The Investigational Kisspeptin/GPR54 Agonist Peptide Analog, TAK-448, Given as Single-Dose Then 13-Day Continuous Subcutaneous Infusion, Stimulates Then Suppresses the LH-Testosterone Axis in Healthy Male Volunteers

Introduction and objective: TAK-448 is an oligopeptide analog of metastin/kisspeptin–the endogenous, 54-amino acid GPR54 receptor ligand. Although KiSS-1, encoding kisspeptin, was originally known as a metastasis suppressor, the precise role of the GPR54 system in tumor biology remains unclear. However, hypothalamic kisspeptin/GPR54 signaling is a key regulator of GnRH release and reproductive function. In animals, acute TAK-448 administration stimulated LH/FSH release, and continuous subcutaneous exposure rapidly downregulated the pituitary-gonadal axis. In phase 1, TAK-448 stimulated pituitary gonadotropin release following single SC bolus at 0.001–6 mg doses. In this randomized double-blind placebo-controlled phase 1 study, safety, pharmacodynamics, and pharmacokinetics of continuous SC infusion for 2 weeks were further evaluated.

Methods: Healthy male volunteers aged ≥50 y received TAK-448 as a single SC bolus (0.1 mg) on D1, followed by continuous SC infusions on D2–14 at 0.01, 0.1, 0.3 or 1 mg/day (n=5–6 per group), or placebo (n=7). Gonadotropins were measured by conventional RIA and testosterone by LC/MS with an LLQ of 2 ng/dL.

Results: 30 men (97% white, aged 50–78 y) were treated. All adverse events (AEs) reported during TAK-448 treatment were mild or moderate (grade 1/2) and none led to discontinuation; the most common AEs were hot flashes (n=5), postural dizziness (3), orthostatic hypotension (2), headache (2), diarrhea (2), and injection-site reactions (2). Two placebo patients had AEs. In men receiving TAK-448, after a 12-hr surge in gonadotropins and a slight increase in testosterone, serum testosterone declined to below baseline values, reached nadir by day 8, and remained low throughout the infusion period. The lowest continuous infusion dose of 0.01 mg/24hr was associated with incomplete testosterone suppression; in all other dose groups, most day 8–14 values were <1.7 nmol/L (50 ng/dL) and a majority were <0.7 nmol/L (20 ng/dL). All values returned to the normal range by 2 weeks following infusion discontinuation. No significant changes in other pituitary hormones or DHEA-S were observed in men receiving TAK-448 and no significant hormone changes occurred in men receiving placebo. TAK-448 plasma concentrations remained nearly constant throughout the infusion period, with average concentrations ~228 (±38) pg/ml at the lowest fully effective dose of 0.1 mg/24hr. Mean plasma concentrations increased in a dose-proportional fashion.

Conclusions: Continuous SC infusion of TAK-448 0.01–1mg/day was well tolerated by healthy male volunteers and, at 0.1–1mg/day, rapidly induced below-castration levels of testosterone, presumably by inhibition/depletion of hypothalamic GnRH. Further evaluation will be required to show whether this novel GPR-54-mediated mechanism for medical castration has additional advantages relative to GnRH analogs.