Authors :
Presenting Author: Jason Lerner, MD – Biohaven Pharmaceuticals
Bharat Awsare, MD – Biohaven Pharmaceuticals; Heather Sevinsky, MS – Biohaven Pharmaceuticals; Eric Ashbrenner, MS – Biohaven Pharmaceuticals; Randall Killingsworth, BA – Biohaven Pharmaceuticals; Racheal Kendrick, PharmD – Certara; Emiel Vereycken, MS – Epilog; Nigel Colenbier, PhD – Epilog; Caroline Neuray, MD – Epilog; Pieter van Mierlo, PhD – Epilog; Jeremy Slater, MD, FAAN, FAES, FACNS – Stratus; David Wyatt, MD – Syneos Health; Irfan Qureshi, MD – Biohaven Pharmaceuticals; Steven Dworetzky, PhD – Biohaven Pharmaceuticals; Michael Bozik, MD – Biohaven Pharmaceuticals
Rationale:
BHV-7000 is a novel, small molecule, selective activator of Kv7.2/7.3 potassium channels, a clinically validated target in epilepsy. Ezogabine and other molecules in this class have been dose limited by adverse events (AEs) typical of antiseizure medications (ASMs) including somnolence. In a Phase 1 study, BHV-7000 was safe and well tolerated at single doses up to 100 mg without dose-limiting AEs. In this study, we assessed the pharmacodynamic effects of single doses of BHV-7000 on electroencephalogram (EEG) spectral power in healthy adults.
Methods:
This was a phase 1 open label clinical trial conducted in 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 of BHV-7000 (standard release formulation) on Days 1, 5, and 9 in a randomized sequence. On Day -1, no dose was given to assess the baseline. EEG measurements, collected by Stratus (Irving, Texas, USA), included a five minute period of resting state with eyes open and five minutes of resting state with eyes closed at baseline, pre-dose, 1h, 2h, 3h, 4h, and 6h post-drug intake. Epilog NV (Ghent, Belgium) performed quantitative spectral analysis (using Fast Fourier Transformation) of all EEG recordings to assess pharmacodynamic effects over time. Cluster-based permutation analysis was conducted to identify statistically significant differences. Plasma levels of BHV-7000 were quantified at corresponding time points with EEG for assessment of concentration-response relationships.
Results:
BHV-7000 was well tolerated at all doses tested. 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 the alpha, beta, and gamma bands. Changes were seen across all EEG channels, indicating a global central nervous system (CNS) drug effect. Furthermore, positive correlations were found between spectral power and BHV-7000 plasma concentration at the time of maximal response in all frequency bands.
Conclusions:
The pharmacodynamic activity of BHV-7000 in the brain of healthy adults was demonstrated in this study by dose- and concentration-dependent increases in EEG spectral power across all canonical frequency bands. Unlike prior reports (Biondi et al. 2022) where the EEG effects of a Kv7.2/7.3 activator showed the greatest power increase in the delta band, the highest spectral power increases with BHV-7000 were seen in the alpha, beta and gamma bands. While changes in spectral power were observed across all frequency bands with BHV-7000, the reduced impact on slower frequencies (delta and theta) is consistent with the low incidence of CNS AEs such as somnolence seen in the first-in-human BHV-7000 Phase 1 study (AES 2023 poster 3.265). These study results support the continued development of BHV-7000 for epilepsy and its potential to deliver anti-seizure efficacy without dose-limiting AEs.
Funding: This study was funded by Biohaven Pharmaceuticals