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

BACKGROUND: SAGE-217, a novel γ-aminobutyric acid A (GABA(A)) 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 t(max) 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 t(max), 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40262-019-00801-0) contains supplementary material, which is available to authorized users.