Abstract Details

Title Characterization of BHV-7000: A Novel Kv7.2/7.3 Activator for the Treatment of Seizures

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) S29 - Epilepsy Diagnostics and Therapeutics (2:00 PM-2:12 PM)

Poster/Presentation
Number 006

Objective Assess in vitro activity and in vivo efficacy, safety, and tolerability of BHV-7000.

Background Kv7 channels are voltage-gated potassium channels encoded by KCNQ genes that exert physiological control over excitable cells. The Kv7.2/7.3 channel subtype generates the M-current in the central nervous system that represents a clinically validated drug target for treating seizures. Positive modulation of M-current facilitates normalizing the excitation/inhibition imbalance that occurs in epilepsy patients.

Design/Methods BHV-7000 was rationally designed from a novel Kv7 pharmacophore platform. Fluorescent and electrophysiological assays were employed to discover and characterize lead compounds. Antiseizure efficacy was evaluated in rats in the maximal electroshock seizure (MES) model; tolerability was assessed by neurological score (NS) and rotarod assays. Cells transiently transfected with mutant (W236L) or wildtype KCNQ2 were used to characterize BHV-7000 activity at Kv7.2 channels.

Results BHV-7000 activates the Kv7.2/7.3 channel with an EC₅₀ of 0.6 μM. BHV-7000 slowed deactivation kinetics and shifted the half-maximal activation potential. In rat primary cortical neuron cultures, BHV-7000 produced a concentration dependent hyperpolarization of the resting membrane potential. BHV-7000 requires the W236 amino acid for activity on the Kv7.2 channel. BHV-7000 demonstrated little to no effect against the human α1β3?2 GABA receptor at 10 μM and no significant activity against cardiac ion channels. In the MES model, BHV-7000 provides protection against seizures with a brain EC₅₀ of 0.12 μM and TD₅₀ >20 mg/kg, measured by NS, a sensitive measure of tolerability. The rotarod assay demonstrated no motor effects across all doses.

Conclusions BHV-7000 is a novel activator of Kv7.2/7.3 potassium channels in development for the treatment of epilepsy. BHV-7000 displays potent antiseizure activity in the rat MES model with no overt neurobehavioral or motor effects, and thus represents a promising next generation ASM for clinical development.

Authors/Disclosures
Kelly Picchione PRESENTER	Dr. Picchione has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Dr. Picchione has stock in Biohaven Pharmaceuticals.
Lynn Resnick (Biohaven Pharmceuticals)	Lynn Resnick has received personal compensation for serving as an employee of Biohaven. Lynn Resnick has stock in Biohaven. Lynn Resnick has received intellectual property interests from a discovery or technology relating to health care.
Michael E. Bozik, MD (Biohaven Pharmaceuticals)	Dr. Bozik has received personal compensation for serving as an employee of Biohaven . Dr. Bozik has stock in Biohaven.
Steven Dworetzky (Biohaven)	Dr. Dworetzky has received personal compensation for serving as an employee of Biohaven. Dr. Dworetzky has stock in Biohaven. Dr. Dworetzky has received intellectual property interests from a discovery or technology relating to health care.

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