Dataset Information

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

ABSTRACT: CONTEXT: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. DESIGN, SETTING, AND PARTICIPANTS:This was a three-part, randomized, double-blind, placebo-controlled, phase 1 dose-escalation study in 176 healthy male UK volunteers. INTERVENTIONS: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. MAIN OUTCOME MEASURES: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.

SUBMITTER: MacLean DB

PROVIDER: S-EPMC4667159 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

MacLean David B DB Shi Hongliang H Faessel Hélène M HM Saad Fred F

The Journal of clinical endocrinology and metabolism 20151026 12

<h4>Context</h4>TAK-385 is a highly selective, oral, nonpeptide GnRH antagonist being investigated as a possible prostate cancer treatment.<h4>Objective</h4>The objectives were to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-385 on LH and testosterone.<h4>Design, setting, and participants</h4>This was a three-part, randomized, double-blind, placebo-controlled, phase 1 dose-escalation study in 176 healthy male UK volunteers.<h4>Interventions</h4>Part 1, single dose ...[more]

PMID: 26502357

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Project description:BackgroundRelugolix is a once-daily, oral, nonpeptide, gonadotropin-releasing hormone receptor antagonist. The aim of this study was to evaluate safety of relugolix over 24 weeks in women with endometriosis-associated pain.MethodsThis phase 2, randomized, open-label, parallel-group extension study was conducted in 101 clinics in Japan. Patients (premenopausal females ≥ 20 years) who completed the preceding 12-week relugolix phase 2 study continued to receive relugolix (10 mg, 20 mg, or 40 mg), placebo, or leuprorelin (3.75 mg) for an additional 12 weeks. Relugolix was administered orally once daily, and leuprorelin subcutaneously once every 4 weeks. The primary outcome was safety, including bone mineral density (BMD) and treatment-emergent adverse events (TEAEs). Secondary endpoints included visual analog scale (VAS) scores for endometriosis-associated pain. Analysis sets were defined as all patients who were administered the study drug.ResultsOf 487 randomized patients in the preceding study, 397 enrolled in this extension study and continued to receive placebo (n = 77), relugolix 10 mg (n = 84), relugolix 20 mg (n = 78), relugolix 40 mg (n = 89), or leuprorelin (n = 69). Baseline characteristics were similar between extension study patients and patients in the preceding study. Frequency of TEAEs including metrorrhagia, menorrhagia, and hot flush was similar in the relugolix 40-mg and leuprorelin groups. Mean (SD) change in BMD from baseline at Week 24 was - 0.2 (1.99)% for placebo; - 1.6 (2.34)%, - 2.6 (2.94)%, and - 4.9 (2.91)% for the relugolix 10-mg, 20-mg, and 40-mg groups, respectively; and - 4.4 (2.16)% for leuprorelin. Mean ± SD change from baseline in mean VAS score (mm) for pelvic pain at end of treatment was - 3.2 ± 12.16 for placebo; - 6.8 ± 10.56, - 9.0 ± 11.84, and - 11.9 ± 11.26 for the relugolix 10-mg, 20-mg, and 40-mg groups, respectively; and - 12.7 ± 12.57 for leuprorelin. Estradiol levels decreased with increasing relugolix dose and remained below postmenopausal levels throughout the 24-week relugolix 40-mg treatment period.ConclusionsTreatment with relugolix for 24 weeks was generally well tolerated and demonstrated similar pain reduction to leuprorelin in women with endometriosis. The dose-dependent loss in BMD observed with relugolix treatment was expected due to an induced hypoestrogenic state. Relugolix demonstrated a similar benefit/risk profile to injectable therapy in this phase 2 study. Trial registration NCT01452685 (ClinicalTrials.gov, registered 17/10/2011).

Dataset Information

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

Publications

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

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