Heavyweight Division: Arvinas Paves the Way for Therapeutics That Degrade Disease-Related Proteins

The use of small-molecule inhibitors for target modulation represents a classical approach in drug discovery, with a proven track record up to clinical use on a variety of biological targets. Historically, this pharmacological intervention focused on targets with well-defined active sites suitable for the accommodation of a small molecule drug. But many proteins —including major cancer drug targets—do not fulfill this characteristic and are considered “undruggable,” representing challenging targets. So, what if, instead of inhibiting a specific target, you could just wipe it out entirely?

Arvinas is a clinical-stage biotechnology company based in New Haven, Connecticut, that has developed an induced protein degradation strategy to recruit targeted proteins for ubiquitination and subsequent proteasome-mediated degradation. This technology, called Proteolysis Targeting Chimeras (PROTACs), shows great potential in harnessing the action of a single E3 ligase toward pathologically important proteins that are currently undruggable.

Unlike small-molecule inhibitors, these chemical probes do not require a catalytic binding site on the target, because they can induce its degradation by binding alternative non-catalytic sites. Even targets defined as “undruggable” by occupancy-based ligands can be detected and degraded. For example, in cancer, mutations close to the inhibitor binding pocket cause drug resistance by making inhibition less effective or ineffective. PROTACs can circumvent this phenomenon due to their ability to form transient interactions to induce functional knockdown of their targets.

Arvinas went public and began trading on the Nasdaq Global Select Market in September 2018. The stock surged in December 2020 when it released interim clinical data further demonstrating the potential of two of their PROTAC protein degraders, ARV-471 and ARV-110. It briefly peaked above $90 last January before falling back.

GEN Edge sat down with John G. Houston, PhD, president and chief executive officer of Arvinas, to talk about the journey to becoming an integrated biotechnology company and how it is staying ahead in the protein degradation space.

GEN Edge: What are the founding mission and vision for Arvinas?

John Houston: When the company was founded in 2013, it was on the back of work by Craig Crews, PhD, of Yale University. Craig’s fascination with the proteasome and ubiquitin system got him interested in thinking about hijacking the ubiquitin ligase system in such a way that he could target a specific protein for degradation. He developed proteolysis targeting chimeras, or PROTACs—at one end of these molecules is a ligand that binds to a specific E3 ligase that’s part of the ubiquitin system. The other end binds a specific protein targeted for degradation. That formed the basis of the company.

Then, they hired a bunch of organic chemists and made sure that they could develop these molecules as small molecules and move away completely from peptides. The first proof of principle was based on whether they could take this novel modality and make real drugs that could degrade proteins. When you roll the clock forward several years, you can see that we’ve taken that concept from proof of concept in vivo to FDA green light and into patients.

GEN Edge: How is Arvinas organized? Are you an end-to-end company?

Houston: I joined Arvinas at the beginning of January 2017. At that point, they were essentially a clinical-stage company. They had these two programs plus several exploratory programs. We had a view that Arvinas could be a modality company that could strike deals with pharma companies to work on their pipelines and come up with protein degraders.

But in 2017, it became clear that we could do more and that we could build a pipeline to drive raw clinical assets. The first one or two years I was here, the focus was to get significant programs that were in the weeds to the point where they had clinical candidates nominated and to raise investment, which we did through a couple of partnerships and then a Series C to an IPO in 2018. That gave us financial independence to map out a future for building a pipeline to take these assets through and allowing the progress of those assets to build the company out.

Our game plan today is to have a fully integrated biotech company where we can take our pipeline through to the market. So far, we’ve been able to expand all the key stages. When I got here, it was all research staff, but now we’ve got clinical operations and development staff as well as the support staff to run that. We didn’t have chemistry, manufacturing, and control (CMC) when I joined or the ability to do all the formulation, initial scale-up, and large-scale manufacturing of the product as well.

It’s been an exciting journey over the last four and a half years to build the company from about 40 employees to now over 110 people. We’ll continue to grow as we build that vision of an integrated biotechnology company.

GEN Edge: How do you choose which proteins to target? Is it a financial or biological question for Arvinas?

Houston: It’s a real mix. When the company was founded, Craig was interested in oncology targets. The initial decision made, which I think was a smart decision, was not to take this novel technology and immediately apply it to novel biology. Instead, they decided to apply this novel modality to known biology.

For example, in prostate and breast cancer, there were drugs already on the market that were effective but had some issues like drug resistance. Craig’s view was that PROTACs, with a different mode of action than inhibitors, might overcome this issue. Our preclinical work showed that in settings where you saw resistance to these drugs or in settings where there was an overproduction of the target receptor, which also causes resistance, PROTACs work. Now we’ve seen its payout in the clinic, so it’s been a good gamble.

The reason we moved into neuroscience was based on experimentation that showed that we can make these PROTACs brain penetrant. Once we knew that we could do that consistently, it opened up the door to neuroscience.

GEN Edge: What was the thinking behind becoming a publicly traded company?

Houston: Our thinking was based on moving away from being just a platform company that helped enable other companies to a company that we built on this pipeline. As soon as we made that decision, we began trying to reach for cash because we needed money to do that.

We’ve done deals with Pfizer and Genentech, where we are certainly working on their pipeline, but we do get cash to do that. We also get very high visibility and recognition that we’re working with some of the best companies in the world. That allowed us to put some of that cash into our pipeline.

But the biggest way to raise cash is by doing investor rounds and an IPO, and Arvinas has been very successful in doing that. There’s been a huge interest in the protein degradation space. The data that we’ve shown has got people excited, and we’ve been able to raise cash when we’ve generated the data that supports the investment game plan. That’s how we’re going to hopefully keep growing, keep the investors focused and interested in protein degradation, and make sure that our pipeline is progressing.

GEN Edge: What is Arvinas’ approach to collaborations?

Houston: For the first few deals, companies came to us saying that they were fascinated by this whole concept. From 2013 to 2016, people didn’t really know what protein degradation was. They knew it was a new modality, but nobody was doing it themselves. Those companies came to us saying, “we’d love to hear about this technology.”

Invariably, what happens when a big pharma company does that? It’s because they’ve got a set of targets that they haven’t been able to drug. So, you get some of the hardest targets coming your way in those deals. They give you the targets they’re struggling with. For a company at the beginning of its lifecycle, those deals are attractive, tough hurdles.

It was gratifying to see Genentech double down with us and then for us to partner with Pfizer and Bayer. They came with a view that they increasingly believe protein degradation offers a modality that’s differential from straightforward inhibitors but increasingly even more differential from some of the molecular and knockdown technologies. In a way, what we are doing is we are knocking down donor targets very specifically in a cell, in the same way as an antisense oligo, RNAi, or even CRISPR.

But we’re doing it with a small molecule. So, we don’t have any of the issues that come with distribution and delivery. We get systemic coverage with this drug because it’s an oral small molecule, whereas all these other knockdowns get sequestered in the liver. Also, you have to take an injection or IV. You have issues with how systemic they truly are. That juxtaposition of the small molecule approach and knockdown technology got these pharma companies very excited and interested in protein degradation. These deals came to us.

We probably wouldn’t do similar deals going forward because if they’re really our focus and enabling their pipeline, we get milestones and royalties as things progress, which is a factor, but we’re not building our pipeline. But any deal we do going forward will probably have elements of building our pipeline as well.

GEN Edge: What has been the FDA’s take on PROTACs?

Houston: We’ve got three drugs that the FDA has allowed to move forward. What they look at is the complete package we provide, which is an extensive safety package when we get to that stage. They know it’s a small molecule and not a biologic or a knockdown technology.

I think the novelty is that we’re hijacking a cellular process, but you could argue that an inhibitor is doing the same thing. But we’re doing this with a more natural process of hijacking a system that goes to the proteasome. I think the questions we got from the FDA were related to all the things you’d expect for a small molecule but nothing that indicated any concern they have for a novel modality.

GEN Edge: How does Arvinas remain an independent company?

Houston: We recently announced our expansion into a new building that’s going to go up in downtown New Haven. That’s a statement of intent by us. We are outgrowing and stripping the place we were at. We started there on half a floor with ten people. We now take over nearly two buildings on that site with over 110 people. The idea is to move by 2024 into this new space and continue to build. It’s very difficult to build an organization with the view that somewhere you’re going to draw a line, build to this stage, and stop. That’s not our game plan.

The team and the people we’re recruiting have a lot of experience in taking drugs through to the market and who really want to do that. We know that the technology works, that we can generate our own pipeline, and that if we want to strategically partner at some point, we can do that and accelerate our growth even further.

GEN Edge: What is the competition like in the protein degradation space?

Houston: We were the very first ones out there in 2013 in the protein degradation space. Now, there are maybe 20–25 small companies working on some version of protein degradation, and the big pharma companies have a protein degradation focus as well. The exciting part of that means that protein degradation is ready for prime time. The biotech industry and the big pharma companies are on board. Being a leader at the beginning has been exciting and challenging.

Being the first in the space was great because, I think from 2011–2015, there was no other company doing this. We were able to lead on a lot of the original IP based on the platform and the different approaches.

Our focus is freedom to operate. As long as we’ve got freedom to operate, we’re quite happy to compete with people. We are pretty happy with our IP position because we were the first there. We were able to lay IP down before anyone.

I’ll be happy if patients are benefiting. The exciting thing for us and our scientists is that we’ve got patients on a trial that have all progressed on their current therapy. It’s gratifying to see those responses. We emerged from having just an exciting platform approach and preclinical experimentation to now working with patients and extending the lives. That’s incredibly gratifying.

GEN Edge: Finally, what is the meaning behind the name “Arvinas”?

Houston: There were two platforms that Craig was interested in when he started the company. One was protein degradation, but he was also excited in another technology that was more a lipid-based tagging approach. He thought that would be the winner. Craig called the name after the Latin word for “fat,” which is “arvini.” He took the plural of it, “arvinas,” which means “fatties.” So, we are the fatties!