Epileptogenic Channelopathies Guide Design of NBI-921352, a Highly Isoform-Selective Inhibitor of NaV1.6

NBI-921352 is the first highly isoform selective inhibitor of Na_V1.6 voltage-gated sodium channels (Na_Vs) to enter clinical development for epilepsy. Nonselective inhibitors of Na_Vs have long been a mainstay of epilepsy pharmacotherapy. Many such Na_V inhibitors are available, but they are not mechanistically well differentiated. They all inhibit via the same highly conserved binding site, and they inhibit the distinct Na_V isoforms equivalently. This broad Na_V inhibition limits the utility of these drugs, as dose levels required to reduce seizures can cause tolerability issues in both the central nervous and cardiovascular systems. The rationale to develop NBI-921352 was to take a precision medicine approach to developing novel Na_V inhibitors. This approach has been validated preclinically, both in scn8a gain-of-function mutant cell lines and in Scn8a gain-of-function mice. NBI-921352 should improve tolerability by stripping away effects mediated by inhibition of the Na_Vs of cardiac cells (Na_V1.5), muscle cells (Na_V1.4), and inhibitory interneurons (Na_V1.1). Despite the selective nature of NBI-921352, the compound retains the ability to reduce neural excitability and increases seizure resistance in rodents. NBI-921352 is currently entering clinical trials to establish whether the improved properties observed in rodents translate to human epilepsy patients