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 7^th 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.

Tim Turner, PhD
Global Project Head for Tolebrutinib, Sanofi
“Based on this preclinical analysis comparing late-stage BTK inhibitors, tolebrutinib demonstrated a superior combination of CSF exposure and potency that exceeded the IC90, a measure of substantial target engagement in the brain. These data make us optimistic about the potential for tolebrutinib to address the drivers of disability in the CNS, and we look forward to seeing the first Phase 3 readouts next year.” 

Sanofi will host a virtual investor session to review data presented at ACTRIMS and provide an update on the company’s broader neurology portfolio. The audio webcast and conference call for investors will include presentations followed by a Q&A session.

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Related Topics and Keywords

Sanofi, tolebrutinib