2026 American Academy of Neurology Abstract Website

Objective:

Assess in vitro activity of opakalim (BHV-7000), a selective Kv7.2/7.3 channel activator, in Kv7.2/7.3 channels with a DEE-causing mutation.

Background:

An 8-year-old boy with KCNQ2-DEE, heterozygous for a Kv7.2 G281E mutation, was successfully transitioned from a first-generation Kv7 activator to opakalim by compassionate use IND. Prior attempts to wean the first-generation activator resulted in status epilepticus and severe dystonia and irritability. To better understand the antiseizure effects of opakalim and the first-generation activator in this patient, we sought to determine whether Kv7.2 G281E, expressed in combination with WT Kv7.2 and WT Kv7.3, forms active channels and whether these channels are activated by the first-generation activator and/or opakalim.

Design/Methods:

To control the stoichiometry of Kv7.2/Kv7.3 subunit assembly, an expression construct was made where Kv7.2 and Kv7.3 subunits were concatenated. A construct was made to achieve one copy of Kv7.2 WT and one copy of Kv7.2 G281E. The concatenated construct, in addition to unconcatenated Kv7.2 WT/Kv7.3 WT subunits, were expressed in CHO-K1 cells and evaluated in the presence and absence of opakalim or the first-generation activator using whole-cell voltage-clamp electrophysiology.

Results:

The construct containing one copy of Kv7.2 G281E produced active channels with ½-maximal voltage of activation like unconcatenated Kv7.2 WT/Kv7.3 WT channels. When treated with opakalim or the first-generation activator, the voltage-dependence of activation for channels containing WT Kv7.2/Kv7.3 subunits or one copy of Kv7.2 G281E was shifted toward negative potentials to a similar degree. The potency of both drugs for potentiating channels containing one copy of Kv7.2 G281E was lower compared to channels containing only WT Kv7.2/Kv7.3 subunits.

Conclusions:

Since the first-generation activator and opakalim activate Kv7.2 G281E-containing channels and the patient responded favorably to replacement of the first-generation activator with opakalim, therapeutic benefit likely arises from potentiation of both WT and Kv7.2 G281E-containing channels, underscoring the potential of opakalim for treatment of KCNQ2-DEE.