Liver injury leads FDA to pause Sanofi’s tests of MS drug acquired in $3.7B deal


Sanofi multiple sclerosis drug candidate tolebrutinib boasts a key feature: the ability to reach into brain and spinal cord tissue to provide its therapeutic effect. But liver problems have been reported in some patients dosed with the experimental treatment, leading the FDA to pause the drug’s pivotal clinical trials.

According to Sanofi, the FDA based the partial clinical hold on observations of drug-induced liver injury. The Paris-based pharmaceutical giant did not disclose how many patients were affected other than to say it was “a limited number of cases.” Multiple sclerosis is classified into four different types based on the course of the disease. Sanofi is testing tolebrutinib across three of them in pivotal studies with a total targeted enrollment of nearly 4,000. In addition, Sanofi began a separate Phase 3 test last December testing tolebrutinib in myasthenia gravis, a rare neuromuscular disorder. That study, with a targeted enrollment of 154, is also on pause.

The partial hold disclosed Thursday stops enrollment of new patients in clinical trials in the U.S. and suspends dosing of the once-daily tablet for those who have been in a study for fewer than 60 days. Study participants who have reached 60 days or more should continue treatment. Sanofi said that most of those observed with liver problems had concurrent complications known historically to predispose a patient to drug-induced liver injury. The company did not go into detail about those complications, but said that in laboratory tests used to monitor liver injury, the elevated measures were reversible in all cases after dosing of the drug was stopped.

The liver problems have come up previously. Sanofi said that after earlier discussions with the FDA about these cases, study protocols were revised in May to update how frequently patients were monitored. Also, enrollment criteria were changed to exclude those with preexisting risk factors for liver problems.

MS is an autoimmune disease in which B cells, a type of immune cell, attack the protective myelin sheath covering nerve cells. Tolebrutinib is a small molecule designed to penetrate the protective blood-brain barrier. The drug blocks Bruton’s tyrosine kinase (BTK), an enzyme that regulates B cell growth and survival.

Tolebrutinib came from Bay Area-based Principia Biopharma, which partnered with Sanofi on the drug’s development. In 2020, the pharmaceutical giant acquired Principia in a nearly $3.7 billion deal whose centerpiece was the drug, known then as SAR441268. At that time, the small molecule was just starting Phase 3 testing. According to Sanofi, more than 2,000 patients are currently on tolebrutinib therapy as part of the late-stage studies. The company said enrollment in the MS clinical trials is continuing outside of the U.S. with revised study protocols and enhanced safety monitoring.

Other companies are also developing BTK inhibitors for MS. Merck KGaA has reached Phase 3 testing with its drug candidate, evobrutinib. Last year, Biogen paid InnoCare $125 million up front for rights orelabrutinib, which has reached mid-stage testing in MS. Both molecules are designed to penetrate into the brain.

The partial clinical hold on tolebrutinib is the latest setback to come out of the Principia deal. Rilzabrutinib, another small molecule drug candidate that came to Sanofi via the acquisition, failed a Phase 3 test last year in pemphigus, a rare autoimmune skin disorder. Sanofi stopped development of the drug in that indication last September. A Phase 3 test of rilzabrutinib is ongoing in immune thrombocytopenia. The drug is also in Phase 2 testing in two other autoimmune conditions: IgG4-related disease and atopic dermatitis.

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