Lack of Rebound Disease Activity in Participants with Relapsing Multiple Sclerosis Following Placebo Run-out in the Tolebrutinib Phase 2b Trial
Anthony Traboulsee1, Robert Fox2, Douglas Arnold3, Sana Syed4, Larry Orogun4, Deborah Dukovic4, Timothy Turner4, Daniel Reich5, Jiwon Oh6
1University of British Columbia, 2Mellen Center for Multiple Sclerosis, Cleveland Clinic, 3NeuroRx Research and Montréal Neurological Institute, McGill University, 4Sanofi, 5National Institute of Neurological Disorders and Stroke, 6St. Michael’s Hospital, University of Toronto
Objective:

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

Background:
Rebound disease activity has been reported after discontinuing some MS disease-modifying treatments. The 16-week, double-blind, crossover, Phase 2b trial of brain-penetrant tolebrutinib in participants with RMS showed dose-dependent reductions in new gadolinium-enhancing T1 and new/enlarging T2-lesions. The unique crossover design with 4-week placebo run-in/run-out periods minimizing placebo exposure enabled assessment of potential rebound disease after tolebrutinib discontinuation. 
Design/Methods:

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.

Results:

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).

Conclusions:
These preliminary findings suggest tolebrutinib discontinuation in participants with RMS does not induce rebound disease activity; longer observation periods are needed to validate this finding.
10.1212/WNL.0000000000202145