GnRH Receptor Antagonist Mono- And Combination Therapy With E2/NETA Add-Back - Pharmacodynamics And Safety Of OBE2109.

GnRH Receptor Antagonist Mono- And Combination Therapy With E2/NETA Add-Back - Pharmacodynamics And Safety Of OBE2109.

J Clin Endocrinol Metab. 2017 Dec 04;:

Authors: Pohl O, Marchand L, Fawkes N, Gotteland JP, Loumaye E

Abstract
Context: OBE2109 is a novel, potent, oral gonadotropin-releasing hormone receptor antagonist being developed for the treatment of sex-hormone-dependent diseases in women.
Objective: We assessed the pharmacodynamics and safety of OBE2109 alone and combined with estradiol(E2)/norethindrone acetate(NETA) add-back therapy on E2 levels and vaginal bleeding.
Design, Setting, and Participants: This was a single-center, open-label, randomized, parallel-group study in 76 healthy premenopausal women with regular menstrual cycles.
Interventions: Menstrual cycles were synchronized administering NETA and women were subsequently randomized to OBE2109(100mg), OBE2109/E2/NETA(100mg/0.5mg/0.1mg), OBE2109/E2/NETA(100mg/1mg/0.5mg), OBE2109(200mg) or OBE2109/E2/NETA(200mg/1mg/0.5mg) once daily for 6 weeks.
Main Outcome Measures: E2 concentrations, bleeding pattern, exploratory bone metabolism biomarkers and adverse events.
Results: OBE2109 100mg and 200mg alone rapidly reduced E2 levels to reach a median level at week 4 of 19.5pg/mL and 3.2pg/mL, respectively. Median E2 levels after combined OBE2109/add-back therapy ranged between 25 and 40pg/mL. OBE2109 100mg or 200mg alone promptly induced amenorrhea. By day 15, >85% of subjects had no vaginal bleeding during the last 4 weeks of treatment. Add-back therapy partially impaired bleeding control: The highest amenorrhea rate (53%) was observed in the OBE2109 100mg combined with the E2/NETA(1mg/0.5mg) dose. The addition of E2/NETA, in particular at 1mg/0.5mg, mitigated the increase of bone markers C-terminal-telopeptide and deoxypyridinoline/creatinine ratio induced by OBE2109 200mg. The most frequently reported adverse events were headache and hot flush.
Conclusions: OBE2109 promptly lowers E2 levels, add-back may be required to prevent adverse bone impact in subjects treated at 200mg and in some subjects at 100mg. Our results provide a basis for OBE2109 regimen selection to treat sex-hormone-dependent diseases.

PMID: 29216361 [PubMed - as supplied by publisher]

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