All right, so why don't we kick it off? My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim, and it is my great pleasure to host this next fireside chat with Arvinas. With us today we have Andrew Saik, Chief Financial Officer, and Noah Berkowitz, Chief Medical Officer. Welcome. Thanks for joining us. Nice to be here. Maybe a question for Noah, a higher level question. Arvinas is obviously best known for being one of the original innovators of protein degrader technology. What have the key learnings been so far? As you look back at your experience in discovering and developing degraders initially targeting the androgen receptor and also the estrogen receptor. Yeah. Thanks, Michael. I think what we've learned over the past few years is we have a way to differentiate by developing degraders, but you have to make sure you're choosing the best targets and your development plan allows you to benefit from that differentiation to make a commercially viable product. In that sense, we find ourselves today on the verge of having the first PROTAC ever that we hope will be approved based on the June 6th PDUFA date for vepdegestrant in estrogen receptor positive second line breast cancer. We have a drug that's partnered out to Novartis, an AR degrader that they have now opened in three phase II studies with abiraterone, with PLUVICTO, and then as monotherapy. We ourselves have three different drugs in the clinic. We announced at our recent earnings call that we'll have two more drugs entering the clinic next year. The key for these five drugs is, is that we have differentiation and we have development plans that are very biotech friendly and we think will bode for great success. Great. A question on vepdegestrant, your ER degrader, which you announced earlier this year that together with your partner Pfizer, you're looking for a third party to further commercialize and perhaps develop the product candidate. Just could you provide us any updates on the process? How has that been going? What t ype of a range do you think would be most beneficial to you? Yeah, I mean, Michael, the process is exactly where you'd expect it to be. Right. We kicked it off a few months ago. We've been allowing interested parties to come in and do their diligence. We have a wide range of companies that are interested in it. Some look like they may want to develop it further, others maybe they're just looking for a commercial opportunity. Right. It's too early to say, kind of who's going to have it. You know, we're being pretty pragmatic about this. I mean, we said a little while ago we view this more as a financial asset than anything, so we're going to take the best bid. We're sort of agnostic as to whether or not the group wants to further develop it or not. We do think that people who want to develop it more could afford to spend a little bit more money on it. Right. That may lend it to being a winner who wants to develop it, but we're agnostic. Gotcha. Okay. And then, yeah, perhaps switching gears and talking about your proprietary pipeline, starting with ARV-102, which has now emerged as your most advanced wholly owned product candidate. And sort of stepping back. First, how well validated is LRRK2 as a target for neurodegenerative diseases? I think it's pretty well validated, although no drug targeting LRRK2 approved yet in the clinic. The idea is that LRRK2, we know for decades already, is there are variants that are associated with Parkinson's disease. Fifteen percent of all familial Parkinson's disease are probably due to the G2019S mutation that is seen often in Ashkenazi Jews. That also shows up in about 1% of idiopathic cases. We understand mechanistically why that genetic association is there. We see the way LRRK2 mediates endolysosomal function and can be at the nexus of that endolysosomal trafficking and also the microgliosis or the neuroinflammation that's seen because of the microglia in the brain. I think that target in Parkinson's disease, on the basis of genetics and also biology, is well understood. In a similar way, there's been tremendous progress in understanding of how it's associated with Progressive Supranuclear Palsy or PSP. There's some variants, again genetic variants for LRRK2 that are associated with the more rapid progression of an already rapidly progressing disease. Typically, patients will go from diagnosis to death with PSP within about eight years. That's accelerated by at least a year when they have certain LRRK2 variants. We know that in PD and PSP there are elevated LRRK2 levels in the brain because that is a measure of increased neuroinflammation, increased endolysosomal trafficking that is trying to deal with that inflammation and rid the brain of pathological proteins such as tau and others. Because of all that, those genetics and the biology in those two diseases, we think it's pretty well validated. Obviously people have their eyes on a competitor in the space that's running the LUMA study, which will report out in the first half of next year, which has non-selected patients who are receiving a LRRK2 inhibitor. That is a registration quality study that could be validating. Right. Maybe talk a bit about how your degrader approach could potentially differentiate from a more classical inhibitor approach. Yeah, I think this is core to we're seeing this again and again in several of our targets, how preclinically we simply demonstrate much higher levels of target engagement and pathway engagement. For the competitor asset that I just identified, the challenge is that it's an inhibitor, a kinase inhibitor. It's not a great kinase inhibitor. It also enters the brain, but it doesn't necessarily achieve as great target engagement in the brain. We know that with our, even though it's a PROTAC, we've figured out the secret sauce for developing small molecules, this PROTAC or PROTACs that can be orally bioavailable and brain penetrant, which we've done with our ARV-102. We know from cyno models, so from non-human primates, that we get into deep portions of the brain, the striatum, different parts of the cortex, the cerebellum. These are all parts of the brain that are involved in diseases such as Parkinson's and PSP. We know that we degrade effectively in those preclinical models. The news this year for us is that we degrade, and we see this by picking up the degraded LRRK2 in the CSF in patients, or, I'm sorry, in healthy volunteers. We reported out earlier this year that, and an update that just came out at the MDS meeting last month, that our degrader can achieve significant brain penetration, that we can achieve 75% degradation of LRRK2 levels in the CSF, and that we have great pathway engagement driving down phosphoRAB levels in the periphery and also BMP in the periphery. The really exciting differentiating data that was just shared at MDS a few months ago last month was that in our healthy volunteer studies, we were able to look at all of the proteins that were shown in the PPMI study. This was Michael J. Fox's follow up of Parkinson's disease over decades and they showed that there are a series of proteins that are upregulated and that's associated with progression of Parkinson's. Those are proteins like CD68 that's found in glial cells or GPNMD there as well. We showed that in healthy volunteers, we downregulated those exact biomarkers that are elevated in Parkinson's disease. Our competitors' inhibitors haven't really been able to achieve it. It is probably because we get into the cell, we have a catalytic effect that can just destroy that target protein. In the case of LRRK2, not only therefore inhibit the kinase activity of the protein, but eliminate it. So its scaffolding function, its GTPase activity, and other activities are unavailable to the cell any longer and therefore diseases can potentially be mitigated. Right, very interesting. I think, as you mentioned, you've shown in your human phase I study, you have shown the target knockdown in serum in circulation and also in CSF, as he mentioned. What level of knockdown do you think you need to achieve? Are there good predictive models that will tell you that hey, 50% or 75% reduction in CSF is sufficient to achieve a change of the clinical phenotype? It's been well established in the literature that Parkinson's disease is associated with a doubling or tripling of baseline LRRK2 levels in the CSF, which evidences, you know, which represents probably increased expression obviously in the deep portions of the brain. The goal is to restore the brain to its physiological levels of LRRK2 and so therefore being able to decrease LRRK2 levels by 50% would be effective. We are very gratified to see that we were achieving 75% knockdown of LRRK2. That's like antisense level knockdown of a target protein of interest with this small orally bioavailable molecule. That would be our goal overall. We don't want to eliminate it entirely because obviously it has physiologic effects, it's important or biological effects. It helps control trafficking of the endosomes and lysosomes. When it's in excess, then it leads to the mistrafficking and helps the cell extrude pathological proteins which then become inflammatory or, yeah, inflammatory in the brain. How are you tracking towards RP2D selection? Also, how would you approach RP2D just given that, as you just said, you do want some reduction, but not too much reduction. How can you thread that needle? Yes. Currently we're enrolling patients in multiple dose cohorts, patients with Parkinson's disease. The reason that we moved to Parkinson's disease in a phase I after the healthy volunteers is we wanted to show that the 75% reduction we saw in healthy volunteers can now be recapitulated in patients that have even higher levels at baseline. They also have activated pathways for neuroinflammation. We want to show that we can calm the brain down through these biomarker measurements. That study is ongoing and we've guided to reporting out results from this study in the first quarter or so of next year. Okay, what additional insights are you hoping to gain in this, in this MAD cohort next year? Is it dose response in patients? I think dose response for biomarkers, it's still 28 days of treatment, so it's not likely at all for us to see clinical benefits. You know, patients' rating scales aren't going to improve. It's too short. One of the additional things is that as opposed to healthy volunteers, we've modified the PD study so that we can look not only at 14 days, but also after treatment and look at the, like, the ongoing and persistent effect of a LRRK2 degrader even after, you know, when treatment has been prolonged. Right, okay. You did announce the phase I-B study in patients with PSP next year. Yeah, help us understand. You talked about the mechanism already, but what drove that decision and what are the next steps for that study? We feel armed with results from our multiple dose Parkinson's disease that allow us to be sure that we're in the right dosing range because we think these neurodegenerative diseases should require similar doses of our ARV-102. We're also, we have to finish our chronic tox, which we're on the verge of finishing. That allows us to file the IND in the U.S. and start that phase I-B study. Armed with the chronic tox, the results of the multiple dose PD study, we'll be able to choose the right doses, open a study that's going to look at chronic treatment in patients with PSP, look at those biomarkers, and associate those biomarkers with things like the PSPRS, the PSP rating scale, which is a regulatory acceptable scale, you know, that could be used for registration. In addition to that, we would be looking at other measurements, other devices that are measuring eye movement or other muscle movement in patients that would characterize our impact on disease. Over what time frame are these clinical outcomes typically assessed in PSP? It's six months, a year and longer. I imagine that our phase I-B would be a study that's looking at what's happening at six months. Then patients would continue for a chronic long term extension portion. We've even shared that next year before we even have the results of the phase I-B, it's possible that we could start a registration quality phase II in PSP because we're armed with all the right information. We know the two doses we can bring into our registration study. We have a rating scale that's acceptable from regulators and shows a difference over the course of a year that can be detected in a reasonable size study. It's a very biotech friendly development path and disease indication. In the meantime, look at what happens with Biogen's LUMA study where they have the LRRK2 inhibitor. Understand a little more on our own about whether we need patient selection to go into Parkinson's disease. As we march forward in PSP, share more publicly about our plans for PD. Right. In terms of PSP, it sounds like you could get a read on clinical outcomes in the phase I-B fairly soon. The potential registration studies, would those be single arm accelerated approval type studies or would they have to be randomized? Controlled? No, be randomized because you're also looking at the rating scale. I think that's almost certainly going to be the primary endpoint and we haven't discussed that with regulators yet. We could look if there are some supportive data from our phase I-B that allows us to have those types of discussions about accelerated approvals. It's premature. The registration quality study is just a few hundred patients and it would be a global study and we're preparing ourselves to run that, start that next year. Very interesting. I guess given the limitations of the Biogen Denali molecule, I guess, how would you interpret the LUMA study if it reads out next year, especially if it's not successful? Can you infer anything from it? Yeah, so there are a few different. Look, if it's successful, wow. We'd be really happy owning a much more potent and I think promising target engaging drug. Right. With R Degrader. If it's not successful, is it not successful because they lack patient selection? They included all comers and maybe you have to focus on the 30% of patients that have LRRK2 or LRRK2 pathway related disease. That would be important to understand. Is it that they just have a not very potent inhibitor and so they're engaging the right target. And there could be signals for this, but maybe not enough inhibition to really have clinical impact. I think there are a whole series of results that could, that would influence our development. Okay. That will be definitely very interesting. Maybe shifting gears and spend some time on ARV-393, which is your BCL6 degrader. Maybe against that, stepping back. It's a new target in lymphoma. How well understood is the target for hematological cancers? It's been a long time now that it's been designated, you know, a promising target in the field. It's been up till now undruggable at this moment. Like when we entered this just about a year ago, there was only one other company in the space. Now two more announced that they have filed INDs. I would say that the target's not fully validated, but our competitor, that's a little ahead of us, has reported out treating up to between 30 and 50 patients and is having, you know, a high response rate. For us, the plan is very straightforward. We announced at our earnings call, we are not sharing data yet because we're not at what we targeted as the efficacious range yet. We've already seen activity and responses in B- cell malignancies and in AITL. By the way, we're enrolling patients with T- cell malignancies. The competitor is not. They're only in B- cell lymphomas. Our goal is to combine this drug with bispecifics and look at targeting large B- cell lymphoma in the second and third line. That is a principal path of development. That creates a lot of value for the company, most importantly because it can really impact patients' lives. The other thing, though, which is interesting, is that we can go after AITL, which is about 3% of all NHL, non-Hodgkin lymphomas. We believe that a monotherapy has a pathway for monotherapy and there's potentially an accelerated approval path there as well. We're already seeing responses in AITL patients. Maybe just stepping back through the ongoing phase I study, is it exclusively enrolling? T- cell lymphomas? B- cell and T- cell lymphomas? Gotcha. Yeah. I think you did note observation of some complete responses in some patients. Yeah. Could you elaborate on that? Not really. Just because we're gonna save it for a conference, but we wanted to signal that the study's enrolling. We started at a low dose, we're doing more and we want to, we're looking for the right target engagement. Are we getting enough drug on board that we're having, you know, 80% degradation or so or even more, and so updates to happen next year. Right. Any comments on tolerability? I'm just asking when I look at the Bristol data from this summer, did have some higher AEs, maybe perhaps because it's a cerebral image type degrader, but any view on tolerability differentiation of your molecule? I think too early to tell. I think that their tolerability looked pretty good. I mean, I think in a way it's validating for that target with a degrader. And you know, so far our tolerability is good, but you know we're early, we're in dose escalation. Right. Yeah, you mentioned already sort of fast to market potentially in AITL. How do you envision longer term development plans for 393? Yeah. Next year we expect to start pretty early in the year a combination with glofitamab that takes us down that strategic path of combining and being able to target second and third line large B- cell lymphoma. Obviously we have combinability with many other drugs, and we've shared that preclinically. EZH2 inhibitors, BTKIs, BCL2 inhibitors, anti-CD20s, we want to combine with bispecifics because we know BCL6 degradation increases CD20 expression and the orthogonal approach combining the bispecific pathway and our BCL6 signaling pathway seems to create synergy. We want that combination, but we will look at others. Presumably it's just not priority for us. Right, super interesting then. Yeah, I just did want to spend some time on 806 as well which is your KRAS G12D degrader which is also in phase I now. In general, how much room for differentiation do you see in the KRAS G12D space? There are other degraders that are being pursued. Astellas has some data that was presented. There are inhibitors as well. How do you think, how do you think it'll fit into the landscape? Yeah, so we're not first to the party. We have to win to stay in this game. We think we have a lot of reasonable, there are a lot of compelling data that have already been shared publicly that suggest we can win. First, in preclinical models we're 25-40 times more potent than the Rev Med inhibitor and Astellas degrader. That has to do with our ability to make degraders. We believe we're the best at making degraders at Arvinas. That allows us to choose those that have this greater potency. Potency was a problem for Astellas' degrader because they couldn't achieve as high exposures as they needed in patients because they ran into transaminitis. We think potency could play well in our competitiveness with theirs. The next thing is degraders are better than inhibitors when it comes to what RevMed has reported out as the primary mechanism of resistance to KRAS inhibitors. That is overexpression or amplification of KRAS. You can't overcome that with an inhibitor because your PK and your dosing is locked in, but you can overcome it with a degrader because our catalytic activity will continue to degrade the overexpressing protein. That shouldn't be as significant a mechanism of resistance for us. We're in dose escalation. We'll see soon. Data to be reported out next year. The study is going faster than expected. Great. Have you disclosed anything about the selectivity over KRAS wild type of your degrader? Yeah, it does not hit KRAS wild type at all. Okay, great. And then yeah, as you mentioned, We d o have a pan KRAS degrader that's in the clinic, in the lab. And there is a longer term ambition to bring a better pan KRAS degrader to the clinic. Gotcha. Okay, super interesting. I know we're running short on time, but I just did want to squeeze one more in, announcement around your newly announced programs that are moving forward. Yeah, what are those targets that you announced recently? There are two and we're excited about them. We're very excited about them in different ways. One of them is an SBMA target, another biotech-friendly neuro or neuromuscular disease target, so complements our interest in LRRK2 very well. SBMA, or Spinal and Bulbar Muscular Atrophy, is a disease that hits people at about 30 and it lasts for about 30 years, rendering them weak, unable to walk, difficulty swallowing, difficulty taking care of themselves, their daily activities. This debilitating disease is found when you have polyglutamine added to the androgen receptor. We can degrade androgen receptor very well. We already licensed out a drug to Novartis for the degradation of androgen receptor, which is advancing nicely in the clinic. We now have a separate drug that can target AR, especially the polyglutamine form. Think of it, next year we'll start a healthy volunteer study. We will be able to do biopsies of their muscle if the regulators permit us. I think they will. That will allow us to show an on target effect. We will be able to look at what we're doing to AR in muscle, choosing the right doses, and I think moving into this rare disease or orphan disease very rapidly. That's one. The other one is an HPK1 degrader. HPK1 plays in the IO space. What's very interesting about it is that we have a potent dose dependent engagement of HPK1, which down regulates T- cell receptor activation, and it's a driver of energy. Think of this drug as having, in our models that were just shared at SITC last week, great single monotherapy activity, probably by preventing anergy and allowing the immune system to respond to various solid tumors. We may be able to combine with PD-1, and we showed great synergy where we combined with pembro and you can awaken anergic cells. We are better than the HPK1 inhibitors out there, and we also differentiate—we are better than some other IO compounds in that we wake up or activate NK cells in addition to the T- cells and also macrophages. It is an immuno-activating drug that we think is differentiated. More to follow when we start in the clinic next year. Thank you. I think our time is up. I really appreciate the time. Andrew and Noah. Thank you. Good to speak to you. Thank you.