Okay, great. Good morning, everybody. Sorry, I had some technical difficulties, and hopefully we won't lose audio during this presentation. Thanks for joining us. I'm Tazeen Ahmad. I'm one of the Senior SMID Biotech Analysts here at B of A. It is my pleasure to be spending the next few minutes with Arvinas, and joining us from Arvinas this morning is Randy Teel. Randy, good morning. How are you?
Good morning, Tazeen. Thank you for having us.
Of course. Maybe just do a quick overview of the company, if you could. I think most of us are familiar, but just give us a sense of what the platform is and some of the advances that the company's made over the last year. There's been a few, and then we can go into more detail about some of the things to look forward to.
Absolutely. I, of course, have Ron Peck, our CMO, on as well, who will handle a lot of the heavy lifting when it comes to the clinical trial starts and ongoing data and results there. Yeah, thank you again for having us, Tazeen. Arvinas was founded back in 2013, coming out of IP from Craig Crews at Yale University, and it's fun to think about that now nine years later. I think we could probably come up with 40 or 50 names approaching greater companies off the top of our heads, but Arvinas was the first in the space, and we're proud to be where we are. We're largely focused in oncology and neuroscience.
The three programs that we have in the clinic right now, one for estrogen receptor and breast cancer and two for prostate cancer that target the androgen receptor. We've also got some neuroscience programs coming on as well, at least one of which will have an IND, we expect, in before the end of 2023. In terms of the platform, you know, I think we're differentiated in a couple of ways. I think first is really around productivity, what we've created, which is, those programs we have in the clinic, at least two of them we consider to have proof of concept of showing some initial, phase I efficacy and tolerability, and excited to be where we are.
In both of the programs that are out front, ARV-471 breast cancer and bavdegalutamide or ARV-110 in prostate cancer will be in phase III pivotal trials by the end of next year. The ARV-471, we'll have two starting by the end of this year, one as monotherapy and one in combination with IBRANCE (palbociclib), and ARV-110, in a phase III study by the end of next year. You know, I think getting to that point, something we're quite proud of. When it comes to the platform itself, we feel very confident that the strides we've made in ligand screening, progress with identifying, leveraging new E3 ligases, ability to predict and model transformation, building in drug-like properties, you know, we're investing to make sure we stay out front.
Maybe before we pass over to Ron, for some more detailed questions, I can go through, you know, what's coming up for the company. I just mentioned, you know, for ARV-471, that we'll plan to start two pivotal studies by the end of the year. In addition to that, we also plan to or have already started studies in the EU adjuvant space, combination with everolimus, and an umbrella trial with our partners at Pfizer, assessing some other combination agents with ARV-471. Then we'll have data by the end of the year as well, so that's data from our phase II, which we call VERITAC, that will be coming up by the end of the year.
On the prostate cancer side, it will actually be the second androgen receptor program, ARV-766, that we expect to share data by the end of the year for the phase I escalation. It will start its phase II by the end of the year. A whole lot coming up in the coming months.
Right. Okay. A question that we get all the time, from investors still is, your partnership with Pfizer.
Mm-hmm.
ARV-471 in particular, you know, how did that come about? You know, there are a lot of now protein degrader companies, both private and public, and I think that, people want to read the tea leaves as to what Pfizer may or may not have seen.
Mm-hmm.
At this point, are we correct in assuming that whatever they saw is already in the public realm? Why did you think that Pfizer would be the best partner here going forward?
We initiated those conversations back in the wake of our data around San Antonio in 2020. In December is when we showed the first phase I data for ARV-471. At that point, it really gave us the confidence that based on what we had seen at that point, that we could really aim to try to make ARV-471 the endocrine therapy now ultimately across the backbone of care, we'll. That really opened our eyes to the potential, right? We're starting with that phase I and the phase II in very late line refractory patients. Ultimately, we would like to move earlier to first line, likely in combination, and even into the adjuvant space, which is a pretty large unmet need.
If you could get an endocrine therapy like an ER degrader into that space, I think it would have a lot of potential. Really, what we were looking for in a partnership with Pfizer was we felt pretty good coming out at the end of 2020. We had just done a capital raise as well, but what we really were interested in was the ability of a partner to accelerate and broaden that development. Give us the confidence and capability to move earlier into first line, ultimately into adjuvant. We ran a process there, and Pfizer ultimately turned out to be, you know, a great partner and has been for the past, almost a year now.
Mm-hmm.
Obviously a lot of breast cancer, but that's really what the driver was, broaden and accelerate the program.
Okay. Now, we think it makes sense to start in the refractory patient population, but, you know, how long do you think it'll be before you're able to kind of move up in the lines of therapy? You know, how should we think about, you know, these, the percentage of patients who have ER-independent disease in second line and higher? How does that influence how you think about, you know, the opportunity in the earlier lines of therapy?
I'll talk as best I can and pass it to the CMO. Yeah. By the end of the year, we'll start the trial, you know, in earlier metastatic breast cancer too, but beyond that, Ron will be best equipped to share.
Mm-hmm.
Yeah. Hi, thank you for including us. As Randy said, we are gonna be starting two phase III studies imminently. The first in the later line where we've seen our initial data, and we've been very excited about what we've been seeing in that setting. Then second would be in combination with IBRANCE in the frontline setting. The intent is that we would be starting these two studies in parallel, and that gets to the question of how soon will we move into the earlier line. We'd like to get into the earlier line as soon as we can. There's even a bigger opportunity that we have talked about since the partnership with Pfizer, and that is adjuvant therapy.
We haven't provided any specific guidance on when we would be interested in going in that direction, but certainly one step in that direction is that we will be starting before the end of this year, a neoadjuvant proof of concept study in that earlier setting, really more just to get some data in this population, and if nothing else, it provides more momentum amongst investigators to be able to get the interest in doing a large adjuvant study. We also are very interested in looking at opportunities further down the line to build out a robust lifecycle program, and that comes into the way of starting to test newer combinations. We are initiating a trial with everolimus, which is a targeted therapy that has been used in conjunction with endocrine therapy.
It's been approved about 10 years ago. We are initiating a phase 1b study this quarter, so that's already on clinicaltrials.gov. Then we have another trial that was just posted as well with Pfizer, which is referred to as the umbrella study, which is essentially a we'll call it an incubator for multiple combinations that could position us for a very robust lifecycle program with the intent that ARV- 471 would be the drug of choice or the backbone of choice for all patients with ER-positive breast cancer. That trial was just posted, starting with the first combination of abemaciclib.
Okay. As far as designing these studies goes, how, you know, how have you been interacting with Pfizer? Are they in charge of it, or are they seeking your input?
Before we had the agreement signed, sealed, and delivered, one of the metaphors that we had used in discussions with their partners was the concept of a co-piloted arrangement. Which means that this is aside from the 50/50 economics of the deal, this is truly both teams working together and in conjunction. We have a very experienced clinical team. A lot of us have spent years in big pharma and have even worked on breast cancer drugs, and a lot of us actually even have relationships with some of the folks in the past who are on the other end of the deal with Pfizer, and it's worked out quite well. This is truly a co-directed program.
Maybe it's a question about safety for ARV- 471. I think you will have phase 1b safety data coming out in the beginning part of 2023. Was that delayed from what your original timelines were?
We had initially guided towards the end of the year. One thing that we have been doing in general as we've matured as a company or a clinical stage company is move away from interim updates. I think for our early data for bavdegalutamide especially, we had multiple interims of a phase I study, and we just thought that we did not need to do that anymore. The added thing for four-seven-one is that we've got a partner who obviously will have the same kind of mindset. We decided that we would wait for this phase 1b to be more mature and put the expectation out in the first half of next year. That does not, though, in any way mean that there is a change in our strategy.
We have still guided towards the end of this year for the initiation of those two phase III studies. That does not, you know, that should not be interpreted as anything other than just getting away from interims.
What should we expect to see on the safety profile based on what you know?
The safety profile, it's essentially looking, of course, at the combination of palbociclib and ARV- 471, and if you just take those individual components apart, palbociclib, its main toxicity is neutropenia. There are a couple other things that don't overlap with whatever a ER-directed therapy could do. We are gratified in the safety profile that we have from phase I with ARV- 471, where we had in 60 patients, no dose limiting toxicities all the way up to 700 mg. Only, I think, one discontinuation and one dose reduction, and overall, it's really just a profile that we've heard really good things about from the investigators. In essence, our expectation is that we would not expect surprises, but of course, you have to do the trials to do that.
Mm-hmm.
That's phase I, is to see how the profile looks, make sure there's nothing unusual untoward. Then number two is around pharmacokinetics. Going into the trial from a PK perspective, we were not expecting, essentially going into this thinking that there's a low likelihood of drug-drug interaction. One thing I'll just bring up is that, while we have not shared data, we have been just giving enough of a sort of a foreshadowing to say that thus far we have not seen any impact on exposures for ARV- 471. We have done this because of the recent news with Sanofi discontinuing their program, and their SERD had an association with a drug-drug interaction with palbociclib resulting in lower exposure.
We felt like we needed to be preemptive to say that our drug does not have the same profile as theirs in terms of their drug being a CYP3A4 inducer, ours is not. We also felt the need to just kind of preempt to say that we had not been seeing the same impact on exposure. Just wanted to kind of hit that off.
Okay. Yes, we have been getting a lot of questions on that as well. Let's move to the phase II VERITAC trial for a second. What should we be expecting for the readout for the second line plus patients, you know, what are some of the key differences maybe in your trial design or the patient population that you're enrolling here versus what we saw for phase I?
Yeah. To just take one small step back for the audience, this is our phase II expansion. It was a seamless phase I, II trial, and it was looking at two different doses, 500 mg and 200 mg, both of which are, you know, well within exposure ranges that we were shooting for based on preclinical data. The trial was designed to really inform the optimal selection of a phase III dose. It was actually designed before the FDA started to put more scrutiny on optimal dose, so we were fortunate to have done the right thing in the beginning. In terms of population, it's actually quite similar to the phase I.
The one thing that we take efforts to just orient about for the trial and especially the phase I initially was that this is a population where 100% of patients had received a prior CDK4/6. That is unlike the trials with the SERDs that have been in development in terms of phase I data for I think maybe with the exception of maybe one trial. Ours is 100% post CDK4/6. That's gonna also be the case for the phase II expansion. We also do permit chemotherapy. There is a slight difference in that we have permitted up to three lines of chemotherapy for the front line, which is pretty significant.
For phase II, we limited it to one prior chemotherapy, which is essentially the same as all the other trials. It still will be chemotherapy pre-treated. With all that taken together, what we guide in terms of what good looks like, based on what we see in phase II is, you know, in phase II, we saw a clinical benefit rate of 40%. That was data back at San Antonio last year. Put that into context, there's molecular profiling data that's been published to say that 2/3 of patients have ER-independent resistance once they've progressed through CDK. It's important for us to orient towards that because there's a ceiling for how much even the miracle ER therapy could work.
You know, that's why we're so excited with our phase I data. If we can see CBR rates that are in that high 30%-40% range, then that is a sign that we're, you know, essentially looking to max out on the benefit for those who still have ER dependency. That's phase I is CBR. We will also have safety in all patients as well. I mentioned the safety profile from phase I.
Mm-hmm.
It's really, I think, essentially more of the same relative to safety.
When should we expect to see all that?
That will be, San Antonio this year.
Okay. Should we expect to see anything on PFS?
Well, what we said in the past is that our intent was not to include PFS. The data snapshot that was driving this abstract was really to focus on the primary endpoint, which was clinical benefit rate.
Mm-hmm.
Which means that there has to be a follow-up of at least six months from the last patient. PFS doesn't normally mature with that sort of follow-up, so we just wanted to guide towards the primary endpoint of efficacy CBR. But we, you know, will certainly intend to share the PFS once it's sufficiently mature to share with the investor community.
Okay. Just to be clear, not to expect that at San Antonio. It'll be at some later point.
Sure.
Okay. Maybe just to go hypothetically into discussion of protein degraders in general. Now, you did talk about, you know, differences in your platform versus other companies, but I think people are still trying to kind of get their heads around why Sanofi would drop the entire AMEERA program. It does, you know, of course you know, theoretically have a much better compound than they do, but what are things that we can, you know, look to today to really get confident that protein degraders as a mechanism make sense, especially for the types of cancers that you were initially looking at?
Yeah, certainly. ER was a great place for this company to start with regard to testing this new platform. As Randy said, we've been doing this since 2013. One of the reasons for ER was it was a validated target, but it was a perfect setting for a PROTAC, because there was already more than a proof of concept for another sort of a degrader that was out there, which is fulvestrant. Fulvestrant, very different. It doesn't degrade directly like ARV-471, which hijacks the ubiquitin proteasome system. It gets in there and really manipulates the cell's own protein degradation process. It works indirectly. It hits the ER, changes the conformation, downstream effect of degradation.
Nonetheless, fulvestrant, which has shown ER degradation between 40% and 50% in humans, has proven to be, at least today, the most effective endocrine therapy on the market. It has a frontline indication based on superiority against aromatase inhibitor in a monotherapy trial. That's been the gold standard for endocrine therapy to this point. Degradation, you know, and it was through a degradation ultimate effect. ARV-471 is, in our, you know, our view, as you would expect, based on its mechanism, the best degrader that's out there. This, you know, it starts with the totality of the evidence that we have in the preclinical setting.
Obviously, when structures become available of the SERDs, we do need to sort of convince ourselves that this is still the case for ARV- 471. We have synthesized a number of the SERDs that are out there, and fortunately, it's continued to support our thesis that using an agent that directly manipulates the ubiquitin proteasome system is the best approach. It's the best degrader. That's also... That sort of translates into greater potency. That's the, you know, it's the iterative mechanism, of course, from PROTACs, and that is also showing its, it's translating into our clinical data. I've already mentioned essentially the most resistant population, at least the data we've had at San Antonio, it's 100% post CDK 4/6.
in terms of other therapies, we also have heavily pretreated populations. We have nearly 80% of patients had prior chemotherapy, including more than half who got that chemotherapy in metastatic setting. There's literature out there that shows that prior chemotherapy really does have a negative impact on outcome, even as a prognostic factor. Number two is we had 80% of patients receiving prior fulvestrant. So any way you cut it, most resistant, still getting the CBR of 40%. We also have proof of mechanism data, that we believe, is the best data out there in the metastatic setting.
We had data from 14 patients who had paired biopsies, showed ER degradation in all of them, had a mean and a median ER degradation that was better than has been reported for fulvestrant. All told, it, you know, it really reinforces the confidence that we have, and of course it'll be, you know, up to the VERITAC data to, you know, see how that is playing out.
Okay. Now, you listed a series of studies that are going to be starting soon. Could any of them potentially be used for registration?
Not these studies that we just listed. The neoadjuvant is a small, non-comparative trial that's out there. Umbrella is really just starting to test new combinations. The registrational trials are the two that Randy had mentioned, that we've been guiding for some time, for starting before the end of the year.
Okay. Do you have a sense on how long it could take to get those enrolled?
Yeah, I would say that, I mean, well, first of all, we, you know, haven't really put out the trial design. You can, you know, you can. Normally in oncology trials, we, you know, they're designed so that we can get them enrolled quickly so that, you know, then it becomes just the follow-up. We can't really provide specific guidance. What I would say is, you know, once we are far enough along, we will provide details on that trial and, you know, can, you know, be more prepared to talk about more specifics like enrollment.
Okay, great. Now, maybe let's move on to castration-resistant prostate. You did post your data, get some questions around the subgroup that you chose. I thought it might be a good idea maybe to talk through it for a minute or two. The T878X/H875Y subgroup, that was the one that seemed to show the real benefit, and I think people are still trying to understand why would that be such a narrow, a narrowly defined benefit? Is even that the right way of interpreting it, or did it just so happen that that was a subgroup that had the strongest signal and you still expect to see signals in other subgroups? If you could maybe spend a minute on that.
Yeah, certainly. I think the first place to start is to understand this population as a setting where AR-directed therapies are being tested. When we had first presented the efficacy data for this program, this goes back to ASCO 2020, and we wanted to just orient the community to say, you know, this, to our knowledge, was the most advanced population where an AR therapy was tested. There is a lot of information out there that tells us that, once you get this far out, you start to see a lot of androgen receptor independent mechanisms of resistance. A very similar story to the ER-AR effect. There's, you know, multiple things that happen. It, I think the terminology is linear plasticity.
There's neuroendocrine differentiation as one example, and just the emergence of a lot of drivers of AR independent resistance, whether it's p53, BRCA1 and BRCA2, etc. It's a tough place to test a new AR degrader. Even though we knew that this could overcome some of the mechanisms of AR dependent resistance, there's a lot of other factors that an AR drug is not gonna be able to work on. Nonetheless, we started to see early on this signal all the way back to this ASCO 2020 oral presentation that we had the first two PSA50 responses were both in patients who had T878 / H875Y mutations. It was not something we anticipated.
It's not that bavdegalutamide is a better degrader for those mutations than it is for wild type. In fact, aside from one mutation, which is the L702H mutation, this drug preclinically works as well on wild type as it does these common mutations like T878 / H875Y . What we started to realize, and it's not just us, I think there's been this sort of seen with a compound that Orion has in partnership with Merck, that these mutations seem to be a signal of retained AR dependency. You know, very much like what we didn't talk about with ESR1 mutation seems to predict a little bit more about AR dependency. Same thing for prostate cancer.
We at least we're starting to see this, and it played out in phase II, our ARDENT trial, that sure enough this population continued to benefit more and more. We in fact designed the phase II expansion to really test this hypothesis, and it reinforced that in fact this is a population that benefits great in this post-NHA setting, enzalutamide abiraterone. The question to your point is how does it work in earlier settings? I will say before I get there that this population where we still have the same benefit is a population that we think is gonna emerge as a potentially pretty important opportunity because the second these enzalutamide abiraterone, the other two drugs in this class, are now firmly established in an earlier population, castrate-sensitive.
In fact, what's gonna happen is patients will develop resistance much earlier in their journey. We believe that this is an opportunity that could become more important. We have an oral therapy, and we will have a blood-based diagnostic working with foundation, so it becomes easier to identify the patients. Just to finish off and is that there is we think a bigger opportunity in the pre-enzalutamide abiraterone population, meaning, which right now looks to be the castrate-sensitive setting. We, you know, there were some interesting findings pre-clinically about how this, how bavdegalutamide looks compared to enzalutamide in cell lines. It's much more potent. And even separate from that, there's opportunities in combination that we can think of.
We do think that it will be potentially a bigger opportunity and also one where we fully expect that it will be more active in that early setting.
Okay. Now, I guess what was the conversation like with FDA that led you to decide that you did wanna do a pivotal phase III program for this?
Yeah. What we submitted to the FDA is a proposal for a pivotal phase II trial where patients will be selected for these mutations, response rate as a primary endpoint. We had good reason to be interested in that. There was a precedent with rucaparib in this population, getting a single-arm approval. We felt that with a precision medicine approach, it made sense. What we heard from the agency is, well, if this is, you know, the interest, then here are the things that we'd be looking, you know, looking for relative to specifics around eligibility prior to therapy, patient numbers and whatnot. At the same time, we also got feedback on a confirmatory phase III, which we had part of this package because that's part of the accelerated approval pathway.
When we took all this information back to the company, we really stepped back and said, "You know what? The most efficient thing to do is to start with the phase III. This is instead of doing a part one, part two, let's go with the phase III." It provides, let's say, a more compelling data set, frankly, having a control arm, and we can also use this type of package outside the U.S. We felt that this was ultimately the best approach for the company.
Okay. A similar question to what we talked about for breast, do you think that this trial should enroll quickly? Do you have like a rough sense of when we should expect to start to see data here?
Yeah. We haven't provided any details on that trial. We will certainly do that once you know we're far enough along, and then I think it's probably the same answer. What I will say though at least is you know one thing that we're you know whenever you get into a precision medicine approach you know we do a lot of homework due diligence to really you know convince ourselves that there is a feasibility. You know, us looking into this is really doing that. You know we feel that we will you know be able to find a way to complete this.
The good part of this is that it's a population where the benefit should be, you know, we have confidence in the benefit, so we don't need to design a very large study. Certainly, by the time that we're ready to disclose the trial design, we will certainly provide, you know, more specifics about expectations on enrollment.
Okay, got it. Maybe let's in the couple minutes or so that we have left, both Ron and Randy, I was curious about the rest of your pipeline. I think people seem to be razor-focused as well they should be. These are the most advanced indications that you have. Really, you know, if we think about the company as a platform, like what direction should we be expecting you guys to go in over the next 12-18 months, let's say?
Yeah, I think as we look ahead to, you know, having conversations in the next year, 12, 18 months, like you said, it'll be quite a bit broader. So we've talked about having four INDs through the end of 2023, at least one of which in neuroscience. That's something we've talked about for a long time. We think that the promise, you know, where the really big value and capability for a PROTAC is probably first in the undruggable space. You know, what has historically we've been unable as an industry to, you know, wedge an inhibitor in there tightly to inhibit. But with a PROTAC not needing to bind tightly, we think that opens up the undruggable space, and you will, you know, certainly see some of that coming out as well as in neuroscience. So in neuroscience, you know.
Mm-hmm.
We had some positive news as an industry last week for sure. Historically, you know, having a modality like a PROTAC that might even be able to be orally delivered, get into the brain, not just into the brain, but into the cells of the brain, and degrade pathologic proteins before they ever become a problem and form plaques and things like that could be pretty transformational. We'll start to see some of that. We're aiming at some of the bigger, more obvious indications, you know, the Alzheimer's and the Parkinson's, but also thinking about narrower, you know, pure play tauopathies and things like that.
Right. Okay. Yeah, maybe just on Alzheimer's, is that something that you would still wanna pursue given the positive data set from Biogen, as you said, was great for patients and expectations that some of the other large companies will be releasing some important Alzheimer's data sets in the near term.
Yeah, absolutely. I'm certain there's plenty of room there for improvement. I think a PROTAC could play there quite well.
Okay, perfect. With that, we're out of time this morning. Thanks so much, guys. It's good to see you virtually. We hope to see you in person sometime soon. We'll look forward to the update at San Antonio Breast Cancer Symposium and hope to talk to you right afterwards.
Absolutely. Nice to speak with you.
Have a good rest of the week, guys. Thanks.
Thank you.
Bye-bye.