Sanofi released new Phase 3 data for its BTK inhibitor tolebrutinib in non-relapsing secondary progressive multiple sclerosis (nrSPMS), showing a 31% improvement in delaying onset of disease progression compared to placebo.
But safety issues that have dogged the drug class could complicate the readout.
Tolebrutinib is a BTK inhibitor, and it and other related drugs have faced issues with elevated liver enzymes. In the Phase 3 readout, those signals showed up again — 4.1% of patients on tolebrutinib had their liver enzymes jump to three times the normal limit, compared with 1.6% in the placebo group.
A smaller group in the trial, called HERCULES, showed even sharper liver enzyme increases: 0.5% of patients saw their liver enzymes spike to 20 times the normal limit, and one of those patients died after needing a liver transplant and suffered post-surgery complications. Every other case resolved without medical intervention, but Sanofi had to implement more rigorous monitoring of patients.
Robert Fox, a clinician at the Cleveland Clinic and chair of the HERCULES global steering committee, said that if tolebrutinib is approved, he wouldn’t be surprised if it came with a boxed warning.
Robert Fox“Would I be surprised if it’s in a black box? No,” Fox said. “But predicting whether it is or not, that’s not something I can do.”
More intensive safety monitoring has lessened the amount of patients whose liver enzymes exceed the 20-fold threshold, but hasn’t eliminated cases entirely, a Sanofi spokesperson told Endpoints News.
The spokesperson also said the company is still working through unblinding its safety data and can’t give an exact number of cases after the new protocols were instituted (the patient who died after a liver transplant received the drug beforehand). Sanofi presented the data at the 2024 ECTRIMS conference in Copenhagen. It plans to file with the FDA by the end of 2024.
Despite the safety concerns, Fox said the data represented an impressive milestone in MS treatment — the efficacy results were statistically significant, with a p-value of p=0.0026. Fox noted that there isn’t anything on the market to slow secondary progressive MS’ disease progression, and that approved drugs only reduce the frequency of relapse episodes.
Tolebrutinib “actually does something where none of the other therapies do anything. So that’s where we are, and so that is the decision that a clinician will have to consider,” Fox said. “If this were to be available for clinical use, how much anti-inflammation does my patient need, and how much slowing [of] that insidious progression does my patient need?”
Sanofi acquired tolebrutinib as part of its $3.7 billion acquisition of Principia Biopharma in 2020 and has made it a central part of its new pipeline focus around immunology in addition to amlitelimab (bought from Kymab), lunsekimig (developed from Ablynx’s platform) and rilzabrutinib (also from Principia), among others.
But the FDA placed a partial clinical hold on the drug in June 2022 in both MS and myasthenia gravis, an autoimmune disease, after reports of liver injury. While the partial hold remains in effect for other Phase 3 MS studies (it was “modified” to account for the new monitoring protocols, the spokesperson said), Sanofi discontinued development in myasthenia gravis in early 2023.
Sanofi released data from two other Phase 3 relapsing MS trials earlier this month comparing tolebrutinib to standard of care, which showed mixed efficacy results. While neither study hit their primary endpoints, a pooled analysis showed they successfully delayed the time to disability.
Safety data also presented at ECTRIMS across these two trials were more numerically balanced between the active and standard-of-care arms, but there were still cases of liver enzymes rising 20 times above the normal limit and patient deaths, though the latter were deemed unrelated to treatment. Another Phase 3 in patients with primary progressive MS is expected to read out in 2025.
Editor’s note: This story has been updated to correct the p-value from 0.026 to 0.0026, that previously released mixed data came in RMS studies, not nrSPMS, and that patient deaths in these studies were not linked to treatment.