The US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to tolebrutinib for the treatment of adults with non-relapsing secondary progressive multiple sclerosis (nrSPMS). This decision is based on promising data from the HERCULES Phase 3 study, which showed that tolebrutinib delayed the time to the onset of 6-month confirmed disability progression (CDP) by 31% compared to placebo (HR 0.69; 95% CI 0.55-0.88; p=0.0026). Further analysis of secondary endpoints indicated that nearly twice as many participants who received tolebrutinib (10%) experienced confirmed disability improvement compared to those on placebo (5%) (HR 1.88; 95% CI 1.10 to 3.21; nominal p=0.021).
FDA Breakthrough Therapy designation is granted to medications that target serious or life-threatening conditions and demonstrate preliminary clinical evidence showing substantial improvement over existing treatments. This designation is intended to accelerate the development and review process for drugs that could offer significant benefits to patients.
Erik Wallström, MD, PhD, Global Head of Neurology Development at Sanofi, commented, “This Breakthrough Therapy designation demonstrates the potential for tolebrutinib to delay disability progression, addressing a critical unmet need for individuals living with multiple sclerosis. We are excited to collaborate with the FDA during the regulatory review of this innovative treatment for non-relapsing secondary progressive multiple sclerosis, a condition for which no approved therapies currently exist.”
In the HERCULES study, while tolebrutinib showed efficacy in reducing disability progression, some liver enzyme elevations were observed. Specifically, 4.1% of participants receiving tolebrutinib experienced elevations greater than three times the upper limit of normal (ULN) compared to 1.6% in the placebo group. A small percentage (0.5%) of those treated with tolebrutinib experienced peak ALT increases exceeding 20 times the ULN, all occurring within the first 90 days of treatment. However, the majority of these cases resolved without medical intervention, and the implementation of more frequent monitoring has helped to minimize the risk of severe liver-related issues.
Tolebrutinib is currently being investigated in clinical trials, with ongoing regulatory submissions being finalized for the US and preparations underway for the European Union (EU). Sanofi has indicated that it will confirm once the regulatory submission for tolebrutinib has been accepted. Additionally, the PERSEUS Phase 3 study in primary progressive multiple sclerosis (PPMS) is ongoing, with results expected in the second half of 2025.
It is important to note that tolebrutinib is still under clinical investigation, and its safety and efficacy have not yet been reviewed or approved by any regulatory authority. As with all experimental therapies, the outcome of ongoing studies and regulatory reviews will determine its future availability for patients.
Overall, the FDA’s Breakthrough Therapy designation for tolebrutinib highlights its potential to make a significant impact on the treatment landscape for people with non-relapsing secondary progressive multiple sclerosis, a condition that currently lacks approved therapies. The clinical trial data supports tolebrutinib’s potential to provide meaningful benefits by delaying disability progression and even improving disability in some patients.
