Liver injuries prompt clinical hold on Sanofi BTK drug

One of the main assets of Sanofi's $3.7 billion buyout of Principia Biopharma has run into trouble, after the FDA placed it on partial clinical hold while a safety signal is investigated.

The regulator is requiring Sanofi to stop dosing some patients in phase 3 trials of the BTK inhibitor tolebrutinib (SAR442168) in multiple sclerosis and myasthenia gravis, following reports of drug-induced liver damage in some subjects. The hold on dosing applies to subjects in the trials who have received the drug for less than 60 days.

Sanofi said that most of the cases involved patients who were already at elevated risk of liver side effects due to concomitant medical conditions, and elevated enzyme levels used as biomarkers for liver injury fell after treatment with tolebrutinib was halted.

The drugmaker also said it had been aware of the issue and modified the protocol of the study last month to increase the frequency of liver toxicity testing and exclude recruitment of people with risk factors for liver disease.

Those changes haven't been enough to prevent the FDA from taking action, although outside the US the studies will continue as planned with the tighter safety monitoring.

Tolebrutinib is one of three clinical-stage BTK inhibitor candidates that Sanofi acquired with the Principia takeover, and the second to suffer a setback after rilzabrutinib failed a trial involving patients with rare autoimmune skin disorder pemphigus last September.

Rilzabrutinib remains in development despite the miss, but the tolebrutinib development is potentially more serious as the drug is in competition in MS with other BTK inhibitors from Merck KGaA, Roche and Biogen.

First among these is Merck, whose evobrutinib became the first BTK inhibitor to show proof-of-concept in relapsing MS, and is in phase 3 testing with a data readout due next year. Meanwhile, Roche's fenebrutinib and Biogen's orelabrutinib are still in mid-stage testing.

All the BTK inhibitors are designed to be able to cross the blood brain barrier and enter the central nervous system, dampening down the autoimmune response that leads to neuronal damage in MS.