Everyone, welcome to day two of the Cantor Global Healthcare Conference. My name is Li Watsek, a biotech analyst here at Cantor, and it's my great pleasure to have our next company, Arvinas, with me for a fireside chat. We have CEO Randy and CSO Angela here with me. Maybe to kick us off, I would love to turn it over to Randy to give us a quick overview of where the story stands today.
Thank you very much, Li, and thanks for having us. I think what a lot of people know about Arvinas is that we invented the PROTAC technology and now have the first program that's out actually serving patients. We're excited that our first program is now being launched, which is fantastic for patients with breast cancer. What I think folks right now are catching up with is that we've transitioned our focus to the pipeline, but a lot of the pipeline programs are now very rapidly moving towards their first data in phase I. There's a whole lot coming in just the next few months and over the next nine months for all four of the programs that we now have in the clinic.
We have a program, ARV-393, which is a BCL6 degrader for hematology, which will have its first phase I data by the end of this year. That's in patients with subsets of NHL, so that's coming up pretty quickly. We've got a LRRK2 degrader in neurodegeneration, which will have its next biomarker data from phase I in just the next month at the MDS International Congress in Korea. So that's coming up very quickly. We've got a new program that started in the clinic earlier this year for a disease called Kennedy's or SBMA. That'll have its first phase I data in both healthy volunteers and patients in the first half of next year. Then to round it out, we're just now starting another program in the clinic, an HPK1 degrader called ARV-6723, which is our first IO program. So a lot of opportunity there as well.
All four of those are now coming into a pretty rapid succession of data. At the same time, since I took over leadership earlier this year, I've been really clear about a desire to have Arvinas focusing on where Arvinas can win. We've got a number of programs in the clinic. We've got a demonstrated ability to move programs into the clinic, thanks to Angela and her team. Now, the question is, which of those are we going to wholly own and move forward? Right now, all four of those, we're able to move to the important inflection points and data points with the capital that we have. Our cash runways into the second half of 2028. All the data that we've just been talking about is well within that.
We've got a very strong focus on making sure we're efficient in moving the capital right where it needs to be to move those programs to important data. But right now, we're really in a bit of a transition from focusing on VEPPANU to focusing on the pipeline, and now we've reached a point where all those data are now quite imminent. So it's a great time to be sharing at the conference.
Maybe on that point, can you talk a little bit about how you prioritize, just given you have a lot of things going on and you're looking at programs in oncology and CNS. Would love to just get your thoughts on how you approach maybe capital allocation and internally, how do you look at these programs in terms of priority?
The two biggest areas we have are in oncology and neurology, and all of the programs can roughly segment under those two headings. We don't really make a bias or a preference towards oncology or neurology. What we're trying to focus on is now that we know PROTAC degraders can work, where's the right place to take them, and what's the right target to hit with that technology? The programs that we have in the clinic right now are all able to be moved forward and hit their important points with the capital that we have, like we've talked about. So the prioritization that will come is really when we see the data from those trials and helps us make decisions. I think a great example of that is we've had a KRAS G12D degrader in the clinic.
We haven't shared the phase I data yet, but we announced earlier this year that that's a program that will move forward only with a partner. So that's one where we've decided that Arvinas isn't the right company to take that forward. I think the prioritization that you may see coming up will be based, again, on the data that we see. So we are really focused on where Arvinas is the right company to make the difference and figuring out where we can invest strongly to win. That didn't feel like the space coming from behind in KRAS G12D. So that's how we think about it. Going forward, as we think about prioritization, clearly, we will run what we can. The idea is to hold on to wholly- owned assets that help us create value for patients and shareholders.
But at this point, we have the ability to move them all forward through phase I.
How many programs can you develop internally? I guess it's a goal to just pick one or two and move forward, just given the resources that you have.
Over time, the resources that we have can certainly grow. Right now, we're in a comfortable position with cash. We don't have the need to go out and raise. But as the programs move forward, phase I's have a tendency to turn into phase II's. They have a tendency to turn into phase III's. And as that happens, we'll bring in cash if we need to, pending success and generating some excitement. But I don't think there's not a goal around we are going to try to move forward one or two or some specific number.
We're going to move forward the programs that we're excited about, investors are excited about us moving forward, and that will really help us make the decisions.
Now it's in the hands of your partner, c an you just remind us quickly what additional milestones or royalties that we should expect?
So VEPPANU, as now it's known on the market. Rigel, that deal included about $85 million in upfront and near-term transition, you could call them milestones. An additional $320 million of milestones down the road, primarily commercial oriented, and tiered royalties between mid-teens and mid-20s. So that program is now getting to patients. Like I said, it's been launched. So Rigel has been enthusiastic in suggesting it may be their largest program out there. So we are very happy with them as a partner and their ability and commitment to get that to patients. So look forward to seeing its trajectory.
Now, turning to the pipeline, I want you to start with BCL6 PROTAC ARV-393. Why is a degrader approach better than an inhibitor approach here? I think that's very important because it's going to be context dependent.
I agree with that. It's a great place to bring in Angela, please.
Sounds great. Inhibitors classically have not had substantial activity against these transcriptional regulators like BCL6. There are inhibitors that have been described, but they have very poor anti-tumor activity in vivo. What's required is actually the PROTAC. The PROTAC's the perfect mechanism to remove the driver of certain subtypes of non-Hodgkin lymphoma. By removing it durably and keeping the resynthesis rate under wraps, that's exactly what we overcome. Inhibitors can't overcome that rapid resynthesis rate. Because we have this catalytic mechanism of degradation, we can overcome that rapid resynthesis rate that happens within an hour and drives the tumor.
Then just from your own preclinical studies, d o you compare with the inhibitor approach?
We have. Yes. We have shown just that. The inhibitors cannot overcome that resynthesis rate. We have shown in a very elegant way that the E3 ligase dependence of that degradation is required to overcome that resynthesis rate, not just binding to the target itself.
You've guided to some initial data later this year, but it sounds like it's going to be at a lower dosage. What should be the expectations here for the readout? What do you hope to learn?
I think of the readout that we'll have first for the BCL6 program is really in two parts. As you said, we're going to share some data by the end of this year. That will be a release that's focused on safety and PK and PD, and primarily on patients with T cell lymphomas. Our phase I study is enrolling subsets of NHL, patients with both LBCL and also with AITL predominantly.
As you noted, and we said publicly, we started at a dose in this trial that was pretty well below exposures where we would have predicted efficacy. That is why we are going to start in T cell patients, where there seems to be a bit higher sensitivity, and we are going to then release additional data in the middle of next year or so that will include more patients with B cell lymphomas. That will allow us to collect more patients and accrue more patients at exposure levels and doses that we expect to be efficacious, and also allows us to, at the same time, release the first data from the combination trial. We have a monotherapy escalation ongoing, and we also have a combination escalation ongoing with glofitamab. We will split it up like that over the course of a couple disclosures.
Maybe on the combination front, too. Going back to the preclinical data, I think a PROTAC is, as Angela said, a very elegant way of hitting a target that an inhibitor is not hitting very well. But the space that we are heading into in NHL is going to be very clearly a mix of both monotherapy and combination. We have a lot of combination data as well preclinically that we will hope to translate into the clinic as combination as well, beyond the glofitamab study.
That is important mechanistically because we know that by degrading BCL6, we are actually impacting CD20 expression and enhancing the activity of the T cell engager.
Just to clarify, for the data that you will be sharing later this year, do you have any patients at a therapeutic dose?
Yes, absolutely. It has been going on for some time, and as we have escalated, we have only in the past few months got to exposures that we would have expected to be efficacious. That is why we are going to let that run a bit longer before showing the LBCL data. Yes, there will be some, and there are some. We announced, I believe a year ago, that even at low doses we had seen some patient responses across both LBCL and AITL. There is activity for sure, there is no question about that, b ut not as many as we would like at this point.
As you know, BMS, their BCL6 degrader also show some pretty nice data, 54% response rate in the DLBCL patient population. What would be a good outcome for you, just from a monotherapy activity perspective? Then we can talk about combination.
We were very gratified to see that. The history lesson for us is we started with targets like AR and ER. Being the first company in the space we used well-validated targets to prove the technology could work. Then we moved very rapidly thereafter to targets like BCL6, which was really considered an undruggable. Seeing BMS come out with that initial data was gratifying that the target was doing what we expected it would. If we want to make comparisons like that, the better time will be middle of next year when we share more LBCL data. I think that BMS and a couple of other companies, as they and we show data, we will get a better idea of what a BCL6 degrader can do. There has not been another modality that has hit the target. I think obviously we would love to have a monotherapy activity that is sufficient for late-line usage as monotherapy.
The larger opportunities for both patients and for a biotech company will be moving earlier in combinations, such as with glofitamab that Angela just mentioned. As we look at the data coming out towards the end of the year focused on AITL patients, there are no specifically indicated therapies for patients with AITL in the second line. There is no standard of care to try to beat. If I was a patient with second-line AITL, what I might hope for with some therapies could be an upper 30% to low 40% response rate. That would be nice to get to over time as we get to an efficacious range.
Whether we see that in early dose escalation, we will see. That is what you would be expecting as a patient for therapies that have made it through phase II and phase III. I think that is a good bar to see if we have efficacy and activity in late lines that we would then hope to take forward in combination, in earlier lines.
In terms of combination with glofitamab, can you talk a little bit about the synergy here? I believe you guys have shown some pretty nice preclinical data. Then, second, maybe just update us on where you are in terms of the combination.
So preclinically, we've shown some very nice combination data and synergy, both if you start the experiment with the two molecules together or if you add on our molecule after glofitamab treatment. So, we see equivalent activity in both cases. We think this is really exciting. And the durability of the response as well as the depth of the response that we're seeing is really fantastic. So we see complete responses with that combination. The nice thing about that for patients is that it brings better activity to glofitamab. That's what we would predict from our preclinical data, and we'd also say that this allows the patient to move away from chemo.
So, we think this is a huge opportunity. In addition to glofitamab, we've looked at several other combinations. We've looked at all oral combinations that include some of the major pathways that drive NHL. BTK inhibitors, we've looked at EZH2 inhibitors as well as BCL2 inhibitors like venetoclax. In all cases, we see complete regressions preclinically. We think those are really great all oral opportunities. Then, also on the antibody side with RITUXAN, as well as POLIVY and other mechanisms, CD19 mechanisms we've looked at, again, all complete responses when you add our molecule onto those. We're really excited about the opportunity for this compound, ARV-393, to be broadly combinable.
That's really how the field has evolved. The solution sets for patients with NHL have expanded over time by adding new therapies to deepen and extend responses in patients. A lot of the therapies that have been available have been bispecifics and antibodies and CAR T cells and transplants and things like that.
We think that a tolerable, orally available compound that has a good tolerability profile and the ability to be combined with other agents has a pretty bright opportunity to be combined in different settings. Even though even across both B cell and T cell lymphomas, we would expect to start in monotherapies in later lines, the idea is to move earlier. For LBCL, you might start third-, fourth- line monotherapy, move towards second- line in combination with glofitamab or another bispecific, something like that, and then an opportunity to displace chemo in the first line. On the T cell side, maybe you start second line plus as a monotherapy and then look to combine in first- line AITL, which is a much larger opportunity than late line, and combine there with chemo.
There is a bit of a mix and match across lines with what the available treatments are, where you can combine with chemo, where you can displace chemo, where you might look for all oral options like Angela talked about. There is a pretty broad set of opportunities to explore once we get through the monotherapy escalation and the first combo escalation, which I think will help us chart a path forward.
What would be a good outcome from the glofitamab combination?
Well, the glofitamab combination, glofitamab by itself is quite active in late lines. What we would want to see, and we may have to wait till further in a dose escalation to see this, we would want to see that we are adding onto what glofitamab can do, which is pretty dependent on the patients we end up enrolling, how late line they are, what the treatments have been. As we get closer to the data next summer, we can talk more specifically about that. But in principle, we need to see that we're doing something on top of what glofitamab 's already doing.
In terms of the development strategy for this molecule, it sounds like you guys want to take more of a maybe sequenced sort of approach, maybe start with monotherapy and move into combination, or do you plan to maybe move both in parallel?
I wouldn't call it sequenced. We've been asked this a few times, I also wouldn't skip over the monotherapies. There's a world where you could look for monotherapy late-line activity and then just go full bore into combinations earlier. I do think that especially for a small company, it's advantageous to move as a monotherapy in later lines to, w hich both gets the drug to patients with high unmet need, but very importantly, makes it a lot easier to do a lot of the combinations that you'd want to do in earlier lines, given the number of options that we have.
I wouldn't think of it as first you do late line, then you move earlier. There's going to be plenty of overlap in the Gantt charts. I also wouldn't say we're going to skip over the late lines and go straight into combos only.
It's probably also important to address contribution of-
Exactly.
So you have some monotherapy activity.
That's right.
Maybe switching over to LRRK2 ARV-102. You guys have shown very good biomarker data here, LRRK2 expression reduction. That's all good. I think what we struggle, investors struggle a little bit is how should we think about the translation into the clinical outcome. Then we've seen some setback from LRRK2 inhibitor. Maybe help us understand why do you guys still have very high conviction on this program?
I think I'll let Angela speak to the inhibitor combination. The short answer is I don't think we learned a whole lot from the LUMA experience. From the broader question of how we move this forward, I think we have quite a bit of data, both clinically, which you just mentioned. We had, I would say, fantastic biomarker data earlier this year at AD/PD, and we're going to have fantastic biomarker data again next month at MDS. And I think those data sets will both show features and impacts on biomarkers that are unlike any inhibitor has shown. So we think that's really important. It's also predicted by the preclinical data that we already had that showed that versus inhibitors, the PROTAC degrader was doing a far better job of inducing lysosomal number and function, reducing tau in some models.
So we've had a good reason to believe for a long time that an inhibitor would not do the job that a degrader could do. I hope I didn't take too much of what you would say, but please.
I will add by saying there are other labs now that are showing that LRRK2 reduction blocks uptake of pathologic tau and uptake of pathologic proteins. The inhibitors do not in their hands. Rick Livesey and his team at Talisman have been able to show this. It is always nice to see other groups actually replicate that the endolysosomal function that you have when you reduce the target and degrade it is very different than what you see with an inhibitor. We do not think that the inhibitor is at all comparable to the PROTAC, because it leaves some of the disease biology on the table. LRRK2 is a large multifunctional kinase. It has a scaffolding function that mediates neuronal death. It has a GTPase activity that mediates neuroinflammation, and then the kinase domain.
Unfortunately, kinase inhibitors are always battling high levels of ATP, so they are catalytic. They bind to the catalytic domain, but they require binding a one-to-one stoichiometry that gets overcome very easily with time. A PROTAC durably reduces the whole protein that impacts all of those functions. What we are seeing from a translational perspective is as you reduce LRRK2, and we have been able to show this very nice dose-dependent reduction of LRRK2 in CSF, of healthy volunteers, and now in patients. This means something for the whole field. It means that the ubiquitin-proteasome is intact in neurodegeneration, which is really important. It also shows that we have comparable pharmacology in the elevated LRRK2 state, which is driving this dysfunction and putting the brakes on this lysosomal clearance system. What we showed in our biomarker results is that we actually reduce those endolysosomal biomarkers.
We reduce the neuroinflammatory markers in a dose-dependent manner. That has not been shown for the inhibitor. You see a small trend in GPNMB, which is a key endolysosomal marker in Parkinson's disease. Then at MDS, we will be expanding those findings into some new biomarkers that are synaptic biomarkers. You were mentioning, how do you read through?
This is at least how I think about read-through. I would want to see some sort of synaptic functional change that I can say, okay, it looks like this molecule is doing something in the brain to a synaptic endpoint. In this case, we are seeing two different synaptic endpoints change. We are seeing what is called ASH, which is amplitude of saccadic hypometria, so it is eye movement, it is ocular motor, digital readout of how your eye tracks to a rapidly moving target. In Parkinson's disease, even within our 28-day period, we saw a deficit in that endpoint. We were able to show with ARV-102 that we actually improved that endpoint even in a very small number of patients. Those are the data you can expect to see at MDS. We have been sort of socializing this so that people can understand what it means.
This means that we are seeing synaptic impact in the basal ganglia, which is exciting. Then we are also seeing changes in CSF biomarkers, and those CSF biomarkers are synaptic markers of cognitive resilience in Alzheimer's disease, so this includes Neuronal Pentraxin 2, so we are actually increasing that. Then cerebellin 4, which is a prognostic marker of Parkinson's disease progression. So it is really the composite of these data that would give you belief. So that is kind of a long-winded answer to your question.
What do we know about the correlation between the synaptic sort of endpoints with the clinical outcome?
With the UPDRS?
Yeah.
There are publications that have linked this ASH measure, the ocular motor function, to the UPDRS. It has been described in the literature. More recently, there was a publication from the company that we have been working with, NeuroLight, on that topic.
Do we know if Biogen has shared that data?
I do not know that Biogen included those data in their clinical trial.
For the phase I-B study, in PSP, you sort of pushed that out into 2027, pending the regulatory feedback. Can you just talk a little bit about what the gating steps are here?
For sure. That study itself, and the fact that we're going forward in PSP is another difference. We've decided to not go to PD first. Maybe ultimately we will. PSP is a much more homogeneous population, and there's even opportunities within PSP to even look for a more homogeneous group, which we think will be helpful. Patients with PSP progress, unfortunately, quite rapidly. Within five or seven years of diagnosis, a lot of patients will pass away, which is clearly much faster than for Parkinson's. That also means that they will progress along a rating scale much faster on an annual basis, which means you can run a shorter study.
With that as the sort of the intro, on the phase I-B study itself, the plan that we'd laid out earlier this year was to begin a phase I-B study in the U.S. this year, and then also a global registrational study. We are now going back and forth with all three major regulatory agencies in the U.S., Europe, and Japan. The good side of that is it allows us to do a bit of harmonization across the regions, so that when we start the trials, we are making sure that they are applicable globally. Right now, that program, after finishing its phase I in Europe, before we started in the U.S. with that phase I-B, the FDA asked us to come back with the full chronic tox data, which we have now done, and are now going back and forth to resolve that hold.
When we start those studies next year, we will provide an update as a result of what those conversations with the different agencies have been, update on what exactly those plans will be. But the specific answer is, we want to get to a satisfactory position with the different regulatory authorities on the overall development plan so that we can move forward as efficiently as we can. That could still involve multiple studies like we had before. That could change, but for now, we will keep that guidance the same as we get through the conversations with all the regulatory agencies.
It is going to be early next year?
Hard to say. We just loosely pushed it off to 2027 while we sort through the conversations, and then we can narrow that down.
What would be the endpoints here for the study?
Look, ultimately, over time, it's very likely to be something like the PSP Rating Scale, or a subset of that rating scale, which there's been innovations there to make it a bit more homogeneous and a bit more specific. Over time, it's likely to be a rating scale like that. In the shorter term, Angela did a nice job of laying out a whole lot of different biomarkers that we could be looking at to inform the connection between degrading LRRK2 and the ability to ultimately show a change versus a placebo on a rating scale. But over time, that's what it's likely going to be.
Maybe just lastly, touch on ARV-027. That's also a very interesting program. Maybe give us a quick update.
ARV-027 is an AR degrader, an androgen receptor degrader, that we are specifically aiming at polyglutamine repeat androgen receptor, which is what's found in patients with Kennedy's disease, also called SBMA. Patients with SBMA, which are almost all men, it's an X-linked disease, and so there's one copy of AR. They've got mutated AR, polyQ extended AR. And we know that those polyglutamine repeat AR causes disease. The aggregation of polyQ AR in muscle is what causes SBMA, and so our goal is to degrade it, not degrade some upstream factor or transcription factor, but to degrade the actual cause of disease. You pointed out that that program is interesting. We started that program in the clinic early this year, and we've had a lot of interest in it from investors, investigators, potential partners, because I think it is quite a simple story.
PolyQ aggregates, it causes disease, we can degrade it. It's not as simple as that. We'll have to get through all the regulatory plans and how the trials could evolve, but it's in phase I now, and that will include both healthy volunteers and patients with SBMA, which means when we share those data next year, it should be unusually predictive of success because we're degrading the actual cause of disease. It's an exciting opportunity. We've got a lot of engagement from the patient community as well. The Kennedy's disease patient community is quite strong and enthusiastic. A lot to come there we can talk about in the future.
Seems like the biological rationale is very strong here. A cause effect.
It is very clear.
Thank you so much, guys.
Thank you.
That is all the time we have.
Thank you so much, Li.
Great. Thank you.
Appreciate it.