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

ABSTRACT

Intoduction In the phase 2b trial (NCT03889639), brain-penetrant Bruton's tyrosine kinase inhibitor tolebrutinib was well tolerated with dose-dependent reductions in new/enlarging MRI lesions. Objective/Aim: Report MRI, efficacy, and safety outcomes at Week (W)96 (2 years) of the phase 2b trial long-term safety (LTS) extension (NCT03996291) in relapsing MS patients with highly active disease (HAD). Method(s) In the double-blind portion of LTS (Part A), patients continued their core study tolebrutinib dose (5, 15, 30, or 60 mg/day). In the open-label Part B, all participants received 60 mg/day. HAD was defined as one relapse in the year prior to screening and one of the following >1 gadolinium (Gd)- enhancing lesion within the prior 6 months, or >=9 T2 lesions at baseline (BL) or >=2 relapses in the prior year. Outcomes included Gd-enhancing and new/enlarging T2 lesions, annualized relapse rate (ARR), and Expanded Disability Status Scale (EDSS) score. Result(s) 61 patients met the HAD criteria at BL;60 continued in LTS Part A and 59 transitioned to Part B. As of 7 March 2022, 55 (92%) patients remained on study. New Gd-enhancing lesion counts remained low in the 60/60-mg arm through W96 and were reduced in other arms by W48 through W96, except for 5/60 at W96 (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 lesion counts remained low for 15/60, 30/60, and 60/60 mg. T2 lesion volume remained unchanged for 60/60 mg. The most common treatment-emergent adverse events (TEAE) were COVID-19 (20%), nasopharyngitis (16.7%), headache (13.3%), and upper respiratory tract infection (8.3%). There was no dose-relationship for TEAE/serious AE in Part A and no new safety findings for patients switching to 60 mg in Part B. Of the patients who received tolebrutinib 60 mg/day for a minimum of 8 weeks, ARR was 0.10 (95% CI 0.02, 0.66) and 92.9% remained relapse-free at W96. Mean EDSS scores were stable through W96. Conclusion(s) Through LTS Week 96, in the HAD cohort, tolebrutinib 60 mg demonstrated favourable safety (similar to the overall population), tolerability, and low ARR. New Gd-enhancing lesion counts remained low for the 60/60-mg arm.