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.
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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.
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/).
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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