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.

Data availability

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

  1. JP Johnson Jr

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    For correspondence
    jpjohnson@xenon-pharma.com
    Competing interests
    JP Johnson, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5762-5138
  2. Thilo Focken

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Thilo Focken, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  3. Kuldip Khakh

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Kuldip Khakh, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  4. Parisa Karimi Tari

    In Vivo Biology, University of British Columbia, Vancouver, Canada
    Competing interests
    Parisa Karimi Tari, was previously employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  5. Celine Dube

    In Vivo Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Celine Dube, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  6. Samuel J Goodchild

    In Vitro Biology, Xenon Pharmaceuticals Inc, Burnaby, Canada
    Competing interests
    Samuel J Goodchild, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  7. Jean-Christophe Andrez

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Jean-Christophe Andrez, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  8. Girish Bankar

    In Vivo Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Girish Bankar, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  9. David Bogucki

    Chemistry, Medipure Pharmaceuticals, Burnaby BC, Canada
    Competing interests
    David Bogucki, was previously employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  10. Kristen Burford

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Kristen Burford, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  11. Elaine Chang

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Elaine Chang, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  12. Sultan Chowdhury

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Sultan Chowdhury, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  13. Richard Dean

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Richard Dean, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  14. Gina de Boer

    Compound Properties, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Gina de Boer, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  15. Shannon Decker

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Shannon Decker, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  16. Christoph Dehnhardt

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Christoph Dehnhardt, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  17. Mandy Feng

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Mandy Feng, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  18. Wei Gong

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Wei Gong, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  19. Michael Grimwood

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Michael Grimwood, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  20. Abid Hasan

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Abid Hasan, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  21. Angela Hussainkhel

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Angela Hussainkhel, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  22. Qi Jia

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Qi Jia, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  23. Stephanie Lee

    Compound Properties, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Stephanie Lee, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  24. Jenny Li

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Jenny Li, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  25. Sophia Lin

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Sophia Lin, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  26. Andrea Lindgren

    Compound Properties, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Andrea Lindgren, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  27. Verner Lofstrand

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Verner Lofstrand, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  28. Janette Mezeyova

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Janette Mezeyova, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  29. Rostam Namdari

    Translational Drug Development, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Rostam Namdari, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  30. Karen Nelkenbrecher

    In Vivo Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Karen Nelkenbrecher, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  31. Noah Gregory Shuart

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Noah Gregory Shuart, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  32. Luis Sojo

    Compound Properties, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Luis Sojo, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  33. Shaoyi Sun

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Shaoyi Sun, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  34. Matthew Taron

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Matthew Taron, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  35. Matthew Waldbrook

    In Vivo Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Matthew Waldbrook, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  36. Diana Weeratunge

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Diana Weeratunge, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  37. Steven Wesolowski

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Steven Wesolowski, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  38. Aaron Williams

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Aaron Williams, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  39. Michael Wilson

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Michael Wilson, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  40. Zhiwei Xie

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Zhiwei Xie, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  41. Rhena Yoo

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Rhena Yoo, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  42. Clint Young

    In Vitro Biology, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Clint Young, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  43. Alla Zenova

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Alla Zenova, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  44. Wei Zhang

    Chemistry, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Wei Zhang, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  45. Alison J Cutts

    Scientific Affairs, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Alison J Cutts, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4986-573X
  46. Robin P Sherrington

    Executive Team, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Robin P Sherrington, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  47. Simon N Pimstone

    Executive Team, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Simon N Pimstone, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  48. Raymond Winquist

    Executive Team, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Raymond Winquist, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  49. Charles J Cohen

    Executive Team, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    Charles J Cohen, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..
  50. James R Empfield

    Executive Team, Xenon Pharmaceuticals, Inc., Burnaby BC, Canada
    Competing interests
    James R Empfield, is employed by Xenon Pharmaceuticals, Inc. and may hold equity in Xenon Pharmaceuticals, Inc..

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

  1. 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

  1. Received: July 24, 2021
  2. Preprint posted: August 31, 2021 (view preprint)
  3. Accepted: February 23, 2022
  4. Accepted Manuscript published: March 2, 2022 (version 1)
  5. 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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  1. JP Johnson Jr
  2. Thilo Focken
  3. Kuldip Khakh
  4. Parisa Karimi Tari
  5. Celine Dube
  6. Samuel J Goodchild
  7. Jean-Christophe Andrez
  8. Girish Bankar
  9. David Bogucki
  10. Kristen Burford
  11. Elaine Chang
  12. Sultan Chowdhury
  13. Richard Dean
  14. Gina de Boer
  15. Shannon Decker
  16. Christoph Dehnhardt
  17. Mandy Feng
  18. Wei Gong
  19. Michael Grimwood
  20. Abid Hasan
  21. Angela Hussainkhel
  22. Qi Jia
  23. Stephanie Lee
  24. Jenny Li
  25. Sophia Lin
  26. Andrea Lindgren
  27. Verner Lofstrand
  28. Janette Mezeyova
  29. Rostam Namdari
  30. Karen Nelkenbrecher
  31. Noah Gregory Shuart
  32. Luis Sojo
  33. Shaoyi Sun
  34. Matthew Taron
  35. Matthew Waldbrook
  36. Diana Weeratunge
  37. Steven Wesolowski
  38. Aaron Williams
  39. Michael Wilson
  40. Zhiwei Xie
  41. Rhena Yoo
  42. Clint Young
  43. Alla Zenova
  44. Wei Zhang
  45. Alison J Cutts
  46. Robin P Sherrington
  47. Simon N Pimstone
  48. Raymond Winquist
  49. Charles J Cohen
  50. James R Empfield
(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
eLife 11:e72468.
https://doi.org/10.7554/eLife.72468

Share this article

https://doi.org/10.7554/eLife.72468

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