On March 25, 2019 Arvinas, Inc. (Nasdaq: ARVN), a biopharmaceutical company creating a new class of therapies that degrade disease-causing proteins, reported the initiation of patient dosing in its Phase 1 clinical trial of ARV-110, the company’s oral androgen receptor (AR)-targeted PROTAC protein degrader (Press release, Arvinas, MAR 25, 2019, View Source [SID1234534600]). The study will evaluate the safety, tolerability, and pharmacokinetics of ARV-110 in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on standard of care therapies. Arvinas believes ARV-110 is the first in a new class of targeted protein degraders to enter human clinical trials and anticipates preliminary data from the study in the second half of 2019.
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"With ARV-110 we are harnessing the body’s natural protein disposal system to degrade AR, a key contributor to the progression of prostate cancer," said John Houston, Ph.D., President and CEO of Arvinas. "Given the promising results seen in preclinical studies, it is our hope that ARV-110 will overcome known mechanisms of resistance to standard of care agents and offer a new treatment option for patients. We believe this is the first time a patient has been treated with this new class of targeted protein degraders and we look forward to furthering our understanding of ARV-110 as a potential treatment for men with mCRPC and the broader field of protein degradation."
The Phase 1 open-label, dose-escalation clinical trial will assess the safety, tolerability, and pharmacokinetics of ARV-110 and is expected to enroll approximately 28-36 patients with progressive mCRPC. In addition, the study will evaluate the biochemical and clinical activity of ARV-110, by assessing prostate specific antigen (PSA) levels, AR degradation, radiographic measurements of evaluable lesions, and other exploratory markers of disease burden. Additional information on this clinical trial can be found on www.clinicaltrials.gov.
About Metastatic Castration-Resistant Prostate Cancer (mCRPC)
In the United States, prostate cancer is both the second most prevalent cancer in men and the second leading cause of cancer death in men. The American Cancer Society predicts that one in nine men will be diagnosed with prostate cancer in his lifetime. Metastatic castration-resistant prostate cancer (mCRPC) is defined by disease progression despite androgen deprivation therapy and is often correlated with rising levels of prostate-specific antigen (PSA).
Current AR-targeted standard of care treatments for mCRPC are less effective in patients whose disease has increased levels of androgen production, AR gene or gene enhancer amplification, or AR point mutations. Up to 25% of patients do not respond to second-generation hormone therapies like abiraterone and enzalutamide, and the vast majority of responsive patients will ultimately become resistant, resulting in poor prognoses for men diagnosed with this devastating condition.
About PROTAC (Proteolysis-Targeting Chimera) Protein Degraders
Arvinas’ PROTAC protein degraders harness the body’s own natural protein recycling system to degrade disease-causing proteins. PROTAC protein degraders recruit an E3 ligase to tag the target protein with ubiquitin, which directs its degradation through the proteasome, a large protein complex that breaks down the ubiquitinated target protein into small peptides and amino acids. As the target protein is degraded, the PROTAC protein degrader is released and acts iteratively to destroy additional target protein.
PROTAC protein degraders offer numerous potential advantages as a therapeutic, including broad tissue distribution, routes of administration that include oral delivery, and simpler manufacturing than other new modalities, such as cell-based therapies. Arvinas has developed and optimized a proprietary library of protein targeting ligands, E3 ligase ligands, and linkers, which allow the company to rapidly identify and optimize efficient protein degraders with favorable characteristics for successful drug development.
About ARV-110
ARV-110 is an orally bioavailable PROTAC protein degrader designed to selectively target and degrade the AR. ARV-110 is being developed as a potential treatment for men with mCRPC. ARV-110 has demonstrated activity in preclinical models of AR mutation or overexpression, both common mechanisms of resistance to currently available AR-targeted therapies. Arvinas believes the differentiated pharmacology of ARV-110, including its iterative activity, has the potential to translate into improved clinical outcomes for patients.