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

Okay. Great. Welcome, everyone. I'm Yigal Nochomovitz, one of the biotech analysts here at Citi. It's my great pleasure to introduce John Houston and Ron Peck from Arvinas. John Houston is the CEO. Welcome. So maybe as a starting off point, John, if you could sort of outline Arvinas' broad strategy for those listeners that are less familiar with the story and talk about what is the near-term mission for the company and as well what is the longer-term mission for Arvinas?

Thanks, Yigal, and great having an opportunity to talk to everyone today. Yes, for those of you who don't know, Arvinas was founded in 2013 on the pioneering work of our Founder, Craig Crews from Yale University and focused on protein degradation. At that time, people saw this is a very novel and innovative approach to coming up with a new therapeutic approach to disease, basically designing heterobifunctional molecules that hijack the cells own ubiquitin proteasome system to push proteins that were causing disease into the degradation machinery and break them down, so a very different from inhibition. And if need to be -- go into details on that, since then, Arvinas has had [ all Cs ] of first trying to prove the utility of the platform all the way through the initial flurry of targets where we showed we could get degradation, then as a company built up leading to our IPO and becoming a public company just prior to getting our first compounds into the clinic. And those compounds are ARV-110, which is an androgen receptor degrader, which is in patients for metastatic prostate cancer and the ARV-471, which is an estrogen receptor degrader in patients with metastatic breast cancer. And I see as the first occurred. Since then, obviously the first to getting to patients, first data to show that PROTACs, which are the heterobifunctional molecules, actually showed good exposure, good safety and then most recently in both trials showing the first significant signals of efficacy in a very -- in both very late-stage patient populations. So very exciting in terms of the programs progressing, exciting for the patients in those trials. But in general for the industry, the small pivot of industry are protein degradation, also very exciting showing that the protein degradation platform really does have utility as a potential new therapeutic approach. So Arvinas' game plan, obviously, is to progress both those programs. As you may have seen recently, we did a significant deal with Pfizer on ARV-471, which will be a co-development, co-commercialization on a global level. It will allow us to very comprehensively move that compound forward. It will allow us to build the company even more significantly because our overall game plan is to become a fully integrated biotech company that can take the rest of our pipeline -- protein degrader pipeline all the way through the clinic onto the market. ARV-471 is going to be the lead program for allowing us to do that followed very closely by ARV-110 and the rest of the pipeline behind it. And the company has been scaling in size over the last several years. We are now over 250 people strong in the Connecticut base, although we access a significant number of [ CRO chemists ] as well. So really deploying quite a significant amount of resources was protein degradation. So we are primed in a very nice way right now to take advantage of the rest of our pipeline, move it forward aggressively and really position PROTACs and protein degradation as a truly new effect of paradigm for treating the patient.

Thank you. That was a great intro. So as far as I understand, while you are a protein degrader company. At least for ARV-471, you don't really see the protein degraders as the competition, rather the competition commercially are the SERDs. So maybe you could talk about the competitive landscape in the SERD space relative to what you're building with ARV-471? And then just more generally, how is your chemistry platform and drug discovery platform differentiated when it comes to the other protein degrader companies?

Yes. A great question. And as you know, Yigal, going back several years, we used to get asked this question a lot about the competition in the space. Initially, there wasn't much competition that was with us, maybe 2 or 3 other companies that were very early. Because of the data that has been generated by Arvinas and to be fair other companies now showing that protein degradation is a viable new modality, there's a lot of companies in the general protein degradation space either generating heterobifunctional molecules or PROTACs, [ BITACs, MONOTACs, GLUEs, LITACs ], it just really exploded as a whole of many industry in the space of hijacking a cellular process. But we've migrated our dialog away from competing with other protein degraded companies, because I think there's a big space out there. There's lots of room for companies to do well. And really the maturation of an approach like this is not talking about, which ligases are you using, which company has got the best degrader platform. It's actually what's your pipeline like and how well is your pipeline progressing. And so we're certainly at that stage where when we look at the competition, we're definitely doing from a pipeline perspective. So with our prostate cancer drug, we are looking at the profile we need to have to be a leader in that space and looking at the competition. And with ARV-471, in particular, because of the set of cells that are ahead of us, looking at that competition and saying what would the best-in-class profile look like and would ARV-471 reach that best-in-class profile with the recognition that we are a true degrader. A lot of the other SERDs have different level of degradation when we receive that data. But nonetheless, they have been ahead. And our old game plan in terms of the competition is closing that gap, finding innovative ways of getting ahead of the SERDs, but more importantly, showing that ARV-471 actually has a best-in-class profile. And so we will have a position in the market regardless. Now clearly, Ron can go into more detail in terms of ARV-471's positioning to set of other SERDs, but that's really our perspective right now in terms of the competition, it's pipeline. But in that last part of your question about chemistry, clearly since the company was founded in 2013, the whole insight and competitive positioning we've had because of the chemistry insights, there is no 2 ways about it. Our chemists do know how to make drug-like molecules. They understand all the nuances of PROTACs. They understood fairly rapidly how to make them orally by available. They know how to make them brain penetrant. They know the features of the PROTAC that can be adapted to give you different features. So the chemistry is a major part of the intellectual drive that we have in the company. How it's differentiated is through length of time in the role. I mean there's no doubt about our chemist have been solely focused on PROTAC design since 2013. We have the vast majority of chemists still in play that we had from 2013, and we've obviously built on that as well. So there's years of experience. It's an understanding of the science around it and allied with a really superb biology team.

Great. Well, you sort of touched on the theme of my next question with respect to a little -- getting into a little bit more detail on ARV-471 profile at least based on the Phase I work that you've done. Obviously, you had several good tumor responses in the late-line breast patients where all 100% of patients had progressed on a CDK4/6 inhibitor. So given that, could you talk a little bit more detail as to how competitive a profile you see for ARV-471 relative to the SERDs?

Yes. I'll hand over to Ron, our CMO to talk about that in detail, but clearly the data we've generated so far and our last data released in December on ARV-471 really encouraged us that ARV-471 has the potential to have that best-in-class profile from a clinical benefit perspective, from a safety perspective, even a degradation perspective. We are seeing a hit at the mark early, but it is early. But maybe Ron, you can go into a bit more detail about your views on the positioning of ARV-471 in terms of the rest.

Yes, certainly. And thank you, Yigal, for inviting us also. So the way that we are seeing this, as John said, I mean, I think across a number of different parameters, we do believe that the profile really is on a path to best in class. We believe that the Pfizer partnership is a further validation to the promise and the potential of ARV-471 even in this competitive environment. So just to walk through the key findings in more specifics, you mentioned that this is a 100% post CDK4/6 inhibitor therapy population. That's critical because there is emerging data to point out that this is a population that has a particularly high level of therapeutic resistance to endocrine therapy. So there is a publication that we've cited in the December disclosure that nearly -- that shows that nearly about 70% of patients have ER independent resistant. So it doesn't matter what kind of modality is used against ER. It doesn't matter how perfect the drug is, or these patients will progress and not respond. That's very different from the trials that have been reported for the competitor agents within this broader SERD class. And the other thing just to know is that there is also emerging clinical data that supports this very aggressive phenotype of the tumor after you progress on CDK4/6. There is a trial that was presented at ASCO called VERONICA study. This is, to our knowledge, the largest prospective clinical trial of fulvestrant in the setting post CDK4/6. Fulvestrant demonstrated a clinical benefit rate of 14% as a single agent. And so that's really the benchmark that we are looking at with regard to how to get a sense of what ARV-471 is doing in this setting. As John mentioned, our clinical benefit rate in the Phase I data back in December showed a clinical benefit rate of 41%. For those who are not familiar, clinical benefit rate is actually the preferred primary endpoint of Phase II trials of endocrine therapies. That's the endpoint that all the other trials are looking at with the other agents in Phase II. It's a summation of complete response, partial response and durable stable disease being at least 6 months. We had a clinical benefit rate of 42% in this setting compared to the 15% that I mentioned earlier. So efficacy clearly looks good. We have a confirmed response. We had other patients who had tumor regression as well that didn't meet confirmed response, but still showing tumor regression in many of the patients that were on trial at that time. Secondly, safety is particularly important in this setting. In ER positive breast cancer, the setting where even in earlier settings of metastatic disease, you could be on therapy for years. And then also you think about adjuvant therapy for ER positive breast cancer. ER positive breast cancer represents 80% of all breast cancers. And adjuvant therapy for breast cancer is extremely common. And there are a lot of patients there. It's still a high unmet medical need with patients recurring after that. So having a good safety profile is critical. And that's another point of differentiation for ARV-471 compared to a number of the other drugs that are in this class that had been hampered with GI toxicity, even things like visual disturbance, bradycardia. So we think that the safety profile and the efficacy are really notable at this stage. And then, as John mentioned, we've data from paired biopsies that shows that the drug is doing what it's supposed to be doing, which is degrading ER. We saw this in all patients that there was degradation in ER with some patients just having degradation up to 90% and average of degradation of just over 60%, which is more than has been reported for fulvestrant in human tumors.

Did you see -- were you able to do an analysis of the correlation of the degree of degradation in the clinical response?

Yes. So the data are not sufficient to be able to analyze that the number of patients is too small to do that. Also with this nearly 70% ER independent resistance, you end up taking patients off the table just for that. So it becomes really impossible to look for that right now.

Okay. And just remind us when are we going to get the next update from this Phase I? Is that's happening soon or no?

Yes. So...

The end of Phase -- yes, for ARV-471, the end of -- yes, Ron could [indiscernible] end of Phase I data will be at the San Antonio meeting later this year.

Okay. And just -- are you able to give us a rough sense as to how many patients and the duration of therapy for that to update?

Yes. So we have not provided specific guidance. What we can say is that at the time of the December disclosure, we were still dose escalating; we had not reached any dose limiting toxicities or anything. There was really quite minor safety findings, Grade 1 and Grade 2 adverse events. And so we were dosing at that time at around 500 milligrams -- just starting at 500 milligrams. So dose escalation has proceeded. We have also -- we will also have data. So we will have more data in terms of patients. We will also have more data on paired biopsies at that time and also, of course, more safety.

Okay. Great. So I'm really interested in your combo strategy. You're doing a study, which I believe you recently started for ARV-471 plus palbociclib in first-line metastatic breast. And this is in the -- again in the post CDK4/6 setting. I'm curious, I understand that the goal of the study is mainly for safety and dose finding, not for efficacy. So just -- I'd be interested to know a little bit more as to why efficacy isn't the focus for this first combo study and when would you be embarking upon such a combo trial where efficacy is the focus for, say, combining with palbo?

Yes, certainly. So as you would expect, it's very difficult to understand the contribution of 2 drugs when you know that the established drug; in this case, palbociclib is active on its own or in combination with other endocrine therapies. And we also know from the monotherapy experience, we have direct evidence of what this drug can do for patients. So for us, in order to be as efficient as possible in development, the focus became safety and to confirm the recommended dose for the combination for Phase III studies. So the center -- the focus was on safety. In order to ensure that we can enroll as quickly as possible, we did not restrict prior CDK4/6 therapy. We allow prior CDK4/6 therapy. So in that way, it also becomes very difficult to learn anything from that efficacy perspective. We believe that the monotherapy experience, including the VERITAC expansion, is really going to be the most important thing for understanding the potential. And we think we're ready in a good place with understanding the profile of the drug by itself.

Okay. Good. Is there any kind of guidance you can give in terms of how much of an efficacy boost you might expect with ARV-471 on a background of a CDK4/6 inhibitor, or is that just time will tell?

Yes. Certainly with our partners as we start to think about registrational programs in more detail, certainly we have a very keen eye on determining what is something that's clinically meaningful, something that we believe is achievable with ARV-471 and certainly, our goal here is just to show a superiority, but we have not disclosed any of the details in terms of what that might look like.

Okay. Are you -- how far away are you from potentially doing a randomized study with -- yes.

Yes. So with the announcement of the partnership in July we had with Pfizer stated and it's also stated in our press release that we have the plan to initiate a multi-indication Phase III program beginning in 2022.

Okay. Now you're also starting in the second half of this year, I understand that a Phase Ib for ARV-471 plus everolimus in third-line metastatic ER positive breast cancer setting. Could you talk a little bit about why you chose everolimus to do this study as well as what are the targeted therapies might you consider for future combo work?

Yes, certainly. So the way that we went about this is to start off with the basic -- with what we already know about the profile, our confidence in this as a potential best in class. And then, it was the imperative that we want to develop as the drug of choice for patients with ER positive breast cancer. And that means thinking about this with the current paradigm, which is both monotherapy. Endocrine therapy is using monotherapy setting. It's also used in combination with targeted therapy. So if you go back nearly 10 years ago to the approval of everolimus in combination with the aromatase inhibitor, exemestane, you'll see from the study known as BOLERO-2. That was the basis for approval that everolimus had a pretty substantial improvement in progression-free survival when added to endocrine therapy, namely exemestane to the tune of about a 65% roughly improvement in progression-free survival or hazard ratio of about 0.35. So it's pretty substantial. Our sense is that while it may not be the preferred way to give endocrine therapy, it is certainly a choice that it is being used and it seemed to be also preferential for the patients with more aggressive disease where chemotherapy might be an alternative choice for those. So the idea is that if we can find out how to administer this drug when it's in maybe the more difficult patients where you need a boost in efficacy adding on top of a backbone of ARV-471, that would be one approach. It's not the only combination that we're interested in even before the partnership with Pfizer. And so there is a list of combination partners that we have been thinking about. We've already begun to align with Pfizer around some of the basic ones. I won't go into those in detail. I think if you look at the targets that are certainly exist today and you think about that have already been validated in breast cancer, ER positive breast cancer and you think about combinations that may be of interest in the future based on some emerging science and emerging therapies, then you pretty much come up with a list of therapies. And we have the interest with Pfizer to pursue multiple other combinations by way of other trials.

Okay. Thanks. And then moving to a discussion of the adjuvant landscape, you had a so-called the window of opportunity trial for ARV-471 that originally was telegraphed as an adjuvant breast cancer study, but apparently, it evolved into a neoadjuvant trial that's supposed to start in the second half of this year. So just curious as to what was more compelling about neoadjuvant versus adjuvant that resulted in the change and the design of this study? And are you enroll a combo cohort with palbo as well in this neoadjuvant trial?

Yes. I think it's worth to me just making certain clarifications and I guess, level set on what these terms mean. So we had in the past referred to a window of opportunity study. Those are very commonly done in ER positive breast cancer. They are very short duration treatment studies, and they are done with treatment preoperatively. So it's generally typically 2 to 3 weeks or 4 weeks of therapy really in the window between the time that a patient has consented for this trial, patient with early-stage breast cancer and the time that they have their definitive surgery already scheduled. Hence, the terminology window. And the idea is that you can learn about biology and the impact of the drug on, for our case ER degradation, other biomarker endpoints. We ended up moving towards a neoadjuvant design. So the difference there is really just duration of treatment. So whereas window study is short duration, get to the post biopsy and let the patient go on for surgery. This is more with the intent of longer duration treatment. We got additional data as a result of the longer duration treatment. You get clinical endpoints. You get more informative safety in the early breast cancer setting. And really, this is more of a springboard for getting early on into pivotal adjuvant studies. The neoadjuvant is really just a window. It's just a model for evaluating the drug in the early breast cancer setting. So this is really more a decision because we thought this was going to be a better way to accelerate a start of a pivotal adjuvant program.

So -- just so I understand correctly, in the neo -- in this neoadjuvant trial, once they've had their surgery, do they continue on the therapy or no?

We haven't disclosed the details of the design.

Okay.

And -- but the main thing is that these studies typically are more about getting the data earlier in terms of biomarkers, still in this case, but also some additional clinical endpoints, which really help to be able to create momentum and interests among the investors that were doing adjuvant study.

Okay. And I think you also mentioned the VERITAC trial, which is the Phase II dose expansion in second-line metastatic ER positive. So could you talk a bit about, I don't know, to the extent that you're able to comment, what is the late-stage development strategy going to look like for ARV-471, both as a monotherapy or as a combo of the approved agents because you're doing preparatory work across the spectrum from -- as you say from neoadjuvant all the way through first, second, third line metastatic?

Yes. I think -- well, I think one thing I'll start off saying is that the partnership with Pfizer allows us to go much deeper into this space. That's one of the reasons. And the other one is allowing us to accelerate, hence our excitement about having the partnership. We have not yet disclosed details about the registrational program. I already mentioned that there is the plan to initiate a Phase III program in the metastatic setting across different lines in 2022, which is just next year. So -- and then I would say that essentially the goal here again is to have the data support indications that allow patients to have this as a drug of choice across lines of therapy. Certainly, we're doing the palbociclib combination. Palbociclib is certainly standard of care in combination of aromatase inhibitors, in combination with fulvestrant for patients who have already gone through aromatase inhibitor therapy. And then, for later line settings, the program will meet the needs of registering the drug in settings where it's going to be most useful. And we are again looking at ways over the longer term to get this -- to make this a drug of choice for all settings.

Okay. And maybe, John, I can ask you this one. Just in terms of the Pfizer partnership, could you talk a bit at least to the extent that you can, how much does having Pfizer onboard accelerate the overall strategy and the overall plan for ARV-471 in terms of getting to the -- getting to filing an NDA?

Yes. I mean I won't go into the specific details other than the fact that it's much more comprehensive in terms of the game plan, and it does accelerate ARV-471. So it really take the box quite significantly for us in terms of seeking a strategic partner that would enable ARV-471 to get to more patients and hopefully, get to the market in a cohort fashion. So we are excited to the fact that the game plan that's been laid out and the joint plan of development between Pfizer and Arvinas will achieve that. But yes, it will be more comprehensive and it will be accelerated.

And just let me squeeze in one more in ARV-471 and then, we'll switch over to ARV-110. I'm curious what is your understanding, or what is your view as to the reason why ARV-471 has been so clean on the safety so far?

Good question. We get this a lot. And before we had data, it was sort of the -- I think folks started to develop expectations that we would have some of the similar types of safety signals, which we haven't. Really, it's not 100% clear what is clear to us and we had this tailwind even before we saw our data back in December was that it's not clear that these things are ER on target effects, things like bradycardia has not been seen for -- with drugs like fulvestrant certainly in some of the other older drugs. Visual disturbances seems to be limited to 1 or 2 of these other drugs. GI toxicities has been more of a pattern for the broad SERD class. I mean we speculated about certain chemistry explanations for that, that are not shared by ARV-471, but I think the main takeaway is that it tells us that a lot of these things that we've seen with the broader SERD class are not ER dependent.

Okay. Let's switch to ARV-110 before we run out of time. So for ARV-110, could you talk about what you believe are the attributes that make this molecule a best-in-class AR degrader in your view?

Well, it's -- I think the difference just to highlight is that while in breast cancer, we're in competition with this broad class SERDs, even as the only PROTAC. For prostate cancer, we have a different set of competitive set. We are aware that BMS is developing a degrader. They started after us. And -- but otherwise, it's other set of non-AR directed therapies that are sort of really more things that we're tracking right now. I think for -- what I would say about ARV-110 is number one, we're going against the age-old target, but with a whole different mechanism of action. AR has been a validated target since I think it was the 1940s. And so the idea of going with the time-tested target is critical and gives us faith even before we had our data. Number two is that ARV-110 as an oral PROTAC offers other advantages for this older population, who has had to go through IV therapies, chemotherapy. So having an oral therapy is still going to be quite a differentiator, especially when you look at the other therapies that are in this space. I think the other thing is that when you look at other regimens that are being tested such as multi-kinase inhibitors, either alone or in combination with anti-PD1 or anti-PD-L1 therapies or other types of biologic treatments. Those will introduce toxicities that could be really a challenge for patients, who have already gone through things like chemotherapy. And really, we'd like something that's a little bit easier on them. So I do think that there is -- those aspects between convenience and safety. And then, we talked about AR and then we have the data right now that tells us that we have a proof of concept, even in the very late-line setting. So just as a reminder, in the disclosure that we had in December, these patients were really unfortunately quite beat up. They had very few, if any, alternate treatment options at the time. 80% of patients have gotten prior chemo, meeting -- our lines of therapy was 5. And actually 80% of patients got both enzalutamide and abiraterone. So it's a pretty far advanced setting and frankly a setting where there is a lot of AR independent mechanisms of resistance, but despite that, this drug showed clear activity.

Okay. Great. I just want to pivot for a second. We have a question coming in from one of the listeners. They are asking about the drug-drug interaction reported last year with rosuvastatin. Could you remind us what we learned about that interactions since it was reported? Does it in any way limit the market reach of ARV-110 given the broad use of statins? Was it specific to rosuvastatin? And does it have any implications for the overall PROTAC platform?

Yes, I'll start with the last one. This is not a PROTAC-wide observation. We see very different things between ARV-471 and ARV-110. So that's an easy question. With regard to what we've learned, well, very simply, it was something that we came up with quite early. We saw in 2 out of 2 patients who were on rosuvastatin. Rosuvastatin is particularly unique in its impact on drug-drug interactions through the BCRP, a transport pump. And other statins are not as, let's say, dependent on just BCRP. So essentially, what we've done is we've excluded drugs like rosuvastatin from being used concurrently with ARV-110 that has not in any way impacted enrollment. Number two is that we have not seen the same types of diverse events that we saw early in the program when we -- before we discovered that interaction. So that shows that it really made a difference by making that change in the protocol. And then the last point I would make is that we have a very robust clinical pharmacology plan to investigate drug-drug interactions to really get a better handle on -- is this really going to be limited to drugs like rosuvastatin, are there other drugs that may be impacted, but certainly when you think about rosuvastatin, again it could be that this is something that could be unique, we'll find out with more data. And also in advanced prostate cancer population, this has not been a hindrance at all in the program since there are other choices for patients and a lot of these patients, they are more aware of the seriousness of their prostate cancer.

Okay. Good. So obviously, you have a relatively important readout coming up soon as far as I understand the interim readout from the ARDENT Phase II trial in the second half of this year. So help frame expectations for just how much data we're going to receive at this update? And then to the extent that you can comment, what you believe you need to achieve on a PSA50 response to justify continuing to develop this drug?

Maybe just to be clear on -- does that -- I mean, the game plan is still in the Phase I data by the end of the year. The whole game plan there was to make sure that we have completed Phase I because this would be the fourth time we've got an update on ARV-110. So it would be end of Phase I. And then the idea was to have interim readouts of ARDENT. And of course, that's going to be the data set we have there. It's totally dependent on what stage of the trial is that. So Ron, can maybe talk to aspects of how the trial is designed and the expectations over a period of time.

Yes. So maybe I'll just focus my comments on Phase I for now. Then, I'll tackle the other question you asked about expectations. So the Phase I where we left in the December disclosure is that we are still doing some additional dose escalation. In Phase I, I think that the highest dose that we have reported back in December was 700 milligrams. We had started the Phase II study at 420 milligrams administered daily that being the ARDENT Phase II expansion. So to think about a follow-up on the Phase I, which would essentially be the completion of the dose escalation, it would be looking at additional patients looking at higher dose levels and more information on safety at these alternative doses that were investigated in Phase I. And I think your second question was around...

The bar -- I mean, the bar for success, what do you think there?

Yes. I think what I might do is just kind of refer back to the ARDENT because this is -- the Phase II expansion was really designed with the early efficacy data in mind. So when we had our first disclosure, which was a year ago at ASCO, we saw that -- number one, we saw early responses PSA50; we saw RECIST confirmed response. And the most notable activity was in patients that had certain mutations in the AR receptor. And so what we wanted to do in Phase II was to ensure that we were really stratifying based on AR biology, and we included a cohort of patients with the same mutations, both of which were present in the most profound responders. And in December, we had presented some data, not from the ARDENT, but from Phase I with more data in that particular subset, patients with 875 and 878 AR mutations. And we saw that even with now up to 5 patients back in December that there -- they continue to be a pattern where those patients again in this very late-line setting, where there's a lot of AR independent resistance that they still seem to do, let's say, a bit better than the broader population. And better enough that we felt that we -- and still feel that this is a population that could be a basis potentially for accelerated approval once we get additional data in that setting and move forward with a pivotal study that would be in future. So -- and in that population, so again this is sort of, let's say, a precision medicine population based on AR mutations. What we would think would be a basis for [ its own ] approval could be a RECIST response rate in the -- about 25% would probably be the floor we think for what could support accelerated approval. That's based on a review of some of the publications that the FDA has come out with, others have come out with looking at response rate as a basis for approval across multiple tumors. And you see a range in 20% -- and that 25% is somewhere sort of in the middle of that range. We feel especially, given what I talked about earlier, the unmet medical need, the older population and the value that this could be for patients that could be, let's say, a low bar for thinking about this type of approach.

So I understand correctly. You're referring to the T878A, H875Y group, is that correct?

Yes.

Okay. And just wondering is it understood biologically why it appears that those patients -- mechanistically, it's easier to degrade their mutant AR?

Yes. So I would, I guess, correctly, is that this we don't believe is a consequence of the drug in that we have robust preclinical data looking at the ability of ARV-110 to degrade AR in vitro systems, in vivo systems and also looking at wild-type versus other mutation forms. And this is not in our opinion or in our strong belief. This is not because it's ARV-110 degrading 878 and 875 any differently. It degrades in these laboratory settings consistently across with one exception being this mutation L702H, which we now ARV-110 degrade and is also in a low frequency and castrate-resistant prostate cancer. On the other hand, we do think that this is likely sort of an indicator of which tumors, which patients have tumors that are still addicted to the AR pathway that this is some marker of AR -- of responsiveness to AR therapy. Here, these are patients who have already progressed through second generation drugs, inhibitors, abiraterone/enzalutamide, but these patients may still be addicted to the AR pathway, such that a degrader can do the job.

Okay. Thanks for the clarification. And John, just one final question before we wrap up here, just at the level of corporate strategy, are you currently envisioning entering into a partnership with ARV-110, similar in scope to what you've achieved with Pfizer for ARV-471?

Well, at the moment, we're going to progress ARV-110 ourselves. We have the ability to do that. I think it's a very clear path that Ron indicated even maybe a fast track method for moving forward. But obviously, we remain open to the idea of a strategic partner helping us at the point where we are that can go faster or more comprehensively. So we're always remain open to that, but right now, our plan is fairly aggressive. And we can do that with the investments we have to take this compound forward ourselves. But yes, you will never get me saying we are not open to good partners and acceleration of our programs.

Makes sense. Well, thank you both very, very much for the insights, and we look forward to further conversations.

Great. Thanks, Yigal. Fun.

Thank you very much. Good to talk with you.

Bye.

Take care.