Concentration of evobrutinib, a BTK inhibitor, in cerebrospinal fluid during treatment of patients with relapsing multiple sclerosis in a phase 2 study

Background Evobrutinib, a highly selective Bruton's tyrosine kinase (BTK) inhibitor, demonstrated a low annualized relapse rate (75mg twice-daily: 0.11, 95%CI 0.04–0.25) in a phase 2 randomized controlled trial in patients with relapsing multiple sclerosis (RMS; NCT02975349). This was maintained in an open-label extension (OLE) through 108 weeks (0.12, 95%CI 0.06–0.22; 75mg once-daily for ∼48 weeks, then 75mg twice-daily). Evobrutinib concentrations in the brain achieved high BTK occupancy in an experimental autoimmune encephalomyelitis model. We investigated evobrutinib distribution into cerebrospinal fluid (CSF) in patients with RMS. Methods Plasma and CSF samples were collected 2–3 hours post-dose from phase 2 OLE patients (75mg twice-daily for >1 year, including ≥6 days uninterrupted dosing before sampling) and evobrutinib concentrations measured. Plasma protein binding was measured ex vivo in sub-study participant samples to determine free plasma evobrutinib concentrations. Results Nine patients from one center were enrolled: 89% female, median age 50.5 years and median disease duration 6.9 years (at phase 2 study baseline); all had stable RMS. In plasma, mean total evobrutinib concentration (95%CI) was 115.0 (71.8–184.3) ng/mL and free evobrutinib concentration was 5.5 ng/mL. Evobrutinib was quantifiable in the CSF of all patients; the geometric mean concentration in CSF was 3.21 (2.27–4.55) ng/mL; 58% of the free plasma concentration. Conclusion Evobrutinib administered at an efficacious, steady-state dose was detected in the CSF of patients with RMS at concentrations consistent with free plasma concentrations. Therefore, evobrutinib may inhibit BTK-expressing cells, including B cells and microglia, in the central nervous system. Evobrutinib, a highly selective Bruton's tyrosine kinase (BTK) inhibitor, demonstrated a low annualized relapse rate (75mg twice-daily: 0.11, 95%CI 0.04–0.25) in a phase 2 randomized controlled trial in patients with relapsing multiple sclerosis (RMS; NCT02975349). This was maintained in an open-label extension (OLE) through 108 weeks (0.12, 95%CI 0.06–0.22; 75mg once-daily for ∼48 weeks, then 75mg twice-daily). Evobrutinib concentrations in the brain achieved high BTK occupancy in an experimental autoimmune encephalomyelitis model. We investigated evobrutinib distribution into cerebrospinal fluid (CSF) in patients with RMS. Plasma and CSF samples were collected 2–3 hours post-dose from phase 2 OLE patients (75mg twice-daily for >1 year, including ≥6 days uninterrupted dosing before sampling) and evobrutinib concentrations measured. Plasma protein binding was measured ex vivo in sub-study participant samples to determine free plasma evobrutinib concentrations. Nine patients from one center were enrolled: 89% female, median age 50.5 years and median disease duration 6.9 years (at phase 2 study baseline); all had stable RMS. In plasma, mean total evobrutinib concentration (95%CI) was 115.0 (71.8–184.3) ng/mL and free evobrutinib concentration was 5.5 ng/mL. Evobrutinib was quantifiable in the CSF of all patients; the geometric mean concentration in CSF was 3.21 (2.27–4.55) ng/mL; 58% of the free plasma concentration. Evobrutinib administered at an efficacious, steady-state dose was detected in the CSF of patients with RMS at concentrations consistent with free plasma concentrations. Therefore, evobrutinib may inhibit BTK-expressing cells, including B cells and microglia, in the central nervous system.