Alrighty, good morning everyone. Day two of our London Healthcare Conference. My name's Akash Tewari. I'm a pharma and biotech analyst here at Jefferies. I have the pleasure of hosting the Arvinas Management Team. John, why don't I hand it off to you for some intro remarks, and then we'll get started. Yeah, thank you. It's great getting an opportunity to talk about Arvinas. It's been a very kind of interesting few months for Arvinas. We had our first pivotal data on vepdegestrant, the first prototype to get to that point. It was positive, but the reaction was generally not positive enough. That then became a kind of a trigger for a series of events where both Pfizer and ourselves decided to find another party to take the drug to the potential launch, which should be based around next year if we get approval, and the date's in June. What it allowed us to do is to really reset the company. That resetting of the company is really focused on the five early development assets that we have. Three currently in phase 1/2 that have just been going through their GLP tox that should be ready for the clinic next year. That is exciting for us because it allows us to think about that reboot as Arvinas 2.0, moving the company forward with an array of different exciting programs. Hopefully, we'll get to talk today about LRRK2 in particular, our first neurodegeneration prototype, brain penetrant, and the focus on potentially Parkinson's disease, but also progressive supranuclear palsy. We also have a KRAS G12D program that is doing exceptionally well, and a BCL6 program. Those three in particular are moving forward very well in phase I, with plans to think about what we do next in phase II as we go through next year. A number of data points are going to come out next year, both for LRRK2 and BCL6, and maybe even the KRAS G12D program. Good data should allow us, again, to move the company forward in a significant way. We will see our two new programs, one focused on Kennedy's disease, a rare inherited disease, and then the other HPK1, which is an immuno-oncology target. It is a very exciting time for the company. We are still in a very strong financial position with money into the second half of 2028. That That allows us to take this reset company and its new programs through to significant inflection points in terms of data over the next two years. Understood. That's very helpful. I'll start a bit on vepdeg only because we also did get an announcement this morning about adjuvant hitting. I think internally we kind of have a view, it'll be curious how many of those patients may have actually had prior CDK 4/6, and then therefore the benefit was really driven by ESR1 mutant patients and not head-to-head just outperforming AI. I'm curious if you had just an initial take on the announcement this morning. I think the broader question becomes, should we just, in terms of a transaction that gives you upfront cash and an outright sale of that asset, what are the chances of that occurring right now? Is that something where we should more just kind of write it off at this point? T wo halves to that, yeah, we just saw the Roche press release. I think it's great that AstraZeneca is showing positive activity in an adjuvant study. We certainly, with vepdegestrant, had a plan with Pfizer to move into first line and also eventually adjuvant. Our belief was a mechanism like vep's or a mechanism like giredestrant, there's no reason why it wouldn't work in a setting where you've got a lot of endocrine-sensitive tumors. I'll be interested to see the details. There wasn't much in the way of the detail there. Yeah. You're exactly right. What's the pretreatment? What's the balance? Although I wouldn't expect much in the way of ESR1 mutation there in an adjuvant setting. That's interesting just in itself because those companies made bets to go forward with adjuvant, including AZ. In terms of our process, we've got a very active process working with Pfizer. We're taking the lead to find a third party to take the compound forward. Lots of interest. I think vep's profile is a best-in-class profile when you look at it, certainly in that second line setting. That best-in-class profile includes the benefits in terms of efficacy, but probably more importantly, the tolerability safety. We don't have excessive diarrhea or GI issues. The compound's eminently combinable. I think there's still a significant opportunity for vep. We're looking forward for that type of partner, and we're getting a lot of interest. Okay. That's interesting on the partnership side. Tell me this. In terms of the urgency your team has and Pfizer has to get that asset partnered out, because I mean, you're going to get approval pretty shortly. Yeah. Is this something that could be an early 2026 announcement, or it's not helpful to really put timeframes on it? Number two, when you think about a deal that makes financial sense, not just to Pfizer, but more importantly to your team, what does that look like for vepdeg? Yeah, so in terms of the process, that's ongoing. We've talked to a significant number of companies. As I say, they're now in the position to decide whether or not they want to put a bid in. I imagine at some point next year, we'll be able to close a deal. Certainly, we want to do it before the prolificity to be able to hand over what is a launch-ready asset. Our team and Pfizer have done a great job getting the asset launch ready. Yeah, at least a couple of months before the actual prolificity. In terms of the deal itself, I think we're open, and Pfizer are open to whatever the types of bids are. There's two components to it. One is the value of the asset, and we think the potential of the asset, not just in second line, but if a company wanted to come in and develop it further, but also the costs of vep as well. For us, there's going to be a combination of looking at an offer that comes in that does it defray the costs that we have left remaining with vep, or does it have an upfront? Both Pfizer and ourselves are open. Okay, so both lower upfront and then just royalties? Yeah, I mean, because yeah, we still have a significant number of patients on drug. They're doing well on the drug, so there's a closeout cost related to vep. Understood. Maybe just kind of stepping back, once we get through the vep announcement, I think the other question I get from investors, and we think about this too, is there's a difference between catalysts and then "stock moving catalysts." I think the thing we've empirically seen, and by the way, this is not just a phenomenon with degraders, but you'll see this with siRNA, right? They'll be like, "Okay, I have an HPLT3. Yeah. Great. My phase 1/2 data is I am knocking down the target, and it works, right? That rarely ends up being a particularly stock moving catalyst because to a certain extent, people assume, and rightfully so, that your team and some of these other biotech's can make drugs, right? Yeah. The question is, again, target validation through clinical efficacy. Right. If I were to say, let's say for BCL6 and some of your oncology portfolio, that you could do something maybe similar to what we've seen Chimera do, where they also had an oncology portfolio, but they said, "You know what? We are going to get to the point where we can show proof positive that we have a safe drug that does what it says it's going to do, but we're really not going to pursue spend beyond set point." Is that a conversation that's happening internally with Arvinas right now? And what drugs would kind of fit into that bucket? Yeah, no, absolutely is. What we've done right now with this reset is give our company optionality. There's five programs. Some of them are very biotech friendly in terms of the speed of trials and the size of the trials. Others, like Parkinson's disease, clearly not. Yeah, we've exactly had the discussion you're mentioning, which is where could we take these programs to in terms of a proof of concept? What data sets would we need to maybe attract a strategic partner for those? For the others, how quickly can we move the programs forward? They've got more of a less difficult approach for us in terms of moving them forward. PSP, I think, is an example where that would be regarded as biotech friendly for us. Even with BCL6, there's elements of what we could do there to take it to proof of concepts and some of the combination studies. It gives us optionality. What we're not saying is we're going to take all five programs forward to phase III and launch. That's not what we're saying. We're saying take these programs over the next year, year and a half, get them to data inflection points, give the company optionality, and that way a mix of moving forward ourselves plus strategic partners. Understood. That's how we'll manage the burn over the next two years. Right. Cash out to 2028. Let's say you take that framework where, let's say, three out of five or maybe more of those programs become, we will get to the point of proof of concept, but after that, it's not prudent to further develop them, absent a partner. Would it be fair to say there is additional cash runway to be had if your team went forward with a strategy like that? Yeah, I mean, in terms of partnering? As in, let's say, forget even, let's say you did partnerships where there was no cash upfront, but it was just simply, I am going to get to the KRAS initial data, and then after that, we're going to look for a partner or not. Yeah. Could we get cash runway out, let's say to the end of the decade? Yeah. So I mean, Andrew's not going to let me quote or give a new. Sure, sure. It is obvious that right now we have got money into the second half of 2028. That is based on those programs, based on getting them all through to that period of time. If there was a change to that, whether or not we partnered or whether or not we decided to do something different, yeah, ideally that would certainly release cash. You would have more cash. I am not going to be giving guidance beyond the second half of 2028. That's fine. That's the great thing about a platform company. You do have the ability, obviously, to generate your own pipeline. Arvinas has got a fabulous track record of actually showing that we can take molecules from discovery, and what we see in preclinical translates into the clinic. We've done it with bavdegalutamide. We've done it with luxdeglutamide. That's now with Novartis, our AR degrader. We've done it with vep, even though people maybe not liked the scale of the positive result, but nonetheless, it still worked. There's no reason to believe that we'll not do that with all the other programs. We've got a proof of concept and a technology that works. That gives us a lot of confidence in moving these programs forward. Understood. Akash, I just say that if you're looking out towards the end of the decade, we're not offering guidance on it, but people know that we have a $1 billion upfront and milestone deal around luxdeglutamide that has also royalties, and then this will produce outcomes in one direction or another. Is that contemplated in your 2028 runway or no? Not going to, no, we're not. It's not contemplated. Right? Yeah, okay. Yeah. That's a great point. Yeah, definitely no. It's a great point. Other than the ones we know are coming in right now. Right. Because we passed the milestone. That is true. Okay, LRRK2, and I want to make sure we have kind of expectations set. There's a competitor program from Denali that is hitting that target, but maybe not with the same therapeutic window, maybe with a patient population and a trial design that are we going to see a clear signal? I think the question we get from investors. I'd love to kind of, from your perspective, because there is going to be a read across to your value. A, are you comfortable with the Denali program having a read across to the Arvinas LRRK2 program? Number two, do you expect that trial to be successful, or will there be a trend? And if there is a trend, how should we look at that data with your clinical development strategy? Good question. Do I? Sure. Yeah, thanks for the question, Akash. As folks know, the LUMA study is going to read out in the first half of next year for Biogen. This would be an indication potentially for a LRRK2 degrader in Parkinson's disease. The study and the asset have some challenges. We're hopeful for patients that the study is successful. The challenges are the study itself does not have any patient selection. The study is taking all comers, whether they have LRRK2 mutations or not. In addition to that, the asset itself is a LRRK2 inhibitor, and it is an inhibitor that gets brain penetration, but is not necessarily the strongest inhibitor in the world. You have to think about how that will influence interpretation of our data as they come out. We have a degrader that appears to be more potent. When I say that, the measure of that potency is that when we look at healthy volunteers, we show that we can achieve 75% degradation of LRRK2 in the CSF. We also know that with that degradation, we're reducing biomarker levels that are indicative of neuroinflammation and neuronal cell death. We're seeing these biomarkers go down, even in healthy volunteers. In April, Biogen reported out results from their healthy volunteer phase 1b or phase I, and they didn't move biomarkers of neuroinflammation. There's a measure of pathway engagement where our degrader exceeds it. That may be because our degrader, by degrading the entire protein, is able to engage all aspects of LRRK2's activity. LRRK2 is a kinase, but it also has many binding domains that make it relevant for scaffolding and also RAB engagement. By virtue of the fact that we degrade, we may be eliminating all of these functions. We know that there are mutations in LRRK2 that have nothing to do with the kinase domain of the protein that are responsible for LRRK2's effector function. By virtue of degradation, we stand to do a little better than inhibition. What are some outcomes? The study could be positive. I think that would be great for patients and great for the LRRK2 field. If you have better engagement with the degrader, that would bode pretty well for us. If the study is ineffective, it could be because there was not patient selection. It could be because the inhibition of the kinase activity was inadequate. There may be some signals in that regard that still become validating for LRRK2, but they weren't able to overcome it with their inhibitor and their trial design. I think there are a number of outcomes here that could be. What's your base case? Promising. I think because of the lack of patient selection and because our general view is that kinase inhibition isn't enough for this complex protein, we think that the study will be trending, but not stat-saved. Understood. That's quite helpful. Now, there's that dynamic of biotech friendly and then maybe partnership friendly, and you think about Parkinson's. You're going to have data on your Parkinson's program in the back half of next year. I can't help but think, I mean, if you show a signal, first of all, tell me, for your Parkinson's study, what are you doing in terms of patient selection that maybe we're not appreciating with your program versus Denali and Biogen? Number two is, what if that shows a trend as well? Maybe that's more, I just need longer duration, right? What's the bar for your program? Do you expect to be showing a statistically significant signal in your readout, let's say, back half of 2026? Yeah. So just a couple of points, Akash. The study is going to read out really in the first few months of 2026, not the back half. This is a study involving some tens of patients with Parkinson's disease who are being treated with two different doses of the drug compared to placebo. There is not patient selection because the population is too small. Overall, we are looking to reaffirm the findings that we had in healthy volunteers, but in patients who have Parkinson's disease. It gives us a better evaluation of safety because patients are older. They are going to have an average age of 60 or so. They have comorbidities. On top of that, there should be a higher level of neuroinflammation at baseline by virtue of their Parkinson's disease. We certainly know that they have two to three times the level of LRRK2 at baseline compared to healthy volunteers. We are looking to the degree of engagement we get with this pathway. It is a biomarker-driven pathway result. It will report out early next year. I think we have to look at what comes out of Denali. We have to look at the rapidly evolving space for patient selection to determine where we go in Parkinson's disease. A critical point, if I could shift direction for a moment, is that our goal as a smaller biotech company is to choose diseases where we think there is a greater opportunity for success, and that we can manage as a company independently. That is why we are focused on PSP, progressive supranuclear palsy, a much more homogeneous disease. For example, all patients with PSP by definition have 4R tau as their underlying pathological protein in the brain. It is a disease where they have neuroinflammation. We know that tau propagation from these patients in their brains is due to endolysosomal trafficking dysfunction that is caused by LRRK2. Patients with LRRK2 mutations have a more aggressive form of this already aggressive disease, which typically patients go from diagnosis to death in seven years. It could be even more aggressive when you have LRRK2 mutations. Focusing on PSP is something we know we can do on our own, that we can start a phase I study next year, maybe even start a registration quality phase II within a year of that and be able to put together a package in a much shorter amount of time than a Parkinson's disease program would. I definitely want to hit more on PSP because I think you're absolutely right there. I think it's important on your Parkinson's readout. A, are you retrospectively going to look at patient selection and maybe certain genetic modifiers? I mean, what is the subset population where you feel like a LRRK2 is going to have the greatest effect? Number two, because I can't help but think if I was strategic, I wouldn't be just interested in PSP. I would be interested in Parkinson's. I mean, if you're able to show, because to your point, it's not about getting LRRK2 levels to zero. It's getting them back to a normal range. It's a biomarker-driven study. You have to look at that in a CNS disease. What if you're able to show neuroinflammation getting into a normal range? I can't help but think that's a major catalyst if we're thinking about this with a bit of nuance, right? A, what is the population where you think you're going to have the greatest effect? Do you feel like you have some of those patients right now in your data first half, not back half of the year? Number two, if you are able to show clear biomarker signals in terms of neuroinflammation, why isn't that a read across? Why not pursue Parkinson's also? Look, if we were to see just very convincing results for biomarker engagement in the broad population of patients we're testing, we would increase our conviction both for PSP and PD, no doubt. We're not doing patient selection, but we will be able to look retrospectively at various genetic markers and levels of LRRK2 at baseline, levels of the inflammatory pathway stimulation at baseline. So we will be doing the multivariate analysis that will help us. What is the subset? What is the patient population where you feel like you'll have the greatest effect if you were doing patient selection? Yeah. So overall, endolysosomal dysfunction is at the root cause of neurodegenerative diseases such as Parkinson's, PSP, and even Alzheimer's disease, right? The trafficking is most dysregulated in patients that have LRRK2 or LRRK2 pathway mutations. There has been some work that appears in the literature suggesting that this can be broad and represent some tens of percent of the overall disease population. I think it's premature to. Understood. We do know you have at least some of those types of patients in your upcoming data? We suspect we do, yeah. Okay. Suspect. All right. Now on PSP, and I think you're spot on here. Again, there's a perception maybe there's not a "h uge placebo-controlled catalyst." I mean, we're seeing time and time again, natural history, open label data. You can start updating patients on the PSP cohort throughout 2026. If that's the case, how many patients do you have in PSP right now at levels that you think are therapeutically efficacious? How much durability would we be able to show? Could we actually start to see a trend, not just on the biomarkers, but maybe on some clinical endpoints as we enter the back half of 2026? Yeah. We have not started the study yet. The goal is to file the IND in very early 2026 and follow in short order with a PSP study that will be U.S.-based. The study is going to be some tens of patients, more than the number of patients we will report out for Parkinson's disease. It will be biomarker-related, but because of the rapid progression of disease in these patients, we expect you can see clinical measures of activity within six months. There is a regulatory acceptable rating scale called PSPRS, meaning it is accepted by regulators as a registrable endpoint. I am not saying our phase I PSP study is going to be registrable, but I am saying we are going to start correlating the biomarkers to that clinical activity. I mean, let's put it this way. In a rare disease, why couldn't it be? Yeah, because I just want to say that before we've had that discussion with regulators, it wouldn't. Okay. That is not a, okay. But fair to say that's something you might pursue. Oh, yeah. A discussion we will have. Let's put it this way. In terms of tiers of interest for your team internally, it almost seems like LRRK2 and PSP is an order of magnitude, also taking kind of just the time aspect that investors are looking at. Is that fair to say that that program should be where we're spending the majority of time in terms of understanding the commercial value? Yeah. Yeah. I mean, it's clear that's our current lead program. It's got the most kind of energy and excitement within the company. We have the optionality of PD and PSP. So absolutely, that's an area to look at. BCL6 and KRAS G12D are also very exciting programs right behind it. If you wanted to rank and to say what one thing we should look at, it's definitely LRRK2. BCL6 and KRAS G12D are really, really good. I'll just. I'll touch on this in 10 seconds. At our recent earnings call, we shared that we have responders for our BCL6 degrader with T-cell malignancies and B-cell malignancies. No one else has reported responders in T-cell malignancies with this target, which is also then a rare disease subset that can be pursued. More to be discussed in 2026 about that program. I'm going to sneak in just one more question because I'm just going to try. Look, in terms of, again, if I was going to invest and say, "Okay, I'm building some of the parts, I start with LRRK2, PSP." Is it fair to say the next thing that's about to have clinically mean it's the AR degrader with Novartis, right? I mean, you mentioned you have a lot of royalty payments and clinical milestones there. I mean, just very quickly, 2026, could we get any types of payments towards Arvinas that maybe we're not seeing? And how excited is Novartis on that program? We've got three ongoing trials in different combinations, which we're very excited about. They haven't given us the schedule of when those read out, but some of those do have milestones associated with them. 2026? They haven't given us the timeline for when they're going to be doing the readouts. You'll be the first to know when we get it. Understood. Thank you so much, everyone. Thank you so much for the Arvinas study. Oh, thank you. Thank you. Appreciate it.