학술논문
NBI-921352, a first-in-class, NaV1.6 selective, sodium channel inhibitor that prevents seizures in Scn8a gain-of-function mice, and wild-type mice and rats
Document Type
article
Author
JP Johnson; Thilo Focken; Kuldip Khakh; Parisa Karimi Tari; Celine Dube; Samuel J Goodchild; Jean-Christophe Andrez; Girish Bankar; David Bogucki; Kristen Burford; Elaine Chang; Sultan Chowdhury; Richard Dean; Gina de Boer; Shannon Decker; Christoph Dehnhardt; Mandy Feng; Wei Gong; Michael Grimwood; Abid Hasan; Angela Hussainkhel; Qi Jia; Stephanie Lee; Jenny Li; Sophia Lin; Andrea Lindgren; Verner Lofstrand; Janette Mezeyova; Rostam Namdari; Karen Nelkenbrecher; Noah Gregory Shuart; Luis Sojo; Shaoyi Sun; Matthew Taron; Matthew Waldbrook; Diana Weeratunge; Steven Wesolowski; Aaron Williams; Michael Wilson; Zhiwei Xie; Rhena Yoo; Clint Young; Alla Zenova; Wei Zhang; Alison J Cutts; Robin P Sherrington; Simon N Pimstone; Raymond Winquist; Charles J Cohen; James R Empfield
Source
eLife, Vol 11 (2022)
Subject
Language
English
ISSN
2050-084X
Abstract
NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC500.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for NaV1.1, 134 X for NaV1.2, 276 X for NaV1.7, and >583 Xfor NaV1.3, NaV1.4, and NaV1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.