Arvinas, Inc. (ARVN) Earnings Call Transcript & Summary

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It's a natural signal to a cell to a degree that proves me. And it does do so by shuttling it off to the proteasome, which is basically a multi-protein complex of proteases that degrades the protein into peptides and then ultimately into amino acids and completely eliminates -- or nearly completely eliminates the protein from the cell. So it's really quite elegant. Again, we're taking advantage of the way the cell naturally degrades a protein and telling the cell, degrade this protein right now completely to reverse a disease.

Okay. Great. And so we had, I guess, the first clinical example presented -- efficacy example presented at ASCO with your lead drug, ARV-110. Can you talk about that and talk about that specific molecule, what you're targeting and put all the results into context for us? And then maybe we can go into some specifics.

Sure, absolutely. So ARV-110 is a PROTAC that targets the androgen receptor, which is a -- has been known for decades as a driver of prostate cancer, both in the premetastatic and metastatic setting. We have a lot of preclinical data that were presented at multiple different forums that degrading the androgen receptor leads to tunable inhibition, reduction in PSA, downstream signal inhibition, et cetera. So ARV-110 enter the next Phase 1 trial in March of last year, 2019. And what we showed at ASCO which was really very exciting to us is really the first evidence of a PROTAC having efficacy in the clinic. So we had 2 patients with deep PSA responses, including 1 patient with a RECIST response. These were patients that were really heavily pretreated both with existing standard of care as well as chemotherapy. And we also showed the first evidence that the PROTAC was degrading the androgen receptor in humans. Of course, we've shown that multiple times. Preclinically, a very robust degradation. We actually will be able to show that in a paired biopsy in a patient. So that's the first evidence of that. And then ARV-110 is generally well tolerated. We had presented early safety PK data back in October. Compound continues to be well tolerated and allowing us to continue to dose-escalate beyond the 280-milligram dose that we showed the data for at ASCO up to 420. So it was really the first proof of concept for PROTAC protein degraders. We're benefiting patients where traditional inhibitors had failed and really validates the confidence in the whole platform and our pipeline, which includes ARV-471, an estrogen receptor degrader which is also in Phase I trials.

Okay. And so you talked about those 2 deep responses that you saw that was at a 140-milligram dose. You also saw some results at a higher dose, at double, 280 milligrams. Patients were not as followed for as long as a period of time, but I think perhaps The Street was a little bit disappointed not seeing any PSA responses in that population. Can you talk to that nuance of the trial? And do you think we could ultimately see some PSA responses in that cohort?

Well, I think you're right. The 280-milligram dose at the time of the ASCO presentation was really too early to follow up in terms of PSA responses. I don't really want to speculate on whether we'll see PSA responses in that cohort or higher doses. I just would say, obviously, we're following them as well as the 420 mgs that we started to dose. I think that it's important to keep in mind how heavily pretreated the patients are. And that may affect the ability for the androgen receptor to still be driving the disease in those -- in that setting. And that's something that we're learning and we're generating hypotheses on and we're following in terms of the molecular status of the patients, including, obviously, the AR mutational status, where we saw our patients with respond -- that had the responses had a very interesting AR mutational profile, which we're very aggressively pursuing. And -- but we also saw mutations in other genes, which, again, may signal that those tumors may not be solely dependent on the androgen receptor. Again, too early to speculate in terms of what those genes are and what are the drivers. We're collecting more data as we add more patients to that 280 mg cohort that you highlighted as well as our higher doses as well.

Okay. So you're adding more patients to that 280 cohort? I mean you're already dose-escalating above 280.

Right.

Why are you continuing to add more patients at 280?

Yes. So it's a safe dose. It's been proven as a safe dose. So because we didn't feel like we -- that cohort was particularly informative again in terms of PSA response, we wanted to add patients onto that cohort while we're dosing higher. So we're being pretty aggressive here and -- to generate more data. Not just PSA data but molecular data, really trying to understand what the profile is of the patients that might be able to -- might respond. So I think it's a -- again, it's aggressive way to go because we just feel like that 280 mg cohort just didn't give us enough data to see whether there was a dose response, which is, I think, the genesis of your original question.

Right. Okay. And that's pretty important to figure out what you think about Phase II expansion?

Well, we're already thinking about the Phase II expansion. I think that as we go higher, we're already adding sites to be able to enable that Phase II expansion. Certainly, it would be important for us to help select the dose that we go into that Phase II expansion. Obviously, as we've talked about before, there's nothing to stop us from actually testing multiple doses. So again, backfilling, as we're calling that 280 mg cohort, will help us determine what dose or doses are appropriate for that expansion.

Are you dosing at 140 as well or just 280 as far as the lowest dose?

Yes. We're not adding currently any patients to the 140.

Okay. And what about an additional biomarker data? You saw one patient that looked pretty intriguing. I think maybe people have been expecting a bit more biomarker data. Do you think we'll see some more in the future?

We certainly hope so, yes. I mean we guided all along that getting pre and post-treatment biopsies from this particular population would be really difficult. It turned out to be so. Really only got 2 usable pairs from the study so far. One was at the 35 mg dose, which was too low in terms of exposure to really be meaningful, and then the 1 pair that we showed at 280 mgs. I can tell you that we talk to investigators all the time, asking them to look for patients where we can get particularly the post-treatment biopsies so we can get more AR degradation data. It's really very important to us. We hedged on that in the trial in terms of also collecting circulating tumor cells to look at AR levels. I have to say the only disappointment of the study so far for me is that the CTCs have been completely uninformative. We just haven't got a lot of patients with very many CTCs. And even in those CTCs, not many are -- have we been able to detect the androgen receptor. So it's really been completely uninterpretable. We will continue to try to collect them as well as the paired biopsies to get that additional biomarker data that you asked about. We're working hard on that. We'll just have to see as we go through the trial.

All right. And we've talked about this also where you had commented on genetic profiling of some of these tumors. There were some AR variants that were detected. Do you think that really makes a difference as we think about interpreting the data?

Yes, I think so. I think you talked about the investor reaction. I think -- a couple of things, I think, that were important to recognize. One is that the preclinical profile of the compound is seemly translating into patients. So when you look at the whole cohort and you just focus on the 140 to 280 mg doses, those are the doses where we're getting exposures that correlate with our tumor growth inhibition preclinically. That's about 12 patients. And then when you look at those patients that only have forms of AR that are degraded -- degradable by ARV-110, so we've always said that ARV-110 does not degrade the L702H mutation, it doesn't degrade V7. And then -- so you look at the 7 patients that have degradable forms, then we had 2 responses out of those 7. So that's about a 29% response rate. That's higher than the 20% that we had guided to. So I think that, that's important. And then you lay on top of that the heavily pretreated nature of the patients that we already talked about. That may signal that they may not be dependent on the androgen receptor. I think that's important to overlay. So it's not escaped our notice that the 2 responders have those 2 mutations in AR. As we go forward, we're already implementing a patient selection strategy to follow -- to try to get additional patients with that mutational profile to see if those truly are exceptional responders. And that could obviously lead to potential accelerated approval pathway. Again, really too early to say for sure, but that -- those are the type of approaches that we're taking as part of the expansion, as part of the backfill to really follow up that signal, to chase that signal that we've seen. And it's really a very strong signal. The 2 patients with that -- those 2 AR mutations, both were very deep responders, 1 a RECIST responder. And so that's very intriguing to us.

Okay. And so when do you think we'll be able to see some more data? I think certainly, digging into those other -- those patients treated at 280 is probably on a lot of people's minds. When do we get to see that?

Yes. So we'll definitely be showing more data by the end of the year and then also talk about the status of the expansion cohort at that point.

So you think you'll be in an expansion phase by the end of the year?

Well, we're going to guide to -- yes, we hope to be. Certainly, that's our intention. As I said, we're already implementing the plan by enrolling more sites. And so we'll give a more detailed update toward the end of the year.

Okay. And then on -- let's see. When you presented the data at ASCO, you had -- also had an investor session. You had also talked about ARV-471, some early data in your ongoing breast cancer trial. Can you talk about that molecule and what you've seen so far?

Sure. ARV-471 is a PROTAC, a very potent degrader of the estrogen receptor. Again, known for decades as a driver of breast cancer via -- or expression mutation. And we have a lot of preclinical data where degrading the estrogen receptor by greater than 90%-plus leads to tumor growth inhibition of tumors that are dependent on the estrogen receptor. When we combine ARV-471 preclinically with a CDK4/6 inhibitor, in this case palbociclib, tremendous regressions in pretty much all the tumors we've tested. So really a very potent molecule and brought that into the clinic in August of last year. In October of last year, we showed the first cohort data, where, again, we saw a very nice safety profile. We also saw exposures that were already in the range that predicted of efficacy based on preclinical exposures. So as John mentioned in his part of the investor call after ASCO, we've continued to dose-escalate beyond that first 30 mg cohort that we showed in October. And we've also seen, much like ARV-110, evidence of estrogen receptor degradation in paired biopsies. So really, the -- we didn't -- have not obviously shown that data yet, but that second demonstration of proving the mechanism of degradation in humans, which, again, is really very exciting.

And of course, with the paired biopsy analysis, is that easier to do in a breast cancer setting versus a prostate cancer setting [indiscernible] people see a more comprehensive dataset from this trial than the prostate cancer trial?

Yes. We have always said that we felt that we'd get probably more paired biopsies from the breast cancer setting than the prostate cancer setting just because of the nature of the disease. I would say that so far, that's what we're seeing. Hopefully, that will continue. Again, much hype with the ARV-110 trial. Today, Ron Peck, our CMO, constantly talking to our investigators, trying to get more patients on that have paired biopsies. So it's really a big focus of ours. Hopefully, we'll, again, continue to enroll patients where we get those paired biopsies and we can continue to show the mechanism of degradation, which we think is an important part of the study, for sure.

Okay. And how do you think such a drug would be used in the context of a selective estrogen receptor modulators? Currently, there's one that's widely used on the market. There's a number of clinical development. How do you see that competitive space [indiscernible]?

Yes. No, certainly, the SERDs space, fulvestrant being the first one, standard of care, has become very, very crowded, a lot of agents historically and currently being tested in clinical trials. We feel like our PROTAC, because it's an active degrader and, as I mentioned before, bringing the E3 ligase to the estrogen receptor, tagging it, degrading it as opposed to the other SERDs, which are more of passive degraders, will ultimately have an advantage of having more robust degradation and has always been felt and has been shown that more robust degradation leads to better clinical outcomes for patients. So we think that, that's how it's going to fit in. It's being truly -- a true degrader, an active degrader. Ultimately, it's the same thing that we talked about with prostate cancer. We want to move into earlier lines of therapy. Right now, our patients are, again, pretty heavily pretreated, at least 2 prior endocrine therapies plus a CDK4/6 inhibitor, up to 3 lines of chemotherapy, but that's the inclusion for joining the trial. So a lot of those tumors may not be driven by estrogen receptor. But ultimately, we want to move that -- our drug into earlier lines where estrogen receptor is more likely to be the driver. We will really be able to see what kind of response rates, what kind of progression-free survivals that, that will show how well the drug is working. These later lines, it's trickier because there's a lot of tumors. It's well known, and I think it's being seen by the other SERDs being tested, a high percentage of the tumors are not -- no longer dependent on ER.

Okay. Let's move beyond cancer. Talk a little bit about CNS. Where are you in your program now with -- I believe tau is one of your first targets that you're going after. When do you think you'll be in the clinic with that?

Yes. So tau is our most advanced neuroscience program. Right now, we are in the lead optimization phase. We have a line of sight through a clinical candidate, which we believe we'll nominate in 2021 and be in the clinic in 2022. We also have a program against alpha-synuclein. A little bit farther behind, so we're not really guiding on when that will be in the clinic. But those are our 2 main drivers for our neuroscience.

Okay. And these PROTACs are pretty large molecules. Are you able to get it into the brain effectively?

Yes. So we've shown that data, again, back in October for tau in particular. So yes, we have blood-brain barrier-penetrating PROTACs that degrade tau in vivo models and really get very high levels, micromolar levels, of the PROTAC in the brain, which can then lead to profound degradation. Greater than 95% of the tau in the data that we've shown in the brain of mice has been degraded. These are with peripheral administration or parenteral administration. Looking at an oral delivery that'll also across the blood-brain barrier. So that's really one of the breakthroughs that we had probably up to a couple of years ago now that we're really going to hopefully exploit in this phase for patients.

Okay. Then maybe, Ian, in our last few minutes, can you -- there are a lot of other companies that are using the PROTAC platform in various ways. Can you talk about what -- how your approach differs from maybe these other PROTAC companies?

Yes. And I think, as I mentioned earlier on at the beginning, we are the first company that was founded on the PROTAC platform. So everyone else following us on PROTAC is really copying us, to be honest. And there's a bunch of companies, and they have great scientists. But in terms of the actual PROTAC technology, it's really -- there's no differentiation with what they're doing versus what we're doing. Obviously, we were the first company to be founded. We're just shy of 7 years now, solely focused on PROTACs. We have 150 people in-house here in New Haven. We have another 150 chemists offshore in China and other countries. So in terms of the scale and the experience that we have and, of course, having 2 compounds in the clinic, I think that's really what differentiates us, of being able to turn these -- as you mentioned, on the larger side of small molecules but to turn them into drugs, I think, has been the key aspect of what we've been able to do. We expect other companies to come along, and they've announced plans to get into the clinic, and that's great for patients. But I think it's our know-how not just in terms of oral bioavailability, but blood-brain barrier penetration we talked about, our expertise, I think that's really what distinguishes us from the other companies.

All right. Great. Well, that's all the time we have for this morning. Thank you so much for joining us, and we certainly will keep track of your progress.

Thanks, George. Really appreciate the opportunity.

All right.

Have a great day.

So long, Ian.

Take care.