Abstract Details

Title Comparative CNS Pharmacology of Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating MS

Topic Multiple Sclerosis

Presentation(s) S46 - MS Therapeutics and Clinical Decision Making (2:12 PM-2:24 PM)

Poster/Presentation
Number 007

Background Modulating CNS neuroinflammation represents a paradigm shift for treating MS. Tolebrutinib is a covalent BTK inhibitor designed and selected to optimize both potency and exposure to modulate BTK signaling within the CNS.

Objective Compare three BTK inhibitors in Phase 3 development in multiple sclerosis (MS) according to relative potencies and CNS exposure.

Design/Methods We used in vitro kinase assays, cellular activation assays, and pharmacokinetic (PK) sampling of cerebrospinal fluid (CSF) in the non-human primate (NHP) cynomolgus to compare tolebrutinib, evobrutinib, fenebrutinib under identical conditions. We then evaluated the CSF PK of tolebrutinib in healthy volunteers.

Results Kinase assays demonstrated that tolebrutinib reacted with BTK 65-times faster than evobrutinib (K_inact/K_i = 4.37 x 10^-3 and 6.82 x 10^-5 nM^-1*s^-1, respectively). Fenebrutinib, a reversible antagonist had a K_i value of 4.7 nM. Because of the slow off-rate (1.54 x 10^-5 s^-1), the forward rate was also very slow (3.28 x 10³ M^-1 * s^-1). Estimated cellular potency (using B cell activation) was consistent with kinase data (IC50 = 0.7 nM, 34.5 nM, and 2.9 nM, respectively). In NHP, we observed similar levels of exposure in the CSF after oral doses of 10 mg/kg for each candidate. However, tolebrutinib CSF exposure (4.8 ng/mL) (kp,uu CSF=0.40) exceeded the IC90, while evobrutinib (3.2 ng/mL) (kp,uu CSF=0.13) and fenebrutinib (12.9 ng/mL) (kp,uu CSF=0.15) failed to reach the IC50. In healthy volunteers, a single oral dose of 60 or 120 mg resulted in bioactive CSF levels between 2 and 4 hrs. (0.51 and 1.03 ng/mL, respectively).

Conclusions Next-generation drug candidates in MS must achieve pharmacologically-relevant concentrations in the CNS to address the existing treatment gap. In these NHP experiments, tolebrutinib was the only BTK inhibitor to show bioactive CSF levels, adding to the evidence that tolebrutinib has potential to slow disability accumulation via modulating neuroinflammation.

Authors/Disclosures
Timothy J. Turner PRESENTER	Timothy J. Turner has received personal compensation for serving as an employee of Sanofi. Timothy J. Turner has stock in Sanofi. Timothy J. Turner has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
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