Open-Label Analysis Highlights Long-Term Safety of BTK Inhibitor Tolebrutinib


There were no observed tolebrutinib dose effect for treatment-emergent adverse events in the double-blind portion, as well as no new safety signals seen for those who crossed over in the open-label extension.

Jiwoh Oh, MD, PhD, staff neurologist and medical director, Barlo Multiple Sclerosis Program, St. Michaels Hospital, University of Toronto

Jiwoh Oh, MD, PhD

Data from a long-term extension study (NCT03996291) of a phase 2b trial demonstrated that treatment with tolebrutinib (Sanofi) 60 mg/day for 2.5 years was safe for patients with relapsing multiple sclerosis (MS), with no new signals observed. Patients maintained low annualized relapse rates (ARR) and stable disability.1

Presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, the most common treatment-emergent adverse events (TEAEs) observed with tolebrutinib were COVID-19 (24.8%; n = 31), headache (13.6%; n = 17), nasopharyngitis (12.8%; n = 16), upper respiratory tract infection (11.2%; n = 14), cystitis bacterial, arthralgia and back pain (7.2% each; n = 9), and pharyngitis (6.4%; n = 8).

Led by Jiwoh Oh, MD, PhD, staff neurologist and medical director, Barlo Multiple Sclerosis Program, St. Michaels Hospital, University of Toronto, the study included 125 individuals with relapsing MS who were on tolebrutinib 5, 15, 30, or 60 mg/day for the double-blind portion of the trial, and subsequently switched to 60 mg/day for the open-label extension (OLE). As of July 7, 2022, 107 (85.6%) of the participants were still on treatment, with some discontinuations because of perceived lack of efficacy (n = 5), progressive disease (n = 4), participant’s decision (n = 3), AEs (n = 3), immigration (n = 2), and planned pregnancy (n = 1).

In the double-blind portion, there were no observed trends between tolebrutinib dosing and TEAEs or serious AEs. Upon switching to 60 mg/day in the OLE, no new safety signals were observed. For patients who received the 60 mg/day dose for at least 8 weeks (n = 124), ARR was 0.20 (95% CI, 0.14-0.28), and 73.4% remained relapse-free. These findings were similar to what was previously observed in the phase 2 double-blind study.

Original findings from the phase 2b study, published in Lancet Neurology in 2021, revealed a dose-dependent reduction in the number of new gadolinium-enhancing (GdE) lesions with tolebrutinib treatment. The 60-mg dose was the most efficacious, with an observed mean number of lesions of 0.13 (standard deviation [SD], 0.43) compared to 1.03 (SD, 2.50) for placebo. Furthermore, 28 of the 31 participants (90%) who received the 60-mg dose had no new GdE lesions after 12 weeks of treatment, compared with 44 of 59 participants (75%) in cohort 2 placebo period observed at week 4.2

At the 2022 AAN Annual Meeting, investigators announced 18-month data from the long-term extension of the phase 2b study, with findings that showed low new GdE lesion counts for those who stayed on 60 mg tolebrutnib and reductions in lesion counts for those who switched. New/enlarging T2 lesion counts remained low for those on continuous treatment through week 24, increasing slightly at weeks 48 and 72. Compared with baseline, T2 lesion volume change remained low at week 72 for those who continued on 60 mg tolebrutinib (mean, +0.39 [±1.99]).3

In June 2022, the FDA placed a clinical hold on the phase 3 trials for tolebrutinib, citing reported cases of drug-induced liver injury. The affected studies included GEMINI 1 and 2 in relapsing MS; PERSEUS in primary progressive MS; HERCULES in nonrelapsing secondary progressive MS; and URSA in generalized myasthenia gravis. A month before the decision, Sanofi revised global study protocols to update both safety monitoring and enrollment criteria to exclude those with preexisting factors related to hepatic dysfunction.4

The phase 3 URSA study, a double-blind, placebo-controlled trial, assessing tolebrutinib in patients with myasthenia gravis was then discontinued in February 2023. Announced in a quarterly report, there were no specific reasons for the discontinuation. URSA was set to include 154 patients with the disease, with a 28-day screening, period, followed by 26 weeks of treatment and a 2-year open-label extension, with change in Myasthenia Gravis-Activities of Daily Living score as the primary end point.

1. Oh J, Syed S, Li T, Salloum N, Turner TJ, Fox RJ. Safety and clinical efficacy outcomes from the long-term extension study of tolebrutinib in participants with relapsing multiple sclerosis: 2.5-year results. Presented at: 2023 AAN Annual Meeting; April 22-27; Abstract 002056
2. Reich DS, Arnold DL, Vermersch P, et al. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor in relapsing multiple sclerosis: a phase 2b, randomized, double-blind, placebo-controlled trial. Lancet Neurol. Published online August 2021. doi: 10.1016/S1474-4422(21)00237-4
3. MRI, safety, and efficacy outcomes in patients with relapsing MS: 18-month results from the long-term extension study of tolebrutinib. Presented at ACTRIMS Forum 2022; February 24-26; West Palm Beach, FL. Abstract P102
4. Media Update: Patient enrollment of phase III tolebrutinib trials paused in the U.S. News release. Sanofi. June 30, 2022. Accessed April 20, 2023
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