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
- Xenon Pharmaceuticals, Inc., Canada
- University of British Columbia, Canada
- Xenon Pharmaceuticals Inc, Canada
- Medipure Pharmaceuticals, Canada
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 & Moller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC50 0.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756X for NaV1.1, 134X for NaV1.2, 276X for NaV1.7, and >583X for NaV1.3, NaV1.4, and NaV1.5). NBI-921352 is a state-dependent inhibitor, preferentially inhibiting inactivated channels. 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 rat seizure 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 was well 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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All the numerical data used to generate the figures in contained in the excel data source file included in the submission.
Article and author information
Author details
Funding
Xenon Pharmaceuticals, Inc.
- JP Johnson Jr
- 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
All of this work was funded by Xenon Pharmaceuticals, and all of the authors are, or were previously, employees of Xenon Pharmaceuticals.
Reviewing Editor
- Baron Chanda, Washington University in St. Louis, United States
Ethics
Animal experimentation: All animal research was overseen by the Xenon Animal Care Committee and the Canadian Animal Care Council (CACC) according the recommendations of the CACC (https://ccac.ca/).
Version history
- Received: July 24, 2021
- Preprint posted: August 31, 2021 (view preprint)
- Accepted: February 23, 2022
- Accepted Manuscript published: March 2, 2022 (version 1)
- Version of Record published: March 8, 2022 (version 2)
Copyright
© 2022, Johnson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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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
eLife 11:e72468.
https://doi.org/10.7554/eLife.72468
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