Comparative CNS Pharmacology of the Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis.
Journal
Drugs in R&D
ISSN: 1179-6901
Titre abrégé: Drugs R D
Pays: New Zealand
ID NLM: 100883647
Informations de publication
Date de publication:
05 Jul 2024
05 Jul 2024
Historique:
accepted:
16
05
2024
medline:
5
7
2024
pubmed:
5
7
2024
entrez:
4
7
2024
Statut:
aheadofprint
Résumé
Tolebrutinib is a covalent BTK inhibitor designed and selected for potency and CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells. We applied a translational approach to evaluate three BTK inhibitors in Phase 3 clinical development in MS with respect to their relative potency to block BTK-dependent signaling and exposure in the CNS METHODS: We used in vitro kinase and cellular activation assays, alongside pharmacokinetic sampling of cerebrospinal fluid (CSF) in the non-human primate cynomolgus to estimate the ability of these candidates (evobrutinib, fenebrutinib, and tolebrutinib) to block BTK-dependent signaling inside the CNS. In vitro kinase assays demonstrated that tolebrutinib reacted with BTK 65-times faster than evobrutinib, while fenebrutinib, a classical reversible antagonist with a K Tolebrutinib was the only candidate of the three that attained relevant CSF exposure in non-human primates.
Sections du résumé
BACKGROUND AND OBJECTIVES
OBJECTIVE
Tolebrutinib is a covalent BTK inhibitor designed and selected for potency and CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells. We applied a translational approach to evaluate three BTK inhibitors in Phase 3 clinical development in MS with respect to their relative potency to block BTK-dependent signaling and exposure in the CNS METHODS: We used in vitro kinase and cellular activation assays, alongside pharmacokinetic sampling of cerebrospinal fluid (CSF) in the non-human primate cynomolgus to estimate the ability of these candidates (evobrutinib, fenebrutinib, and tolebrutinib) to block BTK-dependent signaling inside the CNS.
RESULTS
RESULTS
In vitro kinase assays demonstrated that tolebrutinib reacted with BTK 65-times faster than evobrutinib, while fenebrutinib, a classical reversible antagonist with a K
CONCLUSIONS
CONCLUSIONS
Tolebrutinib was the only candidate of the three that attained relevant CSF exposure in non-human primates.
Identifiants
pubmed: 38965189
doi: 10.1007/s40268-024-00468-4
pii: 10.1007/s40268-024-00468-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
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