Good afternoon, everyone. I'm Ken Shields, Vice President of Equity Research on the Targeted Oncology Team at Leerink Partners. Welcome to the second day of our Global Biopharma Conference. Pleased to have Arvinas here with us. We have Randy Teel, Senior Vice President, Corporate and Business Development, and we have Ron Peck, Chief Medical Officer. So welcome. Hope you guys are enjoying Miami so far.
Great. Thanks for having us, Ken.
Yeah, sure. So Randy, maybe you could kick us off with the high-level overview of Arvinas, the PROTAC discovery platform and-
Absolutely. Yeah, happy to, and thanks again for having us down here in Miami. Yes, so we're Arvinas. We've been around since about 2013. Definitely consider ourselves a pioneer in the protein degradation space. We make PROTAC degraders, which degrade, not just inhibit, proteins of interest, really proteins that cause disease. We're active across both oncology and neuroscience. Our farthest along program in oncology is vepdegestrant, which is an estrogen receptor targeting degrader. It is in pivotal studies, alongside our partners at Pfizer. We did a deal with them a few years ago. We have a global 50/50 deal with Pfizer to co-develop and commercialize vepdegestrant. It is in a monotherapy, second-line-plus, metastatic breast cancer trial right now that's expected to read out, in the second half of this year. Behind that, also in oncology, we also have a program in prostate cancer.
It's an androgen receptor degrading PROTAC called ARV-766. It's expected to have some durability in PFS data in the middle of of this year, ahead of getting started on a phase III trial thereafter. On the neuroscience side, we just very recently announced the first in-human dosing of ARV-102, which is a LRRK2 degrading PROTAC degrader. That started in human volunteers just a few weeks ago and is exciting as it's our first neuroscience-oriented degrader. So it's an oral degrader that crosses the blood-brain barrier and is expected to degrade LRRK2, and obviously, that's exciting to be in patients with that. A number of other programs behind those, BCL6 is another target of interest that is expected to start human trials in the first half of this year. And then behind that, a whole raft of others.
The PROTAC platform that we have has really been, you know, quite productive at getting clinical candidates and have a lot more coming on behind, you know, led by KRAS G12D. But again, thanks for having us, and I'd like to kick off with a bit of intro 'cause Ron typically gets to answer almost all the other questions.
Yeah. Well, thanks for that, though. That was great. So yeah, let's just dive right into Vepdegestrant. You provide an overview of how this compares with other ER degraders, like Fulvestrant?
Yeah, certainly. So at least mechanistically, of course, it is very distinct from the selective estrogen receptor degraders, which are referred to as SERDs. When you talk about SERDs, that generally refers to the drugs that are. Well, fulvestrant is a SERD and everything that is built off of the SERD platform, if you will. So mechanistically very different, and we believe that the clinical data are already indicating the potential for this to differentiate. How it differentiates is likely due to what we think is a differential potency for degradation. It is a very tremendously potent degrader preclinically, and we've also shown that in patients.
But more importantly, the efficacy and safety data that we have, both as monotherapy and now recent combination data, really show what we think is the potential for best-in-class. We can talk more about that as we go into it.
Sure. Then, you know, you guys are obviously enrolling VERITAC-2, the pivotal trial, which you mentioned in the second-line-plus setting. Just wanted to confirm, you guys were guiding to data in second half, also enrollment completion in second half 2024. I think there was some confusion, but it is event-driven. Can you confirm that you're confident that the data will come on your end?
Yes, that continues to be our guidance, and part of the reason why they're both in the same vicinity time-wise is that these patients progress very rapidly. So, we will complete the enrollment follow-up that's needed to get sufficient events. We expect to be not that long beyond the point of enrollment completion, and we've also powered the study for survival, so there's additional patients being enrolled prior to the PFS report.
Okay. So before we sort of get into expectations for those results, I mean, obviously, they're top of mind for a lot of people, but maybe we can talk about Radius's oral SERD elacestrant, which was approved in the second-line ER+, HER2-negative breast cancer, but only in ESR1 patients. So with your data upcoming, how likely is it can show a benefit in the whole population versus just ESR1+? And is the trial powered to show a benefit in the non-ESR1 patients?
Yeah, so what I would say is, you know, given the confidence that we have overall with this as a molecule, we think that, again, based on the efficacy we've seen from phase II and a very advanced population, and the data we see in combination, it all tells us that this could be, from an efficacy side, best in class. So what does that translate into in terms of expectations for the second-line phase III, which is the VERITAC-2 study? And I'll back up to say that there's two primary endpoints. It's progression-free survival in the ESR1 mutant population, and then separate in the analysis in all comers. They're independent. We can have a positive study, whether one is positive or the other or both.
And so, while we expect that the efficacy is likely to be better in the ESR1 mutant population, because the efficacy that we're seeing and because of the potency of the drug, we think that this has as good a chance as any of the novel ER therapies to have a meaningful benefit in the wild type. Now, the next question is, will that translate into an approval across all comers? And this is where we have to be cautious because it's very clear that the bar is going up. The FDA has given a SERD ESR1 mutant indication. The same was the case for the drug capivasertib, which also could not get an all-comers indication. And then the same thing is happening with PARP inhibitors in the prostate space.
So the FDA is getting much more stringent on what the data are. We do think while it's not powered for efficacy per se in the wild type, we do think that there's a sufficient number of patients to provide the FDA with data that if we have a meaningful benefit, that we could potentially get that. So even while that's not a guarantee, what we have in terms of our plans, new plans of starting a combination trial with CDK4/6 plus vepdegestrant. The data that were presented at San Antonio showed remarkable activity, not just in ESR1 wild type or mutant, but also data that is very consistent in the wild type.
So even if we don't get a broad indication with the monotherapy, we have confidence that we can get it in a subsequent approval of a combination.
Yeah, and that will be in the second-line combination study, specifically second-line, not second-line plus. Okay. Yeah, and it seems like, you know, your partner, Pfizer, and you guys are also willing to explore it in combination with other CDK4/6 inhibitors. You guys have the TACTIVE-U study. Why do you think Pfizer is open to evaluating in the different combinations, not just palbo?
Yeah, I think it's very simple, and it's actually was reinforced by Pfizer's recent Oncology Research and Development Day, where vepdegestrant was a very big part of the story of what's coming next, is that vepdegestrant is being positioned as the backbone of choice as an ER therapy in breast cancer. And from the very beginning of the partnership in 2021, they were I mean, we agreed that we needed to go beyond just palbo, and have a test with other combinations, including Ribo and Abema.
Okay. Yeah, so how do you think, vepdegestrant compares versus other sort of next-generation oral SERDs, like camizestrant from AstraZeneca?
Yeah, I think, I think overall, I mean, I think that, we believe that the PROTAC, based on, the data that we have, that we've shown in phase II, CBR between 37% and 40% in as highly resistant a population as has been tested for these, these novel ERs. We think that that is, that plus the, remarkable data that we can talk more about with, palbociclib and second line, that all tells us that this could be a best—we'll call it best, in ER therapy, if you will, best novel ER therapy.
So we were whether it's the AZ approach, AZ SERD or the others, we, we believe that this could be a competitive product, not just from the efficacy side, but also on the safety side, where we've had really remarkable, a very good safety profile.
Okay. Well, yeah, what could you walk us through some of that data that you mentioned in second line?
Yeah, second, so we talked about efficacy. Safety-wise, you know, it's been really well tolerated. If you look at the profile that we have, and you compare it with even aromatase inhibitors, profile really looks quite good. We have some nausea, and but it's not been an issue. There's been very infrequent discontinuations, very infrequent dose modifications, and if you talk to the experts who've worked with these drugs, with vepdegestrant as well as the SERDs, you'll hear from them that they really believe that this has potentially a safety advantage against the whole SERD class.
It seemed like some investors may have been focused on neutropenia. Maybe you could speak to that, or is that coming from CDK4/6?
Yeah.
Can you talk to that?
Yeah. So vepdegestrant itself doesn't have a neutropenia signal. Just wanna be clear about that. Now, this brings up the combination data that we had at San Antonio. So I'll say a little bit about this and give the bigger picture. So this is, this was our phase Ib in combination with palbociclib. This is a trial that we had initiated to inform the dose plan for the frontline study, VERITAC-3, so the palbo combination, phase III. And San Antonio was the first time that we had presented the complete data. So I'm gonna start with the efficacy, and then we'll talk about safety. Efficacy, I'll start with, I guess, the punchline, which is that we were amazingly pleased with the outcome.
It was also something that really received a lot of positive reaction from the investigator community. And what it was most remarkable about it is, number one, it was a very advanced population, much more advanced than trials that have usually been done with combinations. And so we had, you know, we had 87% prior CDK, 46% prior metastatic chemo, and 80% prior fulvestrant. So as far advanced as possible and very high involvement of liver metastases. Despite that, we had results that I think have never been seen in this population before. So we had a 42% response rate, and these were not transient responses. These, the response duration was about 10 months.
It's pretty remarkable in a population where the median progression-free survival for standard of care, fulvestrant is about 2 months. 42% of patients were getting responses, 10-month median duration, and we had a median progression-free survival of 11 months. All this is much greater than has been shown for trials recently reported for CDK after CDK. For instance, those trials have shown no more than 5 months progression-free survival, response rates no more than about 20%. This is pretty remarkable data. On the flip side, for safety, now we knew that we were going to have more neutropenia. Neutropenia is the main toxicity of palbociclib. The greater neutropenia was expected because we knew that the exposure of palbo was higher compared to historical data.
We know that VEPDEG, for instance, has a minor effect on P-glycoprotein and on 3A4. These are not unusual for targeted therapies, and it was enough to increase the exposure 50%. That's versus a normal variability of about ±30%. So just a little bit higher, and neutropenia was expected to be higher. Despite that, with dose modifications, which is how a palbo neutropenia is normally handled, only three out of 46 patients had to stop due to neutropenia. The great majority just continued until progression. Number two is that we had no cases of febrile neutropenia. That's the most important thing for oncologists is, will my patient have an increased risk of life-threatening infection?
And the answer is there were no febrile neutropenia cases. So even at a dose that will not be the dose that we will be taking forward into the second line or what will end up being the dose that goes into the latter stage of the Phase III study, it still was quite tolerable.
Okay. Well, thanks for that. And then looking at the frontline, an overview of the frontline strategy, it seems like you're weighing whether to run the study in combination with palbo or potentially Pfizer's new CDK4. What do you think are the factors that will influence which final combination partner for the frontline?
Yeah, certainly. I mean, both we and Pfizer see this as a good problem to have. And it goes back to the second-line data. The second-line data tell us that, you know, that there's something that is happening in a very positive way with this PROTAC and combination therapy with the CDK-targeted approach. And so for us, that reads through to the frontline setting. And so we have the ongoing VERITAC-3, that's the palbo study. We have a study lead-in, which is basically looking at two different doses of palbo, the 175, to pick a dose to go into the control arm, randomized portion of the Phase III.
We'll expect to have those data likely towards the end of this year from the lead-in to pick the dose. And then, as you mentioned, Pfizer has the CDK4 inhibitor. This has gotten a lot of attention, not just within Pfizer, but also in the academic community, because it looks like it could be—I think there's a lot of hope that this could be the targeted therapy of the future for frontline. So, that means for us that we want to generate data as quickly as possible with vepdegestrant and CDK4. That trial has already started.
First patient's been dosed, and in the meantime, in a very accelerated fashion, we're positioning ourselves to be able to start a phase III in 2025 with the CDK4/6 plus vepdegestrant. Now, will we have two phase III studies running in parallel? The answer is likely not. That wouldn't be the most effective use of resources, and we want to be focused here. So over time, between the data that we'll get from the lead-in, the rapidly growing data for the CDK4/6 that Pfizer has, plus the data that we'll be generating with the combination, we'll have enough data to make a choice as to what will end up being the focus for phase III for frontline.
Okay. Yeah, and what did we learn from Pfizer's R&D day about this novel CDK4 inhibitor? What do you get by sparing CDK6 ? And what gives you confidence in its combinability?
So, four is basically the business end of the anti-tumor effect. And six is what is driving most of the toxicity. So if you can just focus and have a selective inhibitor of four, you can get to exposures and coverage of CDK4 that are much greater than what you can do with the CDK4/6. So there's a really strong rationale for that. The data that they've presented in post-CDK is better than I think has been ever shown for any kind of CDK4-targeting therapy. So that all bodes quite well for this. So yeah, we're quite excited. I think in terms of how these two can combine, I think both we and Pfizer are confident. Is that a guarantee? No.
That's why we have to generate the data. Do we expect that we'll have a drug interaction that requires a dose reduction? We think probably not, but we need to generate the data. Probably not, because the drug has a much better therapeutic index than palbociclib. So, whereas palbo, we were on the cusp, so any interaction could have had an effect.
Okay.
One other thing that investors tell us that they took away from that innovation day was just the clarity around Pfizer's breast cancer strategy, too, which was really the two-pronged approach, where atirmociclib is the next generation palbo, you know, on the CDK side of the spectrum, and then VEP on the endocrine therapy backbone. So the sort of clarity of those two thrusts, where VEP is being positioned as the backbone endocrine up and down the spectrum in breast cancer, was, was clarifying as well. So we've heard that a lot.
Okay, thanks. So why don't we shift to prostate cancer, ARV-766. Can you provide a brief overview of this asset and its target product profile?
Yeah. Yeah, I mean, it's a very exciting program. It's one that hasn't probably gotten a whole lot of attention, frankly. If we were a one-drug company, I'm sure we'd get a lot of excitement out of it, but there's so much that we're doing. ARV-766 is our second-generation AR degrader. It's a pan degrader. Our first generation was bavdegalutamide. We had great data at ESMO, where we showed a progression, an rPFS of about 11 months, in a population that was all post-enzalutamide abiraterone, many of which got prior chemotherapy as well. A number of prior lines of therapy still had this benefit.
Now, the problem with bavdegalutamide was, is more that it—there was one mutation it didn't degrade, and that is patients who have the L702H mutation, which is the most common mutation that's found in AR in prostate cancer, after they've gone through all this prior therapy. So the advantage for 766 is, again, it's a pan degrader, meaning that it hits all the known mutations as well as wild type. It also turns out to have a better safety profile. Bavdegalutamide, we thought, would have been a very competitive product from a safety side. This even looks better, and we've even had anecdotes of patients who feel better coming off of drugs like enzalutamide, abiraterone, apalutamide, coming onto this therapy. So very, you know, very exciting program.
Okay, so it's basically the improved version of that, wider mutational coverage-
That's right.
Potentially safer.
Just to be clear, the AR mutations, which is the population that still retains AR dependency, is about 20%-25% of cancer resistance. Still a pretty good number.
Okay. Yeah, and then you talked about phase two dose expansion data coming up in mid-2024, which also has some PFS data. Can you help set expectations for this readout?
Yeah, yeah, and here, we're focused on the patients with the mutations. Again, those without mutations have an extensive amount of resistance to anything that hits AR. So it's all about the resistant population, the mutation population. We already had shown in the update that we had at ESMO that we had a 41% PSA50. And what does good look like? Anything that is in the 40%-50% range would be good in this setting. That would put it in the same range of what a PARP inhibitor does, and PARPs are, of course, approved in that setting. We've said that we would have PFS data in the middle of the year.
And the other thing is that, from a safety side, what we wanna show is just continuation of what we're seeing, which is a safety profile that could be competitive across all classes of drugs used in this setting.
Is there sort of a PFS benchmark that you could point to? I know you mentioned there was 11 months for the older asset, but that was not in every mutation type,
That's right.
So how do you think about that?
Yeah. So if the best reference for that is if you look at our presentation at ESMO, we included a benchmark table. We had bavdegalutamide at the top, and we had all the new standards of care in there, you know, in post-NHA. So that included chemotherapy, which is cabazitaxel, PARP inhibitors, and Pluvicto. And if you look at the PFS, the rPFS, all in those in the post-NHA setting, in their respective populations, you'll see somewhere between 7.5-8.5 months. Eight, eight actually was the lower bound of the confidence interval for PFS.
So essentially, if we can see something that is in that range, that would be exciting, especially for an oral therapy, once a day, safety profile, what it is, and a blood-based selection mechanism.
Okay. Then you've also guided to speaking with regulators for initiating a phase 3 this quarter. So what are the or in 2Q, what are the key considerations in terms of designing a registration program?
This is really the number one, I mean, I'll go with the easy stuff. So in the castrate-resistant setting, you know, we're obviously for monotherapy, you know, in this late-line, highly resistant setting, we're gonna wanna use this precision medicine approach. When we get into earlier settings, like castrate sensitive, that's where we don't think we're gonna need a biomarker, right? But in the late line, we need the biomarker. So a precision medicine approach, post-NHA, the details get into what's the control arm versus what are the requirements for prior therapy. And here, you know, there's basically a couple of different approaches. Retreatment with the NHA still, you know, is used as a part of control.
You can see that in some of the more recent trials designed, but there's also the possibility of using chemotherapy as a control as well. But either way, we think that this could be a really winning strategy, and we think that this could be a very important product for prostate cancer.
Okay, thanks for that. So why don't we talk about the LRRK2 degrader? Yeah, I mean, you guys recently initiated a phase I trial. It's your first neuroscience program. How are you thinking about developing the asset, and maybe Randy, potential partnerships? You guys have been historically focused on oncology, so-
Yeah, I can-
How do you see the neuroscience?
I can start, and I'll let Randy finish. Yeah, I mean, look, within the company, this is a big milestone for us. We always had two therapeutic areas, but oncology always had a start. And also, I'll say, the PROTAC platform is perfectly suited for neuroscience. A lot of the targets are non-druggable, and we are the first, and so far, I think the only, who have been able to show that we can get very high levels of CNS penetration. We have great data preclinically with this in non-human primate. So a very exciting program, and I don't know if you want to talk about the BD side.
Yeah, absolutely. Definitely no surprise, right? So these are potentially really large indications. So LRRK2 is relevant in Parkinson's as well as in progressive supranuclear palsy. But certainly, and we've said this for a long time, that if we start looking at phase II, III, you know, Parkinson's trials, or we've got degraders for tau, which could be relevant in Alzheimer's, no question that BD will be a really important part of that strategy going forward. But, you know, the first-in-human study is a single ascending dose, you know, not terribly large, and so we feel great about doing that on our own. And we may not be that far away from, you know, even in a small number of human subjects, being able to see degradation of LRRK2.
So that'd be a pretty big milestone event, as Ron said, for the company, if we can... and the industry, if we can show that an orally dosed PROTAC degrader can cross the blood-brain barrier and degrade its target, which we expect to be able to show with this first study.
Yeah, and the other thing I'd add, and, Randy may have already said it, but the LRRK2 is a great case for differential biology, because there are inhibitors, Denali and Biogen have an inhibitor out there. But this is, biologically, this is one where there's other functions of the LRRK2 that an inhibitor won't be enough for. You have to really just knock it out.
Okay. And then you mentioned, I guess, some tau degraders, or is there anything else in the early pipeline you guys are excited about?
Yeah, there's tau. There's Huntington's, is another target that we're really interested in. So we have a pretty big program. Overall, we have more than 20 preclinical programs across oncology and neuroscience, so there are a lot going on.
Okay.
The next program to enter the clinic will be BCL6. It's an ARV-393, so that's a recent announcement as well. Not quite started yet, but this half of the year. So that's relevant in hematology and possibly solid tumors, too, but that's the next one entering the clinic.
Yeah, and that's our first truly non-druggable target, BCL6. There is actually one competitor, that is, Bristol Myers Squibb. They actually had a safe to proceed on their IND just a couple of months before us. So, and essentially, it's a very smart company with an obviously history in hematologic diseases. So the fact that they've, that they're competitors is just a positive for us. It validates the target.
Is that, an inhibitor, or is that also a degrader?
It's a degrader as well.
Okay. Okay, well, anything else you guys want to highlight as we're sort of wrapping up? We're coming up on time.
You know, I think one thing that we've talked about lately, especially since the San Antonio disclosure, where we expanded the development plan for VEP with Pfizer, is what we're really trying to set ourselves up for is the second-line monotherapy is expected to be the first launch, obviously, if that trial reads out well, and we get that successfully approved. But thereafter, you know, there's a lot that we've talked about with combinations, so keeping it all straight can be tough. But we're really trying to set up an initial launch in the second-line monotherapy and then sequentially moving through the second-line combination therapy as well for VEP, and then ultimately to the first-line combo. So I think that series of launches, at least potentially over the next, you know, before the end of the decade, sets us up really well.
We're in a favorable, you know, capitalization position right now, ended December with $1.27 billion in capital, which brings us into 2027. So we're well situated to get through that, at least that first launch and a little bit after that. But, certainly, we'll also be thoughtful about maintaining a good balance there and, and staying strong as we, head hopefully into commercialization.
Okay, great. With that, I think we'll wrap up, and thanks, thanks for being here, guys.
Thanks very much for having us.
Thanks.