Arvinas, Inc. Aktie

Great. Thanks for joining us. I'm Terence Flynn, Morgan Stanley's U.S. Biopharma Analyst. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, very pleased to be hosting Arvinas this morning from the company, Randy Teel, the company's CEO, and Andrew Saik, the company's CFO. Thank you both for being here. Really appreciate it. Looking forward to the conversation.

Maybe to kick it off, Randy, you've been in the seat now for about 6 months. Just talk to us about your priorities. What are you most focused on these days as we enter the end of the year here?

Yes, thank you very much, Terence, and thanks for having us at the conference. Maybe also definitely talk about that as we go through the day or through the half hour. I want to talk a little bit about the company where we are right now, mainly because we've been around a little while, right? So the company is now 13 years old and has certainly gone through some phases.

We really have led the way in PROTAC discovery and development. And it's been really gratifying that just in the past few months, the first program that we invented is now in the market and serving patients. So it's off, treating second line plus breast cancer patients, which is obviously pretty thrilling for all of us at the company to have discovered the technology and have the first drug out in the market.

And we have now shifted, as we'll talk a lot about, to our earlier stage pipeline. So, we decided to not invest in the commercialization of that, but to focus our capital Phase 1 programs that we have that we now have 4 of. And I think one important feature for investors looking at Arvinas these days is that we've been talking for a while about milestones and catalysts from that pipeline coming out in the future, and now the future is very rapidly approaching.

So as we sit here in September and look out over the next year, year and a half, all 4 programs, including one that's just starting in the clinic this quarter, I would expect, to have important data coming out. So just to set the scene a little bit, we've got 4 programs in the clinic. The first is a BCL6 degrader for hematology indications and subsets of NHL. That program will have its first data by the end of the year.

We've got a neurodegeneration program that degrades LRRK2. That will have some important biomarker data coming up at a conference next month. We just began a rare neuromuscular program for Kennedy's disease, also known as SBMA. Started that in the beginning of the year. It's been enrolling well and we expect to have data in the first half of next year. And to round it out, we have an HPK1 degrader for use in immuno-oncology indications, just starting the clinic in this current quarter. And so, no commitments on data yet, but starting the trial now, maybe we'd expect to have data in a year or so. So we've been pushing those programs forward, I think, very effectively. We have made some important decisions.

To get to your point on priorities and prioritization, over the first 6 months of my tenure here, we've tried to be very focused. I've tried to lay down a very clear priority that where we invest, we're going to invest to win. And if we don't feel like we're positioned to do that, that will be a place for someone else to jump in and we'll talk a bit about that.

The last point I would make is, from a capital perspective, our guidance is into the second half of '28, so we certainly have the capital we need to get through these important inflection points. So when it comes to my initial priorities, it has really been to look at the pipeline. I've been at the company for 8 years, so it is not as if I've learned a great deal about the company in my first few months as CEO. I certainly continue to be impressed and amazed and proud of the team that we have and how well we've done at moving important programs into the clinic.

And right now, it's really about moving those phase 1 programs to their inflection points and seeing where the data are, where they end up, what makes sense as next steps for each program, whether that's to pile in and invest more, whether that's like happened for the KRAS program earlier this year, we decided that would only move forward with a partner, whether that's the call, that's what we're thinking about.

And also making sure that we turn ourselves a bit from being a company that was on the precipice of being a commercial company, to now being back to a company that's in phase 1. Those companies look different. They operate differently. They feel differently. And it's been very important to me and the team that we ensure that we are acting like a young phase 1 company and not a company that is about to be a commercial breast cancer company.

Okay, great, great, perfect framing. Maybe let's just jump into the assets that you walk through here. I mean, 393 (sic) [ ARV-393 ] is your BCL6 degrader. Maybe just give us an update and kind of, like you said, you know, data by year end, walk us through, the trial and maybe level set us on expectations in terms of what we should be focused on.

Yes. So ARV-393 is a degrader for BCL6. And BCL6 really, given our history, I'd say our formative years in AR and ER as our first targets. BCL6 was one of our first targets that's certainly an undruggable. There had been BCL6 inhibitors moving through preclinical studies, none really that I know have made it to the clinic.

And one reason for that is, and that makes BCL6 an ideal target for a PROTAC degrader, is that deep degradation of the BCL6 is important. It's rapidly resynthesized. And BCL6, just for a little more stage setting, is an important factor in B-cell development, functions in germinal centers to allow B-cells to rapidly allow to develop into mature B-cells and allow some DNA mutation without apoptosis that's important for B-cell maturation. It should turn off after that. If it doesn't turn off, that's where you start to have problems with BCL6.

So the study that we're running is in subsets of NHL. We are enrolling pretty broadly across both B-cell lymphomas, like LBCL, and T-cell lymphomas, like AITL. The landscape in that setting, which is an important context, is pretty crowded when it comes to other therapeutic modalities. If you're looking at antibodies, bispecifics, chemo, there's CAR-T therapies, there's transplant as an important modality. It's pretty crowded. If you're looking for oral therapies, it's not very crowded. If you're looking for BCL6 targeted agents, it's not very crowded.

And the way that the space has typically evolved is to add on additional therapies to deepen and extend responses, and that's what we'd like to do with a BCL6 degrader. So you made a point in your question about the conduct of that trial. We've been clear to say that for a couple of factors, we began that trial dosing at levels that we did not expect to be efficacious. So we made it through a few rounds of enrollment in different cohorts at levels that, especially in B-cell lymphomas, we would expect to be below an efficacious range.

So as we get to that first data, what we've decided to do is focus the first data release by the end of this year more on the T-cell lymphoma patients, and then save a disclosure for B-cell lymphoma patients more for the middle of next year or so. That allows us to focus on a population with very high unmet need, which later line, second line plus T-cell patients certainly are. And also, just through the way the trial was run, we mentioned about a year ago that we'd seen responses in both T-cell and B-cell lymphomas.

I think that unmet need absolutely led to an enrollment of a disproportionate number of T-cell patients versus what we would have expected. So we're going to focus on them first. The other thing that does is that as we get to the B-cell patient disclosure, more focused on those patients next summer, we also can discuss our ongoing combination therapy.

So we have an escalation ongoing with 393 (sic) [ ARV-393 ] as monotherapy, but we're also dosing with glofitamab in patients as well. So that will allow us to disclose both of those next year. So when it comes to this first data disclosure, there really is no specifically indicated therapy for second line plus T-cell lymphoma patients. So we will be looking for initial signs of safety, of course.

Obviously, we've been able to dose as we'd like to, so that feeling pretty good about that. PK, PD, degradation of BCL6, and of course, some early signs of efficacy. Now, in an escalation study, especially where I've said we would not expect early doses to be efficacious, we'll keep the expectations a bit more modest there.

But if you look over time, what a patient in second line AITL or diseases is getting, think of a 40% or so range of ORR. So that's what we'd be like to be seeing to make sure that we have good single agent activity in these patients. And then clearly, as we get to be dosing at a range that we'd prefer to be dosing at, we'd expect to continue to see improvement there. But that's how we think about the first set of data in the last part of the year.

Okay, great. And just remind us, is it like typical three-by-three design?

Yes, it's pretty typical design.

Okay. And then have you said how many cohorts? I know you said it's more predominantly T-cell versus B-cell, but have you said how many cohorts you've gotten through yet at this point?

I think we've said, assumed dozens of patients, but in terms of number of cohorts, haven't talked about it.

Okay, got it.

Okay. The important question I think will really be, now that we are, and we've said this, dosing at a range that we would expect to produce efficacious exposures, that's what we'll be most focused on. There certainly will be some patients that were dosed well below where we'd expect to see.

Okay. And how much follow-up will you have on those initial set of patients?

It'll vary much, it'll vary, right? So patients that are dosed the highest will have the least follow-up.

Yes, okay. And is this a, is this a medical conference? Is this something like an ASH update or this is a corporate?

We've said a medical congress. I think as an aside, that's really important for us in terms of making sure that, especially in a space where there's multiple players and a lot of combination options, I think it's really important for us to get word out about the trial, what's ongoing, how it's done, how it's performed, especially as the doses have increased. That being said, going back to what I said about acting like a younger phase 1 company, we certainly, over our history as a company, have used both medical congresses and done our own releases, and both are in play. We've said for this to expect a medical congress -- but I'm much more worried about making sure we get the data out at the right time in the right way.

Okay, makes sense. And I guess in terms of the monotherapy versus combo. So again, T-cell monotherapy is the approach, but in B-cell it sounds like combo. So the data update next year, it's sounds like it's going to be both monotherapy but also some combo data with glofitamab initially, or is it only going to be monotherapy data next year?

With combo. Combo data as well.

They have both.

Yes.

Okay.

Exactly.

All right.

Yes, and importantly, the patients treated with the glofitamab combo, those are LBCL patients, B-cell lymphoma patients, and I think as we look -- if we look at the landscape, right, and you may be getting this question, but as we think about development, across LBCL and other B-cell lymphomas and across T-cell lymphomas, there's really an opportunity to think about what you do in the late line versus what you do in the early line.

As monotherapy, the opportunities are really in the late line. Those opportunities can come a bit quicker. Trial timelines are shorter. Responses for patients are often unfortunately shorter, and so it's a bit quicker to run those trials. And we do think that those are important for demonstrating efficacy, allowing the sort of inflation of the number of combination trials that we can run to show that individual contribution of components. But that being said, it's pretty clear that there's unmet need in the earlier lines as well, especially as combination therapies with bispecifics or even chemo in some settings.

And those are also where there's a greater commercial opportunity. So as we think about a development path, it's going to include both. It won't necessarily be the case that everything has to be done in a sequence. You should expect some overlap so that even as we're moving into late lines, we're moving into earlier lines.

And I think the glofitamab combo is a great example of that, where it isn't that there's no opportunity for a glofitamab combo in later lines of LBCL, but the opportunity certainly gets more attractive as we move earlier into second line and places like that. So we'll be looking across the whole treatment landscape for places where we think it's right to put a BCL6 degrader.

Okay. Maybe just talk to us about the baseline characteristics of the monotherapy B-cell cohort versus the combo cohort? Is it all late line or does it differ because you have glofitamab in one of the combo arms? So meaning those are going to be like slightly earlier stage patients?

Yes, yes on that front, but they're all in this setting pretty late line. Like I said, even though there is not a tremendous number of options that are oral and certainly not BCL6 therapies approved, there are none. That being said, there are a lot of therapies in the space. And so patients that are going to be on a phase 1 trial get to be pretty late line.

And what, again, you said 40% ORR and T-cell. What's kind of the bar you're setting for the data mid next year?

So I think the easiest way to do that is to wait a little bit. So like I said, BCL6 was one of our first undruggables. So we were quite gratified to see that, as there are other players in a similar space, BMS being one of them, that they've had response rates over 50%.

So I think that as we look at what a combination or a, B-cell target looks like. We're going to actually have to look at what how the landscape is evolving because of those therapies. And that's, on the course of a year away. And I think there's a few data disclosures in between that will help inform that.

But right now, over 50%, of course, you've always got to look at the patients that you are cross-referencing. It's very hard to make these cross-trial comparisons. But I think it'll be easier to set a number of expectations when we get closer to those data. But we've been very gratified to see good response rates for BCL6 degrader in the clinic already.

Okay. And anything in terms of just given the pathway, anything -- any predicted safety, tolerability things that are on the watch list for the class as a whole that we should think about?

Not really. And by class if you mean class PROTAC degraders, definitely the answer is no.

I just meant BCL6.

Yes, if you mean BCL6 degrader. As we did our GLP tox, the only thing that was prompted for us to be paying attention to is eosinophilia. Of course, in phase 1, we'll be looking for everything. As we've looked at the other degraders that have shared some clinical data. I wouldn't say that there is a commonality between them. I don't think we've seen that.

They've also been still early releases, so that's going to be a place to watch it evolve. I do think it's worth pointing out, as we think about eventual differentiation from competitors here, it's a big space, especially as you move forward in combination, I don't think it's a winner-take-all kind of space.

I think that the way we develop and how we develop and the speed which we develop is going to be very important. And there will be opportunities to differentiate, whether that's deeper responses, whether that's safety, whether that's tolerability. It's a bit hard to speak too much with, when we're not sharing the data yet, but I think overall combinability, being able to combine well with a broad set of other therapies in the NHL space will, I think, be a very strong indicator success, which is one reason that we were quite pleased.

We put out a lot of preclinical data, a lot of preclinical models with many different combination agents, and we're really happy with what we both saw in terms of tumor regressions and inhibition, but also just the combinability and tolerability of those in the preclinical models, of course.

And then maybe just remind us, like, again, I know there's not any clinical data yet to do a cross-drug comparison to Bristol's BCL6 degrader, but on a preclinical basis, what do you think differentiates your drug the most from their compound?

Yes, I think that there's some comparisons that we've done. And doing our best to suss out exactly which compound they're using is always a good exercise to do. We did a couple things. One is that we built in some lenalidomide-like activity into our molecule that we do not believe that they did, which could allow for some stronger potency that you might otherwise need to get from adding on another agent. So that is a possible benefit.

And there were some differences that we have seen, again, cross-trial, cross-preclinical trial comparisons of looking at tumor regressions versus inhibitions that do make us think that we may have an edge there; it could play out. Those will really have to come to bear in the clinic, of course. Yes.

Okay. Makes sense.

But if we were to see differentiation, that could be a rationale.

And then again, I guess a couple of questions on just the kind of next steps. So would you guys, because again, B-cells, the bigger market versus T-cells, but let's say the data in, T-cells proves more promising would that be something that you'd go forward with or would you necessarily want it to be active in both settings kind of how do you weigh like that development path like going for just T-cell versus going for T and B cells together?

I see this the T and B cell a little bit like the question around what line are you going after?

Yes.

Which is that the T-cell patient population is much smaller right? The second line plus population is smaller. It gets more commercially attractive as you move into first line, which is certainly a possibility. That being said, the unmet need is pretty remarkable, right? In later line LBCL patients, there are treatments that patients are getting out to the third, fourth line. Once you hit second line in AITL, there's, I think I said, there's no specifically indicated therapy, and you're essentially getting a salvage.

You're getting whatever the physician feels might best work for you. So there's a very high unmet need in later line T-cell patients. That I think, if I could say, is greater than LBCL. I'd hate to say that one patient's need is greater than another's, but I think there's a bigger dearth of treatments in that space, even if it's smaller, on the LBCL side, there's opportunity up and down the landscape.

So I certainly think that we would not let's say be T-cell only. I think we'll be active in both.

Yes. Okay. Okay, got it. And then I'm assuming that, again, this one seems like more likely of a partner opportunity, just given the scale, especially, B-cell lymphomas, large market, seems like, again, if you're competing against Bristol, much easier to do that with a partner by your side. Is there something that -- again, I know you obviously data dependent, but is there something I'm missing, like why you would keep this versus partner or do some kind of collaboration?

Well, maybe I'll make one point and then invite Andrew to jump in, too. Look, as I said at the start, we need to find the places that we're going to focus.

Yes.

It's very clear that looking at the landscape for NHL, that combinations are going to be important. The gate that we've got to get through first is strong monotherapy activity and combinability. We've chosen to go with Glofit first, but that is not where we would expect to end. We would expect to begin other combinations.

Now, as we get there and we gain conviction and investors gain conviction, if we think it's the right thing to bring in partners, certainly we will look at that, but I also think that there is there's a lot of work to do here on our own before we get there. But, Andrew, any other comments on partnering?

Yes, no. I mean with regard to partnering, it's important that we keep an asset or 2 for ourselves and our shareholders where we think we can win. Right. And I mean, you know, I'll use 806 (sic) [ ARV-806 ] as a good example. We love 806 (sic) [ ARV-806 ] .

The results were great. It's going to come out late. It was an infusion as opposed to an oral. It's in a very competitive space. We felt like that was a space where a partner could do better, right? Somebody who's got more skin in the game in the overall RAS market wants to be in that space.

For us, it would have been a new entry. We would have been late. It would have been tough, right? BCL6 is different, right? So we're one of the, we're tied for the lead. There's 3 of us. We're pretty much neck and neck. We know where to go with it. There's lots of large pharma with interest in helping us with combination studies. That could take many different forms, right? It doesn't have to be an out-license, it could be partnership, it could be letting them run 1 line of therapy, we run another.

And Randy mentioned, there's also an AITL opportunity, which we could easily handle ourselves, right? We'd look for an accelerated pathway with the agency. That could be a quicker to market, couple hundred million dollar revenue stream. Very biotech friendly. So there's different ways to look at this. Okay. But we need to let the data mature a little bit to pick our path.

Yes. okay, great. Maybe just moving on to 102 (sic) [ ARV-102 ] which is your LRRK2 degrader for Parkinson's. You mentioned, Randy, some biomarker data next month. So again, I guess maybe just frame for us. Where that's going to be and what the relevant benchmark is.

Right. Yes. So the LRRK2 degrader is ARV-102, and the intention is to develop that program for both PSP, which is progressive supranuclear palsy, and then ultimately Parkinson's disease as well. And right now where we are is we've completed 2 phase 1 studies in Europe. So we did one in healthy volunteers, one in patients with Parkinson's.

The first data from that came out earlier this year at AD/PD, and then, Terence, as you said, we'll have another a bit next month as well at MDS. And what we showed back in March, AD/PD, was some pretty unprecedented movement in biomarkers.

Now, these are patients or healthy volunteers that are only being treated for 28 days. So for a disease like Parkinson's, which we went into, it's certainly a lot easier to enroll Parkinson's patients than rare disease patients.

After treatment with 28 days, we would not expect to see changes in disease therapy. It's a slowly progressing disease, as you all know.

But what we did show is that some biomarkers relevant for the endolysosomal function, which is critical for the degradation of proteins like tau and synuclein, which are ultimately what aggregate and cause diseases like Alzheimer's and Parkinson's. What we were able to show is that even after 14 days of treatment, we were able to induce strong reductions in those biomarkers in ways that LRRK2 inhibitors had been unable to ever show. So we thought that was pretty exciting.

We clearly know there's a big step down the road of actually showing that degrading LRRK2 can benefit and change the course of disease. That's not where we are. The data that we'll show next month includes a couple other measures. I think the really interesting one is an oculomotor measure.

Essentially, the way that works is if a patient has Parkinson's, their ability for their eyes to track an object will decline slowly over time.

That is now a test that, companies are looking at doing to try to get a preview of disease-related changes that will happen later on. So what we will be showing is data that describes after only 28 days, that we may be able to see some changes in those biomarkers. Now, obviously, it will later have to be shown whether changes like that will eventually predict changes in the course of disease.

But it's a really interesting piece of data to look at, and I think it's a really important illustration of how we, and we'll talk about this when we get to SBMA as well, of how we are very interested in using biomarkers to accelerate our ability to help patients identify that they have disease and identify patients for treatment and get to faster approvals over time as well and run better trials. And so we'll also be looking at additional biomarkers as well, which we'll talk about next month. The eye movement one is the one that's, I think, really easy to understand.

And is that -- is it -- so is it versus some kind of baseline or like how do you?

Yes. Think about it as a patient is going to decline at some rate. And then hopefully with the addition of AVR-102 that we are able to slow the change in that rate.

Okay. And what...

And again, it's only up to 28 days. Right. So expectations are should not be high there, but it's a really interesting new approach that we think will have some promise going forward.

Yes. Okay. What -- and then -- so then how do you gauge like clinical meaningfulness given the newness of the scale, I guess, right?

It's going to have to evolve with the trials that we are running, in the future, probably a good time to jump into that. Right. So we are looking at starting the next trials for ARV-102 in 2027, which was a change in plan that we announced a couple months ago. And just so everyone's on the same page, what happened there is we had been planning to move from the phase 1 trial that we did in Europe and then move into 2 additional trials, a phase 1B in the U.S. and a registrational type study that was more global. We filed the IND with the FDA and they put us on a clinical hold and said don't start. We hadn't started yet. It was a please don't start kind of hold. And they asked us to send the completed chronic tox data before we started that. So this is going back a couple months.

We said we would finish that study and submit it. We've now done that. And so we're now interacting with the FDA on a path forward there. The silver lining of that, which is clearly a pushback, is that we're now simultaneously having discussions with the FDA and with the EMA and with the PMDA in Japan, which I think gives us an opportunity that we wouldn't have had if we'd moved right ahead with the Phase 1B to harmonize some of the studies that we're doing in the path forward. So until those discussions are done, what we've said is we're going to push the start of the trial to 2027, which I realize is a bit vague, but we can, narrow that down as we come up with a clear path.

Okay.

And then when we complete these discussions with the agencies, we'll identify what the new path is, any changes to what we've said before, and, whether or not we'll continue with that same general design, which I'll describe as smaller trial first, bigger trial, or whether we might try to go with the, a single trial.

Yes.

But we'll talk about that when, as we get through those discussions.

Okay. Have you provided any more details on what the nature of the FDA request was? It sounds like more chronic tox data.

No, we haven't. It was really a -- we had done a pre-IND meeting a year and a half, couple years ago. And got the indication that going with the in-life portion alone would be sufficient. And they said that they'd like to see the full chronic tox data. And of course, I think any time you send data to an agency, they're going to have some questions. So we're responding to questions and working through the responses.

And has it been generally consistent in terms of the personnel at the FDA that you've been acting with since the initial, whatever this year and a half period that you talked about or has there been turnover?

I think you can assume there's been turnover.

Okay.

Yes. I don't mean to imply that is causing anything, but certainly there has been changes, and the team that we're working with now is not necessarily the same group that we've worked with before.

Okay, understood. I know the trial is -- you guiding to '27, but are you hoping to have the FDA hold resolved like by the end of this year? Or is that also a '27 event?

I think, so for me, the FDA hold is clearly important. Right. What's even more important is coming up with a plan for what the next steps for the program are that we can be clear across geographies. Because I think given the data that we've seen, the conviction that we have, we want to move this forward rapidly and aggressively.

To do that, I actually think we may be better served by having a trial that we can harmonize across the world and not just focus on the FDA so I don't have specific guidance for resolving a hold but I think as we get through the conversations with all the agencies in the next few months we'll have an update.

Okay. And just -- sorry just to be clear, because you talked about Parkinson's, but PSP, that if you do go the registration path, Is that Parkinson's or the PSP?

It's PSP. The next step is PSP.

Okay.

And some important features there. PSP is a much more rapidly progressing disease. Unfortunately, patients who are diagnosed with PSP often pass away within 5 or 7 years. So, on the rating scales that physicians use to grade the disease, patients can be decreasing by 10 points a year. The benefit to that for running a trial is that it can happen on a much faster timeframe. So, a Parkinson's trial is going to be longer. So we think it makes sense to Andrew's point on biotech activity and friendliness.

Right.

It makes sense to start with PSP. And, of course, we'll talk about PD as well, but PSP is the place that we would identify for the next trials.

Okay, great. Maybe just in the last few minutes here, ARV-027. This is for Kennedy's disease. Again, maybe just talk to us about the disease first because it's one that again, rare disease I think not a lot of people are familiar with. What I'm assuming there's a lot of unmet need, but then mechanism of your drug and how it could address the disease.

Yes, absolutely. So this program, ARV-027, is for Kennedy's disease also known as Spinal and Bulbar Muscular Atrophy, or SBMA. And it is a pretty devastating muscle wasting disease. It's a neuromuscular disease. And what essentially happens is in men, and it's almost always in men, what happens is you have a mutated form of androgen receptor called polyglutamine repeat androgen receptor, and it forms aggregates in muscle cells and leads to the muscle essentially wasting away.

It progresses slowly over time. It happens nearly always in men because it's an X-linked disease. The AR is on the X chromosome. Men only have 1, so if there's an issue there, that's where you're likely to get this disease. And the way that the drug works is very simple. It degrades AR. It degrades polyQ-AR.

Men with this disease only have polyQ-AR because they only have 1 copy of the gene. And so it's actually a pretty simple cause and effect, we think, where you have an aggregate protein inside the muscle cell. We're hoping to degrade it and see a benefit. As you implied, very high unmet need. There are no approved therapies in this space in the U.S. anyway.

No other therapies that we know of going after AR as the target, which we think is the clearest and simplest way to attack the disease. We have been in a phase 1 trial since the beginning of the year. We've completed a single ascending dose portion in healthy volunteers. We're now in a multiple dose portion with healthy volunteers. And the goal there is to identify a dose to move forward in even at the tail end of this phase 1 study, some patients with SBMA.

So the idea would be that if we're able to able to show that we can get a PROTAC degrader to be orally bioavailable, get into muscle, degrade AR in muscle, that will be a very strong indication that we can degrade the actual disease-causing protein in patients with the disease. So excited about that.

And I have to, as an aside note, as we've introduced this program this year, it's gotten a pretty strong reception, really because of the simplicity. This is not some upstream factor or some indirect driver of disease. We're degrading the actual protein that's causing the disease. So I feel like there will be an unusually high link between the phase 1 data here and eventual success in a way that is not clear in neurological diseases where there hasn't been a proof or evidence that affecting that target will change the course of it.

And just remind me how you guys have been working on AR, like you said, from the time of the IPO, ER, AR. So again, how does this drug differ from some of your earlier AR degraders?

Yes. We have had a couple of AR degraders. This would actually be our third in the clinic. And folks might remember that we out-licensed one of them to Novartis a couple of years ago. That's luxdegalutamide, an AR degrader. This is ARV-027 is a bit different. It also degrades AR and polyQ-AR. What's different about 027 (sic) [ ARV-027 ] is its ability to get into muscle. So we've designed it and selected it very much for its ability to get into muscle, which is where the important degradation needs to occur. So we do get asked that for contractual reasons as well.

We can't take 027 (sic) [ ARV-027 ] into prostate cancer. Novartis can't take luxdegalutamide into SBMA. If they did, it wouldn't work very well because of the muscle penetrance and so on, but just to be clear about that. Okay. But yes, it's really our third AR degrader, which is another reason that we're excited about this. Arvinas knows something about AR degraders for sure, so good opportunity.

What and then just so to measure this AR degradation, this is a biopsy measurement?

Yes.

Okay.

Muscle biopsy.

And than I guess the question is just what level of change is needed? Like how do you know what that threshold? I know this from the AR degradation, there's always a debate about how much degradation do you need to drive a clinical benefit. So here, how do you judge how much is enough, I guess?

Yes, it's interesting that it's a very similar target, not quite what it's polyQ-AR versus AR, but very similar, but that operate in very different ways. So in prostate cancer, we're degrading AR, which of course is not the, which can be a driver disease, but prostate cancer is not caused by the aggregation of AR. Here we're actually degrading the disease driver. So we think that probably 50% is a good target.

We get asked a lot about, you know, what would the potential side effects be, right now, so, but remember that the men that have this disease will already exhibit some of the effects that you might expect from an AR degrader, like. And so it might be expected that if you degrade all of it, you could make it worse.

But in general, we would expect less effect from treating with the drug. The reason we've come to 50% is that in a preclinical mouse model, where mice are expressing polyQ-AR and exhibit a downward decline in muscle, grip strength, endurance, things like that, if we treat and reduce polyQ-AR by about 50%, we not only see a stoppage of the decline of disease, we actually see full improvement by some measures. So mice that have been treated with 027 (sic) [ ARV-027 ] go back to wild type levels of endurance. I'm not predicting anything about what happens in patients, but if we can see that with only 50% degradation, that's really the target. There's really no need to go higher than that. So that's what we will be aiming at in the clinic.

Okay, great. Well, I think we're up against time, but appreciate it and looking forward to all the data.

Thank you very much, Terence.

Thanks, Randy. Thanks, Andrew. Thanks, everyone.

Hello, and welcome to Arvinas Second Quarter 2026 Earnings Conference Call. [Operator Instructions] I would now like to hand the conference over to Jeff Boyle. Sir, you may begin.

Good morning, everyone, and thank you for joining us. Earlier today, we issued a press release with our second 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 Chief Executive Officer; Angela Cacace, our Chief Scientific Officer; and Andrew Saik our Chief Financial Officer.

Before we begin, I'll remind you that today's discussions contain forward-looking statements that involve risks, uncertainties and assumptions. These risks and uncertainties are outlined in today's press release and in the company's recent filings with the Securities and Exchange Commission, which I urge you to read. Our actual results may differ materially from what is discussed on today's call. A replay of this call as well as today's press release and an updated corporate deck will be available on the Investor and Media section of our website. Now I'll turn the call over to Randy Teel. Randy?

Thanks, Jeff, and good morning, everyone. As a company, we've made significant progress over the past several months. Our focus has been on positioning Arvinas for our next phase of growth, guided by a clear strategic vision. Central to that vision is a relentless focus on advancing transformational improvements for patients. Through continued innovation and disciplined execution, we are focused on unlocking the full potential of our pipeline for patients and shareholders. We've reached 3 significant strategic milestones since the start of the year, beginning with the first-ever FDA approval of a PROTAC degrader, VEPPANU.

Second, we completed an out-licensing of VEPPANU to Rigel Pharmaceuticals, who anticipate making VEPPANU available to patients in the very near future. And third, we made the strategic decision that our KRAS G12D program, ARV-806, will only move forward in the hands of a partner. While we believe 806 has the potential to become a meaningful treatment option for patients, it will require investment that is inconsistent with our current capital allocation strategy.

Taken together, our progress and decisions in the first half of 2026 have positioned Arvinas to fully capitalize on the promise of our platform in oncology and neurology. We fully shifted our focus to our Phase I clinical programs, and we are confident about the opportunity ahead to create important therapies for patients.

With that, I'll spend a few moments diving into our 3 assets with significant clinical data catalysts in the next 12 months. I'll review their differentiated profiles and compelling value propositions. I'll start with ARV-393, our BCL6 degrader. I'll explain why BCL6 is an attractive target, share where we are in the progress of the trial and let you know what to expect in our data release later in 2026.

BCL6 is an exciting therapeutic target with initial clinical validation. BCL6 is a previously undrugged transcription factor and 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.

We believe that ARV-393 has the potential to become a foundational treatment option and pave the way as the first all-oral chemotherapy-free approach for patients with B or T-cell lymphomas. When we initiated our BCL6 program, no company had successfully demonstrated BCL6 degradation or advanced a degrader to the clinic. Based on feedback from the FDA, our trial began with doses well below our predicted efficacious exposure levels, leading to challenges with enrollment and extended enrollment time lines. However, we've seen a clear acceleration in the enrollment of the trial as we've dosed closer to the expected efficacious range. At the same time, enrollment in the glofi combo portion of the trial has been strong since it began in the past few months.

And as we reported late last year, even at the doses we would not have expected to be efficacious, we've seen early responses in difficult-to-treat T-cell lymphomas like AITL as well as in patients with B-cell lymphomas. When it comes to upcoming data for ARV-393, we are on track to share initial Phase I data by the end of the year.

Our safety profile has supported continued dose escalation, though the majority of the data in 2026 will be from the early cohorts dosed below the expected efficacious range. These early cohorts when compared with the overall lymphoma population include a higher-than-predicted proportion of patients with T-cell lymphomas, likely reflecting the limited treatment options for these patients. But as I mentioned, as we've approached the predicted efficacious range, enrollment of patients, including those with B-cell lymphomas has increased.

In 2027, we will plan a subsequent disclosure that will include more mature monotherapy data, including patients with DLBCL treated with ARV-393, both as monotherapy and in combination with glofi. We are optimistic about the potential of this program to benefit patients who have historically experienced poor clinical outcomes, especially given the positive feedback we've received from investigators over the past few months. I'll turn now to ARV-027, our degrader targeting polyglutamine repeat androgen receptor or polyQ-AR. What's immediately interesting about this program is that the polyQ-AR protein is well understood to be the driver of pathology for patients with spinal and bulbar muscular atrophy or SBMA, also known as Kennedy's disease.

SBMA is a rare neuromuscular disorder with between 10,000 and 13,000 diagnosed patients in major markets. Genomic studies suggest that SBMA remains substantially underdiagnosed and ARV-027 has the potential to become the first therapy to target the primary driver of disease. SBMA is an X-linked disease caused by the toxic buildup of the polyQ-AR protein in skeletal muscle. This accumulation disrupts normal muscle function, drives muscular atrophy and over time, leaves patients with long-term physical disabilities and often unable to accomplish daily activities. As an oral therapy, ARV-027 could be uniquely suited as a convenient treatment option to degrade the protein known to cause the disease.

In February, we presented preclinical data supporting the potential of ARV-027 in SBMA. Guided by published preclinical evidence, we had established a target of achieving greater than 50% polyQ-AR degradation in skeletal muscle, a level we believed would provide functional benefit. In an aggressive mouse model of SBMA, 027 showed meaningful improvements in grip strength, endurance and survival. Importantly, while we don't believe complete elimination of PolyQ is required to achieve therapeutic benefit, our preclinical studies did demonstrate that 027 could achieve AR degradation far exceeding the levels required for functional improvement.

Today, I'm pleased to announce that in our ongoing Phase I trial in healthy volunteers, we completed the single ascending dose cohorts and have now initiated the multiple dose portion of the trial. 027 is our first degrader aimed at a target in muscle. With that in mind, our Phase I trial must demonstrate 2 measures that we've never demonstrated before in human muscle tissue. The first step is achieving adequate exposure and the second is to demonstrate AR degradation in muscle. Taken together, these healthy volunteer data would provide proof of mechanism for ARV-027 and meaningfully derisk the program. In the first half of next year, we intend to show data for both of these measures as well as initial safety data from the trial.

Following the dosing in healthy volunteers, our plan is next to dose patients with SBMA. The Phase I trial design already includes a multiple dose cohort in patients with SBMA. We believe this design will accelerate our development plan with the potential to move to a registrational study following the conclusion of the Phase I trial.

Finally, I'll move to ARV-102, our third program with upcoming clinical data and discuss plans for upcoming disclosures and provide a brief update on our regulatory interactions as we plan the next trials for our LR2 (sic) [ LRRK2 ]degrader. As a reminder, there are no approved disease-modifying treatment options available for patients with either PSP or PD, and we believe 102 has the potential to become a paradigm-shifting treatment for these patients. This is supported by biomarker data that we presented in March at AD/PD. These data were the first to show modulation of key biomarkers implicated in both PSP and PD, an outcome that has not been demonstrated by LRRK2 inhibitors. This reinforces the potential for 102 to provide a unique approach in neurodegenerative diseases.

We will share additional biomarker data from the Phase I trial, including ocular motor measures and CSF proteomics at the MDS conference in October. When it comes to our regulatory interactions for 102, as you'll recall, we are currently working to initiate clinical trials for 102 in patients with PSP, both in the U.S. and globally. After successfully completing our Phase I trial in the Netherlands earlier this year, we submitted an IND to the FDA to support the initiation of the Phase Ib trial in the first half of the year. As previously communicated, prior to authorizing initiation of the trial, the FDA requested additional information as well as final data from our chronic tox studies, which we've now completed.

During the quarter, we've also had productive engagement with both European and Japanese health authorities. Interactions with the agencies are ongoing, and we look forward to updating you on our timing for initiating our next clinical trials, which we now expect to begin in 2027.

Stepping back, our accomplishments and decisive actions during the first half of 2026 demonstrate our ability to embrace change, capitalize on new opportunities and execute efficiently. I'm proud of the entire team at Arvinas and how we've assertively concentrated our resources on the most promising opportunities for Arvinas.

With disciplined capital allocation, we are prioritizing programs that address high unmet need and have strong commercial potential. Our pipeline is designed to maximize both clinical impact and long-term shareholder value. With that, I'll turn the call over to Angela. Angela?

Thank you, Randy. The Arvinas approach to breakthrough medicines begins with choosing the right biology. The most important decision is selecting targets where targeted protein degradation can fundamentally change the course of disease. We started with 2 highly validated targets, androgen and estrogen receptor to establish the clinical power of our degrader platform. Today, we're applying those same principles to build the next generation of differentiated disease-modifying medicines across oncology and neurology.

Randy highlighted the progress of our clinical portfolio I'd like to spend a few minutes on 2 oncology research programs that illustrate where we believe protein degradation can deliver unique advantages. I'll begin with ARV-6723, our oral HPK1 degrader and our first immuno-oncology PROTAC.

HPK1 acts as a natural break on the immune system. It limits T cell activation and suppresses antitumor immunity. What's particularly challenging is that HPK1 biology extends beyond its kinase activity. HPK1 also functions as a signaling scaffold. As a result, inhibitors of the kinase activity leave part of the biology intact. Instead, degradation eliminates both kinase and scaffolding functions. We believe that's why ARV-6723 has produced a differentiated preclinical profile compared with inhibitors.

Across multiple tumor models, including tumors with both high and low immunogenicity, ARV-6723 produced robust antitumor activity. In these studies, degradation consistently outperformed both an HPK1 inhibitor and anti-PD-1 therapy alone. Perhaps most exciting is what we've observed in checkpoint-resistant tumors. In 7 preclinical models, ARV-6723 demonstrated meaningful single-agent activity where neither an HPK1 inhibitor nor anti-PD-1 therapy showed benefit. We also demonstrated preclinically that the biology extends well beyond T cell activation.

HPK1 degradation may remodel the tumor microenvironment through enhanced interferon signaling and activation of the myeloid compartment. We believe this broader immune remodeling may be due to elimination of the scaffolding activity that contributes to the differentiated profile we've observed. And if it translates clinically, could support broader combination opportunities and activity in tumors that have historically responded poorly to immunotherapy. We're excited to begin translating these findings into the clinic. We remain on track to initiate enrollment in our Phase I study in the coming weeks. We look forward to sharing updates as the program advances.

Finally, I'd like to highlight our first-in-class oral pan-KRAS degrader program. We recently presented preclinical data demonstrating the potential to overcome key limitations of current pan-RAS inhibitors. Our lead oral degrader showed potent activity across a broad spectrum of KRAS mutations. Importantly, our lead oral pan-KRAS degrader targets KRAS mutations found in more than 90% of patients with KRAS-altered cancers, including difficult-to-treat mutations such as G12R and Q61. It also demonstrated activity against KRAS amplification, a major mechanism of resistance.

We also demonstrated superior antitumor activity in combination with immune checkpoint blockade, highlighting the potential to favorably remodel the tumor microenvironment in a way that inhibitors do not. Together, these findings support the potential for broad activity across KRAS-driven cancers, a differentiated therapeutic index and extensive combination opportunities. We will present these exciting combination data at an upcoming scientific conference.

The team continues to make outstanding progress, and we look forward to sharing additional updates in the coming months. 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 second quarter 2026. As a reminder, detailed financial results for the second quarter are included in the press release we 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 second quarter, we had $567.9 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 developing our promising oncology and neurology programs. Q2 is a very busy period for us as during the quarter, we received FDA approval of the first ever PROTAC degrader VEPPANU and regulatory approval for the Rigel license agreement. These events had a significant impact to our financial statements, which I will summarize now.

First, as a result of the license agreement with Rigel, we recorded license revenue of $62.5 million, of which $35 million was received within the quarter. We have also concluded that the method by which we were recognizing revenue under the original Pfizer agreement is no longer applicable under ASC 606 as a result of the Rigel agreement.

We, therefore, moved all deferred revenue to the P&L, which resulted in a net revenue of $126.4 million, and we recorded a liability of $52.7 million to cover our remaining obligation to complete ongoing development activities. Additionally, we recorded a $50 million milestone from Pfizer triggered by the VEPPANU approval. Separately, we recorded $3.5 million in revenue under a Pfizer research collaboration agreement where the research term has been completed. Total revenue for the quarter was $249.7 million.

Turning to expenses. During the quarter, we introduced a new cost of license revenue line, which represents royalties and other amounts payable to third parties that are directly attributable to revenue under our licensing agreements. Cost of license revenue was $9 million in the second quarter. The $9 million is comprised of payments to Yale under the amended Yale agreement and were triggered by the FDA's approval of VEPPANU and the entry into the Rigel license agreement.

General and administrative expenses were $24 million for the second quarter compared to $25.3 million for the same period of 2025. The decrease of $1.3 million was primarily due to decreases in personnel and infrastructure-related costs of $3.9 million and costs related to developing our commercial operations of $1.4 million, partially offset by an increase in professional fees of $4.2 million, primarily due to the Rigel license agreement.

Research and development expenses were $52.6 million in the second quarter compared to $68.6 million for the same period of 2025. The decrease of $16 million was primarily driven by a decrease in compensation and related personnel expenses of $11 million, which are not allocated by program and a decrease in program-specific expenses of $0.6 million and non-program-specific expenses of $2.6 million.

Our cost reduction programs initiated last year were completed during the second quarter. Non-GAAP R&D was down $8.1 million compared to the same period last year, representing a reduction of 14%. Non-GAAP G&A increased by $0.3 million or 2% compared to the prior year. During the quarter, we recognized all remaining deferred revenue from the Pfizer collaboration agreement. So going forward, there will be no revenue recognition related to the original Pfizer collaboration. Additionally, we booked a liability of $52.7 million to cover estimated remaining liabilities related to the VEPPANU runout costs. So our future obligations under the collaboration agreement will be booked against the accrual and will not impact our P&L.

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 highly differentiated pipeline programs that have the potential to meaningfully improve patients' lives. With that, I'll turn the call over to Randy for closing remarks.

Randy? Thanks, Andrew. We've entered the second half of 2026 with multiple opportunities to advance our mission of developing pioneering transformational therapies for patients. We have important catalysts in the coming months and a healthy balance sheet to reach critical milestones. I'll simply close by thanking the patients, investigators and the entire Arvinas team for their continued support and commitment to helping us achieve our mission.

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

[Operator Instructions] Our first question comes from the line of Nick Lorusso with TD Cowen.

So on 393, can you discuss a little bit more what you're thinking about the development path, especially considering the data coming mid next year with the glofi combo. Could this catalyze like a potentially pivotal trial in an earlier line setting with bispecifics? Any insight there would be great. Yes.

The short answer is yes. The long answer is the NHL space has a lot of opportunities to pursue, right? And so as we've talked about over the years, we think that while there's a lot of therapies across the lines of therapy, across the different diseases now, there's plenty of chemo. There's plenty of CAR-T, there's plenty of bispecifics. What there's not a lot of is orally bioavailable, tolerable small molecules. And so we think that a BCL6 degrader could slot into multiple areas within the disease landscape.

So at this point, as we're in the Phase I dose escalation, a bit early to talk about exactly where we plan to go, but definitely can talk about the options, right? So I think as early options, looking at later line monotherapy makes sense, think about fourth-line LBCL, maybe third-line LBCL, think about later line AITL T cell disease that we've been enrolling patients with already in our Phase I trial. As we move forward with combinations, that could open up further access to the third-line LBCL space, second-line LBCL and perhaps moving ahead in T cell disease as well. So there's a lot of different places that we could go. And I think that the common thread is that to get to any of them, we've got to get through the monotherapy dose escalation, show some efficacy, show some signals there. We've got to show we're combinable with other therapies, most immediately a bispecific like glofi. And once we've done that, I think it becomes a lot easier to talk about where we'll go next, especially as the landscape continues to evolve around us.

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

This is Jacob on for Derek. I was just wondering if you could comment on the path forward for ARV-102 in PSP. And what does the time line and registration path look like for it in light of some of your more recent regulatory interactions?

Yes. So just to rehash a little bit where we are, right? So we began the year with a couple of Phase I trials, one in healthy volunteers, one in patients with PD. And what we plan to do over the course of the year was to start 2 other trials, a Phase Ib in the U.S. and a registrational-oriented study globally. So what we announced a couple of months ago is that after submitting the IND to the FDA, they asked us to wait before starting that study. So that's technically a clinical hold before starting the studies in the U.S. And then this morning, we announced that with a number of ongoing regulatory interactions that we're currently pursuing and going back and forth on, we think it will take into 2027 to start those studies. So overall, the registrational path in PSP we would think about the 2-part study there, the Phase Ib and a registrational study, that continues to be where we aim. A registrational path for PSP where we haven't even dosed patients yet would more likely be a longer period study. The studies we've done so far are only 28 days.

So dosing more like 6 months or a year in patients with PSP would be what we'd be aiming to start with a registrational study. Definitely worth saying that as we go back and forth with the different regulatory authorities, which actually is quite beneficial to be getting feedback from the 3 major agencies all right now, we'll be taking that to finalize the path that we will then set out on, as we've said in 2027.

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

Maybe a follow-up on ARV-393. What will be a good outcome from the Phase I monotherapy cohorts that you're going to present later this year. It sounds like these are going to be at the subtherapeutic levels. And as we think about combination with glofi, would you be able to share where you are with the dose levels right now? Did you start at the subtherapeutic levels as well and early trends on combinability?

Yes. The short answer on that second one is yes. And just as a recap, we've talked about this in other venues. We were the first company to start working on BCL6, at least to bring it into the clinic to our knowledge. And based on that and some other factors, we got some feedback to start with a very low starting dose for BCL6 as monotherapy. And as we talked about with some operational questions that enrollment has been certainly slower than we would have liked.

On the flip side, as we've gotten closer now to the predicted efficacious exposures, we've seen a clear uptick in. And in the combination study, which started a couple of months ago, that enrollment there has been quite strong ever since the start. So when it comes to the data that we will have at the end of the year, you were right to highlight we will be still very much in the -- below the efficacious range for most of the patients.

In the doses that we're at now, we're starting to get to the exposure that we would expect the efficacious. So we'll start to see some of that. We also mentioned that we have been enrolling a greater proportion of patients with T-cell lymphomas than we would have anticipated based on the overall population. So we think it will make sense to focus on that population and the disclosure that's coming up. And then also, as we talked about heading into next year, focusing on LBCL patients as both monotherapy and combo. The data at the end of this year will certainly be focused on mono. We do not anticipate sharing combo data. We didn't start quite as low for the combo as we did for the mono, but it certainly is starting -- it certainly did start at levels that in monotherapy were not predicted to be efficacious in patients with B-cell lymphomas.

Our next question comes from the line of Edward Tinhoff with Piper Sandler.

Looking forward to more data this year, and congrats on all the progress. So I'll ask about SBMA and 227, really interesting mechanism here. Just to confirm the IND cleared there and what are we waiting for to -- I'm sorry, the -- where are you in multiple ascending dosing? And can you kind of characterize -- you mentioned exposure and degradation. What are the clinical endpoints that we would ultimately be modeling or expecting in SBMA?

Maybe I'll pass to Angela in a moment on some of the path forward questions. To reiterate where we are on that question, right? So we have been dosing healthy volunteers with 027. We've now completed the single ascending dose portion of the study and have just begun the multiple dose portion of the study. That will continue. We're expecting to share some data at the beginning or in the first half rather of next year. We do anticipate including some patients with SBMA in the latter stages of that Phase I study. And just to reiterate for everyone, this program, well, SBMA is certainly a rare disease. We're talking 10,000, 13,000 patients in major markets or so. The great thing about this target is that we are hitting the actual driver of disease. So polyglutamine AR is what drives disease.

That's what we're degrading. We're not degrading an upstream transcription factor or some other factor, we're degrading the actual cause of disease. When it comes to the next phases, we've talked about being able to move into registrational intended studies even after Phase I. But Angela I invite you to speak a bit more about plans there and endpoints and so on.

Sure. As we move forward, the goal is to really demonstrate that we can target 50% reduction of the polyglutamine repeat androgen receptor. In our preclinical studies and in other preclinical studies, 50% reduction is the target that we aim to achieve in muscle. So that's our goal from a biomarker perspective, and we'll also look at some other endpoints as well. Those will be the early endpoints. We will not be able to demonstrate functional change until we go into those registrational studies that Randy mentioned. And there, we'll be looking at meaningful scales like the SBMA functional rating scale and those endpoints as well.

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

Congrats on the progress this quarter, guys. I'd like to follow up first on the polyQ-AR. There'll be a couple of patients you said next year. Am I right to assume that we shouldn't expect to see good translation of degradation rates from healthy volunteers to patients that have different levels of protein at baseline? And if that's the case, are there particular measures from healthy volunteers that you think will translate well to eventual degradation efficiency in patients and thereby efficacy and functional endpoints?

And then similarly, on the other data sets where we'll get early data from, I'm thinking of HPK1 where you're going to dose in healthy volunteers to start. Are there particular endpoints that we should be paying attention to when we eventually see that data that you think will translate well?

All right. So on 027, the short answer on translating the degradation of 027 in polyglutamine AR, which the patients may have versus wild-type AR, which healthy volunteers will have, is that it's the same. We effectively degrade wild-type AR and polyQ-AR the same. So that will be really helpful to see, as I mentioned, that as we share the healthy volunteer data in the first half of next year, just to reiterate, there's a couple of pieces there that we have not done before, and we're looking forward to see if we can do. One is getting an orally available PROTAC in muscle. So that alone we haven't been looking for before.

And second of all, getting degradation there. And we think that if we can see degradation of the wild-type AR in healthy volunteers, that will bode very well for our ability to degrade the disease-causing polyQ-AR in patients. So I think the translatability there will be quite good. I can move on to HPK1 question, but Angela, anything to add on the polyQ question?

Just to add, John, that we did look at iPSC-derived skeletal muscle from both healthy volunteers and SBMA patients and the pharmacology was exactly intact, which is exactly what Randy was saying we would translate. And so that's our goal, and that's our reason to believe.

And on the HPK1 program, 6723. So again, as we said this morning, that's going to start dosing patients here in the quite near future. The thinking there is that this is our first IO therapy. So the first couple of trials will look very similar to other oncology trials, right? These will be in patients, not healthy volunteers, just to clarify that. It's an escalation design. We'll be looking at monotherapy. The Phase I also includes combination setting as well. And we think it's really important there to show some initial signs of efficacy and, of course, safety, tolerability and combinability as well. The HPK1 program is interesting, right? So the first IO therapy, it's got quite a large opportunity.

We've certainly got to show, as we're very aware, something that the HPK1 inhibitors have not shown, which is good response rates and so on in patients, but we are really confident that we'll be able to do that based on the preclinical data we have which really goes a long way to show, including some recent preclinical data this year that we can have differential effects in getting responses, get inhibition and affect the tumor microenvironment in ways that HPK1 inhibitors have been unable to do, PD-1 therapies have been unable to do. And so for that reason, we have some good confidence moving into Phase I, but look forward to sharing those data.

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

I had 2, one on BCL6. I think you mentioned, Randy, that the enrollment was a bit slow at the subtherapeutic doses, but you also mentioned that you saw some effective responses at the lower doses. So I was just trying to square those 2 things. I guess I would have thought that if you saw responses below therapeutic doses that would catalyze the enrollment curve. And then secondly, on LRK (sic) [LRRK2 ], could you just comment on the -- obviously, since the last earnings, Biogen and Denali had the Phase IIb for their inhibitor, which, as you know, didn't work, but I'd just love to get your thoughts on that and why the degrader may be a more promising approach?

Yes. So on BCL6, what you said is correct, and you did point out a bit of a contradiction, which we're certainly aware of. So yes, we started pretty far below the predicted efficacious range. And the other feedback that we gotten was around the design and the escalation of it. So not only do we start low -- sorry, not only do we start low, we've also escalated pretty slowly. Seeing the responses that we have has certainly helped. But I think especially where we're doing the trial in the U.S., especially in LBCL patients, there are quite a number of other options that patients can take before they get on to a clinical trial. And I think there's quite some natural hesitance by physicians to put patients on a dose that they might not expect to be efficacious when there are other options out there. So I do recognize that it has certainly picked up as we've gotten closer.

The responses have helped. And it's another reason that we're excited to get some of these data out by the end of the year and especially with respect to T cell patients where we think we'll be the first to share data for BCL6 degrader looking at that patient population. When it comes to the LRRK2 program in LUMA, I think that -- and Angela, try to chime in here as well. As we've gotten asked about that over the past couple of months, the questions have largely followed the same path, which is, look, LUMA Trial didn't work. We didn't expect it to work. Is there anything to learn? And I think that for us, what we've been really focused on since the beginning of this program really was the fact that we don't think that inhibiting the kinase function of LRRK2 is enough. We think there are other aspects of LRRK2. There's GTPase function, there's [ scaff ] function that we know drive activity, inflammation and the lysosomal capabilities by the cells. And we think that those are critical.

So we didn't -- we weren't terribly surprised to see that a program that by their reporting gets something like 30% kinase inhibition, we weren't surprised to see it fail. It doesn't deter us in what we're doing. A LRRK2 degrader, we think can hit all 3 different factors and features of LRRK2. We think that matters. We think that degrading it will even clearly affect the kinase function even more. And it doesn't deter from where we're going, which as we've talked about is first in PSP, where there's really substantial unmet need in a very rapidly progressing neurodegenerative disorder versus PD anyway and then ultimately, PD as well.

Just briefly to add, Yigal, Biologically, we understand why the inhibitors aren't ineffective, right? We saw greater than 50-fold enhanced target engagement and phosphoRab pathway engagement in the brain. And then we'll be talking about some exciting synaptic markers at MDS that will, in our minds, really prove that the degrader is different in Parkinson's disease patients with looking at eye tracking as well as CSF synaptic markers that are unprecedented changes in markers that are prognostic of progression in Parkinson's disease.

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

Just a couple, one on pipeline and maybe one for Andrew. First, on the pipeline, you would expect to enroll tumor types in the HPK1 degrader program similar to what we've seen from the HPK1 inhibitors like gastric, lung, anything there would be helpful. And is PD-1 the most likely initial combination partner initially? And then for Andrew, maybe if you could help us out on how we should think about maybe the modeling of the cost of licensing moving forward? And anything there would be helpful as well.

All right. Yes. So on the -- maybe I'll answer the easiest ones first. PD-1, yes, that is the likely combination partner first. I haven't said specifically which one, but we will certainly get into that as the months go by. Tumor types, not far off either. Things like lung is the right place to be thinking about. That trial will enroll patients that have had prior immunotherapy. And think of it as a traditional sort of escalation trial that we'll get into data. I haven't talked about when, but as that gets going, it gets easier to talk about data coming. Andrew, questions on modeling?

Yes, sure. So yes, a lot of changes to the accounting at a high level, and I'm happy to take a follow-up if this doesn't clear up your question. At a high level, we've been deferring revenue from the original Pfizer collaboration agreement over the life of the collaboration. Due to the Rigel out-license, we deemed that our contributions to that collaboration are complete. And therefore, we took all of the residual collaboration revenue through the P&L.

So going forward, you'll see no additional revenue recognition. We do have tail liabilities on the closeout costs of the VEPPANU development plan. We booked a liability on the balance sheet for that. When the Q comes out, you're going to see a current portion of that of $28.4 million, a long-term portion of $24.3 million for a total of $52.7 million. So additional payments that we make for that collaboration cost will go against that liability. So essentially, our P&L going forward is somewhat cleansed from the previous VEPPANU collaboration agreement.

We will be booking milestones and royalties going forward, but those will be sort of traditional and that there'll be real royalties that we'll receive from Rigel on a go-forward basis. We then additionally, we added that cost of sales line. That was really just to segregate Yale payments from our normal G&A. So you'll see that cost of sales line. For the time being, that's going to be 100% payments to Yale. We have a small royalty that we paid to Yale on any royalties in, and they get a small portion also of milestones going forward. So you'll see those picked up on that collaboration -- cost of revenue line. Please let me know if that answered your question. I know that's a lot.

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

My first question is on LRRK2, and you indicated you'll present additional biomarker data in October. Can you maybe frame for us what the sort of cadence over 2027 will be in terms of additional updates for that program and any additional clinical measures or potential advancements to the next stage? And then my second question on BCL6 is after you present the glofi combination data in mid-2027, as you think about clinical development, can you maybe outline for us how you're thinking about potential comparator arms versus the monotherapy trial and just how you think about that down the road?

All right. Yes. So on LRRK2, I'll reiterate what I said before on where we are with 102, which is really focused on the regulatory approach, right? So what we're focused on right now is incorporating feedback and developing that plan for how we move forward with the trials that we've talked about before while incorporating that feedback. So when it comes to the cadence of trials, really the cadence will be we'd like to start. That's the case. When it comes to providing a bit more clarity on where we're going, as we begin those trials, as we get close or even before, we'll certainly talk about how those are shaping up. But the cadence following the biomarker data that we plan to show at MDS will really be dictated on those trial starts. When it comes to for BCL6, look, as we move, as I said, all roads lead through the monotherapy and the combination right now with glofi, and we'll talk a bit more about where we go after that. There's a lot of options, right?

The bispecifics, there's more than one. Those are potential combinations. There's chemo, there's other things as well. I think that we will really have to watch the landscape evolve to see a bit of where the puck is going to see where it makes most sense for us to combine. I'll reiterate what I said around the opportunity to move earlier and faster with monotherapy approaches and then the ability to follow up with combination approaches that have the opportunity to reach bigger patient populations in earlier lines of therapy.

So beyond that, a bit hard to specify what the details will be. But as we've started talking about this program, as we've shared the progress that we've made, certainly, lots of companies that are interested in the space, including strategic that clearly are following the traditional path in the NHL space, which is to identify ways to build out the treatment combinations that we're able to get to patients to extend responses and get responses to more patients.

Our next question comes from the line of Jit [ Mukerjee ] with U.S. Bancorp BTIG.

It's Blake on for Jit. A quick question on ARV-102. Do you still have an intended PSP population that you're targeting? Or is it going to be an all-comers trial, thinking more on the lines of Richardson syndrome patients or specific LRRK2 variants?

And maybe I'll have Angela give some more color here. The shortest answer is you're not -- you're thinking about it right, right, which is that we could look at all the PSP. Richardson is the largest subtype. When it comes to narrowing more than that, I think it's less likely. But maybe Angela, a little bit more detail on how we think about the population there.

Right. I think that we would not restrict further. Richardson syndrome is really a very uniform progressing population, which is why we like it. and we like the focus there, but this does not restrict us from expanding to all PSP. I hope that helps.

Ladies and gentlemen, I'm showing no further questions in the queue. I would now like to turn the call back over to Randy for closing remarks.

Thanks, operator, and thanks, everybody, for joining this morning. We look forward to providing further updates as we move forward, and thanks again.

This concludes today's conference call. Thank you for your participation. You may now disconnect.

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.

8

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.