Roche and Sanofi MS Trials Highlight Potential, Challenges of Oral BTK Inhibitors

Roche’s fenebrutinib has achieved a significant milestone in the treatment of relapsing multiple sclerosis (MS), while Sanofi's tolebrutinib has displayed mixed results in clinical trials for progressive and relapsing forms of the disease. This week has been particularly noteworthy for advancements in MS treatments involving oral BTK inhibitors, which can traverse the blood-brain barrier due to their small molecular structure.

Sanofi's tolebrutinib did not meet the primary efficacy endpoints in two Phase III studies, as it failed to significantly reduce the annualized relapse rate (ARR) for patients with relapsing MS (RMS). However, it did succeed in a third late-stage trial, showing a significant delay in disability progression for those with a less common form of progressive MS. Despite the mixed results, GlobalData finds tolebrutinib especially promising and projects it to generate approximately $2.6 billion in sales by 2030 across major markets like the U.S., France, Germany, Italy, Spain, the U.K., and Japan. In contrast, fenebrutinib’s projected worldwide sales are only expected to reach $810 million in the same year.

Jefferies analysts maintain a positive outlook on tolebrutinib, suggesting that despite the mixed outcomes, the drug could become a largely de-risked opportunity worth $1–2 billion. Just two days after Sanofi’s announcement, Roche reported that fenebrutinib had achieved a mid-stage success in RMS, showing near-total elimination of disease activity. According to GlobalData, 96% of patients treated with fenebrutinib were relapse-free at one year, with Phase III trial results anticipated by the end of next year.

Spherix Global Insights notes that BTK inhibitors are already well-established in oncology, and U.S. neurologists are eagerly awaiting their application in MS. Nevertheless, safety concerns have created an atmosphere of uncertainty. Both Sanofi's and Roche's BTK inhibitors have faced partial clinical holds due to liver safety issues. Sanofi's tolebrutinib trials were halted by the FDA in June 2022 after instances of drug-induced liver injury were recorded. Similarly, Roche's fenebrutinib experienced a partial clinical hold in December 2023 after incidents of elevated liver enzymes and bilirubin levels suggested liver damage.

Jefferies analysts emphasize that liver safety will be a key focus at the upcoming presentations of Sanofi’s full results from the HERCULES and GEMINI 1 and 2 trials at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis in Copenhagen. Shiv Saidha, a neurology professor at Johns Hopkins University, pointed out the importance of secondary endpoints in these trials. This is particularly relevant after Merck KGaA’s BTK inhibitor evobrutinib failed to show benefits in MS and subsequently halted its development in March 2024.

While Sanofi's GEMINI 1 and 2 trials did not show a reduction in ARR, GlobalData noted that pooled secondary endpoint data indicated a significant delay in the onset of confirmed disability worsening. This aligns with the positive disability progression findings from the HERCULES study, providing some support for tolebrutinib’s potential efficacy.

Jefferies analysts acknowledge a confidence issue regarding the broader class of BTK inhibitors. They note that investor expectations have been dampened following Merck KGaA’s evobrutinib failure in RMS. The pressing question now is whether oral BTK inhibitors can replicate their success in oncology for MS treatments.

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