Safety and Testosterone-Lowering Effects of the Investigational, Oral, GnRH Antagonist, TAK-385 in Healthy Male Volunteers: Results of a Phase 1 Inpatient/Outpatient Study

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 292-325-Breast & Prostate Cancer
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-318
David Burton MacLean*1, Hongliang Shi1, Ajit Suri1, Helene Faessel1 and Fred Saad2
1Millennium Pharmaceuticals, Inc., Cambridge, MA, 2University of Montreal, Montreal, QC, Canada
Introduction and objective: TAK-385 is an investigational, highly-selective, oral, non-peptide gonadotropin-releasing hormone (GnRH) antagonist with an in vitro IC50 of 0.12 nM for the human GnRH receptor. This randomized, double-blind, placebo-controlled phase 1 inpatient/outpatient study (in 4 parts), evaluated the safety, tolerability, pharmacokinetic (PK) profile, and pharmacodynamic (PD) effects of testosterone (T) lowering of TAK-385 in healthy male volunteers to identify dose(s) for further phase 2 studies in men with prostate cancer.

Methods: In part 1, 32 healthy adult men <50 years of age with normal serum T levels (>8.67 nmol/L [>250 ng/dL]), received a single dose of TAK-385 at 80, 120, 180, or 360 mg (6 TAK-385 pts and 2 placebo per dose cohort). In part 2, 40 healthy adult men >40 years of age with serum T levels >6.94 nmol/L (>200 ng/dL) received TAK-385 for 14 days at 20 (2 cohorts), 40, 80, or 180 mg daily (6 TAK-385, 2 placebo per dose cohort). Healthy men in the 20 mg and 40 mg cohorts received various loading dose regimens of TAK-385 (160–360 mg on days 1–3). In parts 3 and 4, an additional 104 healthy men, age >40 years (outpatients, in cohorts n=14–22/dose level), received 40, 60, 80 or 160 mg daily of TAK-385 or placebo for 28 days. Assessments included safety, PK (TAK-385), and PD (T; assessed via LC/MS and luteinizing hormone [LH]). 

Results:In parts 1–4, TAK-385 was administered at doses up to 360 mg. In part 1, 3 (9%) healthy men experienced drug-related adverse events (AE) of erectile dysfunction, urticaria papular, and hot flush (each n=1). In part 2, 18 (60%) healthy men experienced a mild or moderate drug-related AE; most frequent were headache and hot flush (each n=7; 23%). In all men, TAK-385 administration resulted in a decline in mean serum T and LH levels within 6 hours of drug administration. In the 14-day multidose cohorts (part 2), loading dose(s) of TAK-385 reduced the time to T castrate levels from 7 to 2 days, but did not reduce the dose required for sustained medical castration (0.69 nmol/L [20 ng/dL]), as observed at doses ≥40 mg during days 7–14. In the 28-day part 3 and 4 outpatient cohorts, almost all AEs were of mild in intensity or otherwise related to mechanism of action.  TAK-385 at 80 mg and 160 mg/day was associated with sustained castration levels of testosterone between days 15–28. Recovery was complete in most men within 28 days after cessation of dosing.

Conclusions: TAK-385 seems to be generally well-tolerated, rapidly achieves T lowering to below castrate levels in healthy male volunteers, and warrants further investigation in men with prostate cancer as a potential therapeutic alternative to injectable GnRH-directed androgen deprivation therapies.

Disclosure: DBM: Employee, Millennium Pharmaceuticals, Inc.. HS: Employee, Millennium Pharmaceuticals, Inc.. AS: Employee, Millennium Pharmaceuticals, Inc.. HF: Employee, Millennium Pharmaceuticals, Inc.. FS: Investigator, Millennium Pharmaceuticals, Inc..

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: Funded by Millennium Pharmaceuticals, Inc.