Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel Na V 1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy Volunteers

Background and Objective Current pain therapies often do not provide adequate pain relief and have dose-limiting adverse effects. Genetic evidence indicates that Na V 1.7 sodium channels are required for pain transduction and therefore represent an important therapeutic target. GDC-0276 is a novel Na V 1.7 inhibitor developed for the treatment of pain. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetics of orally administered GDC-0276 in healthy subjects. Methods This phase I, randomized, double-blind, placebo-controlled study assessed GDC–0276 as powder-in-capsule (PIC) or cyclodextrin solution (CD) single doses (SDs) of 2–270 mg (seven cohorts) and 45–540 mg (five cohorts), respectively. Multiple (MD) PIC doses were administered as total daily doses of 15–540 mg divided into two or three doses/day, up to 10 or 14 days. Safety was assessed by monitoring adverse events (AEs), vital signs, physical examinations, electrocardiograms, and laboratory tests for up to 15 days after the last day of dosing. GDC-0276 plasma pharmacokinetics were also determined. Results Three stages included 183 randomized subjects. GDC-0276 plasma exposure increased with dose level for all stages. Exposure was higher in the SD-CD cohorts compared with the equivalent SD-PIC dose levels. SDs were adequately tolerated up to 270 mg (SD-PIC) and 360 mg (SD-CD). Hypotension limited tolerability in the 540-mg SD-CD cohort. Multiple PIC doses were tolerated up to 270 mg twice daily, however liver transaminase elevations were frequently observed. No deaths or serious AEs occurred. Conclusion GDC-0276 exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for pain.