Objective:

Evaluate the safety and tolerability of single and multiple ascending doses (SAD and MAD) of oral BHV-7000.

Background:

BHV-7000 is a novel, small molecule, selective activator of Kv7.2/7.3 potassium channels, a clinically validated target in epilepsy. In preclinical studies, BHV-7000 showed minimal GABA_A receptor activation and exhibited potent anti-seizure efficacy in the maximal electroshock seizure (MES) model without negatively impacting neurobehavior or motor function.

Design/Methods:

This was a single center, double-blind, placebo controlled, sequential SAD/MAD study in healthy adult males/females aged 18-55 years. SAD subjects were randomized 3:1 to BHV-7000 (4, 10, 25, 50, or 100 mg) or placebo. MAD subjects were randomized 3:1 to BHV-7000 (10, 25, or 40 mg) or placebo administered daily for 15 days. Safety evaluations included adverse event (AE) monitoring, clinical laboratory tests, vital signs, ECGs, physical examinations, and Sheehan Suicidality Tracking Scale (S-STS).

Results:

Thirty-nine SAD subjects and 22 MAD subjects were randomized to BHV-7000 or placebo. The mean age of the SAD and MAD subjects was 40.1 and 40.0 years, respectively. Most subjects were male (SAD: 87%; MAD: 91%) and white (SAD: 95%; MAD: 91%). Adverse events occurring in ≥2 BHV-7000 treated subjects (BHV-7000 vs placebo) were headache [3/29 (10.3%) vs 0/10 (0%)] and abdominal discomfort [2/29 (6.9%) vs 0/10 (0%)] for SAD cohorts; and headache [3/17 (17.6%) vs 1/5 (20%)] and back pain [3/17 (17.6%) vs 0/5 (0%)] for MAD cohorts. There were low rates of CNS-related AEs; no somnolence was reported. The majority of AEs were mild and resolved spontaneously. There were no deaths, serious AEs, severe AEs, or dose-limiting toxicities.

Conclusions:

BHV-7000 was safe and well tolerated, without the typical AEs associated with other anti-seizure medications. These findings support the continued clinical development of BHV-7000 in
epilepsy.