Medical Castration using the Investigational Oral GnRH antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males.

TAK-385 is a highly-selective, oral, non-peptide gonadotropin-releasing hormone antagonist being investigated as a possible prostate cancer treatment.

Evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-385 on luteinizing hormone and testosterone.

A three-part, randomized, double-blind, placebo-controlled, phase 1 dose-escalation study in 176 healthy male UK volunteers.

Part 1, single doses of TAK-385 (0 [placebo], 80, 120, 180, or 360 mg); Part 2, 14-day TAK-385 (40, 80, or 180 mg) daily; Part 3, 28-day TAK-385 or placebo (40 [with loading dose], 60, 80, or 160 mg) daily. Parts 2 and 3 included men aged 40-70 years.

Plasma concentrations of TAK-385, luteinizing hormone, and testosterone.

Oral TAK-385 was readily absorbed, and steady-state was reached in ≤14 days. Food reduced TAK-385 systemic exposure by 47%-52%. Mean serum testosterone levels declined ≤6 hours after TAK-385 administration. Loading doses up to 360 mg day 1, or 360 mg day 1 followed by 240 mg day 2 reduced the time to achieve castrate testosterone levels from ≥7 to 4 ng/mL. Following discontinuation of TAK-385 on day 28, testosterone levels normalized in most subjects in ≤28 days. Common adverse events included bradycardia, headache, and hot flush (all grade ≤2).

Oral TAK-385 (40-180 mg/day) was well tolerated and effectively lowered testosterone in healthy men. Planned phase 2 doses in men with hormone sensitive prostate cancer are 80 and 120 mg/day.

The Journal of clinical endocrinology and metabolism. 2015 Oct 26 [Epub ahead of print]

David B MacLean, Hongliang Shi, Helene Faessel, Fred Saad

Millennium Pharmaceuticals, Inc. , Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. , Millennium Pharmaceuticals, Inc. , Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. , Millennium Pharmaceuticals, Inc. , Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. , Millennium Pharmaceuticals, Inc. , Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

PubMed