Many widely used oncology therapies work by inhibiting cancer-related proteins. But what if we simply destroyed those proteins rather than trying to block their functions? That’s the idea behind the technology developed by Arvinas, which just offered a glimpse at first-in-human data for its lead product candidate.
Two patients with metastatic castration-resistant prostate cancer (mCRPC) in a phase 1/2 trial experienced blood prostate-specific antigen (PSA) reduction of at least 50% after being treated with Arvinas’ protein degrader ARV-110, the biotech unveiled at the American Society of Clinical Oncology (ASCO) virtual conference. One of the patients also had an unconfirmed partial tumor response at the point of data cutoff. The PSA test is used to detect prostate cancer and to gauge whether treatments are working.
The response is encouraging because both patients had previously tried almost all available treatments, including mainstay anti-androgen drugs such as Pfizer’s Xtandi and Johnson & Johnson’s Zytiga, as well as chemotherapy and Bayer’s radiation therapy Xofigo, Arvinas' chief medical officer Ron Peck told FierceBiotechResearch.
ARV-110 is the lead candidate from Arvinas’ proteolysis-targeting chimera (PROTAC) platform. It capitalizes on the natural mechanism human cells use to dispose of unneeded or damaged proteins. In this process, a protein called E3 ubiquitin ligase tags target proteins with a molecule called ubiquitin for degradation by proteasomes. A PROTAC small-molecule drug contains one region that binds to a disease-causing protein, and another that binds to E3 ubiquitin ligase. The two parts are joined by a linker that’s critical to the drug’s function.
For ARV-110, the target protein is the androgen receptor, which is the main driver of mCRPC. It’s targeted by multiple existing drugs to designed to prevent the hormone from driving tumor growth.
Arvinas' approach offers several advantages over traditional protein inhibitors, the company contends. First, PROTAC doesn’t require the identification of a “functional pocket” on a protein’s surface for binding. “That opens up the door for using PROTACs to hit non-druggable targets, which are estimated to be about 80% of all disease-causing proteins,” Peck explained.
Secondly, it’s highly specific. In preclinical models, including mice, ARV-110 degraded the androgen receptor by almost 95%, according to Peck.
What’s more, while traditional inhibitors have a 1:1 ratio between the drug and the inhibitor, a PROTAC drug has what Peck called a “catalytic” function, meaning one PROTAC can go through the degradation cycle for 200 targets. That could translate into high potentcy, he said.
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Arvinas’ technology has attracted the attention of several Big Pharma companies. The company, a 2015 FierceBiotech’s Fierce 15 winner, has teamed up with Roche’s Genentech in an expanded deal worth up to $650 million. Pfizer signed the New Haven, Connecticut-based biotech for the discovery and development of PROTACs across multiple disease areas for up to $830 million. Bayer recently tapped the PROTAC platform not just for human diseases but also for agricultural products.
Overall, ARV-110 has shown an acceptable safety profile to date. Investigators in the phase 1/2 trial did notice serious abnormal liver enzyme levels in two patients who were also taking the cholesterol drug Crestor. Therefore, concurrent use of Crestor with ARV-110 is now prohibited. Peck said that there was no “uniform consistency in potential for interactions” with other statins.
Peck is confident the early results from the trial support a dose escalation as the research moves forward, he said.