Kisspeptin-54, an endogenous naturally occurring ligand of the G protein-coupled receptor-54, stimulates GnRH-gonadotropin secretion and suppresses metastases in animal models of cancer but is subject to rapid degradation and inactivation. TAK-448 is an investigational oligopeptide analog of the fully active 10-amino acid C terminus of kisspeptin-54. This phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of TAK-448 in healthy subjects and patients with prostate cancer (PC).

Healthy subjects aged 50 years or older received TAK-448 sc as a single-bolus or 2-hour infusion (0.01–6 mg/d; part A) and as a 14-day sc administration (0.01–1 mg/d; part B). In a subsequent, open-label, phase 1 study in PC patients aged 40–78 years, TAK-448 was given as a 1-month depot formulation.

Eighty-two healthy subjects received TAK-448; 30 received placebo. Grades 1–2 adverse events were reported in 26% of subjects during TAK-448 treatment. All dosing regimens resulted in dose-proportional exposures. The maximum observed plasma concentration occurred after 0.25–0.5 hours, and median terminal elimination half-life was 1.4–5.3 hours. T increased approximately 1.3- to 2-fold by 48 hours after a single bolus or 2 hour injections, whereas during the 14-day infusion, at doses above 0.1 mg/d, T dropped to below-baseline values by 60 hours and reached a subsequently sustained below-castration level by day 8. In PC patients, T decreased to less than 20 ng/dL in four of five patients dosed with 12 or 24 mg TAK-448 sc-depot injections. The prostate-specific antigen decreased greater than 50% in all patients dosed with 24 mg.

Continuous TAK-448 infusion was well tolerated by healthy males and resulted in sustained T suppression. Depot injection in patients with PC similarly reduced T and resulted in prostate-specific antigen responses.