FDA Pauses Tolebrutinib Trials in MS, Myasthenia Gravis Over Liver Injuries


The BTK inhibitor is currently the subject of several ongoing phase 3 clinical trials that include more than 2000 patients currently on the therapy.

Jiwon Oh, MD, PhD

Jiwon Oh, MD, PhD

The FDA has placed a partial clinical hold on Sanofi's phase 3 clinical trials for tolebrutinib, its Bruton tyrosine kinase (BTK) inhibitor being evaluated for the treatment of multiple sclerosis (MS) and myasthenia gravis.1

The hold was placed based on reported cases of drug-induced liver injury in patients who received the study drug in the ongoing trials, of which there are 5: GEMINI 1 and 2 in relapsing MS; PERSEUS in primary progressive MS (PPMS); HERCULES in nonrelapsing secondary progressive MS (SPMS); and URSA in generalized myasthenia gravis.

As such, new enrollment in the studies is paused, and any participant who has been in a study for less than 60 days has been instructed to suspend the study drug.

Notably, Sanofi revised global study protocols in May of this year to both 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.

"Sanofi is working closely with the independent data monitoring committee members and investigators around the world to evaluate the effectiveness of safety measures," the company said in a statement. "Sanofi remains confident in the future of tolebrutinib as a potentially transformative oral treatment option for people living with MS."

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.

Data from a long-term safety extension of a phase 2b clinical trial (NCT03889639) presented in February 2022 at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, held February 24-26, in West Palm Beach, Florida, showed a favorable safety profile and a low annualized relapse rate in patients with relapsing MS who received the 60-mg dose of the drug. Treatment over 72 weeks was associated with a reduction in new gadolinium-enhancing lesions.

The most common adverse events (AE) reported were headache (12.8%), COVID-19 (12.8%), nasopharyngitis (10.4%), upper respiratory tract infection (8.0%), and arthralgia (5.6%). There was no dose-dependent relationship observed for treatment-emergent AEs or serious AEs and no new safety signals were recorded.

Identical phase 3 studies GEMINI 1 and 2 (NCT04410978; NCT04410991) each have a target enrollment of 900 participants with relapsing MS who will be randomly assigned to receive 60-mg tolebrutinib or 14-mg teriflunomide (Aubagio, Sanofi) over a treatment duration ranging from 18 to 36 months. Those completing the study will be offered participation in a long-term safety study.

In a previous interview with NeurologyLive®, study primary investigator Jiwon Oh, MD, PhD, said "tolebrutinib is one of the BTK inhibitors that has actually shown evidence of CNS penetration. That’s a big plus. There are very few treatments that we have which have shown efficacy in progressive types of MS. Possibly having a molecule that shows an effect across the spectrum of MS would be incredibly helpful."

1. Media Update: Patient enrollment of phase III tolebrutinib trials paused in the U.S. News release. Sanofi. June 30, 2022. https://www.sanofi.com/en/media-room/press-releases/2022/2022-06-30-05-30-00-2471767
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