FDA Grants Breakthrough Therapy Designation to Sanofi’s Tolebrutinib for Non-Relapsing Secondary Progressive Multiple Sclerosis

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The FDA has granted Breakthrough Therapy Designation (BTD) to Sanofi’s tolebrutinib for the treatment of non-relapsing secondary progressive multiple sclerosis (nrSPMS). According to the company, the BTD was based on positive results from the HERCULES Phase III clinical trial. Additional analysis found that the number of participants who experienced confirmed disability improvement was nearly double with tolebrutinib compared to patients who received a placebo.¹

“This Breakthrough Therapy designation demonstrates the potential for tolebrutinib to delay disability progression, a critical unmet need for people living with multiple sclerosis. We look forward to working with the FDA during the regulatory review of this first of its kind medicine in non-relapsing secondary progressive multiple sclerosis where there are currently no approved treatments available,” said Erik Wallström, MD, PhD, global head, neurology, Sanofi, in a press release.

The double-blind, randomized, Phase III HERCULES clinical study evaluated the efficacy and safety of tolebrutinib in participants with nrSPMS. According to Sanofi, nrSPMS was defined at baseline as having a SPMS diagnosis with an expanded disability status scale (EDSS) between 3.0 and 6.5, no clinical relapses for the previous 24 months, and documented evidence of disability accumulation in the previous 12 months. All participants were randomly assigned in a 2:1 ratio to receive either an oral daily dose of tolebrutinib or matching placebo for up to approximately 48 months.

The primary endpoint of the trial was a reduction in six-month confirmed disability progression from the baseline EDSS score when the baseline score is ≤5.0, or the increase of ≥0.5 point when the baseline EDSS score was >5.0. Secondary endpoints included time to onset of three-month CDP as assessed by EDSS score, total number of new or enlarging T2 hyperintense lesions as detected by MRI, time to onset of confirmed disability improvement, three-month change in nine-hole peg test and T25-FW test, as well as the safety and tolerability of tolebrutinib.

Tolebrutinib demonstrated a 31% reduction in six-month confirmed disability progression. Additionally, results show a 10% rate of confirmed disability improvement in the tolebrutinib group compared to 5% in the placebo group.

While liver enzyme elevations were reported in 4.1% of participants on tolebrutinib compared to 1.6% for placebo, cases were generally manageable with monitoring. Additionally, 0.5% of patients in the tolebrutinib group experienced peak ALT increases of >20xULN, all occurring within the first 90 days of treatment. Only one liver enzyme evaluation required a further evaluation.¹

According to the National Multiple Sclerosis Society, an estimated 2.8 million people are currently living with MS globally. In 2019, around one million people in the United States were diagnosed with MS. For every 1,000 people in the United States with multiple sclerosis, four people are white but not Hispanic, three people are Black but not Hispanic, and approximately 1.5 people are Hispanic. Lastly, an estimated two people are of other races, including Asians, Native Americans, Alaska natives and people of several races or unknown race.²

Currently, regulatory submissions are being finalized for the FDA and are also being prepared for the European market. Additionally, the PERSEUS Phase III study in primary progressive MS is ongoing, with results expected in the second half of next year. Tolebrutinib remains under clinical investigation, and its safety and efficacy have not yet been evaluated by regulatory authorities.¹

References

1. Press Release: Tolebrutinib designated Breakthrough Therapy by the FDA for non-relapsing secondary progressive multiple sclerosis. Sanofi. December 13, 2024. Accessed December 13, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-12-13-06-00-00-2996609

2. MS Prevalence. NMSS. Accessed December 13, 2024. https://www.nationalmssociety.org/about-the-society/who-we-are/research-we-fund/ms-prevalence#:~:text=Prevalence%20of%20MS,in%20the%20world%20have%20MS.