New preclinical tolebrutinib data demonstrated superior brain penetration and potency
New preclinical data demonstrated that tolebrutinib, Sanofi’s investigational oral Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of multiple sclerosis (MS), was the only BTK inhibitor with sufficient central nervous system (CNS) exposure and potency to modulate BTK signaling pathways within the CNS, as compared with evobrutinib and fenebrutinib. These results are being presented in a live poster presentation at the 7th annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum.
Disability accumulation, or worsening of neurologic function, remains a reality for many people living with MS. Inhibition of BTK, an important intracellular signaling pathway within the CNS, is being investigated as an MS treatment strategy. However, to effectively inhibit BTK within the CNS, investigational therapies must cross the blood-brain barrier with sufficient exposure to engage targets and modulate signaling.
In experiments using well-established preclinical methods, tolebrutinib was shown to be more potent than evobrutinib (50x) and fenebrutinib (9.3x), resulting in durable BTK inhibition. The analyses comprised in vitro kinase and cellular assays and in vivo pharmacokinetic (PK) sampling of cerebrospinal fluid (CSF) in non-human primates cynomolgus macaque (Macaca fascicularis). These data reinforce that targeting BTK has the potential to target inflammation both in the periphery and directly in the CNS. Further research is needed to determine the potential clinical efficacy and safety of tolebrutinib in treating MS.