102 - Arvinas' PIONEERING PROTAC Tech to Enhance Cancer Outcomes | Interview with CEO John Houston

Great, nice to meet you.

Absolutely. Great to be here. Arvinas was founded in 2013 by Professor Craig Crews from the University. We're based here in Connecticut in New Haven. The company could focus on making small molecules that could eventually turn into therapeutic modalities. Since then, the company has grown from a very small start. As we stand today, we've got over 250 employees, and we've been able to move our pipeline forward quite significantly from those early days, with a whole series of firsts for the technology and the platform. As you said, having the luxury of being the only company in 2013, there's probably now 35 or 40 companies in the space, including the big pharma companies, really showing that protein degradation is a really significant new therapy.

Yeah, so normally when somebody has a disease and there's a therapy available for them, it can be a small molecule where they take a small molecule every single day, and the idea is that the small molecule inhibits something that's either an aberrant signal or a receptor or a protein or enzyme that's become dysfunctional causing the disease. So you take the pill every day. You have to have the receptor or the enzyme occupied by that compound to stop the signaling. What happens over a period of time is resistance builds up to that compound, and eventually therapy becomes less effective. Now, protein degraders are radically different. There's a natural balance in your cells, and the way that's done is by the ubiquitin ligase machinery in your cell. The cells monitor the normal lifespan of a protein. If it gets past its normal lifespan, the ligase machinery comes in, tags the protein with ubiquitin. Once you get four ubiquitins on your protein, then it's dragged off to this organelle in the cell called the proteasome. The proteasome is basically a garbage disposal unit in the cell for proteins that are past their useful lifespan or a disease protein. The protein is shredded down into peptides and eventually amino acids, which flush back into the cell for future protein synthesis. What Craig did was he said that system could be hijacked. The PROTAC binds to the protein that you want to degrade, and the PROTAC brings these two proteins into close proximity: the ligase and the targeted protein. Ubiquitins get transferred onto the protein, and yes, it gets shuttled off to the proteasome and degraded. The really interesting feature is the PROTAC is then released at the proteasome and goes back and does multiple rounds of this degradation. So it's not an inhibition process, it's not an occupancy-driven process; it's hijacking the cell's natural protein degradation and basically eliminating that disease-causing protein from the cell as much as we can.

Yeah, they're small molecules. They're slightly larger than average small molecules, but they're small molecules.

Absolutely. When the program started a few years back, the focus of the time was validating the platform, and looking at a comparison to fulvestrant. Fulvestrant is a degrader, an estrogen receptor degrader. The molecule is very good, but it is an intramuscular injection, so an oral therapy would be beneficial. And it's maxed out in terms of its ability to degrade the estrogen receptor; you probably get in the range of 40 to 50% degradation. So there's an opportunity to create an oral degrader that was like fulvestrant but oral, and have better degradation, get levels well above 40-50%. So that's how the program started. As we produced our data in mid-December last year, we can see several at the 90% and above degradation. We have a safety profile that is very good compared to fulvestrant and the other SERDs. And most excitingly, a clinical benefit rate as we announced in mid-December of around 42%, which is really remarkable because of the patient population we're in. We tried to do an apples-to-apples comparison as best we could with the other compounds, but in reality we were the only compound going into a trial where 100% of the patients were post-CDK4/6 and 70% of them were post-fulvestrant. So a very highly resistant patient population, probably in the range of 60% or above. So the data is very encouraging and bodes well for the program as it moves forward.

Well, it could be a number of things, and it's difficult to say right now. That will be elucidated in the months and years to come. But these molecules are very different from the SERDs. There's a completely different chemo profile. It's not inhibition per se, it's degradation, although there's some element of inhibition at the receptor. We clearly don't have some of the safety issues and tolerability issues that some of the other SERDs have. We'll track that, and we're hoping that turns out to be the fact that this is a very different chemical and a very different mechanism from the other compounds in the clinic.

We have a set of other potential combinations. The clear path for us right now is getting to the point where we can select the right dose and get into pivotal studies in Phase 3. Right now, the most significant thing that's happened since December is we signed a deal with Pfizer. That deal is a co-development, co-commercialization deal on 471, and that really is going to help us execute our plans even more effectively and be able to accelerate the plans as well. So we're very excited about all of the trials because now we can actually lay out the stall, so to speak, have less of a worry about linearity, do one than the other. There's a lot of parallel activities we can now do with having a partner such as Pfizer. The whole aim is for 471 to become the endocrine backbone therapy of choice for any other combination and seeing whether it has a position as a monotherapy as well.

It's too early to say. Obviously, the trials right now are in that late-stage population, so there's a potential there. Now we have a partner with Pfizer, we're obviously now in those types of discussions about what that indication would be. But it gives us lots of optionality, which is great for patients as well.

Well, rolling the clock back a little bit, a number of companies have been tracking Arvinas and the protein degradation space. Both our AR and our ER programs garnered a lot of interest even at the very early stages. We were quite clear that we wanted to move those programs forward ourselves; we felt we could build the company on the back of that. But then when the data came out in mid-December, the interest was huge. So we decided that maybe we should look at a partnership. We went through a process with a number of companies, and at the end of it, Pfizer was the company standing there as our first choice. We're very excited to have Pfizer. They are local neighbors here in Connecticut, which certainly makes the interactions a lot easier even with the world of COVID right now. Their vision for 471 matched ours, their ambition for 471 matched ours, and so far the collaboration has been excellent, as we thought it would be right from the get-go.

Great. All right, so when it comes to 471, I believe the company has disclosed that the full Phase 1 data set will be presented at the San Antonio Breast Cancer Symposium in December. Can you give us a sense of what the completed Phase 1 data set might look like or what will be included in that release?

So you think the next sort of data presentation will be in the Veritac expansion study?

Okay, great. Exciting. So I wanted to shift gears now and talk about the prostate cancer program, which is also very extensive. I think from the outset it wasn't clear to me the difference between ARV-110 and ARV-776. They both target the androgen receptor. Could you explain the difference?

Okay, that was done by some structural biology, so it was really smart chemistry.

Yeah, when we went into the trial, we knew it would be again in a very late-stage setting. It was third-line plus. But as the trial ran, we realized we weren't just in third-line plus; we were in fifth and sixth line, a heavily resistant patient population. A lot of the tumors were actually not AR-driven. So it was a very tough setting for us. When you look at the different therapies that have gone into later stages, you could maybe expect in that late-stage population around 10% PSA50 responses at best. So we were actually pretty excited when we saw some of the first data coming out, significantly above 10%. And even more excited when we actually got the data on the mutations. In fact, 80% of the patients harboring these mutations show some sort of PSA50 or PSA30 response. So it's quite a significant response. That did change our attitude a little bit, saying even in this incredibly late-stage population, we're capturing a group that probably still has tumors that have an AR-driven disease marked by these mutations. Therefore, maybe there's a faster approval process by generating data around that particularly strong molecular profile, while continuing to profile the compound broadly. The idea is that 110 will have a position certainly in late stage but also moving further up the treatment paradigm, where you'd assume more and more AR-driven disease. So that's the approach we're going to take.

Very exciting. I think it's so interesting that because your technology is able to get more degradation, you're actually able to uncover patients that can actually respond to more AR-driven therapy, which they couldn't do without a technology that could actually do more degrading. It's pretty fascinating.

So the Phase 1/2 study is that right?

Okay, good to know. So I believe the company disclosed that the full Phase 1 data will be expected at the ASCO GU in February. Is that right?

Okay, so we'll get some Phase 2 data at this conference as well?

Okay, and so the full data set, will that include like RECIST response rates and things?

Okay, good to know. Just wanted to get clarity there. So you kind of alluded to this before, but maybe you can explain why you decided to partner 471 but not 110.

The company's in a fairly healthy financial position. We've got about $1.6 billion in cash and other investments. So we have the ability to take 110 and the rest of our pipeline forward on our own, as we have to for 471 and 110 over the next few years.

Yeah, so we have a preclinical pipeline that's now a mix of a whole set of oncology targets moving forward. A while ago, we found that we could actually make PROTACs not only oral but brain penetrant. We got very excited with the idea of moving into neuroscience, hitting some of those classic targets that others have been trying, like tau, like alpha-synuclein, and using the PROTAC technology to see whether protein degradation would work in that setting. So we've built out a neuroscience team over the last few years under the leadership of Angela Cacace. I'm excited about that portfolio because I think when we get the clinical candidates coming out from that portfolio, a whole series of them coming out over the next several years, we'll be able to see whether we can truly drug some of these important targets in the right setting. The breast cancer programs have well-known biology. We knew going into this that if you modulated the androgen receptor and estrogen receptor, it could lead to clinical benefit. There was no ambiguity about that. The ambiguity was with the PROTAC work, with protein degradation work, and would it work in a highly resistant setting. We're on the path to showing that's the case. But when Craig set up the company, what he actually was most interested in was deploying this technology into the undruggable space. Like 80% of proteins that are in the proteome have not been drugged. He believed, and I think he's right, that protein degradation and PROTACs would be an entry point, a significant entry point, into that space that would be very exciting. So the next set of targets are in that undruggable space. We're very excited about those. They'll be the next generation of programs coming over the next two or three years. Our idea is to get to a clinical candidate every year from the portfolio, so we end up with quite a significant overall pipeline over the next few years.

Right, right. Okay, so how close do you think we are from potentially nominating an IND candidate in the CNS space?

That seems to be most interesting. Regarding KRAS, it does seem like it's been druggable now, but the safety profile, I don't know if we're all the way there. So it really does seem like potentially using the PROTAC technology, you could come up with a molecule that has a cleaner profile, and I imagine that would be very competitive on the market.

Okay, all right, very cool. Lots of good stuff there, John. I think really my last question: you touched upon your cash position, which is pretty substantial, gives you a nice runway. Does the company have any other plans outside of just the developmental pipeline to put that cash to work? Anything you can share with us?

Okay, very cool. All right, that's most of the questions I had. John, is there anything we didn't touch on that you think we should talk about with regards to Arvinas?

Yeah, absolutely. And you guys have been quite the leader so far, so I look forward to seeing all the updates in the future. Great. So the company's name is Arvinas. Is there a social media or Twitter you want to share?

Oh, all right, I'll have to give you a follow then, John.