ABSTRACT
Introduction: Phase 2b trial (NCT03889639) findings in patients with relapsing multiple sclerosis showed central nervous systempenetrant Bruton's tyrosine kinase inhibitor tolebrutinib was well tolerated over 12 weeks and elicited dose-dependent reductions in new gadolinium-enhancing T1 and new/enlarging T2 lesions. Objective/Aim: To characterise tolebrutinib's safety and efficacy at Week 96 (2 years) in the phase 2b trial's long-term safety (LTS) extension (NCT03996291). Method(s): In LTS extension Part A, patients continued their core study tolebrutinib dose (5, 15, 30, or 60 mg/day) double-blind until the phase 3 study dose selection (60 mg/day). In Part B, patients received open-label tolebrutinib 60 mg/day. Safety was assessed via adverse event (AE) reporting. Efficacy outcomes included annualised relapse rate (ARR) and change from baseline Expanded Disability Status Scale (EDSS) score. Result(s): 124 of 125 patients completed Part A and transitioned to Part B;114 (90.5%) remained on study as of 7 March 2022. One patient receiving tolebrutinib 5 mg/day discontinued Part A because of progressive disease and 10 discontinued Part B because of AEs (n=3), perceived lack of efficacy (n=4), emigration (n=2), and patient decision (n=1). At Week 96, no new safety signals have been observed. The most common treatment-emergent AEs (TEAEs) were COVID-19 (20.8% [26/125]), headache (13.6% [17/125]), nasopharyngitis and upper respiratory tract infection (both 11.2% [14/125]), bacterial cystitis (7.2% [9/125]), and pharyngitis and arthralgia (both 5.6% [7/125]). No tolebrutinib dose effects for TEAEs or serious AEs were observed in Part A and no safety signals emerged for patients switching to tolebrutinib 60 mg/day in Part B. Of those who received tolebrutinib 60 mg/day for a minimum of 8 weeks, ARR was 0.17 (95% CI: 0.12, 0.25) and 80.6% remained relapse-free. Mean EDSS remained stable to Week 96. Conclusion(s): Through LTS Week 96, tolebrutinib 60 mg/day continues to show favourable safety, and is associated with a low ARR and stable disability status.
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.