ARVN - NASDAQ

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 E

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.