ARN-509 Clinical Program
ARN-509 is a novel 2nd Generation anti-androgen that is targeted to treat castration resistant prostate cancers where 1st generation anti-androgens fail.
Prostate cancer is the second most common cause of cancer death in men in the US. Approximately one in every six American men will be diagnosed with the disease during his lifetime and approximately 29,000 men die annually from the disease in the US. Treatment aimed at eradicating the tumor, typically surgery or radiation, is unsuccessful in 30% of men, who develop recurrent disease that usually manifest first as a rise in plasma prostate-specific antigen (PSA), followed by spread to distant sites.
Because prostate cancer cells depend on the androgen receptor (AR) for their proliferation and survival, men with prostate cancer are treated with agents that block the production of testosterone (eg, GnRH agonists), alone or in combination with anti-androgens (eg, bicalutamide), which antagonize the effect of any residual testosterone. The approach is effective as evidenced by a drop in PSA and the regression of visible tumors. Eventually, however, this is followed by regrowth referred to as castration-resistant prostate cancer (CRPC), to which most patients eventually succumb.
Studies by Aragon founder and advisor Charles Sawyers (MSKCC) have demonstrated that CRPC continues to depend on AR signaling and that a key mechanism of castration resistance is elevated AR levels. Sawyers, in collaboration with Michael Jung (UCLA; Aragon founder), devised a screen for compounds with anti-androgenic activity in CRPC, using prostate cancer cells rendered castration resistant via AR over-expression. The Sawyers and Jung screen yielded the fully-optimized compound ARN-509, Aragon’s lead drug candidate, which exhibits robust activity in mouse models of CRPC.
ARN-509 is unique in its action in that it inhibits both AR nuclear translocation and AR binding to androgen response elements in DNA. Importantly, and in contrast to the first-generation anti-androgen bicalutamide, it exhibits no agonist activity in prostate cancer cells that over-express AR. ARN-509 is easily synthesized, and its oral bioavailability and long half-life allow for once-daily oral dosing. In addition, its excellent preclinical safety profile makes it well suited as either a mono- or a combination therapy across the entire spectrum of prostate cancer disease states.
ARN-509 is currently in the Phase II portion of a Phase I/II clinical trial being conducted at Memorial Sloan-Kettering Cancer Center in New York as well as 15 other institutions across the US. The open-label, study will determine the anti-tumor activity, safety and tolerability in patients with advanced castration-resistant prostate cancer.