MRI, Efficacy, and Safety of Tolebrutinib in Patients with Highly Active Disease (HAD): 2-Year Data from the Phase 2b Long-term Safety (LTS) Study
Robert Fox1, Jiwon Oh2, Douglas Arnold3, Sana Syed4, Zhixing Xu4, Timothy Turner4, Anthony Traboulsee5, Daniel Reich6
1Mellen Center for Multiple Sclerosis, Cleveland Clinic, 2St Michael's Hospital, University of Toronto, 3NeuroRx Research and Montréal Neurological Institute, McGill University, 4Sanofi, 5University of British Columbia, 6National Institute of Neurological Disorders and Stroke
Objective:
To report MRI, efficacy, and safety outcomes at Week (W) 96 (2 years) of long-term safety (LTS) extension (NCT03996291) of the Phase 2b trial (NCT03889639) of tolebrutinib in participants with relapsing multiple sclerosis and highly active disease (HAD).
Background:

In the Phase 2b trial, brain-penetrant tolebrutinib was well-tolerated with dose-dependent reductions in new/enlarging MRI lesions.

Design/Methods:

In the double-blind LTS Part A, participants continued receiving tolebrutinib dose (5, 15, 30, or 60mg/day). In open-label Part B, all participants received 60mg/day. HAD was defined as one relapse in the year prior to screening and one of the following: >1 gadolinium-enhancing lesion within the prior 6 months or ≥9 T2-lesions at baseline or ≥2 relapses in the prior year. Outcomes included gadolinium-enhancing and T2-lesions, annualized relapse rate (ARR), and Expanded Disability Status Scale (EDSS).

Results:

61 participants met HAD criteria at baseline; 60 continued in Part A, 59 transitioned to Part B. As of 7 March 2022, 55 (92%) remained on study. New gadolinium-enhancing lesions remained low in 60/60-mg arm through W96 and were reduced in other arms W48 through W96, except for 5/60-mg (mean±SD at W96: 2.00±3.83, 0.56±1.04, 0.47±1.13, 0.23±0.44 in 5/60-, 15/60-, 30/60-, 60/60-mg arms, respectively). New/enlarging T2-lesions remained low for 15/60, 30/60, and 60/60mg. T2-lesion volume remained unchanged for 60/60mg. Most common treatment-emergent adverse events (TEAEs) were COVID-19, nasopharyngitis, headache, and upper respiratory tract infection. There was no dose-relationship for TEAE/serious AE (Part A) and no new safety findings for participants switching to 60mg (Part B). In participants receiving tolebrutinib 60mg/day for >8 weeks, ARR was 0.10 (95%CI: 0.02-0.66) and 92.9% remained relapse-free at W96. Mean EDSS were stable through W96.

Conclusions:

Through W96, in HAD cohort, tolebrutinib 60mg demonstrated favorable safety (similar to overall population), tolerability, and low ARR. New gadolinium-enhancing lesions remained low for 60/60-mg arm.

10.1212/WNL.0000000000202143