Sanofi Discontinues Phase 3 Study of Tolebrutinib in Myasthenia Gravis


The trial was originally placed on hold because of reported cases of drug-induced liver injury in patients who received the study drug, potentially caused by a preexisting factors related to hepatic dysfunction.

Jiwon Oh, MD, PhD, staff neurologist, University of Toronto

Jiwon Oh, MD, PhD

In its quarterly report, Sanofi announced it has discontinued the phase 3 URSA study (NCT05132569) assessing its Bruton tyrosine kinase (BTK) inhibitor tolebrutinib as a potential treatment for patients with myasthenia gravis. At the same time, the company announced completed enrollment for its phase 3 HERCULES study assessing the agent in nonrelapsing progressive multiple sclerosis (MS).1

In June 2022, the FDA placed a partial clinical hold on URSA because of drug-induced liver injury in patients who received study drug in 5 different trials that spanned across myasthenia gravis and multiple sclerosis (MS).2 The other trials included GEMINI 1 and 2 (NCT04410978; NCT04410991) in relapsing MS, PERSEUS (NCT04458051) in primary progressive MS, and HERCULES (NCT04411641) in nonrelapsing secondary progressive MS. At the time, new enrollment in any of the studies were paused, an any participant who had been in a study for less than 60 days were instructed to suspend the study drug.

URSA was a double-blind, placebo-controlled trial that was set to include 154 patients with myasthenia gravis randomly assigned 1:1 to daily oral tolebrutinib or placebo, combined with standard-of-care. The study included 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 (MG-ADL) score serving as the primary end point.

A month prior to the clinical hold, Sanofi revised global study protocols to both update safety monitoring and enrollment criteria to exclude those with preexisting factors related to hepatic dysfunction. At the time, the company claimed that the majority of drug-induced liver injury cases were reported in participants with medical histories that may predispose them to this complication. Following drug discontinuation, elevated lab values indicating liver injury were reversed.

Published in August 2021, the BTK inhibitor showed promise as a potential agent for patients with relapsing-remitting MS and relapsing secondary progressive MS in a phase 2b study (NCT03889639). An exponential model showed a dose-response relationship between tolebrutinib and new gadolinium-enhancing (GdE) lesions, which was used to reject the null hypothesis of a flat dose-response curve (test statistic, 2.47; P = .03).3 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.

Following the conclusion of that trial, 125 of the 129 eligible participants continued to the long-term safety extension study, and 124 completed Part A to transition to Part B. Led by Jiwon Oh, MD, PhD, staff neurologist, University of Toronto, participants would first enter Part A of the LTS, where they received the same dose (5, 15, 30, or 60 mg/day) of tolebrutinib. Once the dose of 60 mg was selected for the phase 3 trials, participants entered the open-label Part B of the LTS, where they all received tolebrutinib 60 mg/day.

In the open-label period, investigators observed a low number of GdE (mean counts, 0.62 [±1.06]) in the 60/60-mg arm after 72 weeks of continuous treatment. For those in the 5/60-mg, 15/60-mg, and 30/60-mg arms, these lesions were reduced by mean counts of 0.68 (±0.98), 0.86 (±2.42), and 0.47 (±1.33), respectively, at weeks 48 and 72. The investigators also wrote that new/enlarging T2 lesion counts remained low for the 60/60-mg arm through week 24, and increased slightly at weeks 48 and 72.4

Tolebrutinib is currently being assessed in GEMINI 1 and 2, identical phase 3 studies that include 900 patients each with relapsing MS. Patients in these studies are randomly assigned to receive 60-mg tolebrutinib or 14-mg teriflunomide (Aubagio; Sanofi) over a treatment duration ranging 18 to 36 months. Those completing the study will be offered participation in a long-term safety study.

1. Strong sales performance and double digit EPS growth marketing the achievement of the 2022 profitability milestone. News release. Sanofi. February 3, 2023. Accessed February 6, 2023.
2. Media Update: Patient enrollment of phase III tolebrutinib trials paused in the U.S. News release. Sanofi. June 30, 2022. Accessed February 6, 2023.
3. 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
4. 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
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