Sanofi's BTK inhibitor slows MS progression, liver enzymes remain tricky

Sanofi recently unveiled new Phase 3 results for its BTK inhibitor, tolebrutinib, in treating non-relapsing secondary progressive multiple sclerosis (nrSPMS). The data revealed a 31% improvement in delaying disease progression compared to a placebo. However, the persistent safety concerns associated with the BTK inhibitor class could complicate further developments.

Tolebrutinib, like other BTK inhibitors, has been linked to elevated liver enzyme levels. In this Phase 3 study, 4.1% of patients on tolebrutinib experienced liver enzyme levels three times above the normal limit, compared to 1.6% in the placebo group. The HERCULES subgroup showed even more significant enzyme increases, with 0.5% of patients experiencing a spike up to 20 times the normal limit. One patient in this subgroup died following a liver transplant due to post-surgery complications. Other cases were resolved without medical intervention, leading Sanofi to heighten patient monitoring protocols.

Robert Fox, a clinician at the Cleveland Clinic and chair of the HERCULES global steering committee, mentioned that if tolebrutinib is approved, it might come with a boxed warning due to these safety concerns. He noted that while predicting the exact regulatory outcome is challenging, the risk of liver enzyme elevation necessitates rigorous patient monitoring.

According to a Sanofi spokesperson, enhanced safety protocols have reduced instances of liver enzymes exceeding the 20-fold threshold but have not entirely eradicated such cases. The company is still processing unblinded safety data and could not specify the exact number of cases post-protocol implementation. Notably, the severe liver injury occurred before these new measures were applied.

Sanofi presented these findings at the 2024 ECTRIMS conference in Copenhagen and plans to submit the data to the FDA by the end of 2024. Despite the safety issues, the efficacy data were statistically significant, with a p-value of 0.0026. Fox highlighted that current treatments for secondary progressive MS primarily reduce relapse frequency without significantly slowing disease progression. Tolebrutinib, however, shows potential in addressing this gap, which might influence clinical decisions regarding its use despite safety concerns.

Sanofi acquired tolebrutinib in 2020 through its $3.7 billion acquisition of Principia Biopharma. The drug is a key component of Sanofi's new pipeline focus on immunology, which also includes amlitelimab, lunsekimig, and rilzabrutinib. However, the FDA placed a partial clinical hold on tolebrutinib in June 2022 for both MS and myasthenia gravis, following reports of liver injury. While the hold remains for some Phase 3 MS studies, it has been modified to incorporate new monitoring protocols. Sanofi discontinued tolebrutinib development in myasthenia gravis in early 2023.

Earlier this month, Sanofi released data from two other Phase 3 relapsing MS trials comparing tolebrutinib to standard care. These studies showed mixed efficacy results and did not meet their primary endpoints. However, a pooled analysis indicated a successful delay in the time to disability. Safety data from these trials were more balanced between the active and control arms. Despite this, there were still instances of liver enzyme elevations and patient deaths, although the latter were not linked to the treatment.

Sanofi expects results from another Phase 3 trial in primary progressive MS in 2025.