The U.S. Food and Drug Administration has signed off on Arvinas‘ first Phase 1 clinical trial to evaluate ARV-110 as a therapy for patients with metastatic castration-resistant prostate cancer (mCRPC).
The trial, scheduled to begin by April, will investigate the safety and tolerability of ARV-110 in mCRPC patients whose disease progressed after being treated with a minimum of two standard of care therapies.
Medicines that target the androgen receptor, such as Zytiga (abiraterone) and Xtandi (enzalutamide), are widely used for the treatment of advanced prostate cancer. But as happens with many medications, tumors often develop a resistance to these therapies.
In some cases, resistance develops when cells produce a variant of the androgen receptor, called AR-V7, that lacks the domain targeted by current androgen receptor inhibitors. In other cases, cancer cells overproduce the androgen receptor.
Either way, degrading this receptor seems like a promising approach for treating these cancers, and Arvinas set out to do just that. Using their PROTAC protein degradation platform — which tags disease-causing proteins for degradation — the company developed ARV-110.
This compound delivers small molecules to the androgen receptor that function as flags for the cells’ natural protein degrading system. This allows for effective degradation of this receptor.
In preclinical studies, ARV-110 reduced androgen receptor levels by 95-98% in several prostate cancer cell lines. Additionally, in a mouse model of prostate cancer, ARV-110 inhibited tumor growth by up to 100%.
While these cancer cells had not yet been exposed to androgen receptor inhibitors, a study in mice implanted with prostate cancer cells from a patient with acquired resistance to Xtandi, also showed that ARV-110 reduced tumor growth by up to 70%.
“Our PROTAC platform has demonstrated exciting promise in preclinical studies and represents an entirely new approach to treating patients with mCRPC and many other diseases,” John Houston, PhD, president and CEO of Arvinas, said in a press release.
“This [investigational new drug] clearance is a key step forward for Arvinas and for the field of protein degradation,” he added. “We hope ARV-110 will deliver a much-needed new therapeutic option for patients, and we expect to dose our first patient in the first quarter of 2019.”