Describe a case report of KCNQ2-DEE treated with opakalim.

KCNQ2-DEE is a severe neonatal-onset epilepsy syndrome. Most Kv7.2 pathogenic variants are associated with loss-of-function of the Kv7.2/7.3 channel with decreased channel opening. Opakalim (BHV-7000) is a selective activator of Kv7.2/7.3 that restores channel function near wild type levels across 50 pathogenic KCNQ2 variants. An 8-year-old boy with KCNQ2-DEE, heterozygous for a Kv7.2 G281E mutation, experiences multiple daily brief tonic seizures despite treatment with multiple antiseizure medications including a 1st generation potassium channel activator. He has experienced status epilepticus, severe dystonia, and irritability with prior attempts to wean the 1st generation activator.

This 8-year-old boy was initiated on opakalim by compassionate use IND. He received a 1mg test dose as an oral suspension with pharmacokinetic testing to determine maintenance dosing. Then, he completed inpatient cross-titration from the 1st generation potassium channel activator to opakalim. Medication levels, vision assessments, EKG and seizure diaries were documented for >3 months before initiation.

Opakalim 15mg QID showed exposures comparable to the 75mg extended-release QD formulation being evaluated in focal epilepsy. Opakalim was well-tolerated. He had initial improvement with no documented tonic seizures for 2 weeks after reaching 15mg QID, followed by return to approximately baseline seizure frequency. EEG demonstrated near-continuous focal and generalized spike and waves and generalized slowing. Baseline overnight EEG captured 12 tonic seizures with sustained motor activity ≥3 seconds compared to none ≥3 seconds 12 days after opakalim initiation. Increased alertness and interaction were reported initially after the medication transition.

Opakalim demonstrated favorable tolerability and initial improvement in seizures followed by return to baseline seizure frequency, with no worsening compared to prior treatment with another potassium channel activator despite a history of severe exacerbation with multiple previous attempts to wean. He also showed improvement in alertness.