Phase 3 clinical trials testing the drug candidate tolebrutinib in multiple sclerosis (MS) and myasthenia gravis (MG) have been put on partial clinical hold by the US Food and Drug Administration (FDA) due to treatment-induced liver injury in some patients.

As a result, new patient recruitment into the trials has been paused in the United States, and participants who have received treatment for less than 60 days will not receive any further treatment. Those who have been on tolebrutinib for more than 60 days, however, will continue in the trial. 

According to a press release by Sanofi, the developers of tolebrutinib, most patients who developed liver injury had other complications that predisposed them to liver injury, and treatment discontinuation led to a reversal in laboratory values used to monitor liver injury in all cases. 


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The company has now revisited the study protocol. Accordingly, patient monitoring frequency was updated and eligibility criteria were revisited. Enrollment in the trial outside the United States is continuing based on these new criteria. 

“Sanofi remains confident in the future of tolebrutinib as a potentially transformative oral treatment option for people living with MS,” according to the press release.

Tolebrutinib is an investigational Bruton’s tyrosine kinase (BTK) inhibitor. It can penetrate the brain and reach concentrations necessary to reduce the activity of B cells and microglial cells. 

Read more about the etiology of MS

It is being tested in phase 3 clinical trials for the potential treatment of patients with relapsing-remitting, secondary progressive, and primary progressive MS, as well as patients with MG.

Both MS and MG are autoimmune diseases characterized by the body’s immune system mistakenly attacking its own tissues. 

In MS, T cells enter the central nervous system and release proinflammatory cytokines that damage the myelin sheath, nerve fibers, and Schwann cells. T cells also activate B cells that produce autoantibodies against myelin. 

Myasthenia gravis, on the other hand, is characterized by B cells producing autoantibodies against acetylcholine receptors in the neuromuscular junction in most cases.

Reference

Media update: patient enrollment of phase III tolebrutinib trials paused in the U.S. News release. Sanofi; June 30, 2022.