It's good morning. It's Michael Schmidt, Senior Biotech Analyst with Guggenheim. I'm very pleased to welcome the Arvinas team this morning. With us, we have Sean Cassidy, CFO, as well as Ron Peck, Chief Medical Officer. Welcome, guys, and thanks for joining us.
Thank you.
Thanks for having us.
Maybe just starting off with a high-level question, Arvinas is obviously one of the key innovators in the target protein degradation space. Just to, you know, level set with folks, you know, we've seen, you know, an emerging field here develop in recent years. You guys have been at the forefront of that, you know, innovation. Perhaps talk about your platform first and how it compares to other TPD companies.
As you know, our clinical portfolio is primarily driven around heterobifunctional small molecules, and there's lots of other companies out there utilizing that approach for targeted protein degradation. You also see other companies that are exploring molecular glues, autophagy with some private companies. It's a very exciting space. I think the best way, though, to differentiate is to look at the pipeline that these companies are creating, not just to how advanced that pipeline is, but actually how balanced the pipeline is between late-stage assets and early-stage assets. We think Arvinas' pipeline is very well-balanced at this point in time.
As you know, our ARV-471 program in the second-line setting, that's the one we have partnered with Pfizer, entered Phase III in December of last year, and it's set up to do two other Phase III trials coming up in the first-line setting later on this year, in the second half of this year, and then in the adjuvant setting shortly thereafter. Our bavdegalutamide, moving over to our androgen receptor program, our bavdegalutamide compound, that's the lead compound in that program, that's slated for a Phase III start later on this year. ARV-766, which is our second androgen receptor degrader, just transitioned out of Phase I and into Phase II. You can see we have a relatively late-stage set of assets with both our AR program and our ER program.
Then earlier this year, we actually announced LRRK2 a clinical candidate in that program. That's our first neuroscience clinical candidate nomination. It's an orally available compound that's also penetrates the brain very well. Our BCL-6 program, we also nominated a clinical candidate there. As you look at the balanced nature of Arvinas' pipeline, I think it is by far the most balanced and also the most advanced. I think that's the best way to differentiate Arvinas from some of the other protein degradation companies.
Great. Thanks, Sean. Maybe just jumping in right into the pipeline with some clinical questions. Starting with ARV-471, your ER degrader, as you mentioned. You did recently present, you know, phase II data from the VERITAC study, and as you mentioned, you have initiated a phase III trial in the post-CDK4/6 inhibitor metastatic breast cancer setting. You know, that's been an area that has been somewhat of a struggle for some of the oral SERD companies, but we have seen approval recently. Maybe just high level, how confident are you in ARV-471 demonstrating superiority over fulvestrant in this study?
I'll start with I've been told that I sometimes bury the lead, so I'll start with the answer, very. I'll explain why. The whole thesis for developing 471 as one of the first PROTACs, is that was going into breast cancer where there's already a precedent for a degrader being used there. fulvestrant is the most active therapy today that's on the market, with the exception of the new elacestrant compound coming on right now. Up until then, it was fulvestrant. That has been a proof of concept that degradation is a very important means of tackling ER-positive breast cancer, and it's also shown that more degradation is better, and 471 was developed to be a potent degrader.
Pre-clinically, it degrades up to 90%, what we see in the clinic shows that this translates very much into patients. In that regard, we've shown really robust ER degradation in paired biopsies, and that's held up through repeated looks. Number two is that we have a clinical benefit rate in a population that is extraordinarily heavily pretreated and very sick. This is a population that is 100% prior CDK pretreated, it's not just that because there's already a lot of information that patients do very poorly on fulvestrant with that, with a clinical benefit rate of 10-14%. In addition to that, 45% of patients got metastatic chemotherapy, 80% of these patients got fulvestrant.
By our assessment and by those outside the company who are experts in this field, they know that this is a very sick population. Even with that, we showed a clinical benefit rate of around 40% now both in phase I and separately in phase II. Between that, we're just very confident, especially when we see the level of data that were necessary to show superiority from the EMERALD study. gives us a lot of confidence.
Okay. As you mentioned, we did see the elacestrant approval recently in the ESR-high, in the ESR mutation subset only. You know, how does that, you know, read through to your program? Perhaps talk a bit about what do we know about the activity of 471 in the ESR wild-type patients?
It's a good question. It's interesting. ESR1 mutations have now emerged as a signature of a population that may be more ER responsive to therapy. The elacestrant example is probably the best proof that where they show greater benefit in that group. To your point, that's where they got a companion diagnostic limited to that population. However, based on our data and based on what we understand about this as I'll call it a biomarker. It's not a great biomarker. There's activity that we believe is gonna be left on the table, or in the ESR wild-type population. Just as an example, you know, I mentioned the extensive prior therapy of this population more than we've seen for any of the SERDs that have been tested.
Yet we see a clinical benefit rate that is higher than has been reported for fulvestrant in this population. If you look at the elacestrant data, fulvestrant had a clinical benefit rate of between 10% and 14%. Use that as a frame of reference for us in the wild type, we have 20% clinical benefit rate. We have, interestingly, our, while it's a population that ER therapies don't usually have objective responses, we actually have a confirmed partial response in a patient with wild type. Our thesis is that in the phase III study, which, as Sean mentioned started already, we're in a actually a much less pretreated population. We exclude prior fulvestrant versus the 80%.
We exclude prior metastatic chemo, which was 45%. There's a good reason to believe that we will potentially show even greater benefit in the wild type and potentially give us an opportunity for labeling in that group as well.
Okay. The FDA looked at, you know, the wild type subset specifically in the elacestrant trial. Is your study powered sufficiently or do you think, do you anticipate having to demonstrate statistical superiority in the wild type subset as well?
I mean, I can't comment on any feedback that we got from the FDA, but you can think about this as in what we'd have to show is that you have to show some benefit in that group. It doesn't necessarily. What I would say is I don't think it would have to be statistical significant, but you need to show that there's enough benefit in that group that that could explain what you see in the all comers.
Right.
It can't be just driven by the ESR1 mutant group. As I mentioned, I think that we have any, you know, all reason to believe to include that group. It's very much why we and Pfizer decided to test that hypothesis in this trial as well.
Okay. Perfect. Maybe switching over to your plans in the first-line metastatic breast cancer setting, just remind us of where you are with your planned phase III trial in combination with palbo. I know there's been some disclosures recently.
Yes, certainly. Yeah. Back, just around JP Morgan, we had put out an 8-K to just give an update on this program. It was sort of fortuitous from a timing perspective. We had just gotten data toward the end of December that was telling us that there was potentially some effect on the exposure of palbo. Just to be specific, it was, you know, roughly about a 50% increase in palbo exposure versus historical data. Understand that there's usually about a 30% grace range because of natural variability. We're 50% versus 30%. The other thing is that that was associated with a slightly higher rate of grade three, four neutropenia than is reported for palbo historically. It's 60%, 66%, historically 76%.
Not a big difference, but there's at least a connection there. This is of course, you know, let's say different from, you know, what people usually think of for things like drug-drug interactions where you see, you know, several fold increase.
Mm-hmm.
The plan that we came up with very quickly in lockstep with Pfizer is to come up with an approach that we had recommended in a submission to the FDA to amend the trial to really address the question of what is the optimal palbo dose. This is again, it's a palbo thing, it's not a 471 thing. What we had done was we proposed a front-end optimization design that could seamlessly move into the phase III study. We had said that the FDA meeting would expect to happen in the first quarter, we also said that we would update after that.
I would say this, is that, this to us is, you know, it's a pretty, simple, approach to address this. Something that is already for which there's a precedent. A lot of company have had to do lead-in, trial, lead-in portions to address Project Optimus issues. There's a precedent for this. It's also, with palbo, where there's a lot of knowledge about the drug and our partner is obviously the expert. Last thing I would say is that whatever effect we saw in the patients, we did not see, only one patient out of 20 at the recommended dose had to be discontinued. That's actually quite similar to historic and, because it's very easily managed with dose modifications, and there's no increase in infection.
I guess what are possible explanations for this increase in palbociclib? you know, are there any mechanistic, you know, considerations or do you think it's, it sounds like chance may be a factor too?
It's a good question. The answer is that we don't really know it at this point. The things that you would expect for real potent interaction would be things like 3, 4. Not surprisingly, in terms of magnitude, we didn't see any inhibition preclinically for 471 on three, four. Three, four being important because that's the major metabolic elimination route for palbo. There's another mechanism that we are exploring, although we don't necessarily believe that that would be an important driver because I think it only accounts for about 30% of the clearance.
Yeah. Can you walk us through what possible scenarios might be emerging from the FDA meeting and then also the run-in study? What are possible outcomes?
You know, of course, the one that we hope, of course, is that they're fine with this or we can align on any specifics on the approach that we proposed. Worst case scenario, just to be complete, is that we get a feedback that we need to do a whole separate study and a drug-drug interaction looking at different doses of ARV-471 and palbo. You know, for us, we're hoping and thinking that that wouldn't be the case, only that ARV-471 doesn't at the two doses that we studied in the Phase 1b, there was no difference in the exposures between the two doses.
Okay.
In terms of speculating on what's gonna happen, we're gonna update everyone, you know, shortly after we have the meeting. We talked about this earlier in the year that about 30 days after the meeting, we're gonna update folks.
Right
exactly what that path forward looks like. you know, stay tuned on that piece.
Okay. Another debate has been, given that these drugs are more active in the ESR1 mutation context, and those are thought to be less frequent in first-line breast cancer patients. There has been the PARSIFAL study of fulvestrant as well. I guess, what is your confidence that VERITAC-3 might actually succeed in the first place, randomized against AI plus palbo? There's obviously also some precedent from the Sanofi study. I know they have their own issues. I guess, what is your confidence level that the first-line setting is actually something that can be achieved for the ER degraders or the ERs?
Yeah. We do get questions about the PARSIFAL quite a bit. Really what this, you know, our confidence comes from the back to the degradation and the precedent for degradation and the learnings scientifically and from fulvestrant and other things is that we are in a large camp of group that group of scientists and not just Arvinas people, but that believes that degradation is the best means of tackling ER and the best degrader will break through to show that kind of effect. We're very confident on the data that we have, both preclinically, through paired biopsies in the trial, through the efficacy that it all kinda tracks together. We believe that in a properly designed trial, it, you just that the best degrader is gonna come through.
That's, you know, This is the whole thesis for us developing this drug.
Okay. Then can you talk about, there's obviously other CDK4/6 inhibitors, perhaps better CDK4/6 inhibitors than palbociclib. Talk about your plans beyond those two studies we just talked about.
Yeah, certainly. Yeah. This has been something that has been a point of discussion from the very beginning as we were meeting with Pfizer, as they were going through due diligence, and we talked, you know, we aligned on a development plan, and it was quite quick and easy that, this was gonna be something where we want to develop this as the, part-partner of choice for targeted therapies, the backbone, in ER-positive disease. That meant we can't just be beholden, to palbo, and Pfizer was actually very much, aligned with that. The proof of that is that if you look at a trial that is now on ClinicalTrials.gov that initiated, at the end of last year, I still call it the umbrella study because... TACTIVE-U, that's a new name.
That trial is a trial that's evaluating multiple combination regimens with 471 to basically set the stage for the life cycle of this drug so that we can continue to develop this as the drug of choice. The first two combinations that are being explored is ribociclib and abemaciclib. There is, you know, a bigger, let's say, chess game to think about through the life cycle of this drug that also includes other CDKs.
Okay. Then I guess if you wrap up on ARV-471, I guess how should investors think about disclosures from the program over the next 12 months?
Yeah. I think, you know, we're gonna be in the first half of this year. Well, first quarter's going away pretty quick. We'll be disclosing data around the Phase 1b trial. That's the one in combination with palbo, that Ron was referring to earlier. If you extend that just a little bit beyond 12 months, we'll actually have top-line data out of the Phase III trial that started in December. That's in the monotherapy setting in the second line. That we think is gonna be a really, you know, nice validating event for the company, for the partnership that we have with Pfizer and protein degradation actually as a whole.
Great. Well, thank you. Maybe switching over to bavdegalutamide, where you are planning a Phase III trial in the sort of mutation subset, prostate cancer population. Just remind us again here, you know, what your regulatory interactions have been and, you know, where are you tracking towards initiating the Phase III trial?
Sure. Yeah. I'll start with, again, the answer then I'll work backwards. We are continuing to track towards starting the phase III for bavdegalutamide in the second half of this year. Back in November, we had disclosed that we had met with the FDA on what was originally a plan for a single-arm accelerated approval strategy based on a precedent with another drug.
We had announced back then that for all sorts of reasons, we felt that it was best instead of doing a single-arm trial and taking the risk that this wouldn't get there, especially with the evolution and the agencies thinking about single-arm trials, to start with the confirmatory trial and do it as not just a confirmatory trial, start with just the one trial and give us the best chance to show the benefit of this drug, and could also give us, yeah, allow us to market this outside the U.S. as well. that was back in November.
We also announced back then that we would be that consistent with the Project Optimus, you know, experiences with other companies, we were asked to generate some additional data at a lower dose as part of a plan to confirm optimal dose. Our belief is that for 400 we'll end up being there. We have a lot of data with 420 in the clinical trials, and essentially it's a really good set of data for benefit risk in that population. It's just completing that, and this is all being done in parallel to the health authority engagement for the phase III design.
Yeah. Okay. I'm a little bit surprised though. I mean, you have done a pretty extensive dose escalation study. I guess, what else does the FDA need to see to sort of agree with the dose selection?
Yeah. I, well, I can't really get into the specifics, but I think, you know, if you can sort of step back and look at the, you know, the field as a whole, you know, the FDA is really trying to push on optimal dose.
Mm.
There's now a lot out there. There's a draft guidance out there now. Essentially it seems to be that there's a certain number of patients just to essentially, you know, just to do that as part of a due diligence effort. We, you know, we think, we'll be in good shape. We took 1 of the, our existing first in human study to generate the data, so we wouldn't have to lose speed.
Right.
on beginning that process.
Right. This initial phase 3 is obviously in a sort of late stage prostate cancer patient population in the mutation subset. What would a control arm look like in a study?
Yeah, I can't, I can't really comment on that. We will certainly, when we have the design, we will disclose it most certainly. I mean, what I would also say, just to be clear, is that this would be in a biomarker, in the biomarker selected population.
Right.
The other thing is to just understand that while there have been other therapies that are, you know, that are out there in this population, mostly non-AR in this post NHA, there's a very much a need. First of all, a lot of the therapies are for specific populations with exception to chemotherapy. They're, I think generally, except for the PARP inhibitors, they're IV therapies. There's toxicity there. We think that there's gonna be a great need, especially as patients are progressing on these drugs like enzalutamide, abiraterone much earlier in the disease journey.
And what percentage of patients have those mutations?
By the literature, it's roughly about 10%. The literature is sort of broad swath.
Yeah.
the populations. We saw somewhat higher, prospectively in our trials. We think it might be conservative, but, you know, it will still be what we think is especially with the blood-based companion diagnostic, which relates to our partnership with Foundation Medicine, we think that this is the perfect time to have, you know, a precision medicine with a blood-based test, especially for patients who are coming off of-
Right.
treatment much earlier.
Right. I know you're looking at combinations with abiraterone in an unselected patient population.
Mm-hmm.
Just remind us where you are in the phase I study and kind of how we should think about next steps there?
Yeah. First of all, the goal of that trial was to. It was our, it's our first foray into combinations with either the degraders and either of the AR degraders. The first goal is safety and pharmacokinetics. The trial's a Phase 1B, so that's gonna be the main thing. It's actually in a sort of a specific, very sort of unique population. These are patients who are progressing by PSA on abiraterone, and then they stay on the abiraterone and get this combination. Where we think the greatest potential of this would be is in a NHA naive, so the enzalutamide, abiraterone naive or the naive to the other two drugs. That's where we think the big potential opportunity is.
It's also where we're really excited to move the AR degraders in this early space because it gets that out in front of all that resistance that develops late.
Yeah. Okay, great. Last question, just on ARV-766, which is your second-gen AR degrader. I think you guided to data in the second quarter here. Just remind us, you know, how we should think about the potential for that relative to bavdegalutamide, I guess what we need to see in a Phase I to sort of advance this program.
Yeah, certainly. Yeah. The one big difference between ARV-766 and bavdegalutamide is that there's one mutation that ARV-110 doesn't cover, which is the L702H mutation. ARV-766 was sort of in a later set of molecules that we were looking at as we were coming up with different degraders for AR. The one thing that ARV-766 degrades that the other one does not is 702H. Otherwise, Bav covers all the other mutations, covers wild type. There are some different pharmacologic properties. All the different PROTACs are different. Will that translate into anything? It's really hard to say. Most certainly that. In terms of the data, this will be our dose escalation data.
Understand that, number one, this is post enzalutamide abiraterone or similar drug population again, so it's still this late line setting. Number two is that we do not, as you mentioned, select for the mutations. In terms of setting expectations, this is not like a phase II data set in mutation patients. It's gonna be whatever mutations may come in, including those with 702H. We'll report that. It's gonna be safety, PK and whatever efficacy we have.
Mm-hmm. Is there a scenario where you might advance 766 instead of bavdegalutamide given how close they are in development?
We're honestly very excited by bavdegalutamide. You know, we're really excited by the data that we're seeing. The activity is durable in these patients. The level of PSA activity, but also duration of treatment really gets us excited. Our heads are really down on that. We see these two drugs as part of more of a franchise view. Even just for prostate cancer alone, if you think about all the different indications, there are different places that you can position these two drugs. There's opportunities outside of prostate cancer, breast cancer, and non-malignant diseases.
All right, great. With that, I think we need to wrap up. Sean and Ron, really thank you so much for doing the Fireside Chat. Appreciate it.
Yeah. Thanks for having us. Thank you.