Tolebrutinib Phase 2b Long-Term Extension Study: Two-Year Safety, MRI, and Clinical Efficacy Outcomes in Patients With Relapsing Multiple Sclerosis Patients.

Background and Objectives: Tolebrutinib is an oral, brain-penetrant, covalent Bruton's tyrosine kinase (BTK) inhibitor currently under investigation as a disease-modifying therapy for multiple sclerosis (MS). In a Phase 2b trial, tolebrutinib administration was generally well tolerated and produced dose-dependent reductions in new gadolinium (Gd)-enhancing T1 and new/enlarging T2 lesions in participants with relapsing MS. We evaluated the safety and effectiveness of tolebrutinib for 2 years after the end of the Phase 2b trial in a long-term safety (LTS) extension study. Methods: This is an ongoing, two-part LTS extension study conducted at academic sites, specialty clinics, and general neurology centers. Participants who completed the Phase 2b trial on treatment were eligible for enrollment. In LTS Part A, participants continued their core study tolebrutinib dose (5, 15, 30, or 60 mg/day) double-blind. In Part B, all participants switched to open-label treatment with the selected Phase 3 dose of tolebrutinib 60 mg/day taken with food. Safety (the primary objective) was measured by adverse events (AEs). Efficacy measures included new Gd-enhancing T1 lesions, new/enlarging T2 lesions, annualized relapse rate (ARR), and Expanded Disability Status Scale (EDSS) score. Results: Of the 129 participants who completed core study treatment, 125 enrolled in LTS Part A and received tolebrutinib, 124 entered Part B, and 114 remain on study as of February 18, 2022. Mean age at core study baseline was 37.8 years and 69% of participants were female. The most common treatment-emergent AEs were COVID-19 (n=26/125, 21%) and headache (n=17/125, 14%). At LTS Week (W)96, 79% of participants assigned in the core study to 60 mg (60 mg/60 mg arm) had no new Gd-enhancing T1 lesions since the previous scan (W72), 33% had no new/enlarging T2 lesions since LTS W0, and 50% had ≤2 new/enlarging T2 lesions since LTS W0. ARR on tolebrutinib 60 mg/day for ≥8 weeks was 0.17 (95% confidence interval: 0.12, 0.25), and median EDSS scores were stable. Discussion: Over 2 years, tolebrutinib showed an acceptable safety profile, with durable effects on MRI measures, ARR, and EDSS. Conclusions regarding efficacy are limited by the study's open-label design and lack of a comparator group. Classification of Evidence: This study provides class IV evidence. It is an uncontrolled study without a comparator group.