Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males.
BACKGROUND
TAK-385 is a highly selective, oral, nonpeptide GnRH antagonist being investigated as a possible prostate cancer treatment.


OBJECTIVE
The objectives were to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-385 on LH and testosterone.


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


METHODS
Part 1, single doses of TAK-385 (0 [placebo], 80, 120, 180, or 360 mg). Part 2, 14-day TAK-385 (0, 20, 40, 80, or 180 mg) daily. Part 3, 28-day TAK-385 (40 [with loading dose], 60, 80, or 160 mg) or placebo daily. Parts 2 and 3 included men aged 40-75 years.


METHODS
Main outcome measures included plasma concentrations of TAK-385, LH, and testosterone.


RESULTS
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 on day 1 or 360 mg on day 1 followed by 240 mg on day 2 reduced the time to achieve castrate testosterone levels from ≥ 7 to <3 days. TAK-385 doses ≥ 80 mg/d achieved sustained medical castration and trough TAK-385 concentrations >4 ng/mL. After 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).


CONCLUSIONS
Oral TAK-385 (40-180 mg/d) 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/d.
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited (D.B.M., H.S., H.F.), Cambridge, Massachusetts 02139; and University of Montreal Hospital Center (F.S.), Montreal, Québec, Canada H2X 0A9.
David B
DB
MacLean
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited (D.B.M., H.S., H.F.), Cambridge, Massachusetts 02139; and University of Montreal Hospital Center (F.S.), Montreal, Québec, Canada H2X 0A9.
Hongliang
H
Shi
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited (D.B.M., H.S., H.F.), Cambridge, Massachusetts 02139; and University of Montreal Hospital Center (F.S.), Montreal, Québec, Canada H2X 0A9.
Hélène M
HM
Faessel
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited (D.B.M., H.S., H.F.), Cambridge, Massachusetts 02139; and University of Montreal Hospital Center (F.S.), Montreal, Québec, Canada H2X 0A9.
Fred
F
Saad
D000328:Adult; D000368:Aged; D002369:Castration / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018565:Food-Drug Interactions; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011744:Pyrimidinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013739:Testosterone / Q000097:blood; D016896:Treatment Outcome; D055815:Young Adult
D010671:Phenylurea Compounds; D011744:Pyrimidinones; C561634:relugolix; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone