Objective:

Assess the pharmacodynamic effects of BHV-7000 on electroencephalogram (EEG) spectral power in healthy adults.

Background:

BHV-7000 is a novel, small molecule, selective activator of Kv7.2/7.3 potassium channels, a clinically validated target in epilepsy. In a first-in-human Phase 1 study, BHV-7000 was safe and well tolerated.

Design/Methods:

This phase 1 open label study enrolled 11 healthy adult males/females aged 18-55 years. All subjects underwent sequential EEG recordings with the international 10-20 electrode setup at Day -1, Day 1, Day 5 and Day 9. Subjects received single doses of 10, 25, and 50 mg BHV-7000 (standard release formulation) on Days 1, 5 and 9 in a randomized sequence. EEG measurements included a 5-minute period of resting state with eyes open and 5 minutes of resting state with eyes closed at baseline, pre-dose, 1h, 2h, 3h, 4h and 6h post-dose. Quantitative spectral analysis of all EEG recordings was performed to assess pharmacodynamic effects over time. Cluster-based permutation analysis was conducted to identify statistically significant differences. BHV-7000 plasma levels were quantified at corresponding time points with EEG to assess concentration-response relationships.

Results:

Dose-dependent effects of BHV-7000 were observed in EEG spectral power in all frequency bands. The greatest increases in spectral power were seen in alpha, beta, and gamma bands. Changes were seen across all EEG channels, indicating a global central nervous system drug effect. Positive correlations were found between spectral power and BHV-7000 plasma concentration at the time of maximal response in all frequency bands.

Conclusions:

Pharmacodynamic activity of BHV-7000 in the brain was demonstrated by dose- and concentration-dependent increases in EEG spectral power across all canonical frequency bands. The changes in faster frequencies and less so in the slower frequencies (delta and theta) is consistent with the absence of somnolence seen in the first-in-human BHV-7000 Phase 1 study.