Tolebrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), has been specifically developed to enhance its potency and optimize CNS exposure for modulating BTK signaling. The primary objective of this study was to compare the relative potencies and CNS exposure of three BTK inhibitors currently in phase 3 development for MS treatment. Researchers evaluated these BTK inhibitors (tolebrutinib, evobrutinib, and fenebrutinib) to gain insights into their effectiveness and potential impact on CNS neuroinflammation in MS patients under identical conditions. Additionally, CSF pharmacokinetics of tolebrutinib were assessed in healthy volunteers.
The results of the kinase assays revealed that tolebrutinib exhibited a significantly faster reaction with BTK compared to evobrutinib, with a Kinact/Ki value of 4.37 × 10–3 and 6.82 × 10–5 nM–1*s–1, respectively. Fenebrutinib, a reversible antagonist, demonstrated a Ki value of 4.7 nM. The cellular potency, as determined by B-cell activation, correlated with the kinase data, showing half-maximal inhibitory concentration (IC50) values of 0.7, 34.5, and 2.9 nM for tolebrutinib, evobrutinib, and fenebrutinib, respectively. In NHP studies, comparable levels of CSF exposure were observed after oral administration of 10 mg/kg of each BTK inhibitor. However, tolebrutinib exhibited higher CSF exposure (4.8 ng/mL), surpassing the IC90 threshold, while evobrutinib (3.2 ng/mL) and fenebrutinib (12.9 ng/mL) failed to reach the IC50 threshold. In healthy volunteers, administering a single oral dose of tolebrutinib at 60 or 120 mg resulted in bioactive CSF levels between 2 and 4 hours, measuring 0.51 and 1.03 ng/mL, respectively.
These findings provide valuable insights into the comparative pharmacological profiles and CNS exposure of these BTK inhibitors, shedding light on their potential efficacy for treating MS. Tolebrutinib has shown the ability to reach pharmacologically relevant concentrations in the CSF. This supports its potential as a promising treatment option for MS by targeting neuroinflammation and potentially slowing disability progression.
