Protein Degradation: Shifting the Paradigm of Resistance and Undruggables for Unmet Medical Needs in Cancer, Neuroscience, and Beyond

INNOVATION THAT MATTERS

By Rich Soll, Senior Advisor, Strategic Initiatives at WuXi AppTec (@richsollwx)

With a recent $120 million IPO, a $55 million Series C, and a Pfizer R&D deal potentially worth $830 million, Arvinas is poised to transform the “undruggable” landscape, giving patients and healthcare providers new hope.

Arvinas is doing this by developing a new class of drugs that engage the body’s own natural protein disposal system to treat cancers and other difficult-to-treat diseases. The Yale University spin-out is working on an androgen receptor degrader program, ARV-110, for patients with metastatic castrate-resistant prostate cancer, and an estrogen receptor degrader program, ARV-471, for patients with metastatic ER-positive breast cancer. The company will use a portion of its IPO funds to carry these assets into the clinic. The remaining money will go toward expanding its protein degradation platform and conducting preclinical work for its earlier-stage programs.

The biotech’s drugs are based on its PROTAC^TM (proteolysis targeting chimera) platform, which was born in Craig Crews’ lab at Yale University. PROTACs work by recruiting an enzyme – called an E3 ligase – to tag disease-causing proteins with ubiquitin, which leads to degradation via the body’s existing protein disposal system.

Most current drugs are small molecules designed to modulate a function of a protein and require high affinity to their targets and occupancy, are subject to resistance, and have difficulty addressing protein-protein interactions. In contrast, PROTACs – which are also small molecules – engage the cell’s own protein degradation machinery to destroy targeted proteins by tagging them for removal, and a single molecule can do so multiple times, so PROTACs can work at lower doses. Thus, a new drug modality is born that can target many disease-causing proteins that are not accessible to existing modalities.

At the helm of Arvinas is John Houston, who joined the company in 2017 after spending over two decades in the pharma industry with giants like Bristol Myers Squibb and Glaxo Welcome Research and Development in the UK. I recently caught up with Houston, who shared the company’s strategy in moving from a discovery platform to a clinical organization, the possibilities for Arvinas’ transformative platform, as well as his passion for small biotechs.

Rich Soll: The first thing I want to do is congratulate you on your recent IPO. Earlier this year you also raised a Series C, so you are in a strong financial position looking forward.

John Houston: That’s right. It’s been a busy year, going out on the road, telling our story, and launching our IPO from a position of strength, both financially and in terms of our pipeline.

Rich Soll: Arvinas is a great story; the technology really transcends the boundaries of small molecules. How are you capitalizing on it?

John Houston: Arvinas’ drugs are based on its PROTAC platform, which grew out of the work of Professor Craig Crews’ lab at Yale University, whose focus over a 15 year period was on protein homeostasis and the processes by which cells dispose of normal proteins as well as dysfunctional or mutated proteins. While conducting studies directed towards proteasome inhibition for treatment of cancer, Craig was intrigued with the idea of selectively hijacking protein degradation and came up with the idea of PROTACs. These are small molecules, wherein one end targets the protein of interest and the other end brings the E3 ligase machinery in contact with the protein of interest. In this way, Craig was successful in targeting specific proteins to be degraded.

The company was founded in 2013 with an initial focus on oncology, although the platform is disease-agnostic. Since then, we’ve been building small molecule PROTACs that target specific disease-causing proteins that we want to degrade. We are also looking at other disease areas where we can deploy the technology. The last five years for the company have been spectacular in terms of advancing the platform, building the organization, and getting to the point where we have two lead programs that are heading towards the clinic.

Rich Soll: You’re specifically looking at the androgen receptor and the estrogen receptor in prostate cancer and in breast cancer, respectively.

John Houston: There are two or three different reasons that Craig and Arvinas landed on androgen receptor and estrogen receptor. By virtue of the small molecule PROTAC mechanism, all one needs is binding of a molecule to anywhere on a protein, and even a weak binder can bring the protein of interest into proximity to the ligase machinery. Craig realized that the technology would lend itself nicely to a very productive and fruitful way of dealing with undruggable targets, because finding a potent active site inhibitor has been really difficult for those proteins. So that was the original idea.

Craig then stepped back and thought that taking a very novel modality and applying it to very novel biology may be a tough road. But he realized that the technology would also work in settings where there drug resistance arises by overproduction or mutation of known disease-causing proteins, and thus degrading those proteins would have clinical benefit for patients. He felt that such an opportunity existed with androgen receptor in the prostate cancer space and estrogen receptor in the breast cancer space.

In prostate cancer, tumors develop resistance to drug therapy by producing more androgen in the tumor or mutating the androgen receptor or enhancing some aspect of androgen gene expression; all those mechanisms overcome the currently marketed inhibitors. With a degrader, you’re not just inhibiting the receptor; you are binding and dragging in the ligase machinery and achieving a different outcome. In preclinical settings, we’re finding that our PROTACs work in models where there’s overproduction of androgen, a mutated androgen receptor, or overexpression of androgen receptor. We are very excited by our preclinical data; if it translates into the clinic, we should have compounds that address resistance.

The positioning for breast cancer was different. There is an existing drug, fulvestrant, that degrades the estrogen receptor (though by a different mechanism) and works in metastatic breast cancer, so our positioning had to be different. However, fulvestrant is given intramuscularly and degrades only 50% of the receptor in tumors, so we have an opportunity for both better potency and for oral bioavailability. I believe we have done that – the profile of our ER PROTAC looks better than fulvestrant and other SERDs that have tested against in preclinical models, thereby potentially addressing a significant unmet medical need in breast cancer.

Rich Soll: It’s powerful technology. How do you prioritize your targets and prioritize the pipeline, especially as you start to branch out into other therapeutic areas?

John Houston: It’s a great question, and for a big part of this year, we’ve been reviewing our pipeline, including the oncology component, which is the most robust. Included in our pipeline are “Holy Grail” undruggable targets that will be included our next wave of oncology targets (behind our AR and ER PROTACs). So, we’re excited, and we feel validated by the external interest we have for that part of the pipeline.

More challenging are decisions outside oncology. We have been looking at neuroscience and neurodegeneration, because two years ago we did a crazy experiment to see whether or not we could degrade tau after direct injection of a PROTAC into a mouse brain. Since then, our chemistry and biology teams have been working to show that you can make PROTACs, which are slightly larger than traditional small molecules, cross the blood-brain barrier. In the last two years, the team has developed design rules for brain-penetrant PROTACs, and that allows us to look at neuroscience in a significantly new way. The two targets we have disclosed are tau and alpha-synuclein, and we have additional targets behind that. Neuroscience will probably be our next opportunity, and we are developing our strategy in this area.

Rich Soll: Your technology is clearly a major benefit – you can choose many kinds of targets, you don’t need functional activity, and you only need a binder in order to get near the degrading machinery. The whole process can go faster at the end of the day, right?

John Houston: Yes, we can get to degraders rapidly. You only need a molecule that binds, even weakly. Craig Crews has shown some remarkable data that with a micromolar binder, we can get a nanomolar degrader. It is that aspect that makes us believe we can address undruggable targets.

Rich Soll: Have you looked at these weak binders in vivo?

John Houston: We have only looked in vitro to date, but we plan to progress to in vivo soon. You bring out a good point, however. There is a PK/PD disconnect that is really interesting. PROTACs have a catalytic or iterative interaction with their targets, i.e., one PROTAC can degrade many copies of the target molecule, much like the activity of an enzyme. So, the PROTACs are released after target ubiquitylation and go to the next available protein. We have done an experiment showing that after a single oral dose of ARV-110, the androgen receptor is still significantly reduced in the tumor after 7 days. The PROTAC is gone from the plasma after about a day, but the PD lasts for several days. That is pretty remarkable.

Rich Soll: With this technology, we have a fundamental shift in paradigm because you can choose many different targets, you do not need a ligand with bioactivity (only binding), the ligand does not need to be optimally tuned to the target, and the drug acts iteratively. The whole process can go faster.

John Houston: Yes, we can get to lead optimization much faster, where we optimize for the whole molecule and not just the ligand. You do see different features of PROTACs depending on their optimization. Over the last five years, our programs’ initiation and lead optimization are becoming faster as we’ve learned the “ins and outs” of the platform.

Rich Soll: What do you consider most differentiating for this technology platform?

John Houston: As I noted earlier, in the cases of AR and ER, we can address drug resistance that arises via increased receptor expression, by mutations in the receptor, or (for AR) overexpression of androgen. We look better than the current standards of care for patients with both prostate cancer and breast cancer. Most strikingly, with ARV-471 in combination with a cdk4/6 inhibitor in our ER+ breast cancer models, we get profound degradation of the target and corresponding shrinkage of tumors.

Rich Soll: Arvinas has partnered with WuXi to move these programs faster. How has the WuXi partnership enabled Arvinas?

John Houston: I don’t think Arvinas would be at this stage without the partners we have; in particular, WuXi and other great partners in China. The chemistry capabilities have been phenomenal. We have a set of design chemists at Arvinas that design PROTACs and then send out the designs to our partner network. We get compounds back, and with great quality, and we have also done some PK work at WuXi. It’s been a phenomenally productive interaction over the last five years, and we wouldn’t be in the position we’re in today without that relationship.

Rich Soll: On the corporate side of the business, what are your objectives?

John Houston: From a corporate perspective, this year was all about raising capital, both from a Series C and our IPO; we now need to continue driving our pipeline forward. For next year, we expect that our AR program will be in the clinic in the first quarter and that our ER program will be in the clinic halfway through the year. Also, we hope to generate clinical data in our AR program by the second half of the year that suggests we are having an effect – specifically, PSA lowering in mCRPC patients.

Those are some of our big goals as we transition from being purely a discovery platform company into a clinical company. That’s all going to happen in 2019. I also want the rest of the pipeline to progress so that we’ll have a portfolio that can generate clinical candidates on a regular basis. So, 2019 will also require ensuring that additional programs are well resourced and progressing in oncology.

We’re also building our neuroscience team. I recruited a leader in neuroscience, and we will be building that team and moving our targets (tau and synuclein in particular) forward. The final pieces will be in other areas that we may decide to enter, and we’ll make those decisions during the year.

Rich Soll: If you take the long-range view, are you going into commercialization?

John Houston: Yes. In our lead program for patients with prostate cancer, we don’t see any reason we couldn’t commercialize. It may be more difficult in other areas, simply because of the complexity of the disease areas and because many will require combination studies. We’re open to looking at partnering, obviously, if that’s the most effective way of getting a drug developed.

Rich Soll: How would you describe where we are as an industry in drug discovery?

John Houston: We’re on the brink of the next wave of innovation, and the next wave of innovation is absolutely coming from small biotechs. It’s really exciting to see. In the past, you saw it with RNAi and CRISPR. I think protein degradation is going to be the next wave.