Sanofi’s multiple sclerosis hopeful tolebrutinib faced dual setbacks on Monday, with a late-stage failure in one form of the disease and yet another regulatory setback in another.
Sanofi reported a double whammy of bad news for multiple sclerosis drug tolebrutinib on Monday. The investigational therapy failed to slow disability progression in a Phase III trial, while on the regulatory side, it faces yet another delay for an approval application in progressive disease.
Starting with the trial, the BTK inhibitor was being studied in patients with primary progressive multiple sclerosis (PPMS) in the Phase III PERSEUS trial. This indication applies to about 10% of patients with MS. The study failed to meet its primary endpoint, a measure of disability progression when compared with placebo.
Sanofi did not provide specific numbers but said it would not pursue regulatory applications in PPMS.
Leerink Partners, in a series of notes leading up to the readout, had been anticipating the study to be a success. Specifically, the firm believed Sanofi’s offering would beat Roche’s approved MS drug Ocrevus on delaying disease progression compared to placebo at week 24.
The French pharma was also mum on the potential for liver injury with tolebrutinib in the Monday press release. While Sanofi acknowledged the risk of drug-induced liver injury associated with tolebrutinib, it did not provide detailed safety results from the PERSEUS trial, simply noting that results were consistent with previous studies. Leerink had been keenly awaiting these stats to weigh the potential for success of tolebrutinib’s existing FDA application for secondary progressive multiple sclerosis (SPMS).
On the regulatory front, the FDA has once again delayed a decision on tolebrutinib’s application for non-relapsing secondary progressive multiple sclerosis (nrSPMS). In September, the agency pushed back the decision timeline to December 28. Sanofi now says the decision has been delayed again and no firm date has been provided. The FDA requested additional information on an expanded access protocol in nrSPMS.
The FDA will provide an updated decision date by the end of the first quarter of 2026, Sanofi said.
Leerink called today’s updates “disappointing” in a brief note on Monday morning. The firm had been projecting sales of about $1.1 billion for the drug.
Rival Roche also has a BTK inhibitor in development called fenebrutinib, which Leerink said has already demonstrated similar efficacy to Ocrevus in PPMS.
Sanofi’s tolebrutinib has had a tough path through the clinic, with several failures as well as cases of liver injury that spurred clinical holds from the FDA. In September 2024, Sanofi finally reported Phase III success in the HERCULES trial, with the drug delaying disease progression by 31% in patients with nrSPMS. These results teed up the regulatory filing that is now once again being pushed back.
The HERCULES trial also showed an increase in adverse events, including a rate of liver enzyme elevations in 4.1% of patients who took the study drug. Most resolved without issue, but a patient who underwent a liver transplant after treatment died. Sanofi implemented changes to the study protocol to boost liver monitoring.
Designed to be administered orally, tolebrutinib is a small molecule inhibitor of the BTK protein, which under healthy circumstances is important for the development and activity of antibody-producing B cells. Tolebrutinib’s mechanism of action allows it to suppress B cells and the disease-driving microglia.
Sanofi came to own tolebrutinib in the $3.7 billion acquisition of Principia Biopharma in August 2020.
