To assess potential rebound disease recrudescence in participants with relapsing multiple sclerosis (MS) after tolebrutinib Phase 2b trial (NCT03889639) placebo run-out period.

130 participants were randomized (1:1:1:1) to tolebrutinib 5, 15, 30, or 60 mg/day. MRI scans were obtained at screening and every 4 weeks for 16 weeks. Cohort 1 (n=64) received tolebrutinib for 12 weeks followed by 4-week placebo run-out; Cohort 2 (n=66) received 4-week placebo run-in followed by 12 weeks of tolebrutinib.

There was one relapse during Cohort 1 placebo run-out (98.4% relapse-free) vs four relapses in Cohort 2 placebo run-in (93.9% relapse-free). After 12 weeks of tolebrutinib treatment (Cohort 1), 83.3% of participants had no new gadolinium-enhancing lesions; after 4-week placebo run-out, 85.2% had no new gadolinium-enhancing lesions. In Cohort 1, mean±SD gadolinium-enhancing lesion count after 12 weeks of tolebrutinib was 0.37±0.99 and 0.44±1.70 after 4-week placebo run-out. In Cohort 1 participants receiving tolebrutinib 60 mg/day, mean±SD gadolinium-enhancing lesion count was 0.20±0.56 after 12 weeks of tolebrutinib and 0.31±0.70 after 4-week placebo run-out. The mean±SD gadolinium-enhancing lesion count after 4-week placebo run-in (Cohort 2) was 1.03±2.50. At Week 12 in Cohort 1, mean number of new/enlarging T2-lesions was 0.58±1.27 vs 0.95±2.72 after 4-week placebo run-out; meanwhile it was 2.12±5.16 after 4-week placebo run-in (Cohort 2).