Good morning, everyone. My name is Ted Tenthoff, a Senior Biotech Analyst at Piper Sandler, and before I begin, I am required to point out certain disclosures regarding the relationship between Piper and our next presenting company, Arvinas, which are posted at the back of the room and also at the registration desk, Arvinas is the most advanced protein degrader company, actually with a potential approval coming next year. And protein degradation's getting hot again, if you haven't noticed. The stocks are really starting to move. As I mentioned, Arvinas and partner Pfizer, I've agreed to jointly out-license estrogen receptor degrader, Vepdegestrant, which has a June 5, 2026, PDUFA date for ESR1 mutant metastatic breast cancer, and now Arvinas is focused on advancing an exciting early-stage PROTAC pipeline. This includes LRRK2 degrader, ARV-102 for Parkinson's disease, and also progressive supranuclear palsy, pardon me, also BCL6 degrader, ARV-393, B-cell malignancies.
I think you're going to share some preclinical data at ASH this weekend, and also a really cool KRAS G12D degrader, ARV-806, and a lot of stuff preclinical that's been going on beyond this. I'm really pleased to have from Arvinas, Noah Berkowitz, Chief Medical Officer, and also Andrew Saik who's the CFO. T hank you guys for making the trip in on a very busy weekend. A lot to cover. I'm going to jump right in. Maybe you guys can describe LRRK2 and why it makes sense to degrade this target to treat Parkinson's and PSP.
Thanks. I'll field it. G ood to be with you here, Ted, and thanks for having us. W e think that LRRK2, or I'll call it LRRK2, is a well-validated target for Parkinson's disease and an evolving target for PSP, where folks that are in the know in the field are excited by it for decades because we know that about 15% of patients with familial Parkinson's disease have a particular mutation in the LRRK2 protein. It's also seen in about 1% of idiopathic Parkinson's disease. And that's the genetics, which is compelling in its own right. And I should mention there's also genetics now that's being shared about the role of LRRK2 mutations in the progression or severity of progressive supranuclear palsy. T hese being two similar neurodegenerative diseases.
What is shared in common is that there's an accumulation of a pathological protein in the brain. We know that it's alpha-synuclein in the case of Parkinson's disease. It could also be other proteins, but it is something called 4-repeat tau or 4R-tau in PSP. And the reason that there's accumulation is because there's a problem with protein trafficking. Y ou end up having dysfunction in the endosomal and lysosomal systems of cells. That's true for neurons, but also true for the microglia. You have an inflammatory process that you can't rid these 4R-tau repeats, let's say, in PSP. They accumulate, and we believe they contribute to the pathology in the brain. And the idea here with the LRRK2 degrader is that we can eliminate all functions of LRRK2. See, the genetics is compelling.
We know that it's associated with these diseases, but there are a lot of reasons why it can be associated. Maybe it's the kinase activity. Maybe it's the scaffolding activity. Maybe it's the apoptotic signaling activity of this very complex protein. By degrading the protein, we can address all of those features, any one of which can be a contributor to the pathology.
That's really, really helpful. And we can talk about this a little bit as we talk about the molecule, but one of the really important aspects of the PROTAC is being able to cross the blood-brain barrier. E ven though they're large molecules, it really does open up neurological conditions to this mechanism. With that, you guys conducted a phase 1 healthy volunteer study. You reported data. I think it was already back at AD/PD in Vienna back in April. Walk us through what you saw there.
Sure. W hat we established for ourselves, but I think the whole field of anyone that's developing degraders, is that when you have the right know-how and you've figured out the secret sauce, which we believe we have, one can develop orally bioavailable brain-penetrant degraders. L ike you said, a PROTAC, it's not a small molecule. It's like about 1,000. Its molecular weight is about 1,000. Intuitively, you might not think it would be easy to cross the blood-brain barrier. But I guess the way you construct this molecule and the way you then select for your lead compound can lead to the development of something that is brain-penetrant. And we shared at AD/PD that we were successful in that. W e were able to dose our healthy volunteers, demonstrate that we had dose-dependent or we had dose proportionality in our dosing.
We were able to have accumulation, see the drug in the brain, the PK properties were very attractive, and we saw on-target activity, we were able to see that LRRK2 was getting degraded. We demonstrated that when you're in this range of 20-80 mg a day of dosing, that you're achieving something like 75% degradation of LRRK2. That is very exciting because we know that patients with Parkinson's disease, on average, and there isn't tremendous interpatient variability. W hen I say on average, it's like there are big differences between patients and their age-matched controls, but they typically will have two to three times the level of LRRK2 in the CSF as age-matched controls. T he goal would be to take this indicator of the pathology of the disease and reduce that by about 66%, 75%. We're able to do that with the doses we developed. That was the exciting, those were the exciting data shared at AD/PD early in the year.
And you already have patients. Yeah.
And now since then, we had, I think, even more compelling data a few months ago. A t the MDS conference about two months ago, we shared some very exciting results where we developed a hypothesis by looking at PPMI. T hat is the Michael J. Fox Foundation-supported Parkinson's progression initiative that looks at the markers that are indicators of progression in the disease. And that effort through that organization had demonstrated, and this has been published, that there are a series of markers that are associated with neuroinflammation that are elevated in Parkinson's disease and elevate more when Parkinson's disease progresses.
And what was very exciting to us is that when we looked at healthy volunteer CSF, we showed that not only were we degrading the LRRK2, but that the downstream indicators of that pathway that we're interrupting through that degradation were the same seen in the PPMI study, meaning we were able to drive down measures of GPNMB, IBA1, and CD68. All of these are measures of neuroinflammation. And that was in healthy volunteers. Our next goal is to show how good we are in Parkinson's disease. But we're feeling very sanguine about this because when Biogen reported out their results for their LRRK2 inhibitor, they didn't move these biomarkers in healthy volunteers. They were able to move them a little bit in Parkinson's disease with this marked elevation at baseline. But we were able to do that already in healthy volunteers.
That's why now that we're enrolling our multi-dose Parkinson's disease phase one cohorts, and we hope to report those results out in the first part of next year, we're optimistic that we should be able to degrade LRRK2 and even move these biomarkers that are very validating for this pathway, move them even more.
Yeah. No, that's really super helpful. What is the development plan from here for 102?
Yeah. T here's the part that we talk about and the part that we don't talk about. W e'll focus on the part we talk about a lot, which is PSP. Our goal next year, and we've been guiding to this, is we expect to start a phase 1b study in PSP in the U.S. that will follow the filing of an IND in the near future. And that study will allow us to measure biomarkers, think of it in the small number of patients, like in the tens of patients, biomarkers in PSP patients, but also look at their clinical measures of the progression of their PSP. W e'll do that with the PSP Rating Scale, which is a regulatory agency-accepted measure of patient clinical capability. T his would correlate some of the biomarkers that we have with the clinical activity in patients.
Now, on the heels of that, and by heels, I don't mean we wait for the results of that, but some time later, maybe by the end of next year, we would expect to start a much larger phase II study that could be registration quality. It would have to be discussed with the regulators. There are other hoops we have to jump through before we get there. But the idea is it can look definitively at these clinical endpoints. T hat's where we're headed with PSP. W hat we don't talk about too much is PD. And I would just indicate that it's known that Biogen is working on a LRRK2 kinase inhibitor that's in a very large registration quality phase II study called the LUMA study. And that should report out in the first six months of next year. I think it will be important for us to look at it to really evolve our development plan. It's in such near future. We're interested in Parkinson's disease, but we're not guiding yet to how we're developing the drug.
I think that makes a lot of sense. And is ARV a drug that Arvinas could take all the way themselves? Do you envision ultimately partnering it? It probably depends a little bit on if you stick with just PSP or develop more broadly.
It's a great point, Ted, because fundamentally, that's another really attractive aspect of PSP for us. We can run these studies on our own. You can get a registrational endpoint because PSP, which we didn't talk about so much, but it's a disease from diagnosis to death. There's about seven years for patients. T here's tremendous medical need because there are no approved therapies for that disease. And this disease would. The size of the study that one would have to run to have an approvable endpoint is in a few hundred patients. I t's really something that we're focused on as a biotech company. We recognize it's a biotech-friendly development path. And that's our primary focus. But when we start talking about PD, if that's something that we do on our own, if that's something that becomes partnered, that will all depend on the quality of the data that we generate and also the appetite of the marketplace to fund that or the partner to partner in it.
I'm gonna switch gears to oncology. ARV-393 targets BCL6. Tell us about this target and why it makes sense to degrade with a PROTAC.
ARV-393 targets BCL6, which is a master regulator of B-cell maturation. W hen B-cells are maturing in the germinal center, they have to go through a process that perfects their creation of an antibody. And that step itself involves DNA damage. BCL6 is involved in kind of stunning the cell or signaling the cell not to go through its normal programmed cell death pathway, apoptosis, when DNA damage is detected. T hat helps cells develop antibodies, but it also may help some B-cells transform into malignancy, like large B-cell lymphoma. So BCL6 had been an intractable target for many years, but we and others recognized more recently a way to develop a warhead against that. And degradation is a preferred approach right now. So we're in the co-lead in this with a large pharma company in terms of enrolling patients already in a phase I study.
We've seen already from the competitor who will be presenting some data at ASH that when they're in the effective dose range, that you can see 70% response rates and 20% PR rates. That's very attractive for a small molecule single agent in a disease like large B-cell lymphoma. We shared in an earnings call recently that we are not prepared yet to share our data at a conference. That'll be an event for 2026, but we wanted to signal we're advancing in the dose escalation. We've already seen responders in our study. So we already have CRs. And there are two ways that we will differentiate ourselves in this field. One way is that we're focused on B-cell malignancy, but we believe that the opportunity is to combine with bispecifics and entrench this drug in the second, third line plus of large B-cell lymphoma.
That's an important goal for the company. And towards that end, we expect to be starting our combinations with Glofitamab in the near future. The next thing is that we recognize that there's a fast-to-market path here of developing monotherapy for AITL. So an uncommon T-cell malignancy is about 3% of all NHLs, for which there really aren't good treatments after first-line therapy of CHOP. And so our study permits us to move towards AITL for the fast-to-market strategy and establish a proof of concept in the combination. And seeing responders, we're very enthusiastic.
Yeah. It's a really cool program, complicated and crowded development landscape, but it seems like you guys are able to replicate that potency and then have a really unique combo strategy developed that can be really powerful.
Look, we know already, and we've shared this data publicly, that we have incredible synergy with EZH2 inhibitors, like lots of other small molecules, EZH2, BCL2 inhibitors, BTK inhibitors, but we think we want to be in the space where you're going to have a transformative non-chemotherapy-based regimen, and that's going to be with bispecifics. The other stuff we'll explore one day, but it's not in focus for us right now.
Yeah. Totally understand. I always thought KRAS is just an ideal oncoprotein for degradation. Tell us about ARV-806 and the opportunity for G12D.
Yeah. So the reason we wanted to get into this competitive space is because we demonstrated to ourselves that we have a lot of differentiation preclinically. So we know that when you compare our degrader preclinically to the RevMed inhibitor and to the Astellas degrader, that we have 25- 40 times the potency that they do. So with much lower exposures in our preclinical models, we are developing significant tumor growth inhibitions, if not regressions. And that becomes important for the degrader, at least for Astellas, because they had dose-limiting toxicity of transaminitis that prevented them to really dose higher and demonstrate more activity than the RevMed inhibitor. Right? So they were stuck at the 300 mg-600 mg dose range. We believe with greater potency, we may not have those limits. And we are racing through our dose escalation right now. It's going extraordinarily well.
And expect that we can have some cross-study comparison available next year. The other reason we're very excited and have become even more excited over the past six months with our degrader program is that RevMed and collaborators have published over the past year that a principal mechanism of resistance to, let's say, a pan-RAS inhibitor is KRAS overexpression. So about 30%-40% of the resistance relates to this amplification or overexpression. Now, because inhibitors work on the basis of occupancy, a cell can increase the number of its KRAS G12D proteins, and you can now no longer have adequate inhibitor presence, right? Because there's enough occupancy, and you lose activity.
But a degrader is a different story because we have this catalytic iterative activity that allows us to, as long as that drug's present, the cell that's trying to amplify and create more and more KRAS signal, it's just going to be degraded by our degrader. Now, this has to be proven in the clinic. We're seeing that type of signal preclinically. And the goal is to, we look forward to sharing our clinical data next year. So no guidance yet exactly when that will be shared, but suffice it to say we're progressing through our dose escalation very effectively.
Yeah. Another very exciting program. So I'm going to try to squeeze one in here because this was sort of a surprise to me. But ARV-027, you just recently unveiled, is a polyQ AR degrader. Tell us a little bit about this because it's a little bit different than what you've done with a lot of your stuff.
Yeah. So I think this is like a strategic signal about how the company is trying to be smarter about the disease areas we target, right? And look for things that are more tractable for a smaller biotech company. We went in guns blazing in a partnership with Pfizer to develop a degrader. We licensed out a compound because it turned out to be a little much for us in the moment we had to make decisions with our AR degrader to Novartis, which is going extraordinarily well there. And we're very excited about their progressing that. But the question is, the next compounds we're looking at, how do we make sure that we're addressing diseases that we can handle completely on our own?
And so 027, targeting the androgen receptor that is mutant in that it has a polyQ tail, that is a wonderful disease area and target for us. First of all, we think we know the most about AR degraders because we already developed one and licensed it out to Novartis, as I mentioned. But now we've been able to develop, excuse me, we've been able to develop an AR degrader that we can use that was chosen on the basis of its ability to have good muscle penetration and target it to this disease, SBMA, where you have this mutated androgen receptor with polyQ. Now, the disease itself, it's an orphan disease. So there are tens of thousands of patients that have this. The normal disease course is that you go from diagnosis often in your 30s to a slightly shortened lifespan. Maybe patients are dying in their 60s or so.
But the nature of the disease, it's just continuous decline so that patients are going from some slight weakness to real problems swallowing, maintaining their daily living, being bedbound, and so on. And it's a disease of the muscle and the neurons, and one in which there's uniform acceptance that the problem is this polyQ AR. So if we can degrade the polyQ AR, then we have a target that's fully validated and a disease that's an orphan disease that we can address as a biotech. A closing comment on it. So we plan to start a healthy volunteer study next year. We'll do our SADs and the MADs. But the great validating part of that SAD-MAD healthy volunteer work is that we can do biopsies and show that the drug is penetrating muscle and degrading AR. And we'll also add some patients with SBMA. I didn't mention it before, so that's spinal and bulbar muscular atrophy. We'll add some patients to that phase I, do biopsies in them. This would be a proof of mechanism that I think should position us well for a definitive study.
Very cool. Not the Arvinas that people were used to even just a year ago. So I love all the progress and all the hard work you guys are putting in on the pipeline. Andrew, Arvinas ended the third quarter still with a very healthy cash position, $788 million. I think you guys have actually been repurchasing stock, $20 million in the third quarter, probably even more since then. Where's the cash now? How long does this fund the company?
Yeah. So we haven't given a cash update since our Q. So I couldn't update you on the exact cash amount. But we've been pretty clear that even with the cash buyback program, we have cash well into the second half of 2028. It's obviously important to us to fully fund all the programs that we have going on to get them to inflection points so that we can make decisions on future development. And we have plenty of cash for that, right? So that's important and critical to us.
The one thing I forgot to mention is you could partner out with Vepdegestrant, which could bring in some additional funds to fund this. So take a look at Arvinas. I'm still trading at a very attractive valuation and a lot going on. So thank you guys for beFing with us.
Yeah. Thank you.
Thanks.
Thanks.