Good afternoon, everyone. Francesca Giallanza here, one of Tyler Van Buren's associates. Thank you very much for joining me at TD Cowen's 46th Annual Healthcare Conference. For our next session, we have a hybrid, you know, pretty much a fireside chat with Arvinas, and it's my pleasure to introduce Dr. Randy Teel, President and CEO, and Angela Cacace, CSO. Randy, congratulations on your recent appointment, and it's a privilege to have you both here. Thank you very much for joining me. I'll go ahead and kick it off to you to just give a overview of the company and some of the updates that have been going on in the last year or so, and then we can go into the fireside chat.
That sounds great. Frances, thank you very much for having us. It's great to be here today. I think, you know, going over sort of where the company's at could take a bit, right? We've accomplished a lot, but maybe I'll start with the present day, right? Which is, as investors look at Arvinas today, what they're looking at is a company that's in phase I with multiple programs. We just announced last week that we'd started dosing our fourth phase I program, which is an AR degrader. They're looking at a company with four phase I programs. The capital moved them to their next inflection points. Great team, I think. We're doing that with the backing of a platform that already has shown pivotal proof of concept, right?
Our lead program in breast cancer last year had a successful pivotal trial, and we've made a decision, as we can talk about, to move forward with the phase I programs. We've now got a program, a LRRK2 degrader in neurodegeneration. We have a KRAS G12D degrader in the clinic for solid tumors. We have a BCL6 degrading PROTAC called ARV-393 in the clinic for hematology, and as I just said, we've got a fourth program that has just started. On top of that, we've also, you know, done a partnership a couple years ago with Novartis, so an AR degrader called luxdegalutamide is moving forward with Novartis in multiple combination trials in castrate-sensitive and castrate resistant prostate cancer. That's where we are today.
The company itself has been around for over 10 years at this point and really consider ourselves a leader in protein degradation. For those that don't know already, we make PROTAC degraders and so are really focused on anywhere that there's a disease-causing protein that we can degrade with our technology.
Wonderful. Thank you very much. All right, let me take a seat, and we can get started. I think we can start with the neurology pipeline since that's a little bit further along. LRRK2 has strong human genetics but has been historically challenging to target therapeutically. What underpins your belief that degradation could deliver a different and more meaningful profile than kinase inhibition alone?
Maybe I could start with the high level on LRRK2.
Mm-hmm.
Angela, please chime in-
Yeah, absolutely.
... With the detailed answer. Look, so the LRRK2 degrader that we have is in two phase I studies, just so everyone's on the same page. We have done work in healthy volunteers and also in Parkinson's. The patients with Parkinson's disease, that phase I trial will have its next data readout in just a couple of weeks at the ADPD conference in Copenhagen. We can go through all the reasons that we think a degrader makes more sense than an inhibitor in this space. For us, that's a program that as we get through phase I, the plan will be to move it into PSP, which is a rarer neurodegenerative disease, and also hopefully in Parkinson's at some point too. In terms of the program itself, please, Angela.
Sure. LRRK2 is a large multi-domain kinase. It has scaffolding function, GTP. It has scaffolding function, thank you, GTPase activity as well as kinase activity. We want to remove all of those activities, and so a degrader can do that. The mutations spread across the entire protein, and these all contribute to the pathologic endolysosomal activity of this particular kinase that really lead to the buildup of pathologic proteins in neurodegeneration. Our goal is to remove, you know, the entire protein.
Can you share a little bit more about the phase I healthy volunteer and some of the initial SAD/PD data that you shared earlier?
Yes. We're very excited about the healthy volunteer data. The goal of the healthy volunteer data was to show that the first PROTAC in neurodegeneration could actually cross the blood-brain barrier in healthy volunteers. In non-human primate, we had previously shown that we reached deep brain regions that were relevant for Parkinson's disease and also for progressive supranuclear palsy. These are the two diseases of interest for LRRK2. We showed that. In healthy volunteers, we were able to show that we could dose dependently, you know, dose dependently increase exposure in the CSF, and so cerebrospinal fluid, that was important. We could also show that we could reduce LRRK2 in a dose-dependent manner in CSF. Most importantly, we could engage the pathway. In the Michael J.-
... Fox, Marker Progression Initiative, what had been shown in CSF is that LRRK2-driven Parkinson's disease, there are proteins that are elevated in Parkinson's disease, and we were able to show that we reduced all of those LRRK2-driven proteins in CSF. It was important to show that the pathway was engaged.
How would you say that you're sharing upcoming multiple ascending dose data in PD patients, I believe, at the ADPD conference in 2026? How will that inform the next steps in terms of later stage or registrational trials, and what biomarkers would you say we should look at to think that it's, you know, de-risking moving forward?
Next.
Oh, I think my mic's on now.
Yes, we're good.
Great. In Parkinson's disease, it is very important that we move forward, and we look at similar biomarkers. We want to ensure that as we move from healthy volunteers, which are on average about 25 years of age, so very young people. As we move to an older population on average about 60 years of age and also a neurodegenerative disease, we wanna make sure that the proteasome is intact. It's important for us to show that we can degrade LRRK2 in the brain or CSF. We'll be looking at really confirming that we see reduction of LRRK2, at, you know, pharmacologically in the cerebrospinal fluid, and that we're engaging that same LRRK2-driven pathway in Parkinson's disease.
Neuroinflammatory markers, endolysosomal markers, ensuring that we're impacting those same Parkinson's disease markers that are caused by LRRK2 in the cerebrospinal fluid, that will give us confidence that we're impacting the pathway profoundly, and it's something that inhibitors have not done. To date, you know, we've already proven that we can do that in a 14-day healthy volunteer study, something that inhibitors have not been able to show.
Wonderful. How do you think about the translatability of the phase I PD data to PSP?
In PSP, more recently, the University College London studies have shown that genetics and also endolysosome biomarkers are upregulated in progressive supranuclear palsy. LRRK2 is elevated twofold in that disease as well, and that there's clinically meaningful progression in the PSP rating scale within a year. Anytime you see that there's elevated protein expression and clinically meaningful progression that's caused by that elevated protein, a PROTAC-mediated mechanism where you can reduce that protein, you know, a therapeutic hypothesis is now developed. Our PROTAC mechanism, we feel we have great conviction around going into progressive supranuclear palsy. We're headed toward a phase I study, and so waiting for regulatory. Go ahead.
Yeah, absolutely. I believe you have another more newly announced candidate, ARV-027. Can you share a little bit more about that?
Maybe I can give some history there too.
Perfect.
Before we start. Yeah. ARV-027 is actually our third AR degrader to go into the clinic. A quick history lesson for everybody. ARV-110 was the first back in 2019. The second generation AR degrader, we outlicensed to Novartis a couple of years ago for them to take forward in prostate cancer, which I mentioned a bit ago. They're doing so in multiple combination studies. ARV-027 is another AR degrader. It degrades polyglutamine repeat AR, which is known to drive SBMA or Kennedy's disease. It's a rarer disease opportunity, but it's one where, as Angela can expand on, where polyglutamine AR is known to drive disease, and it's a place where we feel very comfortable going since we have a pretty strong history of making AR degraders.
As I mentioned a bit ago, that just began a clinical study in healthy volunteers just in the past few weeks.
Just to expand on what Randy just said, our preclinical data gives us, again, really a lot of confidence. We were able to show in a very aggressive model of spinal and bulbar muscular atrophy that we could degrade in muscle the polyglutamine repeat AR, and that we could rescue muscular atrophy, that we could also rescue the loss of grip strength and endurance and also, you know, prolong survival in that model. Those data as well as human iPSC-derived skeletal muscle, we could get some translational validity that we could actually degrade in a human system that was disease relevant in skeletal muscle.
It seems like it would offer somewhat rapid validation of the platform given the nature of these models and the mechanism itself.
Yes, largely de-risked.
Mm-hmm.
Randy mentioned, because we've put multiple-
Mm-hmm.
.... androgen receptor degraders into the clinic and proven safety, with those other degraders-
Mm-hmm.
... As well.
What gives you confidence you can reduce mutant AR sufficiently to be disease modifying but preserve normal androgen signaling?
In this case, because it's an X-linked disorder, all of the receptor is actually mutant in this disease. We wanna reduce the receptor that is causing the splice titration in the nucleus and causing that disrupted muscle signaling. We also want to reduce the toxic aggregation in the cytoplasm that's also causing dysfunction in terms of contractility and metabolic effect. That's exactly what we saw in the preclinical mouse model. We rescued the function significantly, and I think that gives us great confidence moving forward pharmacologically that we can do something similar and prove the concept in patients with the disease.
Wonderful. All right, I think that we can move on to the oncology pipeline. I think we can just do a quick question on vepdegestrant. As you know, approach the June 5th PDUFA date, ESR1 mutant, breast cancer second line, can you discuss how the search for the commercialization partner is progressing?
Absolutely. As we have said, the most important thing is to get vepdegestrant in the hands of patients and doctors as soon as possible, presuming that it's approved ahead over on the PDUFA date in June. We still very much think that vepdegestrant has the potential to be a best-in-class product, which is why we'd like to do that. There's not a whole lot to say on the partnering process other than to say that we think we're on track to get it done by early June. We're out together with Pfizer working through that process, which is certainly, I think, a novel experience for everyone involved.
It's been a good partnership to do that, and we've had good interest in the program, and we'll keep pushing along, and there will be an announcement when we're ready for it.
Wonderful. You know, you discussed that there's some alternative options that might be considered, if a partner is not secured before the PDUFA. Have you shared those publicly, or will you share them at a later date?
You know, certainly with Pfizer last summer when we first decided to look for a new partner, we had conversations about hypotheticals and ifs and thats and so on. At this point, with the progress we've made towards partnering, you know, if we need to go back to that conversation, we could, but it's not one that we're actively having, right? Obviously, Pfizer has capabilities that could be used, but right now we're moving down the path towards finding a partner to commercialize and potentially develop that further. That's the path that we're on for now.
Got it. I think we can move on to the wholly owned oncology programs. We can start with the BCL6. I think it's a pretty interesting target for a lot of people. It's been historically pretty complex. Can you share more about ARV-393 and the status of that program?
Yeah. ARV-393 for BCL6 certainly is one where at one point we had considered our first undruggable, and I think it still counts as that. Although now we've seen some other parties move programs into the clinic and have some initial phase I data, which is great, right? It shows that the target's a little bit validated and certainly gives us encouragement to continue with our current trial, which is a phase I dose escalation. It's a BCL6 degrader. Angela can go through some of the details on rationale for the target. Out in the landscape right now, we have a competitor who had some initial phase I data, as I referred to, with some good response rate and showed that there's, I think, a clear path. Overall, what we'd like to do with that program is move it into DLBCL.
We are also enrolling in our phase I trials T-cell patients. We have shared, even though we haven't had any official data releases yet, we shared late last year that we have seen some initial responses in patients with both B-cell and T-cell lymphomas. We've shared that we've seen good, robust degradation of BCL6, which is very important as it's a very rapidly resynthesized protein. As we get towards the second half of the year, we'll look for our first in human data, official data release, not just comments in an earnings call. Behind us, there's a few other competitors as well in that space, but we think that really just validates the opportunity that could come to fruition over time.
What makes you think that degradation with ARV-393 is the right strategy to drug this transcription factor versus more traditional, you know, inhibition approaches?
Clearly, degradation is superior to inhibition. Inhibition cannot overcome the rapid resynthesis rate that Randy just mentioned. This protein is rapidly resynthesized within two hours, and so we find that ARV-393 degrades the protein and retains that protein at greater than 90% reduction, and that leads to very durable tumor growth suppression. That's superior to inhibition by far. Inhibitors have never even made it to the clinic because they cannot show that type of durable growth suppression.
Okay. Thinking about the evolving landscape, you know, there's CAR-T, bispecifics, ADCs really already changing lymphoma care. What do you think that ARV-393 needs to show in terms of response rate and durability in a phase I to support moving into later-stage trials?
I mean, ARV-393, I think we'd consider ourselves co-leads in that area, so it's one where we certainly need to be very competitive and as monotherapy will be important, but also in combination. We're about to begin a combination phase I study in combo with glofitamab. Over time, we think that's the way to be moving from the later lines in LBCL up to the earlier second-line setting. We're very focused on giving patients an option that is chemo-free, right, which that could lead to. Again, I think there's both combination and monotherapy options in the rarer T-cell lymphoma patients we talked about before. That's an area that we think we're unique in right now in terms of going after that population to provide a therapy where there's really nothing at all after initial failures.
Both of those will be important. I think the differentiation piece will, you know, as in every case, be, you know, dependent on response rates and durability and safety and combinability. All those features will have to come into play in the, in the trials we show.
Mechanistically, just to add to that, in terms of the combinability, we see an increase in CD20. We also see an increase in interferon signaling, and we also see an increase in antigen presentation in the tumors preclinically. It gives us greater confidence in going into those combos that will avoid, you know, some of the resistance mechanisms that have occurred, certainly with some of the bispecifics.
Right. The orthogonal mechanism should avoid some of the-
Correct.
...you know, toxicities-
That's right.
...CRS that we see with some of the bispecifics in the space.
Yeah.
Yep. Moving away from chemotherapy as well.
Got it. Then when should we be expecting initial data for that phase I data?
Second half of the year.
Second half of the year.
Yeah, for that one, yeah.
All right. Then tell me what the, what's the status on the glofitamab combination?
Starting soon. We haven't said exactly, but it's very quick. Very soon to start.
Got it. All right. I think that we can turn to KRAS. Again, a very, very competitive space and, you know, very exciting space, with ARV-806, which is KRAS G12D. Would love to hear more about this program, thoughts on protein degradation, adding unique value versus inhibition within this, and a little bit more about your clinical data, which has been incredibly, you know, fascinating to look at.
Yeah. The KRAS G12D program, which is ARV-806, has a bit of a different sort of risk and competitive profile. As you pointed out, we're not the first ones in the space with a G12D program. Most folks are looking at what RevMed is doing and what Astellas has done with their degrader. It's certainly a space where we know that if we're going to be competitive in the space, we'll have to bring something competitive. We started our phase I trial in patients with G12D mutations last summer, and it is enrolled very quickly. We just announced last week that we'd actually completed enrollment already.
While we have said that data will be in 2026, the first clinical data will be in 2026, I wouldn't necessarily expect to wait till the very end of the year for that. In the first data release that we show, and I think anytime we talk about differentiation, it'll be important to talk about what we can show and when. In a dose escalation study, obviously, we're starting at doses below those that we think might produce efficacious exposures, and we're moving up as we can. It's a fairly standard dose escalation that is rapidly enrolled.
When we get to our data disclosure, some of the measures like response rate will be easier to look at sooner, albeit with small patients, than some of the other measures by which we might measure differentiation later on, like durability, like tolerability, like combinability, and all those things. What we'll be watching for this year for the G12D program is to make sure that as we get through the initial stages, it's competitive. It needs to be competitive with the other programs compared to where they were at similar stages. Then as we're able to move after the initial dose escalation, as we move into the dose expansions and we're able to expand and to get more patients at doses that we do think will be efficacious, that we can do a good firm comparison across programs.
That's, we're excited about that program. You know, I mentioned earlier that, we've heard a lot of talk about there being a lot of competition in the space, even in terms of clinical trials, but clearly, I think what we've seen is a strong desire from physicians to find another option, even for patients on trials.
Right. Can you share a little bit more about the preclinical data and how it compares? You know, there were some interesting studies that were done that I believe came out a little bit earlier, late last year.
Yes. We shared at the Triple Meeting some of the comparative pharmacology studies that we've done with the clinical mechanisms. We've looked at inhibitors and compared there, and we've also compared to the clinical degrader, and we found that we're 25-fold more effective pharmacologically at, you know, inhibiting proliferation. We've also found that we do, you know, obviously we're a degrader, so we're removing the oncoprotein entirely. You know, really there's a lot of enthusiasm based on our preclinical data in terms of the pathways that we're impacting. We really do reduce Myc, which is one of those proliferative markers that, you know, many strive to reduce. We see that reduction over the entire dosing interval. We do also increase apoptotic markers over the entire dosing interval.
Lots of enthusiasm from investigators there. We also see, in syngeneic models that, you know, we are inducing MHC antigenicity in the tumor microenvironment. We also have been able to show that we see great combinability when compared to the pan-RAS(ON) inhibitor. You know, we see greater complete responses. Given the fact that, you know, some of the pan-RAS( ON)-
Mm-hmm.
... Inhibitor mechanisms inhibit T-cell activity, we do not. We also expect to see less, you know, pathway effects with EGFR inhibitors as well. Greater combinability. We also do not see enhanced compensatory upregulation, because we're degrading, so we're removing the oncoprotein. Those three major differences, we think, are big differences. Again, investigators really do buy into that thesis of removing the oncogene as a benefit.
Got it. From an internal decision-making standpoint, you know, you mentioned that when you get the initial data, it has to be competitive. Do you have a numerical response rate or durability, you know, threshold in phase I that would justify further development?
Maybe in phase I, but I don't wanna get folks too focused on the initial data that will come sooner, right? I think it's been clear that as we've looked at competitors, they've had something like 35% ORRs. That being said, you know, based on the mechanism that we have and the potential for differentiation on other areas, durability could be important, combinability could be important, tolerability could be important, the safety's important. All those things are there. I think as we get through the phase I, as we get into expansion doses, we'll be able to compare more directly. Early on, we need to make sure we're competitive. We're not the first in the space, right? We need to make sure that we're responsibly deploying capital.
The better comparisons will come when we're able to expand and look at efficacious doses because that's what everyone's gonna be comparing us to.
Preclinically, you know, our data-.
Right.
... say we're best in class, but, you know, we'll prove it clinically.
Right.
Right. When should we be expecting the first data update for that?
We've just said 2026.
Okay.
Yeah.
Wonderful. Okay, we have a few more minutes left. Quickly, you also have a pan-RAS degrader that's in the works in preclinical development. Love to hear more about that. You know, obviously, you know, it increases the addressable population significantly more than KRAS G12D alone, but, you know, scientifically would love to hear about your approach.
Yeah. There we're working on targeting the other variants. In pancreatic, G12D is 40% of the population. 90% of pancreatic cancer is driven by KRAS mutations, so we're going after that additional population. We believe that it's combinable, you know, with many other mechanisms, so we're very excited about this approach, tackling the other KRAS mutations. Again, you know, very combinable with in the immuno-oncology space. That's another area that we're really, you know, going to talk about more. Look for more coming there. The other positioning of this asset is really around amplification of KRAS. What has been seen with the other inhibitors is that resistance develops around this amplification, right?
These resistance mechanisms are, you know, an issue, right, for those, other therapies. It's not a solved problem.
Mm-hmm.
KRAS. We feel that a pan- KRAS oral agent could be very competitive in this space and very complementary to these other mechanisms. That's really where we're playing, in the space, is that we will really degrade and tackle this amplification because we have this iterative mechanism of action that overcomes that compensatory upregulation.
Wonderful. We covered a lot of different programs. It's really been amazing to see what has scaled truly in the past year. Stepping back, what program do you really think has the clearest line of sight of becoming, you know, franchise-defining, and what upcoming readouts will be, like, most important in validating that?
I might even broaden your question a little more-
Mm-hmm
... which is to say, you know, we've got four programs in the clinic now. We'll have five by the end of the year, right? We haven't even had time to talk about the HPK1 program, which could also be incredibly exciting in its own right.
I know. Yeah.
That being said-
Well-
... I think we're at a point where we've pretty definitively shown that we can put very interesting PROTACs into the clinic based on the work of Angela and her team, right? I think that as we fast-forward out over the coming years, the focus on differentiation is gonna be most important, right? We have to show that the PROTACs that we see preclinically showing potential for differentiation actually also continue to show differentiation in the clinic, and that will dictate where we choose to take the programs forward in the most robust way. We're not interested in bringing, you know, the fourth program to market that's comparable. We'd like to bring something better. We'd like to choose to invest in places where we can win, and where Arvinas is best situated to make the resource in-investment and the operational investment.
I think we've shown over the past 12 years, in fact, that we're willing to partner programs where we think that they can move bigger, faster, broader in someone else's hands. If it becomes relevant to do that, we can do that too. That's not at all the same thing as saying that we will bring things to proof of concept and then partner them, right? We will pick things that we will take through on our own, and we'll also. This is assuming everything is successful, find areas where others can help us do that. I think from stepping back, that's the broadest way to think about it. The next data update to come is gonna be for ARV-102, for LRRK2.
We'll have KRAS after that, ARV-393 after that, then we'll get to the new programs like ARV-027 that have only just begun in the clinic. It's a bit of a view of what's to come.
Great. I think you just sort of answered my last question, but if there's anything else to add around what would you say is the most underappreciated aspect of the Arvinas story?
Look, I think it's actually right where I started, right? We've had a 12-year, 13-year history now, but right now looking forward, we've got four phase I programs, the capital to move them, and that's all on the foundation of a pivotal trial-proven platform, right? I think that's a pretty strong place for it to be. That's probably the reason that when I'm asked why I'm most excited to be taking the CEO role at this time, that's what I would say. There's not a lot of opportunities out there that look like that. There's not a lot of other companies that have the pipeline that we have and the ability to move them. We have the ability to the inflection points, and that's what we will do and make decisions from there.
Wonderful. Well, thank you so much for joining us, Randy and Angela.
Thank you.
I'm sure you can follow up if there's any additional questions.
Yeah. No, thank you very much.
Thank you so much.