Hello again, everyone. I'm Esra Darroudi, a Senior Biotech Analyst at Barclays. It's my pleasure to have Arvinas with us for our next session. I have Randy Teel, our Chief Executive Officer, and Angela Cacace, our 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. Yeah, so Arvinas, as we start 2026, has four programs in phase I, which is a pretty exciting pivot for us. Over the past year, we've taken steps to really reposition ourselves as a phase I company. That's where we are with four 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, or polyglutamine repeat AR, which will be relevant for patients with Kennedy's disease. We've done all of this, you know, at this point, with a pretty strong foundation.
For our formerly lead program, that vepdegestrant, which was an ER degrader, is an ER degrader, we had positive pivotal data last year, and that program now has an NDA filed with the FDA, which has a PDUFA date in early June of this year. The platform that we have created over the last 12-13 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. As we move forward with our phase I 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 points.
As we look out ahead to 2026, where we will have clinical data for three of those four clinical programs, we think it's a pretty exciting time to be looking at the company. With my, you know, 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 a new role.
Great. You're about eight 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 I. We need to get the data. We need to see what the programs can do. From that extent, it's a bit of 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 I 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. 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 and resource are the right places for us as a biotech company. 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. I really think 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. You talked a little bit about the vepdegestrant and successful phase III study. You're looking for partnerships for that program. How are those discussions going? I guess ultimately, you know, 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 I mean, sorry, into commercialization, how are you thinking about that?
Yeah, it's a great question. The overall goal that's shared by us and Pfizer is to make sure that 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. 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. 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 to take a step back, just talk about the physiological role of LRRK2 and the rationale for targeting LRRK2 and in Parkinson's disease.
Yeah. The LRRK2 program, ARV-102, is the furthest along, and we'll have data coming up next week. I think it'd be great, Angela, to dive in on the rationale for the target and the program. Yeah.
Sure. 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 endolysosomal dysfunction. This leads to accumulation of toxic neurodegenerative proteins. By degrading LRRK2, this will normalize homeostasis of lysosomal function and clear those pathologic proteins. 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. What's been shown in this disease is that elevated LRRK2 causes an increase in progression, clinically meaningful progression in a year. This has been shown by the folks at University College London.
Certainly, in Parkinson's disease, LRRK2 has been implicated as well in progression of that disease. You know, we're encouraged by what we're seeing.
Great. What week 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. In our phase I 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. We also showed, which was unexpected, that we reduced proteins in CSF that are elevated in LRRK2-driven Parkinson's disease. These are pathway biomarkers from the Michael J. Fox progression marker initiative.
Mm-hmm.
That was exciting for us to see. Next week at the ADPD meeting, we'll be sharing our Parkinson's disease data. 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, you know, crossing the blood-brain barrier, degradation in the brain or CSF of LRRK2. These patients will be on average 60 years of age. We showed in healthy volunteers that are on average 25 years of age. Engaging the ubiquitin proteasome with a PROTAC mechanism that we're able to degrade LRRK2.
Mm-hmm.
In the brain of neurodegenerative disease, very important for our PROTAC mechanism to de-risk oral degradation. That's exciting. 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.
One of the, you know, 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, Biogen and Denali's program as well as Neuron23's program. When can we start to sort of see, you know, potential differences in the approach for Parkinson's?
Well, sir, we've already shown the data that differentiates. In healthy volunteers, we've shown that we degrade LRRK2 greater than 50% in CSF.
Mm-hmm.
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.
Mm-hmm.
It has not been reported. You know, last year at ADPD, 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.
Mm-hmm.
You know, it's possible that they have those data and just didn't share it. We shared full pathway engagement in healthy volunteers.
Got it. Great. It's sort of a tricky sort of situation where you know, as we get the data sort of from them, are there scenarios where those studies potentially fail, but then there's still a strong rationale for moving forward with a degrader, particularly around your point earlier, maybe around sort of capital allocation.
Mm-hmm.
How to sort of best demonstrate proof of concept, but then also demonstrate sort of meaningful differentiation from other assets. 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, and we hope very much that they have a benefit for patients in Parkinson's disease.
Mm-hmm.
We think that in that scenario, the differences that Angela has already pointed out in terms of the data that we've shown pre-clinically and with biomarker data in the clinic, we think give us an edge. That's what we would hope is that they're successful and we're able to do better. That's the goal.
Mm-hmm.
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 I-B trial started in patients with PSP in the first half of the year.
Mm-hmm.
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 wanna get too far ahead, there's a few hoops that we need to get through to do that.
Mm-hmm.
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.
Mm-hmm.
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.
Right. For those 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 five to seven years.
Mm-hmm.
Of diagnosis. It's a Parkinsonian-like disease, so it's a movement disorder. You know, but patients lose their ability to communicate. They also tend to lose their ability to eye track, so they can neither look up or down. Very debilitating over time. There are about 25,000 patients in the United States that are diagnosed with this disease. It's a decent-sized rare disease. The progression is very rapid, so you can measure clinically meaningful progression within a year. 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. 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?
There is the PSP rating scale. This is a well-recognized clinical rating scale, and that is recognized by the FDA as the clinical tool. You know, if we stop progression of this disease, you know, within a year, certainly that would be clinically meaningful or even reduce it by certain number of points on that rating scale.
Got it. Great. Thank you. Maybe we can switch over to the KRAS program. Obviously very busy space. You know, I think that 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 inhibitors in other programs.
Sure. Our ARV-806 degrader removes the oncoprotein from the cell, so from the tumor.
Mm-hmm.
That's very different than the KRAS inhibitors that are ahead of us, both the on and the off inhibitors. That removes the driving force that, you know, drives this rapid proliferation within the tumor. 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. 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. 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.
Mm.
It is a reaction to inhibiting the protein. We do not see that because we are degrading. We have this iterative activity as a PROTAC mechanism that degrades and takes out that resynthesized protein.
Mm-hmm.
We overcome that, we degrade so that we expect to have a very durable degradation and removal of the oncoprotein. The other point that I'll make with respect to the KRAS inhibitors that work through a cyclophilin glue-like mechanism is that they do have an immunosuppressive type of mechanism.
Mm-hmm.
because divarasib also inhibits NRAS and HRAS. What we've shown in syngeneic models is that we see superior combinability with anti-PD-1 agents.
Mm.
That's because we don't inhibit the T-cell activity. That's another important point of differentiation.
Mm.
We also feel that we'll have very good combinability with anti-EGFR inhibitors. Again, we won't have that combinable, toxicology profile.
Got it. Great. When you think about sort of setting expectations for that, you know, it's gonna be an early phase I study. Is it primarily safety and maybe looking at translation of degradation to clinical response? How 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. 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? 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.
You're absolutely right in saying that our first data readout from a phase I dose escalation study will have all the standard limitations of phase I 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. 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 is, and the ability to prevent resistance, is probably the area of efficacy where we would most look to differentiate.
Mm-hmm.
That will almost certainly not be ready.
Right.
In an initial data update. Back to safety and how important that is in combinability. Clearly, the space that we'll ultimately look to take a KRAS degrader is in combination with other agents. The combinability will also be critical, and obviously, we'll have no view on that at all, in the phase I dose escalation.
Yeah. You're also developing a pan-KRAS degrader that's in preclinical development. Just given sort of, you know, 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?
Yeah, certainly. You know, 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 inhibit proliferation in a superior manner in an amplified wild type KRAS setting, which is really important. You know, as you mentioned, amplification is a big mechanism of resistance for the inhibitors. You know, we've seen this, you know, it's been reported for the RevMed resistance mechanism. We think this is a very competitive area for us to show mechanistically that we can overcome that amplification setting. These are the first data for a degrader that we've seen published anywhere where this has been shown.
Right. I guess when you think about just the KRAS and the competitive landscape.
Right.
Just in general, you know, again, could potentially be significantly a large opportunity. How are you thinking about sort of future development of KRAS? Is it something you'd think how far can Arvinas take this? Or do you think ultimately you would have to partner this opportunity?
I think it depends on the data we see and how the development plan continues.
Right.
We have two programs so far, right? The G12 D and the pan-KRAS. 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 G12 D, which might be able to get to deeper degradation or at least to better combinability with other agents. We think the franchise approach makes a lot of sense. Both those programs, though, as you point out, going forward, will move from phase one programs into two, will move from monotherapy studies into combinations. 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 three trials at some point. Importantly, though, that's not where we are yet.
We're running a phase I dose escalation that so far has run incredibly well. I think that reflects a lot of excitement on 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.
Mm-hmm.
We're going to be able to get data out this year ahead of where we would have thought. I think that reflects the 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 AR, too, 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. You know, that makes sense. I guess that was sort of gonna be my next question. 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? You know, 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. The 393 phase I study has some, you know, resemblance to the KRAS, where it's a phase I 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.
Right.
393 will have data in the second half of the year for a dose escalation, and that will be the first important look. 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 gonna have to be when we get to combination.
Mm-hmm.
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. Going forward with glofi will be the first step in doing that. We'll start enrolling patients in that in the next few months. 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 gonna start to just need to see some differentiation. 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.
I think we're still in a very strong position there, as we move forward.
Great. Can we expect sort of typical mix of non-Hodgkin's lymphoma patients in that cohort, DLBCL, follicular lymphoma?
Well, I think BMS data was primarily LBCL. One unique feature of ours is that we're also enrolling patients with T-cell lymphomas.
Got it.
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. With that, it looks like we're up on our time. Andy, Angela, thank you so much for your time. Thank you for our listeners, and we'll be back with our next session.
Thank you, Esra.
Thank you.