SAGE-217, A Novel GABA_A Receptor Positive Allosteric Modulator: Clinical Pharmacology and Tolerability in Randomized Phase I Dose-Finding Studies.

Hoffmann, Ethan; Nomikos, George G.; Kaul, Inder; Raines, Shane; Wald, Jeff; Bullock, Amy; Sankoh, Abdul J.; Doherty, James; Kanes, Stephen J.; Colquhoun, Helen

Background: SAGE-217, a novel γ-aminobutyric acid A (GABAA) receptor positive allosteric modulator, was evaluated in phase I, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) studies to assess the safety and pharmacokinetics (PK) of SAGE-217 following administration as an oral solution.Methods: In the SAD study, subjects were randomized 6:2 to a single dose of SAGE-217 or placebo. Doses ranged from 0.25 to 66 mg across nine cohorts. In the MAD study, subjects were randomized 9:3 and received SAGE-217 (15, 30, or 35 mg) or placebo once daily for 7 days. In both studies, PK, maximum tolerated dose (MTD; against predetermined criteria), safety, and tolerability were assessed.Results: A total of 108 healthy volunteers enrolled in the studies-72 subjects in the SAD study and 36 subjects in the MAD study. SAGE-217 was orally bioavailable, with a terminal-phase half-life of 16-23 h and a tmax of approximately 1 h. The MTDs for the oral solution of SAGE-217 in the SAD and MAD studies were determined to be 55 and 30 mg daily, respectively. In both studies, SAGE-217 was generally well tolerated, and no serious adverse events (SAEs) were reported. Most AEs were mild, dose-dependent, transient, occurred around the tmax, and related to drug pharmacology.Conclusions: SAGE-217 was generally well tolerated, and its PK profile was well characterized. Based on this profile, SAGE-217 has been advanced into multiple phase II clinical programs and pivotal studies of major depressive disorder and postpartum depression.

CLINICAL pharmacology; PHARMACOKINETICS; DRUG tolerance; MENTAL depression; POSTPARTUM depression; STEROID drugs; GABA agonists; SAFETY; BIOCHEMISTRY; RESEARCH; HUMAN research subjects; STEROIDS; HETEROCYCLIC compounds; PHARMACOLOGY; ORAL drug administration; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; DRUG administration; PHENOMENOLOGY; PLACEBOS; COMPARATIVE studies; RANDOMIZED controlled trials; BLIND experiment; DOSE-effect relationship in pharmacology; STATISTICAL sampling; PSYCHOLOGICAL factors

Clinical Pharmacokinetics, 2020, Vol 59, Issue 1, p111

0312-5963

Academic Journal

10.1007/s40262-019-00801-0