The phase 3 study, paused at US sites by the FDA, seeks to enroll 154 individuals with generalized myasthenia gravis, both seropositive and seronegative.
The design of the phase 3 URSA study (NCT05132569), assessing the Bruton tyrosine kinase (BTK) inhibitor, tolebrutinib (Sanofi) in patients with generalized myasthenia gravis was presented at the 2022 American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) annual meeting, September 21-24, in Nashville, Tennessee.1
The trial, which is currently enrolling a target of 154 patients, includes a 28-day screening period, followed by 26 weeks of treatment and a 2-year open-label extension. Eligible seropositive and seronegative participants with Myasthenia Gravis Foundation of America Class II-IV disease will be randomly assigned 1:1 to daily oral tolebrutinib or placebo, combined with standard-of-care.
“There is an unmet need for effective treatments in generalized myasthenia gravis with long-term safety. Tolebrutinib is an oral, covalent, irreversible inhibitor of Bruton tyrosine kinase, an enzyme relevant to the pathogenesis of gMG,” author Carolina Barnett-Tapia, MD, PhD, assistant professor, Institute of Health Policy, Management and Evaluation, University of Toronto, and colleagues wrote.
Notably, the trial was paused by the FDA in late June 2022, along with 4 other trials of the BTK inhibitor in multiple sclerosis (MS), because of drug-induced liver injury in patients who received study drug.2 Sanofi revised global study protocols in May 2022 to update safety monitoring and enrollment criteria to exclude those with preexisting factors related to hepatic dysfunction. Study sites outside of the US remain in active enrollment.
The majority of cases of drug-induced liver injury have been reported in participants with medical histories that may predispose them to this complication, Sanofi said. Following drug discontinuation, elevated lab values indicating liver injury were reversed.2
The primary end point of URSA is change in Myasthenia Gravis-Activities of Daily Living (MG-ADL) score from baseline to week 26. The secondary outcomes include change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) score, Myasthenia Gravis Impairment Index, and 15-item Myasthenia Gravis-Quality of Life scores. Additionally, Barnett-Tapia and colleagues will assess the proportion of participants with a2-or-more point reduction in MG-ADL and a 3-or-more point reduction in QMG scores at week 26, as well as safety.
URSA’s open-label extension period is designed to assess long-term safety, tolerability, and efficacy of tolebrutinib treatment. There is a planned interim analysis, triggered once 40 randomized seropositive participants complete the week 12 visit or withdraw early from treatment/study, which will evaluate change in QMG score at week 12.
In February 2022, data on tolebrutinib in relapsing MS presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022, held February 24-26, in West Palm Beach, Florida, suggested that the therapy was safe long-term, with low annualized relapse rates at 18 months.3 The data, from a long-term safety (LTS) extension of a phase 2b trial (NCT03996291), also showed that through 72 weeks of treatment with tolebrutinib 60 mg, new gadolinium (Gd)-enhancing lesion counts were low. By weeks 48 and 72, when all patients in the lower dose groups switched to 60-mg doses, investigators noticed a reduction in new Gd-enhancing lesions.