Sanofi's Tolebrutinib Slows MS Progression in Phase III Study After Earlier Setbacks

Sanofi has announced positive results from its Phase III HERCULES trial, which evaluated the investigational BTK inhibitor tolebrutinib in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). This study follows recent setbacks where tolebrutinib did not succeed in improving relapse rates among patients with relapsing multiple sclerosis (MS).

The HERCULES study, a double-blind, randomized trial, assessed the efficacy of daily oral tolebrutinib compared to a placebo over six months. The primary endpoint was the delay in the onset of disability progression, measured using the expanded disability status scale. The results were promising, showing that tolebrutinib delayed disability progression by 31% compared to the placebo.

Additionally, the study reported that 10% of patients treated with tolebrutinib experienced confirmed disability improvement, whereas only about 5% of patients in the placebo group saw similar benefits. This translates to an 88% increase in the likelihood of improvement for those on tolebrutinib, with a nominal p-value of 0.021.

On the safety front, preliminary data indicated a slight increase in adverse events among tolebrutinib-treated patients. Specifically, 4.1% of these patients experienced liver enzyme elevations exceeding three times the upper limit of normal, compared to just 1.6% in the placebo group. Most of these cases resolved without medical intervention, except for one patient who underwent liver transplantation and subsequently died due to surgical complications. This incident led to the implementation of stricter monitoring protocols, which have since mitigated such severe liver issues.

Houman Ashrafian, Sanofi’s head of R&D, noted that tolebrutinib targets underlying drivers of nrSPMS, demonstrating its ability to delay disability progression. The company plans to submit these findings to global regulatory authorities, starting in the second half of 2024.

Financial analysts have also shown optimism. Jefferies analyst Peter Welford described the HERCULES data as "promising," suggesting that it could pave the way for global regulatory filings and approvals. Welford also highlighted the significant unmet need for effective nrSPMS treatments.

Tolebrutinib, designed for oral administration, is a small molecule inhibitor of the BTK protein, which plays a crucial role in the development and function of antibody-producing B cells. By targeting B cells and the disease-driving microglia, tolebrutinib aims to mitigate the progression of nrSPMS.

Sanofi acquired the rights to tolebrutinib in August 2020 through its nearly $3.7 billion acquisition of Principia Biopharma. Since then, the drug has become a cornerstone of Sanofi’s multiple sclerosis program, which also includes the late-stage antibody frexalimab and the Phase II RIPK1 inhibitor oditrasertib.

Despite these recent positive results, tolebrutinib’s clinical journey has faced obstacles. In June 2022, the FDA imposed a partial clinical hold on the drug and suspended enrollment in its Phase III trials due to drug-induced liver injuries. Earlier this month, Sanofi disclosed that tolebrutinib failed to significantly improve relapse rates in patients with relapsing forms of MS across back-to-back Phase III trials.

Nevertheless, the encouraging data from the HERCULES study mark a pivotal moment for tolebrutinib, potentially positioning it as a valuable treatment option for patients with nrSPMS.