FDA Grants Breakthrough Therapy Status to Tolebrutinib for Non-Relapsing Secondary Progressive MS

On December 13, 2024, the US Food and Drug Administration (FDA) recognized tolebrutinib with Breakthrough Therapy designation for its significant potential in treating adults with non-relapsing secondary progressive multiple sclerosis (nrSPMS). This acknowledgment arises from the promising results of the HERCULES phase 3 study, which highlighted tolebrutinib’s effectiveness in delaying the onset of six-month confirmed disability progression (CDP) by 31% compared to placebo. The study also suggested that tolebrutinib could nearly double the chances of confirmed disability improvement in patients.

Breakthrough Therapy designation is a special status granted by the FDA to expedite the development and review process for drugs targeting severe or life-threatening conditions. To obtain this designation, a drug must show preliminary evidence suggesting a considerable improvement over existing treatments on clinically significant endpoints.

Erik Wallström, MD, PhD, Global Head of Neurology Development at Sanofi, emphasized the importance of this designation, noting its potential to address a critical need for patients with multiple sclerosis by potentially delaying disease-related disability progression. Sanofi is preparing to work closely with the FDA during the regulatory review of tolebrutinib, as there are currently no approved treatments for nrSPMS.

Although promising, the study noted some side effects. Liver enzyme elevations greater than three times the upper limit of normal (ULN) were observed in 4.1% of participants taking tolebrutinib, compared to 1.6% in the placebo group. A small fraction (0.5%) of patients on tolebrutinib experienced peak ALT increases over 20 times ULN, all occurring within the initial 90 days of treatment. Fortunately, nearly all cases resolved without additional medical intervention, thanks in part to more frequent monitoring, which has helped reduce significant liver complications.

Sanofi is in the final stages of preparing regulatory submissions for tolebrutinib in the US and is also preparing for submissions in the EU. The company intends to confirm once a regulatory submission has been accepted. Additionally, the PERSEUS phase 3 study is underway, evaluating tolebrutinib in primary progressive MS, with results expected in the latter half of 2025.

Multiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disease, often leading to irreversible disabilities over time. These disabilities can deteriorate physical and cognitive health, severely impacting patients' quality of life. Current MS treatments primarily target peripheral B and T cells, leaving innate immunity, believed to contribute significantly to disability accumulation, largely unaddressed. Tolebrutinib, however, is an investigational oral, brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor designed to achieve cerebrospinal fluid concentrations that modulate both B lymphocytes and disease-associated microglia.

The HERCULES study (clinical study identifier: NCT04411641) was a double-blind, randomized phase 3 clinical trial. It assessed tolebrutinib’s efficacy and safety in nrSPMS patients, defined as those with an expanded disability status scale (EDSS) between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented disability accumulation in the preceding year. Participants received either an oral daily dose of tolebrutinib or a placebo for up to 48 months.

The study's primary endpoint was the six-month CDP, defined by specific increases in EDSS scores. Secondary endpoints included the onset of three-month CDP, the number of new or enlarging T2 hyperintense lesions via MRI, the time to confirmed disability improvement, and changes in tests assessing physical abilities, alongside safety and tolerability assessments of tolebrutinib.

Tolebrutinib’s recognition as a Breakthrough Therapy underscores its potential as a novel treatment option in a field where treatment innovation is vital. As regulatory processes advance, further studies will continue to examine its safety and efficacy on a global scale.