that, we also have an AR degrader that was out-licensed to Novartis a couple of years ago for AR for use in prostate cancer. So as we move forward with our Phase 1 programs, we're really doing that with a strong foundation of proven science in our opinion. And we've also got the capital to move the programs to the next inflection point.

So as we look out ahead to 2026, where we will have clinical data for 3 of those 4 clinical programs, we think it's a pretty exciting time to be looking at the company. And with my recent appointment, that's the reason that I'm most excited to be here is to lead the company at this point with that string of milestones ahead of us. It's a great time to be starting.

Great. You're about 8 years in Arvinas, but newly appointed CEO. So congrats again. Are you looking at a company now from a different lens from where you were in your seat? Or do you sort of just see this as a kind of continuation, if you will, of the Arvinas story?

Well, I think that some of the most important priorities that we already had are still the priorities. We have the programs in Phase 1. We need to get the data. We need to see what the programs can do. So from that extent, it's a bit of a continuation. What I think is less of a continuation is that over time, what I'd really like to see us do is take the pipeline that we are creating and have created.

And we have spent a lot of time explaining over the years what the potential of our PROTAC platform could be. Now is the time to look at the pipeline that we've created, which, by the way, will grow by one more Phase 1 program by the end of the year with the start of a program to degrade HPK1.

As we go forward, we will need to make sure that the platform doesn't just create clinical candidates that are strong. It needs to create candidates that are differentiated. And we will take a pretty hard look in the coming months to years to make sure that the places that we are choosing to invest in resource are the right places for us as a biotech company. And even if everything is successful, we will look for opportunities as we've done over the past 10 years to find partners to help take programs forward, too. So I really think that, that focus on differentiation and ensuring that in every situation that we create a degrader that it's the right use for that technology will be really important.

Great. And you talked a little bit about the judgment and successful Phase 3 study, you're looking for partnerships for that program. I guess, how are those discussions going? And I guess, ultimately, if the PDUFA comes before partnership, then sort of do you have a sort of backup plan in terms of how you continue to move that program clinically? And how are you think -- I mean, sorry, into commercialization, how are you thinking about that?

Yes, it's a great question. So the overall goal that's shared by us and Pfizer is to make sure that Vepdegestrant, if it's approved by the FDA, is available for patients and physicians as soon as possible. We believe that it has the potential to be a best-in-class program based on the data that it showed.

So it's really important to us to make that happen. In terms of the partnership conversations, they are well on track, and we anticipate getting that done before the PDUFA date. So that's what we're all focused on for now and have made good progress.

Great. Shift to the early clinical pipeline. We see LRRK2 degrader have some upcoming disclosures there. Maybe just take a step back, just talk about the physiological role of LRRK2 and the rationale for targeting LRRK2 in Parkinson's disease.

Yes. So the LRRK2 program, ARV-102, is the furthest along, and we'll have data coming up next week. I think it would be great, Angela, to dive in on the rationale for the target and the program.

Sure. So LRRK2 is a multifunctional protein. It contains a kinase, a GTPase and scaffolding function, all of which accumulate in neurodegenerative diseases and the accumulation leads to lysosomal endolysosomal dysfunction. This leads to accumulation of toxic neurodegenerative proteins.

And by degrading LRRK2, this will normalize homeostasis of lysosomal function and clear those pathologic proteins. So we're encouraged by what we're seeing in our preclinical data. We've shown that we increase lysosome number, increase the degradative capacity of the lysosome, clear pathologic tau. And this would be -- we feel this would benefit patients with a disease called progressive supranuclear palsy.

This is a tauopathy. And what's been shown in this disease is that elevated LRRK2 causes an increase in progression, clinically meaningful progression in a year, and this has been shown by the folks at the University College London. And then certainly, in Parkinson's disease, LRRK2 has been implicated as well in progression of that disease. So we're encouraged by what we're seeing.

Great. And what can we expect as far as the data disclosure that's upcoming and also relative to what you've presented to date for that program?

Sure. Great question. So in our Phase 1 healthy volunteer study, we did show that we crossed the blood-brain barrier -- first, we showed safety data, first and foremost, in healthy volunteers after 14 days of oral dosing. We crossed the blood-brain barrier at exposures where we observed reductions in CSF LRRK2 levels and we also showed, which was unexpected, that we reduced proteins in CSF that are elevated in LRRK2-driven Parkinson's disease.

And these are pathway biomarkers from the Michael J. Fox progression marker initiative. So that was exciting for us to see. So in our -- so next week at the AD/PD meeting, we'll be sharing our Parkinson's disease data. And there, you can expect to see data showing in Parkinson's disease patients that, again, after 28 days of oral dosing, we'll share safety data.

We'll also share data crossing the blood-brain barrier, degradation in the brain or CSF of LRRK2. So again, these patients will be on average 60 years of age. We showed in healthy volunteers that are on average 25 years of age. So engaging the ubiquitin and proteasome with a PROTAC mechanism that we're able to degrade LRRK2 in the brain of neurodegenerative disease, very important for our PROTAC mechanism to derisk oral degradation.

So that's exciting. And then we'll also be looking for those pathway biomarkers for LRRK2 to show that we're engaging the LRRK2 pathway of endolysosomal and neuroinflammatory Parkinson's disease. LRRK2-driven disease markers.

So one of the questions we get more and more these days is would we see the type of data at the upcoming conference that starts to differentiate from the other approaches that we'll be reading out this year, Bioge,n, Denali's program as well as Neuron23's program. And when can we start to sort of see potential differences in the approach for Parkinson's?

Well, answer, we've already shown the data that differentiates. So in healthy volunteers, we've shown that we degrade LRRK2 greater than 50% in CSF after oral administration. We've also shown that we've fully engaged the LRRK2 pathway in CSF. That has not been shown for any inhibitor to date in any CSF study that we've seen. It has not been reported.

So last year, AD/PD, Biogen did share some CSF biomarker data in Parkinson's disease. They saw some trends in cathepsins, but we did not see full pathway engagement from them. It's possible that they have those data and just didn't share it, but we shared full pathway engagement in healthy volunteers.

Got it. Great. And it's sort of a tricky sort of situation where as we get the data from them, are there scenarios where those studies potentially fail, but then there's still a strong rationale for moving forward with the degrader, particularly around your point earlier, Randy, around sort of capital allocation in how to sort of best demonstrate proof of concept, but then also demonstrate sort of meaningful differentiation from other assets. So how are you thinking about those different scenarios as we look for those readouts?

I think first and foremost, we hope they don't fail, right? We hope very much that they have a benefit for patients in Parkinson's disease. And we think that in that scenario, the differences that Angela has already pointed out in terms of the data that we've shown preclinically and with biomarker data in the clinic, we think give us an edge. So that's what we would hope is that they're successful and we're able to do better. That's the goal.

I think the scenario you laid out where it's perhaps not positive overall, but there's something to learn from data that they share, whether that's data that comes sooner or come later from various subpopulations and so on, I think that's certainly possible. For us, the main goal this year is to share the data next week.

To get a Phase 1b trial started in patients with PSP in the first half of the year. And if we do all that and get through some other steps with regulatory agencies and so on, we may have the opportunity to start an even registrational quality study by the end of the year in patients with PSP, although I don't want to get too far ahead, there's a few hoops that we need to get through to do that.

So that will be our plan. And we think that the measure of how relevant LRRK2 is for driving disease is ultimately going to be better assessed by a program that degrades it entirely to take advantage of the fact that we eliminate all the functions, kinase, GTPase and scaffolding function and not impact just one of the functions of LRRK2.

Great. And for those maybe familiar with -- less familiar with PSP, if you can maybe talk about the market opportunity and as well as sort of the treatment landscape for that disease?

Sure. Progressive supranuclear palsy is a devastating life-threatening disease. Those patients die within 5 to 7 years of diagnosis. So it's a Parkinsonian-like disease. So it's a movement disorder, but patients lose their ability to communicate.

So they also tend to also lose their ability to eye track, so they can neither look up or down. So very debilitating over time. There are about 25,000 patients in the United States that are diagnosed with this disease. So it's a decent-sized rare disease. And the progression is very rapid. So you can measure clinically meaningful progression within a year. So it's what we like to refer to as a biotech-friendly disease from that perspective, but it's a very tragic disease.

Got it. And are there clinical comps in terms of guiding you towards a registration study? Is this something that you've talked about after getting feedback from regulators, what would a pivotal study look like for that population?

So there is the PSP rating scale. So this is a well-recognized clinical rating scale, and that is recognized by the FDA as the clinical tool. And so if we stop progression of this disease, within a year, certainly, that would be clinically meaningful or even reduce it by a certain number of points on that rating scale.

Got it. Great. Maybe we can switch over to the KRAS program. Obviously, very busy space, but I think the degrader approach is one that brings potential differentiation there. Validated target, obviously. Maybe you could talk through, at least from the data that you've generated to date about where you think this molecule could be different from what we currently know about KRAS G12D inhibitors in other programs?

Sure. So our ARV-806 degrader removes the oncoprotein from the cell, so from the tumor. And so that's very different than the KRAS inhibitors that are ahead of us, both the on and the off inhibitors. And that removes the driving force that drives this rapid proliferation within the tumor.

So we're very encouraged by the preclinical profile that we have. We're 25-fold more potent than the clinical mechanisms, all of the clinical mechanisms that we've looked at.

We're 40-fold more potent than the degrader that's in the clinic as well. And we're encouraged by the data that [ Astellas ] has shown. The degrader is showing nice efficacy. However, they are running up against their liver tox, and we are more potent. So we feel that, that's a benefit that we do have.

The other advantages that we have relative to the inhibitors is that the inhibitors, you do observe this rapid resynthesis rate that occurs. It is a reaction to inhibiting the protein. So we do not see that because we are degrading. So we have this iterative activity as a PROTAC mechanism that degrades and takes out that resynthesized protein.

So we overcome that, we degrade. So that we expect to have a very durable degradation and removal of the oncoprotein. And the other point that I'll make with respect to the KRAS(ON) inhibitors that work through a cyclophilin glue-like mechanism is that they do have an immunosuppressive type of mechanism because daraxonrasib also inhibits [ NNH RAS ].

So what we've shown in syngeneic models is that we see superior combinability with anti-PD-1 agents. And that's because we don't inhibit the T cell activity. So that's another important point of differentiation. And we also feel that we'll have very good combinability with anti-EGFR inhibitors. So again, we won't have that combinable toxicology profile.

Got it. Great. And when you think about sort of setting expectations for that, it's going to be an early Phase 1 study. Is it primarily safety and maybe looking at translation of degradation to clinical response? And how you think -- how do we -- should we think about those initial disclosures?

I think that's pretty fair. However, I would also say that this is a program where we know that there's a lot of competition out there. So unlike in LRRK2, where we feel like we've got a space where there's no disease-modifying therapies, that's not the case here for KRAS, right?

So we know that over time, we're going to have to show that we can be better than the programs that are coming ahead of us. That could be through safety, that could be through tolerability, it could be through combinability, but it will also need to be through efficacy over time. So you're absolutely right in saying that our first data readout from a Phase 1 dose escalation study will have all the standard limitations of Phase 1 dose escalation studies with a relatively small number of patients, even smaller when you look at those that might be in a predicted efficacious dose, even smaller when you look at how many patients might have been on therapy long enough to show a benefit.

But clearly, over time, we're going to have to be different than the competitors. the first look at efficacy is probably around response rate. That doesn't always correlate well with durability. Durability based on the mechanism that Angela described and the ability to prevent resistance is probably the area of efficacy where we would most look to differentiate, but that won't be -- that will almost certainly not be ready in an initial data update.

And then back to safety and how important that is in combinability. Clearly, the space that will ultimately look to take a KRAS degrader is in combination with other agents. And so the combinability will also be critical. And obviously, we'll have no view on that at all in the Phase 1 dose escalation.

Yes. And you're also developing a pan-KRAS degrader that's in preclinical development. Just given sort of the escape mechanisms and the resistance mechanisms around just KRAS/RAS in general, can you talk about maybe the challenges of moving a program like that into the clinic?

Yes, certainly. We just presented recently just this past weekend at the KRAS AACR Special Conference, and we presented some really beautiful data showing that we work and we actually degrade and inhibit proliferation in a superior manner in an amplified wild-type KRAS setting, which is really important. As you mentioned, amplification is a big mechanism of resistance for the inhibitors. And we've seen this. It's been reported for the RevMed resistance mechanism. So we think this is a very competitive area for us to show mechanistically that we can overcome that amplification setting. And so these are the first data for a degrader that we've seen published anywhere where this has been shown.

Right. And I guess when you think about just the KRAS and the competitive landscape just in general, again, could potentially be significantly large opportunity. How are you thinking about sort of future development of KRAS? Is it something you think -- how far can Arvinas take this? Or do you think ultimately, you would have to partner with this opportunity?

I think it depends on the data we see and how the development plan continues. So we have 2 programs so far, right, the G12D and the [ Pan ]. We think that makes a lot of sense to have a broader agent that could be more efficacious in a broader set of tumors and also to have a narrower focus degrader like G12D, which might be able to get to deeper degradation or at least to better combinability with other agents. So we think the franchise approach makes a lot of sense.

Both those programs, though, as you point out, going forward, we will move from Phase 1 programs into 2, we'll move from monotherapy studies into combinations. And with the intensity of the competitive space, I can imagine a situation where it becomes helpful to have someone else help us run multiple Phase 3 trials at some point.

Importantly, though, that's not where we are yet. We're running a Phase 1 dose escalation that so far has run incredibly well I think that reflects a lot of excitement on the behalf of investigators who are still looking for better options for patients. That trial, we only began late last summer and is already fully enrolled.

So we're going to be able to get data out this year ahead of where we would have thought. I think that reflects excitement, which is good. It also reflects us getting closer to a point that you're talking about where if we're looking at moving forward programs in KRAS and in LRRK2, and we haven't gotten to hematology yet, we haven't gotten to SBMA rare disease yet, it could start to look like a place that some additional firepower could be beneficial.

Great. Yes, that makes sense. I guess that was sort of going to be my next question and moving on to ARV-393, it just seems that there's some acceleration we're seeing with KRAS relative to 393. But with that program, the BCL6 degrader, we know Bristol has had some preliminary clinical data.

What are you thinking about in terms of internal benchmarks to move that program forward? And do you get to a go/no-go decision on the next data set? Or do you think it's something that's maybe more 2027, 2028 to get to a decision-making point for that program?

Right. So the 393 Phase 1 study has some resemblance to the KRAS where it's a Phase 1 dose escalation study. The acceleration of G12D really has more to do with that study than 393 and just the rapid enrollment that we've seen. So 393 we'll have data in the second half of the year for dose escalation, and that will be the first important look.

And I think that for that program where the ultimate development plan will be both as monotherapy and in combination, the real differentiation there for that is going to have to be when we get to combination. We are starting a combination study with glofitamab in the next few months because the -- at least -- I wouldn't say the ultimate goal, but one big goal for the program is to get to a second-line bispecific study.

So going forward with [ glofi ] be the first step in doing that. We'll start enrolling patients in that in the next few months. And I think that between the monotherapy data where we need to be in line with what BMS is showing, when we ultimately get -- which won't be this year for the combination data, that's where we're going to start just need to see some differentiation. The other place -- other point though, there is that in LBCL it's pretty crowded when it comes to bispecifics and ADCs and so on. It's not crowded when it comes to oral options for BCL6. So I think we're still in a very strong position there as we move forward.

Great. And can we expect sort of typical mix of non-Hodgkin's lymphoma patients in that cohort, DLBCL, follicular lymphoma?

Well, I think the MS data was primarily LBCL. One unique feature of ours is that we're also enrolling patients with T-cell lymphomas. So we will also get a view of that, which I think has the opportunity to show a bit of a different story for our program.

Great. Thank you. And that looks like we're up on our time. Randy, Angela, thank you so much for your time. Thank you for our listeners, and we'll be back with our next session.

Thank you, Etzer.

Thank you.

Hello, and welcome to Arvinas 4Q '25 Earnings Call. [Operator Instructions] 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 Teel, 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'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 filing 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. And now I'll turn the call over to Randy Teel. Randy?

Thanks, Jeff, and thank you all for joining us today. It's 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. In 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 4 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're entering a pivotal period at Arvinas. As we've been previewing for the past 6 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'll 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'm pleased to announce today that data from our Phase I clinical trial in patients with Parkinson's disease was accepted for an oral presentation at the Alzheimer's Disease and Parkinson's Disease Conference in March. We'll 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, we now expect to make our first data disclosure for the program by the middle of 2026, and we've 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 I dose escalation trial, and we intend to share data from this trial in the second half of 2026. As announced on our last earnings call, we've 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 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's approved, vepdeg 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're working to have an agreement in place before the June 5 PDUFA date.

Finally, before I turn the call over to the team, I'd like to make two comments on corporate strategy. First, last year, we decided to refocus our resources on our Phase I clinical programs, which we now have 4 of. While we believe vepdeg 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 won't settle for as good as, and we hope patients don't have to choose between efficacy, safety and tolerability. We're 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'll turn the call over to Noah. Noah?

Thanks, Randy, and good morning, everyone. I'll begin with ARV-102, our LRRK2 degrader. As background, [Audio Gap] Angela?

Thanks, Noah, and good morning, everyone. I'll 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 [ luxdegalutamide ], which we out-licensed to Novartis in 2024 is progressing through multiple Phase II 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 at 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 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 I 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 break on the immune system, suppressing 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 an 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 pro-inflammatory tumor microenvironment with increased activated T-cells, NK cells and monocytes. In addition, ARV-6723 was found to reduce immunosuppressive neutrophils while inducing broader pro-inflammatory pathway activation than inhibition alone.

Last week, at AACR Immuno-Oncology Conference, we presented preclinical data demonstrating ARV-6723's robust single-agent activity and out-performance 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're making strong progress in our oral pan-KRAS PROTAC program, a preclinical program that complements our clinical KRAS G12D degrader. Our pan-KRAS PROTAC differentiate from all inhibitors in that our novel oral degrader is designed to target KRAS for elimination. Preclinically, we've 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 onco-protein, we've observed stronger anti-proliferative and [indiscernible] 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'll turn the call over to Andrew to review our quarterly financial information. Andrew?

Thanks, Angela, and good morning, everyone. I'm pleased to provide financial highlights for the fourth quarter and full year ended December 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 the second half of 2028.

At the end of the fourth quarter, we had just over $685 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 recorded $262.6 million in revenue for the year compared to $263.4 million for fiscal year '24. 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 December 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 $70.4 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 have 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-K, which will be issued later today. As I mentioned, we are maintaining our cash runway guidance into the second half of 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'll summarize and then open the call for questions. Over 2026, we anticipate sharing new clinical data from our Phase I trials of ARV-102, 806 and 393. We expect that our polyQ-AR degrader, which has 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 393.

I believe we're entering a period of meaningful execution and value creation at Arvinas. Very few Phase I companies have such a strong pipeline and the capital to reach important milestones and even fewer have a platform that's already announced positive Phase III 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'll hand the call to Jeff to start Q&A. Jeff?

Thanks, Randy. And as a reminder, we're always available to take questions offline if you can't join the queue. But for now, I'll ask the operator to open the line for Q&A. Operator?

Actually, operator, 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 in the past couple of days, we prerecorded the prepared remarks to ensure we 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'll 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 multi-domain 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 neuro-inflammation and lysosomal dysfunction. This is an important consideration when thinking about a differentiated profile as ARV-102 offers the potential for deeper and more durable therapeutic benefit versus inhibitors. Our confidence in this program is bolstered by the data we've generated from our Phase I clinical trials in healthy volunteers in 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, GpNMV 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 kinase 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's turn now to the development plan for ARV-102. As we've previously shared, there is strong evidence that endolysosomal trafficking driven by increased LRRK2 is associated with a clinically meaningful progression often within 1 year of PSP, a progressively debilitating neurodegenerative disease that is typically fatal within 5 to 7 years of diagnosis. We intend to initiate a Phase Ib 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'll say we completed dose escalation for once-weekly administration in our Phase I 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 cancers. 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 [indiscernible] meeting in October that highlighted the clear differentiation of ARV-806 from both KRAS inhibitors and degraders currently in the clinic. These preclinical data showed ARV-806 to be more than 25-fold more potent in reducing cancer cell proliferation compared to clinical stage KRAS G12D inhibitors and the leading clinical stage G12D degrader. The data also showed durable degradation greater than 90% for 70 days -- sorry, for 7 days after a single dose with efficacy responses across pancreatic, colorectal and lung cancer models. We anticipate sharing initial Phase I clinical data in the coming months. There's a very high bar for differentiation, and we believe ARV-806 has the potential to transform the field by exceeding that bar.

Let's 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've already observed responses in both B- and T-cell lymphomas in the early cohorts of our ongoing Phase I monotherapy trial, even in 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 when 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 [indiscernible], 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 [indiscernible] dose sequentially compared to 36% for [indiscernible] 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 down-regulated 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 I combination trial with [ glofitamab ] in the first half of this year. So now I'll turn the call over to the operator for Q&A.

[Operator Instructions] Our first question comes from the line of Jonathan Miller with Evercore ISI.

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're only going to develop programs for which you're going to see differentiated activity. Multiple of these programs are in competitive areas, as you're 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's 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've got something truly differentiated or not?

Yes, John, 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. John, that's probably a question we could spend a lot of the day on, right? So to your point, for each program, it's 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, does not necessarily mean that when you first show data in a very early Phase I trial that it has to be beating a competitor that has expansion data, Phase III data and so on. So I'll pass to Noah here in a little bit to talk 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'll highlight a couple of things, for LRRK2, for ARV-102 or LRRK2 degrader, the competition there is inhibitors. It will be really important to show that degradation leads to a different result in inhibition for a target that has not been proven to modify disease overall by drugs that the industry has produced. So that's a key risk.

For 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's 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'll leave 027 to the side for the moment. But I think for each of those, the Phase I data will be of some interest and as we move forward, we'll have to compare over time. Noah, anything else you want to add, maybe specifically around some of the near-term data updates?

Sure. Thanks, Randy. Yes, we can -- let's take the example of ARV-102 for starters. So in that case, we've signaled pretty significant conviction. We've said we're starting a trial in PSP this year and regulatory permitting. We may even be able to move towards a registration-quality trial before the end of the year. So we believe that we've established our superiority already.

We recognize that there's a property for -- there are properties of a LRRK2 inhibitor that can be exceeded with LRRK2 degraders. We've shown already in healthy volunteers that we have more than 50 -- we can achieve more than 50% LRRK2 degradation in the brain. That's been our target. We've been communicating that clearly because we know in general, like if you want to just simplify in broader strokes that patients with Parkinson's disease have twice to 3x the level of LRRK2 protein expression in the brain compared to their age-match controls. So our goal was to achieve that something that can't be touched by inhibitors. So that's 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. 806 is a very competitive space. We know that there are many other G12D targeting drugs ahead of us, mostly inhibitors and, let's say, one degrader. But fundamentally, that it really makes it easier for us because we know where the bar is. We know that -- and I'm going to speak in broad terms. I'm not setting the bogey here because this is not so -- because it's an imprecise science. But we know that we have to be better than, let's say, 35% response rates in this space to be differentiated. So we're going to have to generate data that gives us confidence that we're better. We'll signal as the year moves on about exactly what level of confidence we have and what -- as we can share data with folks.

But that's clear from the numerous drugs that are in the clinic today that we have to be better than the large majority of them, which would put us in that range. And then when it comes to 393, we're kind of at the front right now. There is a competitor that has shared data, and we do see that there's activity with their drug. But this is really early days, like we are months or maybe -- I don't want to give a specific timeframe that we're behind. It's hard to know. But we're basically at the leading edge of this right now. So we're going to look at the data that's shared by our competitor. We'll look at the data that we generate. We'll 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, over the course of the year, have been able to share with our investors.

And your next question comes from the line of Ted Tenthoff with Piper Sandler.

Randy, congratulations and the whole team, I really appreciate the energy you guys are bringing. It's 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're moving here, but I want to understand sort of what the bar is to moving into registrational studies?

Maybe I'll take the second part of that and then pass back for the expectations for 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 Ib in PSP sooner. And then as we've said, look, all things going our way and pending some -- the 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 in the year 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. But Noah, back to you for the AD/PD view.

Sure. So look, we can't pre-release results, but we can -- I guess -- I can frame it. We shared data months ago about -- 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. Questions 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's 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 and obviously, these deep portions in the brain, which is represented by the CSF levels. And then the biomarker story, right? The biomarkers that we're seeing in healthy volunteers, is that like a once a finding that can't 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'd look at, and we hope that we can answer those questions at the meeting.

That's great. Really looking forward to all the other data and updates and progress this year.

And our next question comes from the line of Tyler Van Buren with TD Cowen.

This is Francis on for Tyler. Just one quick question on our end. Can you elaborate more on the pan-KRAS presentation at AACR and what we should expect to see from it as well as what competitors you're using?

Sure. Maybe I'll pass to Angela in a moment to talk a bit about that. And as you point out, we have a pan-KRAS program that, as we talked about, is moving ahead preclinically behind the KRAS G12D degrader that we 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 our goal in the pan-KRAS story is, of course, to remove the oncoprotein. So we differentiate from the ON and the OFF inhibitors and that we are removing the inhibitor. First and foremost, what's observed when -- as a regulatory mechanism when you treat with an inhibitor is compensatory up-regulation of KRAS. So this is something that's 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'll also share some of the mutant data as well in terms of the activity that we see, the antitumor activity. So expect to see those data as well. I hope that helps. And then we'll also share some syngeneic model data in the presence of an intact immune system. So I think that's also important with respect to the pan-RAS inhibitors with respect to our pan-KRAS molecule that's selective for KRAS versus pan-RAS. So we're not hitting HRAS that affects T cell activity.

And our next question comes from the line of Akash Tewari with Jefferies.

This is Manoj on for Akash. Just one on ARV-393. What are your yearly observations around the plasma exposure dynamics when ARV-393 is used in combo with [ glofitamab ]? Do you expect the need of any specific dose modifications on either 393 or [ glofitamab ] when used in combo in clinics? And also just one more. Do you see any increased interest for vepdegestrant after the recent Roche vepdegestrant data, especially in the earlier settings?

Maybe I'll try to rephrase it. I think the first question around 393 was do we -- in broad strokes was do we expect the need to do any dose modification for 393 with glofi? And maybe I'll let Noah comment on that in a moment, as we have had some data there late last year.

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've always believed. And so really no. I don't see a concern there. It certainly validates what we thought would be the case. And we hope that as we're out with our partners at Pfizer looking for a new partner to commercialize and preferably continue to develop that, that gives somebody the enthusiasm to do that. So no, I don't see that as an issue. But Noah, back to you on 393 and the potential for requiring dose modifications based on the data we've shown to date.

We don't really anticipate that we'll require dose modifications, although obviously, in an abundance of caution, we will have some dose escalation, to evaluate the combination. There's 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 glofi. But we, on the other hand, are not really seeing toxicity in those categories at all. So we will be advancing it cautiously, but don't anticipate dose modifications.

And your next question comes from the line of Yigal Nochomovitz with Citi.

This is [indiscernible] on for Yigal. So digging in more on LRRK2 and the biomarker data to be presented at AD/PD, can you tell us how this data will support the therapeutic hypothesis in PSP? And relatedly, what percent of PSP patients have elevated LRRK2? And are the same biomarker pathways relevant as in Parkinson's?

Yes. I'm going to pass that one pretty quickly over to Angela. We've had a few comments on the biomarkers, but Angela, please dig in.

Sure. So in PSP, there's been some recent publications showing that PSP, you see the same pathways increase. So you see elevated endolysosomal pathway engagement uniformly in progressive supranuclear palsy and LRRK2 elevation in that population. And so we expect within that population that we'll 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's clinically meaningful upwards around 20 to 30 points of the rating scale. So [indiscernible] and his colleagues at the University College London have shown that. So those data point to within that genetically defined population that that's the case. So we're -- any time you see an increase an elevated expression, you know for a PROTAC, that's the place you want to go. So PSP is a place where we can prove a concept within a year. So we're encouraged by that and remain very committed to this therapeutic hypothesis in PSP.

Got it. And separately, is there any update on selecting a third party for vepdeg?

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

And your next question comes from the line of Derek Archila with Wells Fargo.

This is Jacob on for Derek. Just one on LRRK2 from us. How should we be thinking about safety in the upcoming AD/PD readout? I know it's a relatively short study, but given the lung biology associated with LRRK2, do you think there's anything that would emerge or be looking for at this time point to give you more confidence in a longer duration study?

Yes, that will certainly be an important part of the readout, although as you talked about, it's still a relatively short duration. Noah, any other comments to make on safety?

Sure. So overall, the Parkinson's disease patient study that we'll be sharing have had 28 days of treatment for patients. We should keep it. So we're doing standard observations of patients to assure safety and assure that there are no findings. I'm not going to provide the data here on the call, but that's something to look at the meeting.

I think it's important to recognize that there is an on-target activity that you've identified in the lung of patients that requires tracking. And that's why anyone in this space will do things like LFTs -- I'm sorry, PFTs, pulmonary function tests and that could be following that up with high-resolution CT scans of the lung, if there's 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.

The -- I'll point out that it's so standard that there's something called the LIGHT initiative, which is a recommendation from experts about anyone who's dealing with LRRK2 targeting agents should be thinking about pulmonary function monitoring. So it's something we've incorporated into our study, and we'll provide updates at an appropriate meeting.

Got it. And on a related point, does dose selection read through directly from Parkinson's to PSP, do you think?

So we think it's very related. Let's look, what both diseases share here are they both have a toxic gain of function mutation that's associated with the disease or disease severity, right? And we understand how there is a pathway that is activated for -- 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. We have reason to believe that, that can direct benefit. We've done and we've shared earlier on different calls or publications that we have -- that we've been able to do seeding experiments in PSP that show that LRRK2 degradation can interfere with the propagation of 4R tau polymerization. And overall, we're going into this disease where no doubt LRRK2 has a central role. 4R tau is the pathological tau species that is almost pathoneumonic for the disease, right? I mean it's found in all patients with PSP on autopsy. And we know that we should be able to degrade this tau and prevent its accumulation.

And your next question comes from the line of Li Watsek with Cantor.

This is Daniel on for Li. We were wondering if you could shed a little bit of light on the ARV-393 data that you're planning to share in the second half of this year. You've already said that there are early evidence of efficacy. What gives you confidence in your data and the molecule itself that it is worth pursuing? And what kind of data, what type of end should we be expecting in your presentation?

Yes, I'll let Noah comment, but you're right to re-highlight that late last year, we said that even at doses that were below what we would have expected to produce an 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?

Yes. I don't think that we could guide specifically to those findings other than to say that if you're 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.

And your next question comes from the line of Kripa Devarakonda with Truist Securities.

This is Anna on for Kripa. A couple of questions from me. Jumping to the polyQ-AR degrader. Just given that SBMA is kind of a progressive disease and an untapped market, I know it's still an early program, but I was wondering if there's anything you can -- any guidance you can give in terms of the strategy here? And if there's anything you'll be testing that can kind of support any early signs of efficacy? And additionally, for 806, wondering if there's any early indications of any interest within pancreatic colorectal or lung cancer?

Yes, we'll do 027 first, Noah, Angela and then come back.

Yes. I'm going to start like almost at the end and then turn it back to Angela because it will have to do with clinical strategy, which is to say it's really early, so I can't answer the question in great detail there. But I'll 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 negotiation.

So we're 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're not going to rely on surrogacy, you're going to look at things like a 6-minute walk test or other functional measure of patient strength and their ability to not deteriorate, right? Because ultimately, these patients become bed-bound, they develop bulbar symptoms. They -- it does happen over the course of many years, but it is progressive and it's trackable. So that's the strategy. I think those are things we're looking at in that range. And I'll turn it to Angela.

Okay. So preclinically, we degrading the root cause of spinal and bulbar muscular atrophy, which is the polyglutamine repeated expanded androgen receptor in muscle is the goal of the program. And so we've been able to do that with ARV-027. And in the preclinical models, we see very robust reduction in muscle, and this leads to 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 we -- 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 I 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 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, et cetera, and then function. So...

Then maybe I'll rewind one more click before we get back to the KRAS question. But just as a reminder for everybody, this is the third AR degrader we put in the clinic. So Bavdegalutamide was our first years ago, one of the first -- the first PROTAC we put into the clinic, which had some solid signals of efficacy and good tolerability early on.

The next-generation AR degrader was 766, which we out-licensed to Novartis about 2 years ago for upwards of $1 billion in upfront and milestones. So I just want to make sure that's clear. AR is an area where we have deep expertise that we'll take advantage of. Now back to your -- the second question, which was around KRAS. Could you please remind me what the question was? I think it was about moving into PDAC, but what was the question, please?

Yes. Just any early indications within PDAC colorectal versus lung?

Any indications? You mean in terms of development direction?

Early indications of interest, yes.

So clinical trial, I don't think we're going to share where the program is, but we -- other than to say that it's moved faster than expected, which I think we just mentioned on the call. And beyond that, that we've already submitted for a conference. So we'll see what -- how this plays out.

So lots of interest...

And your next question comes from the line of Jit Mukherjee with BTIG.

This is Blake on for Jit. You started getting into this earlier, but how do you think about the pan-KRAS program coexisting with 806? And specifically, is pan-KRAS designed to cover other variants besides for G12D -- or could it with a clean therapeutic window eventually replace 806 entirely?

Yes, it's 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, maybe I'll make a high-level comment and then pass to Noah.

But in general, we've seen them as independent programs, right? There is certainly argument to say the specific G12D degrader could have a profile that better allows for combination with the therapies. That's 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'd like to add on how they could move forward?

Yes. I think that's the key point. We've 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 over-expression. So that's something that the pan-KRAS degrader would be poised to add. I think that, as you know, there's probably about 35%, 40% of pancreatic cancer patients have G12D, but that remain -- that leaves the other 55% or 50% of patients that have other variants.

So they're just in pancreatic cancer alone, there is a larger opportunity for a pan-KRAS than a G12D. Differentiation, we like the idea of potentially using them together, and we like the idea of being able to really overcome resistance pathways. So that's 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 Flyn with Morgan Stanley.

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've partnered others. So how are you thinking about partnering versus retaining rights on each of these?

Yes, it's a great question, Terence. Thanks. And I think stepping up a little bit, right? What we've done here is we've got a platform and a team that has produced some really high-quality clinical candidates that we think could be differentiated. We've got -- I was about to say 3 in the clinic, but as we announced this morning, 4 now just very recently with 027 going in and 6723 for HPK1 entering the clinic later in the year. So that's 5, right? That is a lot for a small biotech to take on. And so that's what -- that's helping the strategy shift from talking about the fantastic platform that we have, to adding on the need for each program to be 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 vep back in 2021. I mentioned the luxdegalutamide deal from Novartis in 2024. And so that -- so partnering certainly has been an important part of our strategy in the past and will be going forward in the future. As far as program by program, 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'll probably save any more specific comments for the future, but it's certainly on our mind to think about how we can best move forward each program.

And your next question comes from the line of Paul Choi with Goldman Sachs.

This is Daniel on for Paul. So two questions for us on the [indiscernible] muscular dystrophy program. So could you guide us on what's the expected time line for the next planned data cut? And what type of data should we expect from the healthy volunteer study that could help derisk the program, including that could there be muscle biopsy for measuring intracellular AR concentrations?

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

A classic healthy volunteer study, but it has a component that 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'll be looking at PK, there is a PD component here that is very strong that we don't have in many other studies. The PD here is we're 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's 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'll also be doing those biopsies. We just -- I don't think we can guide right now to when we'll have those results, but we -- since we just recently dosed our first patients, but we'll keep you updated.

And your next question comes from the line of Michael Schmidt with Guggenheim Securities.

This is Sarah on for Michael. I wanted to circle back to the pan-KRAS degrader. So you've spoken a lot about the preclinical data that you've seen, but I wanted to ask when you might expect it to be IND-ready? And then as well what your current view on the opportunity is in pan-KRAS given that I believe we've recently seen first clinical data from another pan-KRAS agent.

Yes. We haven't talked yet about the exact timing for the clinic for pan-KRAS. So I won't give that guidance quite yet. But although as you can see, we're continuing to put out data at multiple conferences there. So it's moving ahead well.

In terms of the opportunity for pan-KRAS, you're right that there's other programs in the space for sure. Going back to the questions from -- especially from John at the start, it's a place where we're 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'd like to add?

I think we've said what we can on the pan KRAS opportunity for now.

And your next question comes from the line of Sudan Loganathan with Stephens Inc.

First, I wanted to say congrats to Randy for his continuing at Arvinas with this new role. Looking forward to working with you and the team as Arvinas kind of takes on this plethora of exciting new projects.

My first question is, as you move towards initiating the Phase Ib 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 time lines for the PD program? And then finally, can you outline how you're thinking about the trial design evolution in both PSP and PD endpoints, enrichment strategy, duration and what constitutes registrational credibility data set in each indication?

Right. Okay. Thanks for the multiple questions there, and thanks for the comments. Look, to get the Phase Ib started, it's 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're moving forward there and all is on track. With respect to data for PD versus PSP, Noah, I'll ask you to comment there in terms of how the development could affect each program.

Right. So in terms of -- the question was -- there are two questions there, right? What is -- how can the regulatory feedback impact both programs? And then there were questions about enrichment strategy and things like that. So there's no -- we're just filing the IND, right?

So even though we did all this work outside of the U.S., we haven't interacted with the FDA. And so there's an opportunity here. And I think it's 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 with the first trial and opening up this dialogue because the FDA knows a lot about PSP and PD, and we're hoping to get really good feedback. There are -- the risk-benefit of drugs developed in PSP and Parkinson's disease are different. So we're going to start off with PSP. The intent is to eventually have a conversation about Parkinson's disease also. I don't think that we're going to go into details on a call here about the Parkinson's development strategy because we've only guided towards what we're 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 conversations around Parkinson's disease.

You raised the question about what could enrichment strategy look like. So in PSP, it isn't going to be a biomarker or a biomarker enrichment, but there's going to be a patient focus. So we'll be looking at patients that have PSPRS, the more severe and symptomatic form and aggressive form of the disease, I don't remember exactly, but I think they probably represent about 40% of patients with PSP. That would be our focus for enrollment in the study. And we are going to develop a strategy, and we'll guide eventually towards how this gets expanded into the broader population or even if that's necessary. In terms of Parkinson's disease, I think what folks can start anticipating is that we're 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 investment and a lot of publication such as the PPMI.

So the Michael J. Fox Foundation Funded Parkinson's Progression Initiative. And we're 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're seeing in our Parkinson's disease study. So we're 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 these biomarkers to prognosis in Parkinson's disease. And think of this as moving ahead into -- we'll 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 I can't offer more guidance than that, but it gives you a sense of where we could be headed.

And our final question comes from the line of Etzer Darout with Barclays.

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This is Luke on for Etzer. For 102 and PSP, since PSP like doesn't really have any disease-modifying therapies, everything just needs to treat symptoms. What kind of clinical endpoints, even early ones, are you going to be looking for? And what are regulators looking for to really support that move into a registrational trial later this year? And for vepdeg, I guess, in kind of with a worst-case scenario, if you don't have a collaboration lined up by the PDUFA, do you have a backup commercialization plan?

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

Yes. 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'm sorry, our submission quality study down the road. It's obviously going to be used in the Phase Ib, which is not going to be powered to evaluate that fully, but look for -- but it can identify trends between what's 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'll be doing similar type of work in the PSP studies, even the Phase Ib is looking at things like eye movements or other type of indicators or surrogacy for function, right? It's a rapidly evolving space where there are some markers 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 there are things that we're incorporating into our studies because we think they could be very revealing.

That concludes our question-and-answer session. I will now turn the call back over to Randy Teel for closing remarks. Randy?

Thank you very much, operator, and thanks all on the call for all the good questions. I'll close by just saying that now that we've positioned ourselves as a Phase I 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.

That concludes today's call. You may now disconnect.

Thank you for standing by, and welcome to Arvinas Third Quarter 2025 Earnings Call. I'd like to remind everyone that this call is being recorded. [Operator Instructions] Thank you.

I would now like to turn the call over to Mr. Jeff Boyle. You may begin.

Good morning, everyone, and thank you for joining us. Earlier today, we issued a press release with our third quarter 2025 financial results, which is available in the Investor and Media section of our website at arvinas.com.

Joining the call today are John Houston, Arvinas' Chief Executive Officer, President and Chairperson; Noah Berkowitz, our Chief Medical Officer; Angela Cacace, our Chief Scientific Officer; and Andrew Saik, our Chief Financial Officer.

Before we begin the call, I'll remind you that today's discussions contain forward-looking statements that involve risks, uncertainties and assumptions, which are outlined in today's press release and in the company's recent filings with the U.S. 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 today's call as well as an updated corporate deck will be available on the Investor and Media section of our website.

And now I'll turn the call over to John. John?

Thanks, Jeff. Good morning, everyone, and thank you for joining us today. As highlighted in our third quarter earnings release issued earlier this morning, this has been a dynamic and productive period for Arvinas marked by meaningful progress across both our corporate initiatives and clinical development programs.

During the quarter, we announced significant developments, both in our pipeline and enhancing efficiency across our organization, all geared at driving value from our portfolio to deliver benefit to patients and value to shareholders.

Our deep pipeline provides multiple opportunities for value creation, as we work to address the largest areas of significant unmet need in oncology and neurology. We have entered the beginning of a data-rich period with multiple readouts from our early-stage clinical programs, including recent clinical data from ARV-102, our LRRK2 degrader and preclinical data from ARV-806, our KRAS G12D degrader.

We also presented the first preclinical data from ARV-027, our promising new clinical candidate that targets polyglutamine-expanded androgen receptor or polyQ-AR, the root cause of spinal bulbar muscular atrophy or SBMA.

In addition, we also anticipate sharing preclinical data from our BCL6 degrader, ARV-393, at the ASH Conference in December and preclinical data from our new HPK1 degrader, ARV-6723 later this week at the SITC Conference. Noah will also share a promising update from our ongoing Phase I monotherapy trial with ARV-393 later in the call today.

We have a strong track record of translating promising preclinical results into important successes in the clinic with a platform that has consistently shown its versatility and promise. We continue to build on that record with multiple ongoing and planned clinical trials in areas of high unmet need, a pipeline of high-value assets, a strong research engine and cash on hand into the second half of 2028 that gives us financial and strategic flexibility.

In September, we announced that we and Pfizer will jointly select a third party for the commercialization and potential further development of vepdegestrant with the goal of rapidly bringing it to patients, if approved. Vepdeg's new drug application is currently under review by the FDA, and the agency has issued a PDUFA action date of June 5, 2026. Our goal is to have a partner in place before this date to make sure that Vepdeg, if approved, is launch-ready as a potentially best-in-class therapeutic option for ER-positive/HER2-negative advanced breast cancer in the second-line ESR1 mutant setting of ARV-393.

Noah?

Thanks, John, and good morning, everyone. I'll begin with ARV-102, our oral PROTAC LRRK2 degrader, specifically designed to be brain penetrant. Enthusiasm from key opinion leaders and investigators, most recently about the biomarker data we presented at MDS, has further strengthened our belief that this is a truly differentiated program.

Let me begin with some background about ARV-102's target and what has come into focus as potential diseases of interest. LRRK2 is a multi-domain protein with 3 key functions of kinase, GTPase and scaffolding activities. These activities help it regulate endolysosomal trafficking.

When LRRK2 expression or activity is elevated, it disrupts lysosomal function, impairing the clearance of aggregated pathologic proteins that would normally be degraded through the pathway. Degrading LRRK2 may restore endolysosomal homeostasis and provide therapeutic benefit in disorders characterized by lysosomal dysfunction.

Unlike inhibitors that only inhibit LRRK2's kinase activity intermittently, ARV-102 eliminates the entire LRRK2 protein. This is important because the 3 key functions, not just kinase activity, may be linked to neuroinflammation and lysosome dysfunction.

Increased activity, scaffolding and expression of LRRK2 have been implicated in the pathogenesis of neurological diseases, including idiopathic Parkinson's disease, a prevalent neurodegenerative disease, and progressive supranuclear palsy or PSP, a rapidly progressing neurodegenerative disease that is typically fatal within 5 to 7 years of diagnosis. We believe that eliminating all 3 functions of LRRK2 through PROTAC-mediated degradation offers the potential for deeper and more durable therapeutic benefit versus traditional inhibitors.

At the MDS Conference last month, we were pleased to share data from 2 ongoing Phase I clinical trials with ARV-102: one in healthy volunteers and one in patients with Parkinson's disease. Both trials included single ascending and multiple dose portions.

ARV-102 is generally well tolerated in both trials. In the healthy volunteer study, ARV-102 was well tolerated at single doses up to 200 milligrams and multiple daily doses up to 80 milligrams with no discontinuations due to adverse events or serious adverse events observed in the study population.

In the Parkinson's disease study, single doses of ARV-102 at 50 milligrams or 200 milligrams, were well tolerated with only mild treatment-related adverse events, which were generally lumbar puncture procedure related and with no serious adverse events. Pharmacokinetic data were also excellent across both trials. ARV-102 demonstrated dose-dependent PK in both periphery and the CSF, the latter indicating brain penetration.

In terms of pharmacodynamic effects in healthy volunteers, repeated daily dosing of ARV-102 led to LRRK2 reductions of up to 90% in peripheral blood mononuclear cells or PBMCs and more than 50% in the CSF. Repeated daily doses of ARV-102 resulted in reduced concentrations of phospho-Rab10T73 in PBMCs and urine concentrations of BMP. Both of these are important biomarkers for modulation of the lysosomal pathway downstream of LRRK2.

In patients with Parkinson's, we showed that single doses of ARV-102 resulted in median PBMC LRRK2 protein reductions of 86% with the 50-milligram dose and 97% with the 200-milligram dose. Perhaps most interestingly of all, in healthy volunteers treated with 80 milligrams of ARV-102 once daily for 14 days, unbiased proteomic analysis of CSF showed decreases in many lysosomal pathway markers such as GPNMB and neuroinflammatory microglial markers like CD68. A recently published proteomics analysis showed the same panel of biomarkers was elevated in patients with LRRK2-related Parkinson's disease.

We are aware of inhibitor data showing the movement of some of these biomarkers, but only in patients with Parkinson's disease and only after at least a month of treatment to engage the intended disease pathway even in healthy volunteers where the biomarkers would not be expected to be elevated and after only 14 days of treatment is direct evidence that our approach is working as designed. This rapid pathway biomarker response suggests that our total protein degradation approach may have best-in-class impact on underlying disease processes compared to kinase-only targeting inhibitors.

We believe that in totality, our data to date set a very high bar and further strengthen our belief in the promise of ARV-102. The multiple dose cohort of our trial in Parkinson's patients is ongoing, and we look forward to sharing data, including CSF LRRK2 degradation data, at a medical conference in 2026. We also intend to initiate a Phase Ib trial in patients with PSP in the first half of 2026.

I'll now turn to ARV-393, our investigational oral PROTAC designed to degrade B-cell lymphoma 6 protein or BCL6. BCL6 is a previously undrugged transcription factor, a master regulator of multiple cellular processes during B-cell development, including proliferation, survival and apoptosis.

Altered BCL6 activity has been implicated as an oncogenic driver in several subtypes of non-Hodgkin lymphoma, making it an exciting therapeutic target with initial clinical validation emerging. With its iterative activity, ARV-393 potently and rapidly degrades the BCL6 protein, which is critical to overcoming its rapid resynthesis rate and sustaining antitumor activity.

Preclinically, ARV-393 has shown robust in-vitro potency and in-vivo efficacy as a monotherapy. And earlier this year, we presented preclinical data showing enhanced antitumor activity with ARV-393 in combination with 5 classes of small molecule inhibitors in models of aggressive diffuse large B-cell lymphoma or DLBCL.

Our development plan for ARV-393 includes combination strategies in DLBCL. And at next month's American Society of Hematology Annual Meeting, we will present new preclinical data showing the combinability of ARV-393 with glofitamab, a CD20xCD3 bispecific antibody, and an emerging standard of care for DLBCL. BCL6 degradation has the potential to increase CD20 expression, which provides rationale for the exploration of ARV-393 with CD20-targeted agents and in the context of low or loss of CD20 expression. We intend to initiate a combination trial with glofitamab next year and look forward to updating you on our progress.

Turning to our clinical progress to date, enrollments in our Phase I monotherapy trial is ongoing. This is a first-in-human dose escalation trial, and we have not yet achieved the predicted efficacious exposure level. However, this morning, I'm pleased to report that even in exposure levels below those predicted to be efficacious, we have already seen responses in early cohorts in both B- and T-cell lymphomas.

We also see evidence of robust BCL6 degradation and the safety profile of ARV-393 has supported continued dose escalation. We are very pleased with these early data, which we believe support an emerging and differentiated therapeutic benefit of ARV-393. We look forward to sharing additional data from the Phase I trial at a medical congress in 2026.

With that, I'll now turn the call over to Angela. Angela?

Thanks, Noah, and good morning, everyone. I'm pleased to share compelling preclinical data we recently presented that reinforces our confidence in our ability to deliver differentiated treatments across our oncology and neuroscience pipeline. I'll begin with ARV-806, our novel PROTAC degrader targeting KRAS G12D. KRAS G12D is a well-characterized oncogenic driver associated with poor prognosis and recalcitrant to standard treatments across several major tumor types, including pancreatic, colorectal and non-small cell lung cancers. There are currently no approved targeted therapies for KRAS G12D.

At the Triple Meeting in October, we shared preclinical data highlighting the high potency of ARV-806 and its clear differentiation from both KRAS inhibitors and degraders currently in the clinic. These preclinical data showed dose-dependent robust antitumor activity with regressions across preclinical models of KRAS G12D mutant cancers.

ARV-806 forms productive ternary complexes with the on and off states of KRAS G12D, demonstrated in vitro picomolar potency with near complete degradation and high selectivity. ARV-806 demonstrates antiproliferative activity approximately 25x greater than KRAS inhibitors and the leading clinical stage degrader. Importantly, ARV-806 induces durable degradation greater than 90% for 7 days after a single dose with efficacy across pancreatic, colorectal and lung cancer models. We also presented early and very promising preclinical data from our oral pan-KRAS degrader and look forward to sharing more as this program advances.

We are rapidly enrolling a Phase I clinical trial of ARV-806, reflecting strong interest from clinical investigators and underscoring the high unmet need for effective KRAS-targeted therapies. We look forward to sharing initial clinical data from this trial next year.

Finally, I'd like to briefly mention updates from 2 other promising programs that you'll hear more about in 2026. First, at World Muscle in October, we shared exciting preclinical data for ARV-027, a PROTAC degrader designed to target polyglutamine-expanded androgen receptor or polyQ-AR in skeletal muscle. This degrader will be developed for patients with spinal and bulbar muscular atrophy or SBMA, a rare genetically defined neuromuscular disease with no approved treatments and significant unmet need.

Second, this week at SITC, we will introduce our first immuno-oncology focused PROTAC degrader, ARV-6723. ARV-6723 targets HPK1, which functions as a negative regulator of T-cell signaling causing tumor microenvironment immune suppression and could be relevant for numerous solid tumors.

Our preclinical work to date suggests that degrading HPK1 leads to differentiated biology versus HPK1 inhibitors and anti-PD-1 therapies. We anticipate beginning first-in-human studies for ARV-027 and ARV-6723 in 2026. As we begin those studies, we look forward to providing full updates on the unmet need for each disease, the rationale for each high-impact target and why we believe that our PROTAC degraders will represent highly differentiated therapies for patients.

With that, I'll turn the call over to Andrew to review our quarterly financial information.

Thanks, Angela, and good morning, everyone. I'm pleased to provide financial highlights for the third quarter ended September 30, 2025, and expand on our approach to capital allocation, capital returns and development strategy. As a reminder, detailed financial results for the third quarter are included in the press release we shared this morning. I'll begin by briefly touching on some key financial highlights for the third quarter of 2025.

At the end of the third quarter, we had approximately $787.6 million in cash, cash equivalents and marketable securities on the balance sheet compared with $1.04 billion as of December 31, 2024. Revenue for the 3 months ended September 30, 2025, totaled $41.9 million compared to $102.4 million for the 3 months ended September 30, 2024. The decrease of $60.5 million was driven by the Novartis License Agreement, which was entered into during the second quarter of 2024 with revenue recognized through the end of 2024, offset by the recognition of a milestone payment from Novartis of $20 million this quarter as part of the same agreement.

General and administrative expenses were $21 million in the third quarter, compared to $75.8 million for the same period of 2024. The decrease of $54.8 million was primarily due to a decrease of $43.4 million from the termination of our lease of 101 College Street in August 2024, a decrease in personnel and infrastructure-related costs of $7.3 million and professional fees of $3.6 million. Total non-GAAP G&A for the quarter was $14.6 million, compared with $64.8 million in the prior year.

Research and development expenses were $64.7 million in the third quarter compared to $86.9 million for the same period of 2024. The decrease of $22.2 million was primarily driven by a decrease in the vepdeg program of $5.4 million, a decrease in the luxdeg program of $4.7 million and a decrease in personnel expenses and non-program-specific expenses of $15.1 million, offset by an increase in the KRAS program of $4.3 million.

Total non-GAAP R&D for the quarter was $56.9 million compared to $73.2 million in the prior quarter. Total non-GAAP expenses were $71.5 million in the quarter. We expect expenses to continue to decline as we work with Pfizer to ramp down our spend on vepdeg and as our cost reduction programs take full effect. Our goal is to continue with a quarterly run rate spend below $75 million, which will allow us to manage non-GAAP expenses below $300 million in fiscal year 2026.

In September, we announced that our Board had authorized the repurchase of up to $100 million of our outstanding common stock. This authorization underscores the Board's confidence in our long-term strategy and its belief that our current share price is undervalued relative to our long-term opportunity.

As of the end of September, we have bought back approximately 2.56 million shares at an average share price of $7.91 per share. Details of our stock repurchase program can be found in our 10-Q. At the same time, we announced further cost reductions that allowed us to maintain our prior cash runway guidance into the second half of 2028.

We remain committed to investing in areas that will maximize shareholder value as we move towards important catalysts in the coming months. In addition, we will continue to look at ways to reduce costs and increase efficiency while continuing to focus on our goal of progressing our very promising early pipeline.

With that, I'll turn the call over to John for closing remarks. John?

Thanks, Andrew. We are focused on continuing to deliver innovative and differentiated assets in areas of high unmet need. We are operating with scientific rigor and building on our proven track record of success from discovery to clinical to collaborations. We have a deep pipeline with multiple clinical candidates for near-, mid- and long-term value creation and the potential to be differentiated with critically important therapies for patients.

Arvinas is entering a pivotal phase in its growth trajectory. Our clinical pipeline offers a rich set of catalysts throughout the balance of the year and into 2026 with multiple study initiations and data readouts anticipated across our neuroscience and oncology franchises.

With our PDUFA date now confirmed for next year, we are approaching an historic moment with the potential for the first ever approval of our PROTAC therapy. We are well positioned to deliver significant value for our shareholders, our partners and for the patients we serve.

With that, I'll turn the call over to Jeff to begin the Q&A portion of the call. Jeff?

Before I turn the call over to the operator, I'm going to ask that you limit yourself to one question per cycle to make sure we're able to give everyone the appropriate time. You can feel free to join the queue afterwards for a follow-up question. So with that, operator, can you please open up the queue?

[Operator Instruction] Your first question comes from the line of Etzer Darout with Barclays.

Just a quick question on the BCL6 degrader program. Just we're going to see some updated data from [indiscernible] at ASH. I just wanted to -- if you could comment on points of differentiation there that they're doing [indiscernible] and if you could just talk a little bit about the dosing profile that you envision for the molecule and any areas you could potentially differentiate longer term of that molecule?

Great. Thank you so much for the question. And yes, we're very excited about our BCL6 program, and we do believe that we have a profile that will differentiate itself as the compound continues to be developed. Noah, do you want to add some comments?

Sure. Thanks, John, and thanks for the question. Yes. So indeed, we -- and by the way, you broke up a little bit, but if it had to do with dosing -- yes and differentiation. So the drug is being dosed once daily in oral drug. Differentiation has to do there on a couple of different levels.

Number one is that we've already demonstrated and will continue to demonstrate upcoming at ASH some kind of, I guess, a differentiated profile for combinations of a drug and even for monotherapy preclinically. So we noticed that we can achieve complete responses in various models versus tumor growth inhibitions that are seen with some competitor -- or yes, some competitor drugs.

In terms of our program, we're focused in -- we've said pretty explicitly that we're focused in monotherapy for AITL, and we're interested in developing the combination with the bispecific for DLBCL. So there's, at this point, several competitors that have entered the market. One little -- one of them that has already reported data, the others seem to have just filed their IND. We believe that -- and we've shared data here that we have monotherapy activity in T-cell and B-cells. That has not been reported by the competitor that's already reported out some B-cell malignancy responses. And so that's a point of potential differentiation in the future.

Your next question comes from the line of Yigal Nochomovitz with Citi.

This is Caroline on for Yigal. On your LRRK2 program, can you tell us about the first types of signals you'd be looking for in the Parkinson's disease MAD Phase I? And how long do you hypothesize you'll need to dose for the PK effects that you've already observed in healthy volunteers in Parkinson's patients to translate to clinical benefit?

Yes. No, thank you, Caroline. Great question, and I'll hand back to Noah.

Thanks, John and Caroline. Thank you for the question. So yes, we're pretty excited about what we've seen so far with our LRRK2 degrader and the reception that we received at a recent conference at MDS.

So as you state, we are currently moving pretty aggressively through a Parkinson's disease Phase I study that has 28 days of dosing. We expect that this will generate data that's principally biomarker related. And -- but we may also start to collect a little clinical efficacy data that's not expected with 28 days dosing.

Now what we've shared is that we've already been able to demonstrate pathway engagement in ways that competitor LRRK2 inhibitors have been -- at least have not reported to date. So we know in healthy volunteers, we can impact endolysosomal trafficking and also neuroinflammation, at least through microglial pathways -- mediated pathways.

And so now when we look at our Parkinson's disease patients, the idea would be we have patients at baseline who have more than 2, maybe even 3x the baseline level of LRRK2 in their CSF. There's much more activation of these pathways. And it will be important to see how much the degradation that we've already reported out in healthy volunteers, we can recapitulate now in this Parkinson's disease population and look at that pathway engagement. So we've guided to an update on those pathway markers next year, relatively early next year.

And -- but I think that the next step for clinical data will be when we can have more than 28 days of treatment. So for that, we're working our way through the chronic tox study. And so you'll see as we file our IND next year that allows us to move into PSP that we're prepared to continue with chronic treatment of patients, and that will be an opportunity for us to demonstrate the clinical benefits in diseases like PSP and potentially Parkinson's.

Your next question comes from the line of Michael Schmidt with Guggenheim.

This is Sarah on for Michael. I just wanted to ask on your KRAS G12D. So you've mentioned before and we've seen evidence for KRAS amplification as a mechanism of resistance to inhibitors. So -- and the fact that potentially with the iterative activity of a PROTAC might be able to overcome that. So I just wanted to ask if you have any plans to potentially test ARV-806 or maybe even eventually a pan-KRAS in the clinic in a KRAS amplified population.

Yes. Great questions, Sarah. I'm going to ask both Angela Cacace, our CSO, and Noah to give you 2 parts to that answer.

Great. Thank you for the question. We have been studying certainly our G12D degrader ARV-806 in resistant setting. And we look after -- we see amplification of KRAS G12D, and we see that we durably repress KRAS in all conditions. And then for our pan-KRAS degrader, we've also been studying the amplified setting, the wild-type amplified setting. And in the wild-type amplified setting, we're gratified to see some early data that shows that we see very nice tumor growth inhibition. And in cases of PDX models, we've also seen regression. So we're advancing very quickly with our pan-KRAS degrader program, and I'll turn over to Noah for the clinical perspective.

Thanks, Angela. And so Sarah, to your question about amplification and what we've seen. So we specifically, right, in the ongoing Phase I study, we exclude patients that have been treated previously with KRAS inhibitors. So that's not something we're going to see in the dose escalation portion of our study, and you would understand why we would want the cleanest signal. We've made that choice as really anyone would.

But we have learned over the past year, and this is really data that's generated outside of our company, right, that as data -- we see many reports of amplification being a principal mechanism of resistance after patients have been exposed to KRAS inhibitors. So we've obviously -- as Angela has pointed to, we've done work in our models to show that this creates a great opportunity for us moving forward. [Audio Gap] expect some updates over the course of the next year in terms of if we want to expand our targeting or thinking in this regard. It certainly is compelling science.

Your next question comes from the line of Derek Archila with Wells Fargo.

This is Hal calling in for Derek from Wells Fargo. So I guess we have a question on the ARV-102. For the SAD data, do you see any CSF degradation for LRRK2? And then for the MAD data next year in 2026, just wanted to see do you have any expectations? Is more than 50% in healthy volunteer you wanted to repeat or just some expectation for us to set up?

So thanks for the question. Absolutely. So Noah, do you want to take that?

Sure. Yes. So -- but I think we've guided to this. Essentially, we will provide our LRRK2 degradation data when we've completed the MAD in the Parkinson's disease patients. And that's basically what we're going to guide to for next year.

Your next question comes from the line of Jeet Mukherjee with BTIG.

Just coming back to ARV-806. Based on your learnings from other G12D inhibitors and degraders in development, are there any molecular features or attributes that may be correlated to or linked to the GI tolerability and elevated liver enzymes we've seen with some of these molecules? And if yes, does ARV-806 avoid those features?

Yes. Thanks for the question. I mean I think certainly, the -- our G12D compound has a very exciting profile. Obviously, the molecule is different from other G12D inhibitors. Maybe, Angela, do you want to talk to what you think might be some of the kind of the features that give the profile that we see?

Sure. So as we described, our ARV-806 G12D PROTAC really does have some very nice features from a molecular perspective. It binds to both the on- and the off-state and is 25x more potent than all mechanisms that are currently in the clinic that we've tested to date.

But given what we've seen with the clinical degrader, we're also several orders of magnitude more potent at engaging the target and degrading the target durably. So with that in mind, we expect to have greater potency which should translate clinically. And I'll let Noah go ahead and take the liver and other questions.

Yes. So I think our strategy there right now based on the science that's available is to win on that potency issue, meaning we already know from a competitor's degrader that they were limited in their ability to escalate their dose because of transaminitis that was seen. So the fact that we can engage our target at much lower concentrations suggests that we have the potential not to run into those types of toxicities and still get the significant degradation we're shooting for.

So we're looking for more than 80% degradation of our target. We could probably do significantly better than that. And we'll provide updates as we go through our dose escalation cohorts.

Your next question comes from the line of Sudan Loganathan with Stephens Inc.

This is [ Keith Alve ] on behalf of Sudan. I got a quick one on ARV-806. Are you all evaluating how PROTAC medicated KRAS G12D degradation might complement or differ from combination strategies like the cetuximab pairing seen with Verastem's KRAS12 G12D inhibitor?

Yes. So preclinically, we have evaluated combination with anti-EGFR inhibitors like cetuximab. And so we think this is a big advantage because we have a selective approach to degrading G12D KRAS. We combine very well in that case, and we'll be sharing the preclinical data that we've generated in those combinations within the year. Noah?

And yes, I would just add that there certainly are accumulating evidence that combinations of inhibitors with chemotherapy, but also, as you mentioned, with an EGFR inhibitor can lead to cumulative tox which may be limiting for this drug, but creates the -- for this set of inhibitors, but that creates an opportunity for us, especially, right?

Because going back to this potency argument, if we can get our drug on board, which right now requires weekly -- once-a-week dosing and may allow us eventually to also get to once every 2-week dosing, and we can do this with lower dosing -- lower doses, and we might not achieve the same type of cut tox from combinations, that opens up a whole set of opportunities to generate the better benefit risk profile.

So, again, we have to get through our monotherapy dosing. It's moving very fast. And we're hoping that we can get into our combinations next year already, but more to follow on that.

And just to briefly add that tackling the pan-KRAS mechanism is a challenge in that combination setting largely because they're also hitting and in HRAS. And that becomes a big challenge for adding on an EGFR-based mechanism. So our KRAS G12D degrader would avoid that.

Your next question comes from the line of Tyler Van Buren with TD Securities.

This is Francis on for Tyler. So for the BCL6 asset, what combination partners do you believe are most exciting? And where do you think it's most likely to exist in the lymphoma treatment paradigm if successfully developed?

Thanks for the question. Yes, there's a lot of potentially exciting combinations that we can carry out with BCL6. I'll ask Noah to maybe give an overview of where we're thinking.

Sure. So we've shared data about the ability to combine this drug, which uses an orthogonal approach to many of the agents that are currently approved in the B-cell malignancy setting. And we see just beautiful synergies and combinability with -- preclinically with EZH2 inhibitors, BTK inhibitors, BCL2 inhibitors, and also anti-CD20 agents. So those -- that's a whole set of opportunities for combination.

We recognize that the way the field is evolving, there's going to be a significant outsized role for bispecifics targeting CD20 in the -- eventually the first-line setting, but in the second- and third-line setting as well for large B-cell lymphoma. We think that's our -- we want to be laser-focused as a company, and we recognize that's a significant opportunity where we can combine these therapies that have non-overlapping toxicities.

Ours -- we first have to identify a toxicity. But obviously, there is CRS with the bispecifics, and we should be able to combine favorably with those. And that would be our plan. That's why we've announced that next year, we expect to be moving ahead in our Phase I study with combinations with bispecifics.

Your next question comes from the line of Li Watsek with Cantor Fitzgerald.

A strategy question for me. It looks like you're moving more programs into the preclinical clinical settings and then maybe deepening your footprint in neuromuscular space and expanding into I-O. So just curious, number one, your BD strategy here, given that you got 5 programs. And then two, your approach to resource allocation.

Yes. So thanks for the question. Clearly, the last several months, the company has done a significant reset, obviously, with the decision along with Pfizer to find a new partner or out-license vepdegestrant allowed us to focus on the rest of our pipeline. And obviously, KRAS G12D, LRRK2, BCL6 are next in line assets that are in Phase I heading fairly rapidly to Phase II. And then we have 2 programs behind that that should be in the clinic relatively soon: one in SDMA, which we can talk to and the other HPK1, which is an I-O. And we believe that gives us an array of different programs across oncology and neuro. And yes, HPK1 has a huge amount of potential in immuno-oncology.

So we're excited about that. It gives us a lot of flexibility. It gives us a lot of choices. And as ever in the history of -- the whole history of Arvinas, those choices have also included appropriate and well-placed BD opportunities. So we'll always be open for that. We think that some of our targets that really lend themselves to BD opportunities. And right now, as we stand today, all of our portfolio is fully owned by our vepdegestrant, and we did do a great deal with Novartis on luxdegalutamide.

So yes, we move forward with a lot of confidence, and we have some really great exciting data that should be coming out over the next several months and year, and we'll be able to position our portfolio the best way we can. And that could include selective partnering.

Your next question comes from the line of Srikripa Devarakonda with Truist.

Maybe a follow-up question to the previous one. With nearly $800 million in cash and runway to second half of '28, not just in terms of the time line -- the run rate time line, but in terms of what studies you can get through with this cash would be helpful.

And also, as you are advancing your pipeline, do you continue to -- do you expect to continue PROTACs in both oncology and CNS? Or at this point of time, do you think there is a need to prioritize from a therapeutic area perspective?

Thanks for the question. I'll certainly hand over to our CFO, Andrew, to talk about the first half of that question. But in terms of the balance, yes, the company right from its beginning has been an oncology company and the very -- I think it was the third target we worked on was a neuroscience target. So we've been in neuroscience right from the beginning of the company's inception.

And we think PROTACs and the ability to get brain penetrant PROTACs gives us a huge potential advantage in neurodegenerative diseases. So we want to explore that as we go forward with our programs like LRRK2. We'll also be -- now we're very excited to be looking at neuromuscular target like SBMA. And we do still think we've got a lot of differentiation in the oncology space.

So although it may sound like 2 very radically different therapeutic areas, the insights and the ability to use PROTACs in those areas really does allow us to, I think, unlock a lot of differentiated opportunity. So we're going to continue with that for now. We are open and always looking for other opportunities as well. But right now, and I'll hand over to Andrew, we're well placed to fund the programs that we have, certainly after we did the reset that we did. Andrew?

Yes. Thanks, John. So the way I think about capital allocation for at least the next year or 2, the company has had significant spend on the vepdegestrant Phase IIIs the last several years. You're going to see those costs start to ramp down. And what's going to happen is that those costs are going to be replaced by a series of Phase I early phase studies, right? So we're making a bet on the early-stage programs.

We love them. We can't obviously right now tell you which ones we're going to take through on our own and which ones we're going to license. We're going to push on all of them. We think that many of them are highly, highly promising. And we'll be making decisions on those as we go through the development pipeline. So we look at these programs all the way out.

Obviously, we've known our programs for a long time. So they've been incorporated into our spend even before we announced that they were coming into the clinic. So this is not a surprise to us. And we're just delighted. So we're going to continue pushing on our Phase I programs, and we'll make decisions as we go through based on which ones we think make the most sense for us to keep and which ones make the most sense for us to partner potentially.

Your next question comes from the line of Tazeen Ahmad with Bank of America.

Just as it relates to 102, just given the current data that you have in biomarkers, how do we think about the translatability of those into clinical endpoints as it relates to PD? And then I just wanted to know about once you show the PD data in 2026, what do you think is going to be your area of focus that will allow you to support the advancement into a Phase Ib study into PSP?

Thank you. Great question. Noah?

Sure. Thanks, John, and good to hear from you, Tazeen. So yes, 102, it's just such an exciting story for us because just to review and build off of what John and Andrew just said, if you think back, we've been working in oncology, but also developing neuroscience. And here, we are on the heels of a positive registration study for [ VEP-2 ], out-licensing of luxdegalutamide, an AR degrader to Novartis, and we're advancing 2 oncology drugs.

And here now, we have ARV-102 that -- where we've shared some incredible results recently that drive us in this direction for PSP and possibly for Parkinson's disease. So for years -- over the past many years, there's been tremendous investment in the Parkinson's disease community and the PSP community to understand what are the pathways that drive this neurodegenerative disease.

And so there's a large biomarker study called PPMI, and this looks at the natural progression of Parkinson's disease. And it has demonstrated that there are markers such as GPNMB, IAB1 -- IBA1 and also CD68, a series of cathepsin. So markers that are predictive of progression of disease because they are driving neuroinflammation and also driving neurodegeneration because of mistrafficking of proteins. And so that's because of endolysosomal function. So these markers are all elevated in the disease.

And we just reported out a study at MDS that drew tremendous excitement from investigators or scientists more broadly because we showed that in healthy volunteers, we were able to reduce these biomarkers, right? And now we're running the Parkinson's disease study that is looking at all of these biomarkers and we expect that if we degrade LRRK2 as much as we saw in healthy volunteers where we achieved 75% reduction, more than enough to advance this into PSP and PD studies that we should be able to drive down these biomarkers that cause the neuroinflammation and the mistrafficking of proteins such as tau.

So building on that, we have the healthy volunteer data. We're going to report out our Parkinson's disease, LRRK2 degradation and biomarker data. And then next year, things go right, start a PSP study. PSP is a neurodegenerative disease that relies also on this mistrafficking of tau and we know that our drug can correct this mistrafficking. It can improve the -- decrease the neuroinflammation that is also at a root cause of PSP.

And we'll be treating patients for continuously, meaning no longer just limited to 28 days, continue to accumulate biomarker data and correlate that with clinical measures like PSPRS and others. And we will hope to report out in short order the results of that Phase Ib study. And if things go right, we may be able to start a Phase II study even before we have the Phase Ib study has completed. So a registration quality Phase II study. But exactly guiding on when that can start that we have to await clearing our IND and starting the Phase Ib study.

And just to add to that, we do know that human genetics point to LRRK2 and LRRK2 is elevated in the brain of patients in idiopathic Parkinson's disease in microglia as Noah stated. And then also in progressive supranuclear palsy, these same SNPs that elevate LRRK2 also drive increased progression in a clinically meaningful way and time to death.

And so by going in with a clear way to modulate the LRRK2 pathway, we feel that we stand the best chance of proving the LRRK2 hypothesis in disease in both progressive supranuclear palsy and potentially Parkinson's disease.

Your next question comes from the line of Paul Choi with Goldman Sachs.

I wanted to check if you might have any additional dosing cohorts for ARV-393 at the upcoming ASH Meeting, including ones that might potentially be in the target therapeutic range where that you're aiming for. And then on ARV-027, I'm just curious if you thought of other CAG repeat related diseases as being potential areas to explore, including Huntington's or other neuromuscular diseases beyond spinal cerebellar that you focused on initially.

Yes. Thank you. Noah and Angela can probably cover those.

Sure. So to the first question of ARV-393, we've given particular guidance here. I think we would have liked to be able to give a full update at ASH this year on our dose escalation in ARV-393. But in fact, we are not yet in what we had anticipated to be the -- or predicted to be the efficacious range, although fascinatingly to us and very promisingly in our data, we are seeing responses, significant responses, CRs even in T-cell and B-cell malignancies.

So we don't think it's prudent just to report what we're seeing at low dose levels. Usually, studies would want to report out when you know that you're hitting your target fully and you could see the full robustness of the drug. That would be an appropriate time. But certainly, we didn't want to leave you -- people hanging. So we wanted to share that we're making progress, and we're seeing efficacy and tolerability of the drug.

Regarding the 027 question, I'll turn it back to Angela.

Sure. Great. 027, we selected based on its unique profile for degrading the polyglutamine repeat androgen receptor in the nucleus and the cytoplasm, which is really important for a disease driver for spinal and bulbar muscular atrophy. And we reported out some very exciting data showing that we rescue muscle function, including grip strength and endurance to end of phenotypes that are really important for patients with that disease. So that's a very exciting opportunity.

With respect to polyglutamine repeat expansion disorders, we have a robust approach. We're taking to those repeat disorders. We're taking a two-pronged approach also for Huntington's disease. For Huntington's disease, we have identified selective ligands for mutant Huntington and sparing wild type. So we're continuing our efforts. We're early, but we're making good progress there. And then also the idea of tackling repeat expansion disorders is something we're taking very seriously, and we have a very unique opportunity there as well. So that's early, but very exciting space for Arvinas.

Just one more comment, if I could build on that. So look, when we go into the SBMA, we're starting in healthy volunteers. That's the appropriate thing to do. The great opportunity here is this disease is -- it's basically a monogenic disease. We know exactly what the target is, the polyQ-AR. And we know from -- we know that we can degrade it.

So in healthy volunteers, we're going to be able to also do muscle biopsies if permitted, and it's going to be very validating very quickly for this technology. So it's the perfect setup for us to enter a rare disease space because we can get to results and have conviction about our pathway engagement in healthy volunteer studies, which is an unusual opportunity.

Your next question comes from the line of Jonathan Miller with Evercore ISI.

Congrats on all the progress in the early pipeline. I'd like to start with KRAS combos, if I might. You mentioned a couple of interesting potential combo partners for the KRAS program, things that other players in the space maybe had trouble combining with given tolerability profile. How early could we get into combo cohorts? Is this the sort of thing that we could expect to see even in expansion cohorts starting next year? Or should we think about rituximab combos and beyond maybe being a little bit more delayed from that?

And then secondly, just on the HPK1 program, that seems like it's obviously very early still, but potentially pretty interesting. I noticed not much on the deck. When would you expect to show us more of that preclinical data and give us a sense for what indications maybe are the most fruitful for early looking there?

Great questions, and I'll use my usual double act here of Noah and Angela to answer that.

Thanks, John, and thanks for the question. Yes, so to field the 806 question, we're not guiding yet to the timing of combination. So it'd be speculative on my part, but I love speculating. So the bottom line is we're really tearing through our dose escalation right now because there's tremendous interest in this and tolerability, it seems for patients.

And so the idea is we are planning to go into that combination immediately after we do some -- we don't even have to wait until we have our expansions read out completely. We could start that earlier. So we're hopeful if things go very fast, it might be something we could start next year, but I can't offer guidance. It's all going to be clinical data dependent on, right? That's certainly possible.

Great. And then your next question was about ARV-6723, our HPK1 degrader. And so we're very excited about the opportunity for that degrader. It has a very differential profile with respect to both PD-1, and also the kinase inhibitor, the HPK kinase inhibitor that's in the clinic. So what we've been able to show and what you'll hear about at SITC is the impact to T-cell exhaustion and importantly, the impact to the T-cell microenvironment.

We are seeing dramatic changes there and outperforming anti-PD-1 and HPK1 inhibitors in both low and high immunogenic tumor models preclinically. So stay tuned. You'll hear a lot more about our oral immunotherapy that we think will outperform, and also be very useful in the setting that is resistant to checkpoint blockade. So we have a lot of enthusiasm around that asset.

And your final question comes from the line of Andrew Berens with Leerink Partners.

This is Amanda on for Andy. We wanted to know what you've learned about drug-drug interactions with vepdeg that gives you confidence you won't be seeing similar interactions with the new degraders. I mean, there's something [indiscernible] holds or how they're metabolized in different or similar ways.

Yes. Thanks for the questions. I mean, in general, PROTACs are no different from small molecules in terms of how you'd analyze them for DDIs. Every single molecule is different. They get metabolized differently. They interact with other molecules differently. So there's not a generic answer on PROTACs because every single PROTAC is going to be unique and different.

So yes, some compounds like many drugs, you look at to see how they're metabolized to see if they have a drug-drug interaction, you might see some of that, you might not. That's exactly what we're seeing with PROTAC. So there's no difference between a PROTAC and its DDI potential versus any small molecule.

There are no further questions. I will now turn the call back over to Mr. John Houston for closing remarks.

Well, thank you very much, and thanks for everybody's great questions. As you can tell, we're very excited about this next wave of programs coming through our early development pipeline, and we're going to be excited to tell you more about them in the coming months. We've got a lot of interesting data coming out. So again, thank you for your time.

Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.

All right, everyone. I think we'll get started here with the afternoon session. My name is Derek Archila. I'm one of the Wells Fargo biotech analysts. Very excited to have the Arvinas team here. From the company, we have John Houston, Chief Executive Officer; as well as Noah Berkowitz, the Chief Medical Officer from the company. So gentlemen, thanks for joining us and look forward to the discussion.

Thanks for the invite.

Good to be here.

So yes, maybe to start off, kind of set us the -- give us a 1,000-foot view in terms of like what's going on at Arvinas right now and ultimately, what we should be paying attention to for the next 12 months?

Absolutely. I mean it's certainly been a significant year of change and transition. Leading into it, we're very excited by the fact that we're going to have the first pivotal data for a PROTAC ever with vepdegestrant. And we had that data set. It was positive. But clearly, the market reaction and ultimately, the reaction from Pfizer said that it wasn't positive enough.

So that was kind of a mix of real excitement of getting positive data with a disappointment at the reaction to it overall. And that spurred a number of next steps for us because clearly, when you see your stock price go down, we had a reaction where we had to restructure, downsize, reduce our burn rate, extend our runway, get into a beginning of a negotiation with Pfizer about what comes next for vepdegestrant because they made the statement around that time that they didn't want to do further development. They didn't want to do a second-line combination. They didn't want to do a first-line combination. So we're left with the assets sitting waiting for approval in the second-line monotherapy setting. So we've been in dialogue with them, still ongoing, still going well that'll clarify exactly what comes next for vepdegestrant. That will involve 1 or 2 or 3 things that could occur.

One scenario is the asset stays with Pfizer and they launch it and the economics tilt from 50-50 to something more favorable to Pfizer or it could go the other way. They handle the asset, the economics go our way more favorably. And in that scenario, we've clearly said we wouldn't launch it on our own because we don't have that capability, we'd find a third party to do it.

There's also a third option where the companies stay in the 50-50 and both jointly decide to out-license the asset to a third party. Either way, what we're going to find is that we'll be in a position where we aim to monetize vepdegestrant and reduce the costs associated with it significantly. And that should allow a lot of clarity for investors over the coming months and allow them to look at the rest of our portfolio, which is really exciting. And if you will, a reset into Phase I and early Phase II with our LRRK2 program, our BCL-6 program and a KRAS G12C program and also with a couple of more programs coming in behind that.

The other transition is myself announcing I'm going to be stepping down. So we're looking for a new CEO. The initial idea behind that when I thought about it about 1.5 years ago was that we'd find a commercially focused CEO. And really, that would allow the company to move into that space. We're not going to be doing that now. So the new CEO will have a strong R&D profile, BD investor transaction and investor interaction profile. But I'm looking forward to that happening, the fact I can get a break, but also getting the -- something to really drive the company forward through this next phase.

Got you. All very helpful. So I guess as we think about some of the scenarios that you just highlighted around vepdegestrant, I guess, what level of cost savings can you pull if, again, we're not thinking about vepdegestrant anymore to kind of reallocate to the other pipeline?

Yes. I mean, obviously, any cost that we had associated or planned for a launch would not be there. We would not be bringing in a sales force. We wouldn't need the small commercial effort that we have right now. The development costs are all gone because we're not developing it any further. So there's substantial savings. And part of that allowed us to do some of the reorganization already that allowed us to extend our runway. Post any kind of agreement with Pfizer, we'll probably have an opportunity to relook at that as well. No, there's going to be -- there will be savings, no doubt about it. And we'll be able to share that when we get through the deal and see what the nature of it is.

Got you. So I guess does that mean we should expect potentially pushing out the cash runway even further? Or is this already kind of baked in?

Well, no, no. I mean, my CFO would kill me if I actually announced there was a kind of change the guidance. But I mean, clearly, we've got money into the second half of '28. If we do any kind of further cost savings, that could obviously help that greatly. I mean the whole aim is to reduce our run rate for sure and to give us more optionality to hit milestones over the next 2 or 3 years and get it back into the normal sequence where you get data, you go to the market and you're able to raise cash.

Got you. I mean do you think it's fair to say like the decision to -- whichever way it goes is going to be dictated by approval and label? Like do we need to wait that long? Or is that something that could be hashed out beforehand?

In a scenario where we're, say, running a process to find a new partner, clearly, waiting to see the approval will be part of it. But you can clearly move forward quite a bit with the partnering discussions to that point. Our overall survival data will be part of the kind of the FDA discussion and then you have the PDUFA in June. But we're in a good position standing today if we get this resolution to run a process, get a new partner and ideally get an approval, and we'll have a commercial launch-ready asset for anybody that actually wants to do that kind of deal.

Is your hope to get this done before you leave and you bring in a new CEO? Or it isn't?

Well, I mean, that would be nice. I don't know if we'll be able to get it done as quickly as that. Clearly, we've got to resolve Pfizer first. That's step 1. Run a process would be step 2, getting the diligence done in the asset, which probably includes looking at the OS would be step 3. So any kind of process takes several months.

Got you. So maybe like shifting gears to the early-stage pipeline. And you mentioned a couple of assets like LRRK2, BCL-6 and G12D. I mean, LRRK2 is probably one of the more further along ones. Maybe just walk us through that program and why you're so excited there.

Noah?

Sure. I'd be happy to field it. Thanks, Derek. So we're very interested in LRRK2 because we're talking about a target that is relevant for diseases like Parkinson's disease and also progressive supranuclear palsy and potentially other diseases down the road, neurodegenerative diseases. It's of interest because the genetics of LRRK2 link it very clearly to those diseases, both in terms of the diagnosis of Parkinson's disease and also the progression and rapidity of that progression of PSP.

On top of that, we understand the pathway and how LRRK2 by controlling endolysosomal trafficking is responsible for the disposal of these toxic metabolites that accumulate in the brain, whether you're talking about tau or alpha-synuclein and so on. And we and others have demonstrated that if you intervene with LRRK2, you can prevent the propagation, for example, of tau in brains. So it's a well-characterized target, and it's really ripe for development.

The issue is that it's the right target, but there really isn't the best drug candidate out there right now before we came around. So you have Biogen and Denali that's advancing a program, right? We know that the -- their compound is in a registration-quality Phase II study in Parkinson's disease, the LUMA study that's expected to report out next year. But there are some challenges for that study. We're hopeful that it will be positive for patients. But fundamentally, they haven't done any form of patient selection in that study in terms of LRRK2 pathway. And even if that's okay, the issue is that it's a kinase inhibitor and it only achieves 30% kinase inhibition. Now when we think about LRRK2 that's been implicated in these diseases, it's a complex protein that has kinase activity, scaffolding activity and also GTPase activity.

The great thing about a degrader is that you can eliminate all of those activities, and you can profoundly impact endolysosomal function. That's what we do with our degrader. So what we've been able to show already this year, and we shared this in April at ADPD is that we have the first ever orally bioavailable brain penetrant PROTAC, in this case, targeting LRRK2 that can achieve where we see there has good PK properties with dose proportionality and accumulation in the brain. And we see that we engage LRRK2 and we degrade it in the brain.

So I think we're the only company right now that has an orally bioavailable brain penetrant PROTAC that's relevant for neurodegeneration. And that's a promise of our underlying technology. But because we do this degradation, I told you about why that's potentially superior to inhibition. So that sets us up very well to pursue diseases like PSP and Parkinson's disease. And I can just update with you to close out that currently, we're enrolling patients in a Phase I Parkinson's disease study, and we'd be looking to recapitulate the data and even share a look at more downstream biomarker impact of our drug now that we're looking at patients with disease with elevated LRRK2 at baseline and more to follow as we provide guidance on those results.

Got you. I guess based on kind of what you guys know in the literature and maybe preclinical data, like what level of degradation do you really need to show efficacy in patients, do you think?

So it's not known yet because really, it's the clinical data that correlates with those biomarkers that have to be proven. No one's gotten there yet. We do recognize that one of the differentiating features between patients with Parkinson's disease and those age-match controls when it comes to LRRK2 is that PD patients have a little more than twice the expression of LRRK2 in CSF and in brain tissue compared to patients with age-match controls. So one can envision targeting 50% reduction in that LRRK2 to bring them down to the normal level. But there's much more than LRRK2 levels. It's about target engagement, knowing that by degrading that LRRK2, maybe it's 40%, maybe it's 50%, maybe it takes 75%. And by the way, we've been able to show that we can get 75% degradation of LRRK2 in healthy volunteers.

But what you want to do is when patients have inflammation from their microglia in the brain, which is part of the pathology seen in the diseases I outlined earlier, that if you can now through that degradation, interrupt that downstream signaling, show that you have significant reduction in Phospho Rab 10, look at things like CD68 markers of microglial inflammation and show that you could reduce it. When you have all those findings, you're set up, I think, to demonstrate eventually clinical benefit. Those are going to be some of our go/no-go decisions as we dose our Parkinson's disease cohort.

Got you. So maybe going back to your cohort. I guess just remind us when we would expect data. And also, how much confidence should we put on the biomarker data? Like obviously, that's a signal, but do you think that's definitive? And how that you ultimately think that will correlate down the line in terms of registrational endpoints?

Sure. So the current multiple dose cohorts that we're treating in Parkinson's disease involves 28 days of exposure. And as I had mentioned a moment ago, moving these biomarkers that are involved in the disposal of things like pathologic tau would seem to be critically important. So we expect those results and looking at the inflammatory pathways to be able to report out next year. Later this year, we're going to share some results of the SAD, which we completed recently, and we'll share what some of the PK properties of the drug look like in PD patients. We've already shown what we can do in healthy volunteers.

So look at it as stepwise. But the other milestone for us is we have to complete the long-term to tox which is slated to be completed at the end of the year. And you can look for us filing an IND and therefore, preparing ourselves to get started in PSP studies in the U.S. next year. So look for IND filing early next year, which means we've completed the chronic tox, and we are sharing those results without interrupting inflammatory signaling.

Got you. I mean is there anything inherently like toxic or issues with degrading or even targeting LRRK2? Like should we -- is there any on-target stuff that we should be worried about, particularly if we're going to degrade it pretty significantly?

I think the field looks at some data that was shared by Merck, where they published some of their toxicology and also is aware of an interesting founder or a family in Italy that -- where there's some findings. So we know that there is a family where patients have -- where members of the family have a loss -- a total loss of LRRK2. So mutations in both copies of LRRK2. And this family -- and patients in that family develop pulmonary symptoms like pulmonary fibrosis, but starting at the age 30 or so.

So long-term decades of no LRRK2 presence seems to lead to some type of pulmonary finding. So I'll say that's in the background on my mind. We know from the Merck compounds that were published that they had achieved -- they saw a significant amount of collagen deposition in the lung. So there's some -- there would be some concern about that, and maybe that's why Merck abandoned the program. Well, we have already shared that in our short-term tox when we compare head-to-head against those, we have minimal collagen deposition in the lung. That may be a feature of our PROTAC, which is superior to inhibitors, right? And also, we've explained the differentiating feature of the collagen itself.

It may be driven by surfactant accumulation where the -- we have a different -- our surfactant composition is different than what is experienced in patients who are exposed to inhibitors -- or I'm sorry, animals that have inhibitors. So there are differences between inhibitors and degraders. We're watching what's going on with Denali. They've obviously gotten into late-stage development. They do diffusion capacity monitoring of their patients. It's something that we have included in our Phase I studies as well. We haven't seen any pattern to date. And therefore, we expect to be moving ahead full speed ahead.

Interesting. I mean do you think it's like part of the fact that maybe they don't address some sort of like the scaffolding function or the GPA? Like what do you think could be leading to that safety signal? I mean, obviously, you said Denali doesn't see effect.

Well, the safety signal itself is total loss of LRRK because we see something like that in the human -- in those patients. Why the inhibitors have more collagen than our degraders, maybe it has to do with the difference of just inhibiting kinase activity leads to some collagen accumulation or something. But by degrading and reducing and getting closer to normal or even a little below normal, the LRRK2 levels, maybe you reduce that trafficking dysfunction, you have less collagen deposition. I think it's an unknown area. It's not one we're investigating with great detail.

But haven't seen it preclinically yet or...

We haven't seen it.

Got you. Okay.

It's important to reemphasize that we're trying to do a normalization of LRRK2 as opposed to taking it down to...

Right. You're just trying to get -- you're not going to get 0. You want to get to maybe like 50% normalized.

It could end up being more. This is what we're looking at in our study.

I mean do you think like, again, from a study standpoint in the future, if you're trying to normalize, you need to basically follow that biomarker across the trial in terms of just making sure it's normalized and you don't overshoot? Or how do you plan for that?

Yes. I think as you advance the science, you adjust. So I don't know if in the end, it will be, are you going to measure LRRK2 levels in the CSF for the periphery? Is it going to be you're going to look for downstream markers like Phospho Rab and look that you decrease that to some target level. Those are the things that we're learning as we go. But so far, it's all moved in the right direction.

Got you. And so maybe just highlight the connection between Parkinson's and PSP and what you're kind of seeing there and then kind of the plan to move this into the clinic into that indication?

Sure.

You could give it you're on the role.

Yes, sure. So okay. So think of it as Parkinson's disease, huge opportunity, big disease, very complex and a lot of failures in the past. And maybe that's because of the complexity and that heterogeneity. The very interesting thing about PSP is it's well associated with LRRK2 as well. And fundamentally, it's a very -- it's a much more homogeneous disease. Yes, there's some variability in patient presentation where they have the degree of Parkinson-like symptoms they have and the -- all kinds of central findings and the cognitive findings subtly different. But fundamentally, it is a pure tauopathy.

So patients have tau, all patients -- like you can diagnose it on the basis of tau accumulation, and they're all having the same type of tau. So it's 4 our tau that they accumulate. And there's evidence that LRRK2 is involved in the trafficking of tau, and you can prevent the propagation of tau in its accumulation by interfering with LRRK2 dysfunction -- or I'm sorry, endolysosomal dysfunction that's caused by LRRK2. So we like that. Like when you're studying diseases, if you have something that's more homogeneous, it has a higher probability of success. So it's a disease. There are about 30,000 patients in the U.S. with this disease. They have 7-year survival from the time of diagnosis, and that's in contrast to Parkinson's disease where survival is about 30 years or more, right?

And so it's a disease where there's a tremendous unmet medical need, where there's a survival impact. And there is a good way to measure the progress of the disease, one that regulators accept and it's already been reviewed at health authorities. And they're all on board with measuring something called the PSP rating scale, PSPRS. So we have -- we know the progression of the rating scale over the course of those 7 years. We know how to identify patients with PSP clinically. And you can also look at their tau in the brain in an evolving area right now with imaging. And the idea is that for this rare disease, you can do a study with a few hundred patients where you're looking at an improvement in their -- or I don't -- not necessarily that they improve their symptoms, that would be awesome.

But if you prevent the further deterioration in their symptoms, that is an approvable endpoint, and it can be demonstrated in a study with a few hundred patients where they're treated and followed for about a year's time.

So when we sit here today and say that we can start a study later next year that would be a registration quality Phase II, think of it as a study that can go beginning to end in about 2.5 years' time frame. So it's very biotech friendly. So we're going to -- that's a path we're very interested in. And we will evolve this interest in Parkinson's disease, look at whether or not a partnership makes the most sense. Look at whether this LRRK2 degrader or maybe another LRRK2 degrader that we have because we didn't just develop one compound. We've developed a series of compounds. So whether that makes the most sense to move forward, these are all considerations, and we'll offer more guidance as it becomes clarified.

Got you. I mean, how well do you think you'll have interrogated kind of the doses when you kind of -- when thinking about that PSV trial? Like will you do multiple doses? Or again, like obviously, you kind of have zeroed in on how to get to specific LRRK2 levels, like how do you think about that as part of the plan?

So I think the first step is we have to see what comes out of our indicator study, that is the Parkinson's disease study, which is going to show us these inflammatory markers that are relevant for both diseases. So we have to see the results of that. And we haven't finished that yet. We're just started enrolling this quarter. But then the next thing is next year, that involves conversations with regulators and whether or not it ends up being one dose, which is a little higher risk, but maybe it's in our interest or it involves 2 doses, you lower the risk, but of course, you're increasing time a little bit cost. Those are the trade-offs we have to get to, but we have -- it has to be a data-driven decision, and we haven't made that decision yet.

Got you. I want to move on to the rest of the pipeline, but last question on LRRK2. I guess like where do you feel like folks underappreciate this asset? I mean, is it mostly just because are we still trying to prove out biology? Or again, we have to wait for Denali Biogen data. Like where do you think that around the edges, people could get more constructive on it or you'd like to see people get more constructive on this one?

Look, if LUMA is positive next year, people will be wildly excited about it because then you say, okay, we took a modest inhibitor and we saw positive results. And if you come in now with a degrader, you really have opportunity to be best-in-class. That's easy, but that's fundamentally, I think that's a bit of a long shot. If it's slightly positive even though if it's trending, if you see subsets where like patients that are genetically defined as LRRK2 dependent are benefiting for certain, all of those things really would drive further interest in it. Those are the external factors.

Internally, we're continuing to do collaborations with different investigators who have access to data sets to look at these biomarkers that are predictors of disease and severity. And we're looking at how those biomarkers play out when we treat our patients. So I think those will end up being published and those will -- they have the potential to excite the field.

Got it.

I think in general, there's kind of a nervousness about unvalidated or novel targets. And I think that's what we see when certainly investors talk to us about LRRK2, when will you get to the point where you get true validation, how late in your development plan will be that true validation. We get that question about LRRK2, but we get about other targets in our portfolio. I'm sure others are getting that. A few years ago, unprecedented novel targets were very exciting, and that's what the investor base was looking for. Now it was looking for more validation and confirm. So -- but I think as Noah laid out, with the Denali data coming out and ideally our data over the coming months and years, I think that we'll see LRRK2 as being a really important target.

Got it. Maybe shifting gears to BCL6. Maybe just give us an intro to that program and I guess, where you think that starts to fit into the emerging pipeline.

Sure. So BCL6 is a long awaited for a target that has long been in the sites of drug developers. Only recently did -- was there some type of innovation that allowed us to find a ligand to find it. So we have a BCL6 degrader in the clinic that's running a little behind BMS' degrader. There are no inhibitors to my knowledge, in the clinic. There have been some recent reports over the past 2 weeks of 2 other companies that are interested in bringing degraders into the clinic. The good news for this field is you look at BMS' data and you see that they reported out 80% response rates in their first 30-some-odd patients that were treated, both in follicular lymphoma and large B-cell lymphoma, and this is without even measuring BCL-6 or selecting for BCL-6 at all.

So we're, as I said, a little behind them. We differentiated in the fact that our drug was designed to include a little anti-[indiscernible] activity, which is kind of what was in lenalidomide and therefore, could be beneficial in B-cell malignancies. So that might augment the activity.

We've shown up till now that we have really promising monotherapy activity in many preclinical models and that it combines well with synergy with BCL-2 inhibitors, BTK inhibitors EZH2 inhibitors with CD20 targeting antibodies. And we're going to report out before the end of the year about combining with bispecifics, so CD20 targeting bispecifics. And to us, it looks like that best-in-class when you compare. The differentiating property of our Phase I study is that we also include in addition to the B-cell malignancies, AITL, which is a small population of patients with T-cell lymphoma, so angioimmunoblastic T-cell lymphoma. And these patients don't really have any therapy after they failed shock in first line. So there's tremendous unmet medical need.

So when you look at our data as it comes out, we're going to look at whether or not we hit ATL. That's not something BMS included in their Phase I program. So there are no data on that yet. We -- but we're early, like we need dose escalations to get to the effective dose. That was the nature of the study design we have. I think our competitor was able to get there right away. But it's something that will -- as we have the data, we'll share it. And what's great about BCL-6 overall is it's an orthogonal approach to treat these B-cell malignancies and AITL. So you don't have overlapping plaques with things like bispecifics and rituximab and the other agents I made. We don't have hematopoietic toxicity. The drug had a good safety profile in animals. And so far, we're seeing a pretty clean profile in humans.

I guess what's the strategy with this one? Would this be something that you also would kind of take forward maybe in that AITL? Or is this something you would want to partner more broadly given that the space is quite robust in terms of trials?

So we are very interested in AITL as a niche fast market approach. But we see large B-cell lymphomas being treated by bispecifics in the future, whether that's first line, second line, third line. It's for sure evolving in that direction. And we think a combination with bispecifics is the holy grail we're after. We're sharing data about how well it works preclinically. We have the ability to move to that next in our dose escalation protocol. So that's something that we're ambitiously pursuing.

So within that protocol already, you can introduce combinations after you kind of get through the preclinical talks.

Yes.

Okay. Interesting. Okay. And just remind us when we would expect data. So I know there's some data at the end of the year, right? And then the combo data might be sometime [indiscernible]?

Yes. The combo, we haven't begun dosing those patients yet. That's still in the future, but it's something we're putting in the amendment that allows us to do it. So think of that as a 2026 event.

Got you. Excellent. Okay. And then maybe lastly on G12D, just kind of your strategy there. Obviously, a lot of inhibitors, but several degraders, but where do you think you sit with your program?

So look, we're not going to be first to market there, but we've learned a tremendous amount, and we're better positioned because we're not first to market. So we know that what differentiates degraders from inhibitors are that, that degraders can drive neoantigen presentation, which can allow you to engage in IO effect. And then we also know now from Revolution's reports that a main source of resistance is KRAS amplification. So their G12D, which has promise as an inhibitor, develop -- patients develop resistance because they amplify the KRAS and they don't have enough G12D inhibitor on board to inhibit that amplified KRAS.

So what we can do with the degrader is we have a catalytic activity that can continually degrade any amplified KRAS. So we think that, that positions us very well with the degrader and the neoantigen activity I said earlier. The next thing, though, is that we spent our time to come up with a degrader that is differentiated in its core properties. We're 40x more potent in our preclinical models than the inhibitors and the Astellas degrader. And on top of it, the Astellas degrader, not only are we 40x more potent, but they were unable to achieve the exposure levels they needed because they hit some DLTs because of transaminitis that put them in the 300 to 60-milligram range.

We're dosing patients starting in single digits and moving -- the final dose will end up being in low double digits of milligrams. And we just started enrolling in June. The enthusiasm of the investigators is indescribable so that they're just enrolling the cohorts as soon as they open. And we designed a study that only had 5 dose escalations. So we expect you guys can start anticipating when we'll see those results. We haven't guided to it yet, but we're enrolling faster than we expected. And those are some of the things that we'll be looking for, efficacy, tolerability and resistance pathways.

Great. And maybe last question. So we talked about the cash runway going in second half '28. I guess what do you think you can accomplish across those 3 assets within that time frame?

Yes. I mean, I mean, clearly, our plan is to hit key milestones for all those programs and also potentially have 1 or 2 more programs coming into the clinic. The money that takes us through to the end of '28 allows us to hit milestones for BCL6, KRAS G12D and LRRK2 and some of them quite significant. So extending the runway even further could allow us to even further those milestones. So I think we're in a great position. We're in a great position financially. We're in a great position with this resetting into the kind of earlier clinical development with some really exciting targets that have real potential for differentiation and with data points that are going to appear in this 6- to 9-month period. So it's -- even though it's been a tough transition year, I think we're well on the path to that new transition.

Great. Well, John, we'll leave it there. Thank you so much.

Thank you.

Thanks.

Thank you for standing by. At this time, I would like to welcome everyone to Arvinas' Second Quarter 2025 Earnings Call. [Operator Instructions] I would now like to turn the conference over to Jeff Boyle, Arvinas' Vice President of Investor Relations. Please go ahead.

Good morning, everyone, and thank you for joining us. Earlier today we issued a press release with our second quarter 2025 financial results, which is available on the Investors and Media section of our website at arvinas.com. Joining the call today are John Houston, Arvinas' Chief Executive Officer, President and Chairperson; Noah Berkowitz, our Chief Medical Officer; Angela Cacace, our Chief Scientific Officer; and Andrew Saik, our Chief Financial Officer.

Before we begin the call, I'll remind you that today's discussion contains forward-looking statements that involve risks, uncertainties, and assumptions. These risks and uncertainties are outlined in today's press release and in the company's recent filing 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. John?

Thanks, Jeff. Good morning, everyone, and thank you for joining us today.

As outlined in our second quarter earnings release this morning, our business is in a solid position with strong momentum. It was an eventful and exciting quarter at Arvinas with significant clinical and regulatory programs across our pipeline of PROTAC degraders. We continued making significant strides across our early stage programs where we are enrolling patients in 3 Phase I trials across our neuro and oncology portfolio, including the recently initiated trial with our KRAS G12D degrader ARV-806. During the quarter, we also presented compelling first-in-human data from ARV-102, our LRRK2 degrader and preclinical data for our BCL6 degrader, ARV-393.

I'm also pleased to share an update on our antigen receptor degrader, luxdegalutamide, which we licensed to Novartis in 2024. We are pleased to see that Novartis is rapidly progressing the assets and announced the recent initiation of two combination Phase II trials that will further advance luxdegalutamide towards patients. One trial is in metastatic castration resistant prostate cancer and the other is metastatic hormone sensitive prostate cancer, and both will identify recommended Phase III doses and we believe further validate our ability to develop potentially best-in-class protein degraders.

As a reminder, our license agreement with Novartis includes up to $1 billion in development, regulatory and commercial milestones as well as tiered royalties. The accomplishments from across our portfolio are the latest in a long stream of successes at Arvinas. At the same time, we have recognized the ongoing need to enhance our financial position and set Arvinas up for future success. To that end, last quarter we announced a company-wide restructuring that extended our cash runway and included 2 key elements. First, we reprioritized our research pipeline, cutting a number of programs and continuing investment in our assets with the greatest potential value. And second, we streamlined operations across the organization by reducing our workforce by approximately one-third. While difficult, these defective actions bolstered our financial profile and drove efficiencies across the company.

They also enabled us to turn our full attention to our near-term imperatives, which are first working with Pfizer or identifying another partner to advance vepdeg towards commercial launch. Second, achieving critical data milestones from our pipeline in the next 12 months. And third, carefully allocating capital to support those milestones efficiently. I'll return to those 3 imperatives in a few moments, but I'd first like to say a few words about the recent announcement of my planned retirement and the CEO transition for Arvinas.

Having recently strengthened our financial profile and with a clear line of sight into those near-term imperatives, the Board and I agreed it is the right time to initiate a search for a new CEO. As with any public company, succession planning is a priority for our Board of Directors, and I have been talking to the Board about the potential timing of this transition for well over a year. While there never seems to be a good time, we agreed that waiting until after our first pivotal data readout was essential. We are now conducting a rigorous and thoughtful CEO search process spearheaded by independent directors on our nominating and corporate governance committee with the assistance of a leading executive search firm. The board is fully engaged and intense on finding the right CEO to lead Arvinas into our next chapter and help shape our long-term strategy to create value for shareholders and deliver on our mission to serve patients. I'm also honored to continue as Chair of the Arvinas Board once I step down from the CEO role.

For now, our long-term strategy is driven by the imperatives I mentioned above, advancing vepdeg to launch by Pfizer or another partner, achieving critical data milestones and efficiently allocating capital. I'll spend a few minutes discussing our vepdeg strategy before turning the call over to Noah and Angela who will provide updates and discuss upcoming milestones for our clinical programs. Andrew will then provide a financial overview and some thoughts on capital planning.

First, regarding vepdeg. Our collaboration with Pfizer was signed in 2021 with the intention for vepdeg to be developed as a monotherapy and in combinations across the adjuvant first and second line settings. With that plan, the idea of having 50-50 co-development and commercialization was very attractive. We are now on the threshold of vepdeg potentially becoming a best-in-class treatment in its first indication. Second line monotherapy treatment in ESR1 ER+/HER2- metastatic breast cancer.

However, the recent decision to remove the combination pivotal trials from our development plans with Pfizer has created a situation where the 50-50 cocommercialization agreement no longer makes sense and we're actively reworking our collaboration. Should the negotiation lead to vepdeg being returned to Arvinas, we are prepared to seek a party to commercialize and further develop vepdeg. Reaching a positive conclusion for vepdeg is a critical step in maximizing its value while also allowing us to focus on our promising clinical pipeline.

Preclinical data has shown that ARV-102, ARV-393 and ARV-806 are all differentiated from inhibitors and other degraders. With compelling clinical data milestones over the next year, we believe our maturing pipeline will be a significant value driver for the company and our shareholders. Taken together, we are advancing a very exciting pipeline, applying our PROTAC technology to new areas in both neuroscience and oncology where we can truly differentiate from other mechanisms of action.

Operating from a strong financial position underpinned by an extended cash runway efficient capital allocation, and a development strategy that unlocks the potential of our platform to bring patients important treatments, we are confident in our path forward and in our ability to maximize value for shareholders and benefits for patients.

With that, I'll turn the call over to Noah.

Thanks, John, and good morning, everyone. Our pipeline continues to progress at a remarkable pace, demonstrating the vast potential of our PROTAC platform. I'll begin with our most advanced neuroscience program ARV-102. We have designed investigational oral PROTAC degraders to cross the blood-brain barrier and selectively degrade leucine-rich repeat kinase 2 OR LRRK2. LRRK2 is a large multi-domain scaffolding kinase that plays a critical role in effective endo lysosomal trafficking. Unlike traditional small molecule inhibitors that only block LRRK2's kinase activity, LRRK2 degraders eliminate pathologic scaffolding function, GTPAse activity and the kinase activity of LRRK2 implicated in this disease.

We believe our lead LRRK2 degrader, ARV-102 is particularly well positioned to be evaluated in 2 diseases where there are no disease-modifying therapies available. The first is Parkinson's disease or PD, a disease where increased LRRK2 expression and activity contributes to neuro degeneration and its pathogenesis, making it a rational therapeutic target.

And the second is progressive supranuclear palsy, or PSP, a disease where genetic variations in LRRK2 are associated with PSP progression. Additionally, we have published data associating the tau pathology of PSP with LRRK2-mediated endo-lysosomal dysfunction, which again makes this a very rational therapeutic target.

ARV-102 is the only PROTAC we know of in the clinic to demonstrate deep-brain penetration in non-human primates and now blood-brain barrier penetration in humans. As presented at the AD/PD congress, ARV-102 is well tolerated at single doses up to 200 milligrams and at multiple doses up to 80 milligrams. No serious adverse events after single and multiple oral doses and healthy volunteers were observed. Single and multiple doses of ARV-102 demonstrated dose-dependent exposure in the central nervous system by cerebral spinal fluid or CSF sampling. This was associated with substantial degradation of LRRK2 protein in the peripheral blood and the CSF and on-target activity with levels of engagement not reported with inhibitors currently in the clinic.

We believe the high levels of target engagement, enhanced potency and pathway engagement demonstrated with ARV-102 will differentiate it from clinical-stage inhibitors, which in preclinical studies have not shown the same ability as ARV-102 to move important biomarkers in the CSF. These PK and PD properties and acceptable safety and tolerability profile supports further study of LRRK2 degraders in PD and PSP.

Dosing of the Phase I single ascending dose cohort in patients with Parkinson's disease is complete and we expect to present initial data confirming pathway engagement later this year. We will also initiate multiple dose cohorts in patients with PD in the coming weeks as well as a trial in PSP in the first half of 2026.

In parallel to the advancement of ARV-102, we are making nice progress with ARV-393 our BCL6 degrader and ARV-806 our KRAS G12D degrader, which entered the clinic in the second quarter. It is too early for me to share clinical results for these exciting new clinical stage assets, but Angela will share some of the compelling preclinical data supporting the advance of both in the clinic.

But first, I would like to provide some regulatory updates regarding vepdeg. We have submitted the new drug application for vepdeg. This represents another significant first for Arvinas, the first PROTAC degrader to enter clinical trials and have a positive readout in a Phase III trial. It's also the first-ever new drug application submitted for a PROTAC. The NDA was supported by VERITAC-2 data that were presented at the ASCO oral late-breaking session, and simultaneously published in the New England Journal of Medicine. The enthusiasm among physicians generated by VERITAC-2 data was very rewarding. Later this year, we plan to present the patient-reported outcomes data from the VERITAC-2 trial. We believe these data disclosures reinforced vepdeg's profile as a potential best-in-class monotherapy.

I'll now turn the call over to Angela. Angela?

Thanks, Noah, and good morning, everyone. ARV-393, our investigational oral PROTAC designed to degrade B-cell lymphoma 6, or BCL6, is an exciting asset that demonstrates the power and breadth of our platform. BCL6 is a previously undrugged transcription factor, a master regulator of multiple cellular processes during B-cell development, including proliferation, survival, and apoptosis. Altered BCL6 activity has been implicated as an oncogenic driver in several subtypes of non-Hodgkin lymphoma, making it a rational therapeutic target with initial clinical validation emerging.

PROTAC-mediated degradation has the potential to overcome the historically undruggable nature of BCL6. With its iterative activity, ARV-393 potently and rapidly degrades the BCL6 protein which is critical to overcoming its rapid resynthesis rate and sustaining anti-tumor activity.

In second quarter of 2025 we presented 2 sets of preclinical data for ARV-3 93. First at the American Association for Cancer Research Annual Meeting in April, we presented new preclinical data highlighting the therapeutic potential of ARV-393 in combination with standard of care biologics, chemotherapy, and small molecule inhibitors targeting cooperative oncogenic drivers. ARV-393 combinations demonstrated increased tumor growth inhibition, including tumor regressions in preclinical models of aggressive B-cell lymphoma. These data underscore the potential of ARV-393 to become a backbone therapy for development of rational mechanism-informed chemo-free or all oral therapeutic options with the potential to improve patient outcomes and convenience.

In June at the European Hematology Association Conference, we presented new data demonstrating the potent single agent efficacy of ARV-393 in patient-derived systemic models of angioimmunoblastic T-cell lymphoma and transformed follicular lymphoma.

To our knowledge, these are the first preclinical evidence of an efficacious BCL6 targeted degrader in human models of these diseases. These data highlights the broad utility of a ARV-393 across non-Hodgkin lymphoma subtypes with unmet need beyond DLBCL. Later this year we also expect to share preclinical data showing the combinability of a ARV-393 with glofitamab a CD3, CD20 bispecific antibody, and an emerging standard of care for DLBCL that supports our plan to evaluate this combination in an upcoming trial. We are excited about the potential here, given ARV-393's ability to increase CD20 expression, which provides rationale for the exploration of ARV-393 with CD20-targeted agents and in the context of low or loss of CD20 expression. We also plan to share the initial clinical data with ARV-393 later this year.

As you have heard from Noah, I'm pleased to report that we have initiated a Phase I clinical trial of ARV-806, our novel PROTAC degrader targeting KRAS G12D. The trial has progressed rapidly through the first patient cohort, reflecting strong interest from clinical investigators and underscoring the high unmet need for effective KRAS-targeted therapies. KRAS G12D is a well characterized oncogenic driver associated with poor prognosis and resistance to standard treatments across major tumor types, including pancreatic, colorectal, and non-small cell lung cancers. ARV-806 has demonstrated compelling preclinical activity with high potency and clear differentiation from both KRAS inhibitors and other degraders currently in the clinic. Notably, because of the catalytic activity of our PROTAC, ARV-806 has shown it can overcome KRAS resynthesis and increased expression, a major clinically relevant emerging mechanism of resistance that existing inhibitors have failed to address. Our PROTAC binds to and degrades both the active and inactive forms of KRAS G12D, achieving potent and durable elimination of the target rather than inhibition in all models tested.

In preclinical studies, ARV-806 achieved in-vitro potency approximately 25x greater than KRAS inhibitors and 40x greater than the leading clinical-stage degrader, demonstrating strong potential for differentiation from both KRAS inhibitors and degraders currently in the clinic. Furthermore, ARV-806 exhibits dose-dependent selective robust anti-tumor activity culminating in regressions across preclinical models of KRAS G12D mutant cancers. These results highlight the strong therapeutic potential of ARV-806 and support its continued and rapid advancement in the clinic. We look forward to updating you on our clinical progress and anticipate sharing preclinical data from ARV-806 and the first ever data from our oral pan-KRAS degrader program later this year.

With that, I'll turn the call over to Andrew to review our quarterly financial information.

Thanks, Angela, and good morning, everyone. I'm pleased to provide financial highlights for the second quarter ended June 30, 2025, and expand on our approach to capital allocation and development strategy. As a reminder, detailed financial results for the second quarter are included in the press release we issued this morning.

During the quarter, we took significant action to reduce costs and increase efficiency across the organization. These actions included a reprioritization and reduction to our research portfolio, as well as a reduction of approximately one-third of our total workforce. When combined with the announced changes to our vepdeg development plan, our cash runway was extended into the second half of 2028. These changes will make us leaner and more efficient as we work towards a promising stretch of catalyst over the next 12 months.

As I mentioned previously, the restructuring was focused on reducing internal costs without having an impact on the clinical stage programs that will drive value over the next several years. We will maintain our discipline and focused approach to capital allocation, and our development strategy will be focused on bringing pipeline programs through major clinical inflection points.

With respect to vepdeg, we anticipate relatively minimal costs to prepare the market in the coming months. Our current agreement with Pfizer includes establishing a go-to-market strategy that will benefit both sides of the partnership. While we continue to believe that vepdeg is a potentially best-in-class asset, given the changes to the development plan, we have determined that it is no longer viable for us to build out our commercial infrastructure as we had previously planned. As John said earlier, we are in active discussions with Pfizer to rework our collaboration to determine the most efficient way to make this important drug available to patients if approved.

Across our pipeline, we have a rich set of catalysts coming up in the next year for both our oncology and neuroscience portfolios. With our strong balance sheet, we have sufficient resources to move these exciting programs forward to key value inflection points. We've seen great clinical success here in the past, both in the development of vepdeg in partnership with Pfizer, and in the platform validating out-licensing of luxdegalutamide to Novartis. We are excited to continue development of the next generation of Arvinas PROTACs.

I'll now briefly touch on some key financial highlights for the second quarter of 2025. At the end of the second quarter, we had approximately $861.2 million in cash, cash equivalents and marketable securities on the balance sheet, compared with $1.04 billion as of December 31, 2024. Revenue for the 3 months and June 30, 2025, totaled $22.4 million compared to $76.5 million for the 3 months ended June 30, 2024. The decrease of $54.1 million was primarily driven by $45.6 million of decreased revenue from the Novartis License Agreement and the Novartis Asset Agreement, both of which were entered into during the 3 months ended June 30, 2024, and were completed by December 31, 2024, as the technology transfer of our ongoing planned clinical trials of luxdegalutamide were transitioned to Novartis.

Revenue from the vepdeg collaboration agreement with Pfizer decreased $6.8 million related to the removal of 2 Phase III trials from the development plan during the first quarter of 2025. General and administrative expenses were $25.3 million in the second quarter compared to $31.3 million for the same period of 2024. The decrease of $6 million was primarily driven by a decrease in personnel and infrastructure related costs of $4.8 million and professional fees of $2.2 million, partially offset by an increase in costs related to developing our commercial operations of $1.1 million.

Research and development expenses were $68.6 million in the second quarter compared to $93.7 million for the same period of 2024. The decrease of $25.1 million was primarily driven by a decrease in the vepdeg program of $10 million, a decrease in the luxdegalutamide program of $9.5 million, and decreases in personnel expenses and non-program specific expenses of $10.3 million offset by an increase in the LRRK2 program of $2.1 million and the KRAS program of $1.5 million.

Restructuring costs in the quarter amounted to $7.4 million of cash expenses consisting primarily of employee-related expenses which were offset by a reversal of non-cash employee stock compensation and bonus expenses of $6.4 million. The announced restructuring is now complete, and the full benefit in terms of cost reduction will be seen starting in the third quarter.

We are maintaining our prior cash runway guidance into the second half of 2028. We are focused on staying disciplined by investing in areas that will maximize shareholder value as we move towards important catalysts in the coming months. In addition, we will continue to look at ways to reduce costs and increase efficiency while continuing to focus on our goals of progressing our very promising early pipeline.

With that, I'll turn the call over to John for closing remarks. John?

Thanks, Andrew. As you've heard, we see multiple near-term milestones across our clinical development and regulatory efforts. Our programs offer a rich set of catalysts over the next 12 months, including clinical data from ARV-102 and ARV-393 and potentially initial clinical data from ARV-806 and of course the potential for the first ever approval of a PROTAC. During this time, we will also advance ARV-102 in its ongoing trial in patients with Parkinson's and initiate a trial with ARV-102 in progressive supranuclear palsy.

Before opening the call for Q&A, I'd like to reiterate our confidence in our near-term plan to create value for patients and shareholders. This includes advancing vepdeg to launch by Pfizer or another party, achieving the important data milestones I just described and allocating capital to ensure we reach those milestones efficiently. While we made sweeping changes in the first half of 2025, we are always evaluating the best ways to create shareholder value.

With that, I'll turn the call over to Jeff to begin the Q&A portion of the call. Jeff?

Thanks, John. Operator, can you please open the queue?

[Operator Instructions] And our first question comes from the line of Ted Tenthoff with Piper Sandler.

Andrew, just 1 quick housekeeping. The restructuring charge that you mentioned, was that primarily in the G&A line? And then I have a pipeline question for you guys.

Yes. Ted, no, it was actually split up between research and development and G&A. And indeed, most of the stock-based comp would have been recorded in the R&D section.

Great. That makes sense. Awesome. So can you give us a little bit more color on what to expect from 102 data this year? I know that we've still got more to hear about the healthy volunteers for the multiple ascending cohorts. But what should we expect from the single ascending doses from Parkinson's patients?

Thanks, Ted. And yes, the trials were going well. And I'll hand over to Noah to give you some of the details.

Hi, Ted, thanks for the question. Yes, good morning. So as you said, I think you summed it up. We're going -- we expect at a conference, an upcoming conference, to summarize the full healthy volunteer data set that we assembled. And in addition to that, if things work out, we'll be able to present some SADs data, which will -- I'm not going to go into the details of what we'll present exactly, but should be able to signal that we're on track with -- when you compare it to the healthy volunteer findings.

Next question comes from the line of Jonathan Miller with Evercore ISI.

Congrats on -- as I should say, congrats is the wrong word, but good job on getting your restructuring going.

I'd love to follow up on 102 question. Maybe it's a little too early to say exactly what you'll give us in patients this year. But maybe could you talk a little bit about what you hope to see in a more full patient data set? What are your bars for success in patients that can give you confidence going into later on in efficacy readouts?

Thanks, Jonathan. Noah?

Sure. Jonathan, so, yes, thanks for the interest here. I think we've outlined that we expect to start a Parkinson's disease multiple dose study over the course of the next month or so. While I can't really comment about when those data will be presented, the idea is that we're enrolling patients with the insights gained from healthy volunteers regarding a dose range, and that will allow us to establish that in patients who have higher baseline LRRK2 levels and also patients that are more elderly because healthy volunteers tend to be very young, like a little more than college age and Parkinson's disease are going to be more than twice that on average, I suspect.

So we'll be able to demonstrate that we have the same exciting results that we previously reported in healthy volunteers of orally bioavailable brain-penetrant PROTAC and the ability to move biomarkers, which also now we have much more insight into than we did many months ago, right? So we continue to do work to understand what are the best biomarkers that we can track and are going to be most predictive of an impact in the endo lysosomal trafficking and neuroinflammation that is characteristic of Parkinson's disease and PSP. And so we expect we could start tracking this in real patients rather than healthy volunteers.

Awesome. And then maybe on the BCL6, you mentioned in the press release and this call that glofitamab, that combination results to present this year, but you've presented on a number of different combos preclinically. Can you give us a sense of where you might want to start in patients, what combo therapies you may want to start with?

I think we've been -- I've been signaling in conversations. We can certainly speak clearly -- very directly about it here that our interest for BCL6 is to learn what -- find the dose in monotherapy. It's something we're obligated to do. But the real interest is moving forward in combinations, in particular, in DLBCL. And I think it should be clear to everyone that bispecifics in second-line plus DLBCL and maybe eventually in not that far in the future in first line are important drugs in that space. So if we can combine with bispecifics in human beings and get results that look anything like what we've seen preclinically, we think we're well positioned for a new modality of therapy with a real orthogonal approach that enhances the activity of the bispecific.

And remember, one of the great combination properties here is that we recognize that 393 can increase the expression of CD20 which could potentially make the bispecifics even more active. And on top of that, we've been reporting out the great potency with our drug that if that translates into the clinic, then that gives us a great competitive advantage against the only other degrader that's in the clinic currently.

Next question comes from the line of Derek Archila with Wells Fargo.

This is Karl calling in for Derek. So I guess for ARV-102, could you talk a little bit more on the elevated LRRK2 level in PD patients in terms of how much should we expect and how to maybe feel confident that similar more than 50% degradation can be achieved in CSF? And then on the vepdeg, the label potentially, could you talk about maybe the base case, what could be some potential differentiations you could expect versus your competitors?

I think I captured the second question with vepdeg, but there was a lot of cracking of the -- in the transmission to the first question. Did anyone here catch that?

Yes, if you could you maybe just repeat the first question. Just the first…

Yes, of course. Sorry about that. for ARB-102, so I guess the question is the elevated LRRK2 level in PD patients. Could you talk about the expectation of the elevation and how to feel confident that more than 50% degradation in CSF can be achieved?

Yes. So I think it's a great question. So fundamentally, I think it's been established by external sources that there is increased LRRK2 protein expression in the brain and in the CSF of patients with Parkinson's disease. In our own hands, we've already seen in the SAD that there are higher baseline levels of Parkinson's of LRRK2 than we observed in the healthy volunteers. So that's already kind of consistent, but not a surprise to us at all. That was the expectation.

In terms of one of the great properties of the degrader that I think differentiates it beautifully from an inhibitor is that we've already established in the healthy volunteers that we can get really good target engagement in the brain, right? And we know that the inhibitors just don't do that well, right? They're only achieving 30% or so inhibition in the brain. We know preclinically, they're not reaching deep brain regions as effectively as our degrader can. So we're getting higher engagement. And because we have a degrader here, which has that iterative property that at even lower exposures you get continued degradation of the target, we think that should be -- we should be well poised to reduce LRRK2 levels. That's the underlying premise that's been borne out in preclinical models. We've shown it in healthy volunteers, and now we think we can confirm it in the multiple doses in Parkinson's disease patients.

Regarding the second question, I think the question was how -- what differentiates us essentially from -- with our vepdeg from competitors in the space. And more or less it comes down to efficacy, the better PFS that's been seen when compared to fulvestrant control -- monotherapy control, which in our hands, we're talking about 3 months improvement, which other drugs really haven't achieved. On top of that, we have -- we're leaning into some PRO data that you'll see soon that show that the patients experience the drug very well. Certainly, the adverse event profile is more attractive which is to say that there's a lot of GI toxicity seen with other agents in this space. We have reported half or even 33% of that when you compare to different drugs. And I think that, that combination of benefit risk really stands out for vepdeg when compared to other agents.

Next question comes from the line of Tazeen Ahmad with Bank of America.

I maybe wanted to focus on some commercial questions. So as you think about vepdeg and the upcoming launch, you're obviously bullish about its place potentially in monotherapy, but you also talked about needing to be careful about how you're prepping for the launch. So how does this work in terms of setting up a sales force? When do you start prepping for that? How has that plan changed relative to what you would have planned for before?

And then secondly, if Pfizer returns rights for the program to the company, would there be a gap in between when Pfizer returned the rights and when you'd be able to secure a new partner? Or are you kind of in process now for seeking a potential replacement should Pfizer return those rights?

Yes. No, thank you for the question. Yes. So in the second part, I'll tackle that first. Clearly we're in negotiation with Pfizer right now. The original deal that we signed in '21 was a 50-50 co-development, co-commercialization, very attractive deal at the time. We had planned for doing second-line monotherapy, first-line adjuvant. And that would have been a very significant market and a very significant opportunity to share 50-50. With the decision not to go forward with first line or the second-line combo, it puts us into a position where vep at the moment is only focused on second-line monotherapy. So a smaller market really doesn't move the dial for Pfizer in terms of 50-50 and not particularly attractive for Arvinas either. So the dialogue we've been having actively with Pfizer is about how we redo the collaboration so that either they get more of the economics or we get more of the economics.

In a scenario where potentially we get the asset back, our plan is clear that we would immediately look to find the next partner that would help to develop vep and launch vep, which goes back to the first question, which is, as we stated, we are really not building out a sales force at all. Right now, we're focused on, first of all, getting vep approved and also getting launch ready, which is a relatively minimal amount of money that we'll be spending between now and the end of the year. So the idea would be that with that launch readiness, if we got the asset back, we'd run an active process and be in a position for another company to take on the development and launch of vep fairly rapidly. So we're hoping there wouldn't be a particular gap.

Okay. But as of today, could there be a gap between when it got approved and when it launched, if you are not able to secure the right terms then?

No, no. Sorry, say the last bit again. Say the last bit of your question, sorry?

I just wanted to clarify whether there would be a gap in the launch if you wouldn't find a suitable partner in time once it's approved.

So, yes, the suitable partner. So at the moment, the plan is there'll be no gap between getting approval, ideally having a partner in place or having Pfizer launch, there will be no gap at all. I think your question there is if you don't get -- if you get the asset back and you don't get a partner then, yes, we've taking stock of that. Our plan is that we find a partner if we get…

Next question comes from the line of Andrew Berens with Leerink Partners.

This is Amanda on for Andy. We wanted to get your thoughts on the recent readout from the Phase III trial evaluating [indiscernible] second-line HR+ breast cancer and patients that don't have a PIK3CA mutation, which then would include some ESR1 mutant patients. And we're wondering how does this change or if this changes your outlook for second-line ESR1 mutation patients? And if you would ever consider a combination with [indiscernible] to address a broader population?

Thanks for the question. Noah?

Sure. Yes. So we wouldn't -- we really are not surprised by the result. We recognize the opportunity for PIK3 mutation directed drugs to -- in breast cancer. There is overlap, as you had suggested between ESR1 mutations and PIK3CA. So the question comes down to whether it's in our modeling. And overall, we're -- my impression is that it will have little impact on the modeling. I could turn it over to my colleague, Alex, from commercial to offer further comments. But part of your question was whether we would develop it with an agent like that. And the answer to that is someone may, but we won't because we've already established that we're not doing further development on the drug, initiating new studies and combinations. And it would be something that should be very much of interest to another company. We've already scouted that out, but it's not something we'll be embarking.

Next question comes from the line of Li Watsek with Cantor Fitzgerald.

Nice progress on the pipeline. I guess for vepdeg NDA submission, it sounds like you know the PDUFA date very soon. Should we anticipate priority review here? And any guidance on your part for the global filing strategy? Do you need maybe to wait for more mature vep data?

Yes. For the second part of that question, I'll hand over to Noah. For the first part, yes, we're still awaiting details from the FDA. And as soon as we get that information, we'll pass that on. So we and don't have the PDUFA date yet.

Noah, do you want to tackle that second part of the question?

Yes. What we've shared, what we've offered guidance to is our filing of the NDA in the U.S. And obviously, we're waiting on feedback regarding PDUFA date. But regarding global strategy, we haven't offered guidance on that yet. So I think it would be premature.

Okay. And then in terms of finding maybe a potential new partner for vepdeg in the case that you got the molecule back, can you elaborate some of the considerations that you prioritize, what's important for you guys in terms of maximizing the value?

Yes, great question. I mean, clearly, we believe vepdeg is an important drug. We believe it has a lot of value. Because of the partnership we're in with Pfizer and the decisions have been made, maximizing that value is going to be somewhat difficult. So that's why we're in discussion with Pfizer about changing the nature of the collaboration. And ideally, as I said, either Pfizer or Arvinas should go forward with the asset more kind of fuller economics. And in the scenario where maybe we get the compound back, yes, we'll be looking to partner, and ideally a partner that does have the kind of the deal and interest to develop the asset further, both from the U.S. and the global setting.

Our involvement in that, I think, would be relatively minimal in terms of development. Our view is that we vepdeg in the hand of a partner, be it Pfizer or another company, that really takes the compound forward, launches it and progresses with further development.

Next question comes from the line of Akash Tewari with Jefferies.

This is [ Manoj ] on for Akash. What are your expectations around the Denali LRRK2 data in the first half of next year? And if that trial fails or doesn't meet expectations, what signals from that study would you be looking for to give confidence for your own degrader program?

Yes. Thanks for the question. Yes. If the question was expectations for the Denali program last year, I think it's a fantastic question. We think that LRRK2 is an outstanding target. And I think the entire key opinion leader community would agree with us on that. The question is, what is the best drug to address that target. And so we see some virtue in an inhibitor, but it has challenges. And I outlined that earlier that the inhibitor doesn't seem to penetrate the brain as deeply as, let's say, our degrader. And on top of it, it doesn't necessarily engage its target as effectively. We have a broader engagement. Not only are we binding it and degrading it and that we're eliminating because of that degradation, the LRRK2 kinase activity, the [ GTPS activity scaffold ] function. So all of those features make a degrader more attractive than inhibitor. So we think that they may succeed. We know they have the right target, and we are looking forward to learning from their results, learning if there's something about patient selection that could be incorporated and overall whatever signals can come out of their trial.

Next question comes from the line of Evan Seigerman with BMO Capital Markets.

This is Conor MacKay on for Evan. We just had a quick one on the submission of vepdeg. Given the current environment at FDA, we were just wondering if you'd be willing to characterize your recent interactions with the agency and maybe comment on level of alignment there.

And then just one quick follow-up on ARV-806. Would you be able to share a little bit more on how you're thinking about positioning this asset versus the pan-KRAS agent you mentioned today?

Yes. Thanks for the question. The second one, I'll hand over to Noah and Angela for the first one. I'd have to say our whole process with the FDA has gone very smoothly. The interactions have been excellent. Their timing in terms of getting back to us has been really good. So even though we know that there's lots of other pressures on the FDA, and it could impact time lines, we haven't seen that yet with our interactions on vepdeg, which is a really good positive thing for us.

Noah, do you want to add…

Regarding 806, I'll make some comments about clinical, and I'll turn it, when I'm done, to Angela, who may have some comments about some of the interesting differentiation preclinically. This drug entered the clinic a little faster than we expected because of great efficiencies at the team level. Then what we noticed is that there is tremendous appetite for drugs like ours in this space because our cohorts are in demand. So we're advancing through early dose escalation now.

Overall, we expect that there are going to be 5 or fewer dose levels in this escalation. So that's going to at least give you a sense of where we're headed. The key is to look at where we are in monotherapy compares ourselves to data that's out for inhibitors and the very, very modest and unimpressive data that have been presented by a degrader in the clinic, which is limited, had dose-limiting toxicity relating to hepatic function. So we'll compare ourselves to that. We have good go/no-go criteria. But then the intention is to move our IV degrader, which has once a week, possibly once every 2-week dosing. That's something we'll learn from this dose escalation in combination with EGFR inhibitors and with chemotherapy. And that's built into our plan, and that allows us to start moving into eventually first-line colorectal cancer and pancreatic cancer and also opportunities in non-small cell lung cancer.

I'll turn it to Angela.

Sure. Thanks, Noah. So just to comment on some of the other differentiation features of our 806 molecule. It's very potent with respect to its activity. We're 25x greater in terms of potency for antiproliferative activity with respect to the inhibitors and then 40x more effective than the clinical stage degrader. The other piece that I'll mention is that catalytic activity that we have overcomes this KRAS resynthesis rate that has been observed as a major mechanism of resistance in the clinic with RMC -- certainly with RMC-6236. So it's something we're excited about. We think this is a very strong differentiator. Of course, we'll see what happens clinically. So I hope that helps.

Next question comes from the line of Srikripa Devarakonda with Truist Securities.

This is Anna on for Kripa. So in regards to 102, I know you mentioned the elevated LRRK2 levels in Parkinson's. Could you remind us as to what percent of Parkinson's patients could be eligible for an LRRK2 targeting drug? And then a second question, just in regards to neoadjuvant vepdeg and that potential data readout, how would this potentially inform any room for vepdeg to be used earlier in the treatment paradigm and besides commercializing in second-line monotherapy and that fixed combo, any additional plans for development?

Yes. Thank you for the question. Noah, would you like to go to the LRRK2?

Yes. So LRRK2 levels are higher in the Parkinson's disease patients. Now we haven't made a choice that we're only treating patients with elevated LRRK2. And by the way, I should say that, that's something that might be on the table. It's something that we're going to explore. We're going to look at our own data sets as they evolve. We'll look at what's coming out of the Denali program, if it's shared. So that's a possibility.

If your question implies genetically, since LRRK2 is so implicated genetically in diseases like Parkinson's disease, if we -- when we move forward in Parkinson's disease, what patients -- what percentage of patients have LRRK2 implicated disease? Well, in idiopathic -- well, in familial Parkinson's, about 15% of patients are -- have LRRK2 mutations. And there's a higher percentage that have LRRK2 pathway mutations that contribute to other types of familial Parkinson's disease.

When you look at idiopathic, it's down in the few percent range. But beyond those LRRK2 mutations themselves, there are all kinds of pathway perturbations that suggest that LRRK2 could be at the center of this endolysosomal dysfunction that is characteristic of Parkinson's disease and PD. So you start to have 30% of patients that can have SNPs and other biomarkers that are associated with this LRRK2 dysregulation and may lead to LRRK2 elevation. And we have a particular interest in that subset of patients, and that's why we're engaging in a lot of biomarker analysis.

We've been a long-time collaborator with the Michael J. Fox Parkinson's disease biomarker initiative, and this is bearing fruit for us. So I think that we'll -- we have no kind of guidance yet about whether we're doing patient selection or patient enrichment or going for all comers, but these are the types of questions we are investing in right now to ensure that we have the best development plan moving forward.

Now the second question was about neoadjuvant vepdeg, so --

And our positioning, the potential for vepdeg in an…

Yes. So really, we have to keep in mind, there have been no evidence to date to suggest that vepdeg shouldn't be working in the adjuvant setting and in first line. We have every reason to believe that we can be very effective in that space. We know the drug is very tolerable. Cross-study comparisons suggest maybe we're more tolerable than aromatase inhibitors. That could be very important in both of those settings.

But ultimately, a decision is being made in this partnership that because of where we are with timing and the interest probably more than with our partner, in this case Pfizer in first line, that we're just not going to be going forward in those early lines. And that's why we've been giving so much guidance to -- for our intent to out-license this or proceed with renegotiation with Pfizer. But I don't think that we should draw any conclusions that there are any problems in the adjuvant setting or in first line.

Next question comes from the line of Jeet Mukherjee with BTIG.

So perhaps just coming back to the discussions with Pfizer over vepdeg. You've talked about scenarios where perhaps Pfizer gets more economics or you get more economics or perhaps you find a new partner altogether. So based upon where your discussions are right now, would you say that you and Pfizer have very different views on how to maximize value for vepdeg? And are you in active dialogue with other partners? If yes, how are those discussions going?

Yes, great question. I would say that Pfizer and Arvinas and the discussions we are having are aligned in terms of what the best way to get value for vepdeg is. Even though we might have different views about the development future of vepdeg, I think there's Pfizer and Arvinas truly believe there's value to be had there. And that's why we're in these discussions. Clearly, if the asset does come back, and again, that's just one of the scenarios, the other scenarios that Pfizer takes the compound for. But in the scenario where it comes to us, yes, we'd run an active process. But obviously, we cannot run an active process right now because we're in a collaboration with Pfizer, and we don't have the ability to do that.

Our belief is if we get the asset back, we ran a process, there would be companies extremely interested in taking a near-approved drug and with the potential to develop it not only in the first-line setting, but even earlier. So we are very pleased with the progress in terms of discussion with Pfizer. Like I say, if they want to take it forward aggressively and launch it themselves, that would be extremely positive. But if they don't and the outcome is we get the compound, then yes, we'd run an active process.

Next question comes from the line of Ellie Merle with UBS.

This is [ Tejas ] on for Ellie. I think you talked a little bit about some of the preclinical data for the KRAS inhibitors. Can you talk a little bit more about what we should expect with more data later this year? And how might that inform what we think about in the Phase I?

Great. Thanks for the question. I'll hand that over to Angela.

So for the KRAS inhibitors for 806, certainly you can expect to see some preclinical data just showing the differentiation profile that we see relative to inhibitors that are in the clinic. We'll also show some additional data just showing the combinability of the molecule. Noah had mentioned with EGFR mechanisms that's difficult with the pan-inhibitors certainly in the clinic, showing some side effects that would basically preclude that combination. We'll also show data that we think is really compelling from our oral pan-KRAS program, showing that we're making really great strides there as well.

Other additional comparative data that we'll have will include some other models where we're looking at combinability with immuno-oncology approaches and some of the unique features of PROTACs, we think, in this space, also with respect to the resistance mechanisms and overcoming that upregulation that is seen clinically with the inhibitors as well. So we think we have a very differential profile, and it's an exciting opportunity, certainly. And we're seeing that with the over-enrollment and the interest from the investigators that treat patients. So I think it's an exciting time, and I'm sure Noah and the team will be sharing clinical data as soon as we have it. Hope that helps.

Next question comes from the line of Peter Lawson with Barclays.

Maybe just leading on from the prior question. For the G12D and the update, when should we expect the initial first-in-human data update? And kind of if you could talk through how enrollment is going and the number of sites that are open and any other details around that trial? And then I have a follow-up.

Thanks, Peter. Noah, you want to take it?

Sure. So Peter, we just announced that we opened the study for enrollment a little ahead of schedule, and the immediate reaction seems to be very favorable. We haven't offered guidance yet on when we will be sharing data. But you're going to get it soon. We'll get the guidance soon, meaning it will be sometime next year, obviously. I would suggest just track things on clinicaltrials.gov because it's not -- we wouldn't typically be giving you site numbers and things like that for a Phase I study.

Got you. And I apologize, I arrived late on the call. But for the BCL6, so that's what 353, the data in the second half, kind of what should we focus on with regards to the data and kind of other metrics that we may be delivering in that data set?

Noah?

Sure. So we've shared that we'll provide some update of our data set in the second half of this year. I really don't want to get ahead of ourselves and share what that disclosure will be. But the idea is that we're advancing through our dose escalation program. And obviously, in dose escalation programs, the data that you're going to see are going to be more like -- but before you're done with it, safety and PK and early signs of efficacy. So I think you can look for those. Obviously, as we approach the completion of that or as we achieve the completion of that dose escalation or ready for expansion, we would be armed with more efficacy data, but still a focus on target engagement through PK/PD.

Got you. Would that be kind of like the range of like 10 to 20 patients or I presume kind of heavily pretreated. Any details there?

Yes, I would say that's a reasonable guess.

Next question comes from the line of Sudan Loganathan with Stephens.

This is [ Keethav ] on behalf of Sudan. So regarding the recent clinical data published by Celcuity on their advanced breast cancer asset, could you kind of just comment on your insights and what your perspective on that data is? And where do you like see vepdeg's competitive positioning within the treatment landscape?

No, thank you for the questions. Noah, I know you've tackled this earlier.

Yes. I'm not sure if I have more to add than what was said earlier. We recognize -- have always recognized that a drug like Celcuity could demonstrate attractive benefit risk in that -- in the second-line setting and in the first-line setting. There is overlap between ESR1 mutant and PI3 kinase targeting agents. In the end, what physicians are looking for are oral PROTAC, [ hypo ] oral degraders. So in our case, a PROTAC that has an attractive benefit risk profile. So we think we're delivering that. And physicians kind of want to avoid toxicity as much as possible and you get all the benefit they can after first-line therapy before adding drugs that have some toxicity. So the impact on market opportunity in that second-line setting is probably modest, but we haven't been offering specific guidance on market opportunities. So it's difficult to measure that modestly.

Next question comes from the line of Michael Schmidt with Guggenheim Partners.

This is Sara on for Michael. I wanted to quickly circle back to the oral pan-KRS that you mentioned. I would love to hear more details on that and specifically how you would expect to differentiate from later-stage pan-KRAS.

Sorry, we couldn't understand the question. Could you repeat it one more time?

There's a lot of echo.

One second.

[Indiscernible] Pan-KRAS and how it differentiates from other KRAS --

Yes, exactly. So my question was about the pan-KRAS and any thoughts on differentiating from later-stage pan-KRAS and pan-RAS programs?

Sure, sure. So as you know, we differentiate at least with ARV-806 from what we've said publicly. But our pan-KRAS program, we aim to have the same level of potency differentiation as well. We do bind to and degrade. So we degrade. We don't inhibit. So we avoid that upregulation that's observed clinically. So as you're aware, the clinical inhibitors, the pan-RAS inhibitor has shown a major mechanism of upregulation of KRAS as a resistance mechanism in the clinic. So they're claiming around 20% to 30% of patients that are seeing this. So it's pretty profound. So we think we have an opportunity there.

Our oral pan-KRAS also will have great combinability. We'll speak a bit about some of the differential profiles of our molecule relative to the pan-RAS molecules that are in the clinic. We expect that we'll have greater combinability with the immune stimulatory mechanisms like KEYTRUDA and other IO agents because we will not inhibit T-cell receptor activity. So we think that combinability will also provide a major advantage to other mechanisms clinically.

So there's a number of other differential activities that we're observing that we'll be discussing as we move forward and advance the program. But it's an exciting time for us. So stay tuned for more data this year at the triple meeting.

Next question comes from the line of Terence Flynn with Morgan Stanley.

This is Chris on for Terence. Just one question from us. For 393, beyond safety, what do you need to see in order to advance the asset into a combo trial with glofi?

Thanks, Chris. Noah, do you want to?

Sure. So we don't -- probably not a lot, like we weren't expecting any hematopoietic toxicity, which would be the principal toxicity of glofit beyond the CRS seen in the first cycle, but well managed with glofi's dosing over the first month or the first 3 weeks. So it's just a matter of reinforcing that we're not seeing any unexpected toxicities. And I don't have much more to add than that. Pretty clean drug --

Next question comes from the line of Yigal Nochomovitz with Citi.

This is Jon Kim on for Yigal. Maybe just one quick one from us. Can you comment on whether AI was utilized to facilitate the compilation and submission of modules for vepdeg to the FDA? And more broadly, any potential utilization in the early drug development pipeline?

That's a great question. I suppose your definition of AI. Yes, we certainly used a lot of kind of artificial intelligence in all of our research programs, and Angela can talk to the different features of that, whether or not it was used in the actual NDA application. Noah, I'm not sure --

Well, part of the NDA is a submission process. We do work with some vendors. So there is AI that's going on there through our vendors. But in terms of our business overall or the development part of our business, think of it AI as being able to help us with a lot of medical writing, right? So we're going to be able to take documents that we have previously generated across different assets and learn from them. These are things we're doing currently and learn from them to impact our medical writing cost and efficiency in the future.

Think of it also as something that helps in clinical operations to more efficiently review our vendor management, our contracts that there's more clear accountability and roles and responsibilities across different contracts for a company that does rely on a lot of externalized work in clin ops. And then obviously, we're using it in all the time with our status programming, like that's something that's been ongoing. There are many other areas in the company that are beginning to use it. But at least that gives you a sense of how it could have been used for an NDA and in like in our development programs.

And I can comment on how we're using it in research. So we have computational chemistry and computational biology teams that use AI all the time in machine learning algorithms. We've been applying AI to our PROTAC design features as we've been in this for 13 years, we've actually accumulated a lot of real-world data on PROTAC activity and optimization. We are applying that and learning from it. So we iterate our PROTAC designs much faster now. And so we're seeing a big benefit in how we move with speed in research. And so this includes pharmacokinetic properties of these molecules and absorption features as well, which, as you probably know, is really key for PROTAC design.

On the computational biology side, we're using it all the time for how do we go about analyzing our ligand identification data. So this enables us to go after previously undrugged targets and optimize those warheads to utilize in PROTAC for targeted protein degradation. In addition, I would say we use AI to mine real-world data from biomarker features that exist in publicly available data sets. And this sets us up well for deep understanding of pathway biology, and this is how we've been approaching our Parkinson's disease and also our PSP as well as other neurodegenerative diseases and really mining CSF protein changes in those diseases and have set the clinical group up really well to understand how we might use those biologic features to stratify patients. So thank you for the question.

Next question comes from the line of Tyler Van Buren with TD Cowen.

This is [ Ikan ] on for Tyler. Just to go back to the vepdeg and Pfizer collaboration. Has Pfizer indicated its willingness to revise the collaboration or give back rights to vepdeg? And why would they be motivated to give vepdeg back given the amount they have invested to date? Also, wouldn't that require a significant cash outlay by Arvinas? And are you willing to use the existing cash on hand with milestones or royalties to do that?

Yes. Just to reiterate, we're in the current 50-50. The attraction for that 50-50 was the planning on second line, first-line and neoadjuvant -- sorry, adjuvant trials. Now we're currently left in a situation where it's only second-line monotherapy, so less attractive in terms of a market size for Pfizer. They have shown no interest to develop that further. So that's the first important thing, that that will not be developed further by Pfizer. We're in negotiation right now about what's the best way forward in terms of moving away from the 50-50 collaboration we had where either Pfizer takes the asset and launches it and gets more economics or they hand the compound back to us.

I've said really clearly, I'll say it again, if the compound comes back to us, we are not spending any money on the further development of E, none at all. We'd be running a process to find a partner who would then ideally launch the drug and ideally further develop the drug and we gain the benefit -- the forward benefit of seeing the drug on the market. But we have no plans to further develop that if we got the compound back…

That concludes our Q&A session. I'd like to turn the call back over to John Houston for closing remarks.

Thank you, operator, and thanks to everyone for joining us this morning and all the fabulous set of questions. Obviously we look forward to providing additional updates in the coming months. But thank you so much for your time today.

Ladies and gentlemen, that concludes today's call. Thank you all for joining, and you may now disconnect.