FDA pumps brakes on Sanofi's $3.7B multiple sclerosis bet, imposing partial hold over liver injuries

The $3.7 billion centerpiece of Paul Hudson’s R&D strategy for Sanofi has hit a setback. Seeing cases of drug-induced liver injury, the FDA has slapped a partial clinical hold on phase 3 trials of the candidate, raising still more doubts about the merits of Sanofi’s Principia Biopharma takeover.

Sanofi struck a deal to buy Principia in 2020, with Hudson brushing off concerns about the limitations of midphase data on tolebrutinib and broader doubts about the efficacy of BTK inhibitors in autoimmune diseases to make the asset a key part of his attempt to kick-start the R&D engine after taking over as CEO. Now, the FDA has tapped the brakes on Sanofi’s push to get the molecule to market. 

The action affects phase 3 clinical trials of the Bruton’s tyrosine kinase inhibitor in multiple sclerosis and myasthenia gravis. Under the terms of the partial FDA clinical hold, enrollment at U.S. sites is stopped and dosing is suspended in existing subjects who have been in the study for fewer than 60 days. Sanofi can keep dosing participants who have completed at least 60 days in the study.

Officials at the FDA imposed the restrictions in response to “a limited number of cases of drug-induced liver injury,” Sanofi said. According to the company, most patients had “concurrent complications known historically to predispose to drug-induced liver injury,” and the elevated laboratory values were reversible after they stopped taking the treatment.

Sanofi revised the study protocols in May after earlier conversations with the FDA about the cases. The set of revisions included the addition of preexisting risk factors for hepatic dysfunction to the exclusion criteria. The changes are yet to show up on the ClinicalTrials.gov listings for the studies. 

Outside the U.S., enrollment is continuing under the revised protocols. The continuation of the studies in other parts of the world should mitigate the impact of the partial hold given the geographic mix of sites in the trials. U.S. sites account for 13% and 23% of the locations in the two phase 3 clinical trials Sanofi is running in relapsing forms of multiple sclerosis. Analysts at SVB Securities said "a late 2023 readout in relapsing MS could still be possible," adding that the "clinical hold Is concerning but doesn’t sink the program."

The clearance to continue dosing in patients who have spent at least 60 days in the study is another plus for Sanofi. The four multiple sclerosis clinical trials all began around two years ago, suggesting that many patients may be able to continue treatment under the terms of the partial clinical hold. Sanofi said it has enrolled more than 2,000 patients in the program. The total enrollment target of the four trials is 4,080. 

However, the partial FDA hold is still a blow to the fragile confidence in Sanofi’s Principia takeover. Short sellers savaged Principia’s pipeline before the Sanofi takeover, branding it “worthless,” and the release of phase 2 data from a small trial with a complex design failed to quell the questions. The failure of a phase 3 trial of another drug acquired in the Principia buyout, rilzabrutinib, closed off one chance to generate a return on the deal, although success for tolebrutinib would more than offset that setback.