Several cases of liver injury have been identified in phase 3 clinical trials of tolebrutinib.
The FDA has placed phase 3 studies of tolebrutinib for multiple sclerosis (MS) and myasthenia gravis on partial clinical hold. The FDA action was based on a limited number of cases of liver injury in patients in the phase 3 studies, Sanofi, tolebrutinib’s manufacturer, said in a news release.
As a result, Sanofi is pausing U.S. enrollment in the studies, and participants in the United States who have been in the trial for fewer than 60 days will stop taking the drug.
“The majority of the impacted patients were determined to have concurrent complications known historically to predispose to drug-induced liver injury,” Sanofi said. “Importantly, the elevations of laboratory values used for monitoring liver injury were reversible after drug discontinuation for all cases.”
However, U.S. participants who have completed at least 60 days in the trial should continue treatment, Sanofi said.
Following earlier dialogue with FDA about these cases, study protocols were revised in May 2022 to update the monitoring frequency, and enrollment criteria were revised to exclude preexisting risk factors for hepatic dysfunction, Sanofi added.
Sanofi “remains confident in the future of tolebrutinib as a potentially transformative oral treatment option for people living with MS,” the company said.
Tolebrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that achieves cerebrospinal fluid concentrations needed for targeting B lymphocytes and microglial cells, according to Sanofi. It is being evaluated to treat relapsing forms of MS, non-relapsing secondary progressive MS, primary progressive MS, and myasthenia gravis, which is an autoimmune disease that leads to muscular weakness.
Despite the challenges in the U.S. phase 3 trials, enrollment in the clinical program continues with the revised study protocols and enhanced safety monitoring in countries outside of the United States. “Sanofi is working closely with the independent data monitoring committee members and investigators around the world to evaluate the effectiveness of safety measures,” the pharma maker said.
The global program in MS has been enrolling patients since 2019 and includes more than 2,000 patients currently on tolebrutinib therapy with durations of treatment as long as three years.
Earlier this year, Sanofi said that preclinical data showed that tolebrutinib was the only BTK inhibitor with sufficient central nervous system (CNS) exposure and potency to modulate BTK signaling pathways within the central nervous system, as compared with evobrutinib (Merck Serono) and fenebrutinib.
The results, presented in a live poster presentation at the 7th annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, found that tolebrutinib was shown to be more potent than evobrutinib (50x) and fenebrutinib (9.3x), resulting in durable BTK inhibition.
“These data reinforce that targeting BTK has the potential to target inflammation both in the periphery and directly in the CNS. Further research is needed to determine the potential clinical efficacy and safety of tolebrutinib in treating MS,” Sanofi said in February.