eLife (Mar 2022)

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

  • 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

DOI
https://doi.org/10.7554/eLife.72468
Journal volume & issue
Vol. 11

Abstract

Read online

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.

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