Sanofi’s multiple sclerosis drug candidate, tolotinib, has a key property: the ability to enter the brain and spinal cord tissue to deliver a therapeutic effect. But reports of liver problems in some patients receiving the experimental treatment led the FDA to suspend a pivotal clinical trial of the drug.
According to Sanofi, the FDA is based on Partial clinical hold Observations on drug-induced liver injury. The Paris-based pharma giant did not say how many patients were affected, saying only that “the number of cases is limited.”Multiple sclerosis is divided into four different types According to the course of the disease. Sanofi is testing tolaibrutinib in three of the pivotal studies, with a total target enrollment of nearly 4,000 people. In addition, Sanofi started a separate Phase 3 trial in December testing toletinib in myasthenia gravis, a rare neuromuscular disorder. The study, which targeted 154 people, was also on hold.
The partial suspension, disclosed on Thursday, will stop recruiting new patients in U.S. clinical trials and suspend once-a-day tablets for those who have been in the study for less than 60 days. Study participants who have reached 60 days or more should continue treatment. Sanofi said that most of the patients with observed liver problems had concurrent complications, historically known to predispose patients to drug-induced liver injury. The company did not detail these complications, but said that in laboratory tests used to monitor liver damage, the elevated measurements were reversible in all cases after dosing was stopped.
Liver problems have arisen before. Sanofi said that following earlier discussions with the FDA about the cases, the study protocol was revised in May to update the frequency of monitoring patients. In addition, inclusion 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 that coats 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 comes from Bay Area-based Principia Biopharma, which partnered with Sanofi to develop the drug. In 2020, pharmaceutical giants Acquired Principia for nearly $3.7 billion, the centerpiece of which was the drug, then known as SAR441268At that time, the small molecule was just beginning Phase III testing. According to Sanofi, more than 2,000 patients are currently being treated with tolertinib as part of a late-stage study. Enrollment in MS clinical trials is continuing outside the U.S. with revised study protocols and enhanced safety monitoring, the company said.
Other companies are also developing BTK inhibitors for MS. Merck’s drug candidate, evobrutinib, has entered Phase 3 testing. last year, Biogen pays $125 million for InnoCare for rights to olabrutinib, the mid-term test has been reached in MS. Both molecules are designed to penetrate the brain.
The partial clinical hold on tolatinib is the latest setback for the Principia deal. Rilzabrutinib, another small molecule drug candidate that came to Sanofi through an acquisition, Failure Phase 3 testing last year in pemphigus, a rare autoimmune skin disease. Sanofi halted development of the drug last September. A phase 3 trial of rilzabrutinib in immune thrombocytopenia is ongoing. The drug is also in Phase 2 testing in two other autoimmune diseases: IgG4-related disease and atopic dermatitis.
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