Tolebrutinib slows down disability progression in non-relapsing secondary progressive MS

Results from a phase III clinical trial show that tolebrutinib can significantly slow down disability progression in people with secondary progressive MS who no longer experience relapses.

The study

The phase III study, called HERCULES, recruited 1,131 participants with non-relapsing secondary progressive MS (SPMS). These participants had to have a diagnosis of SPMS with no relapses in the last two years, evidence of disease progression in the previous 12 months, and an EDSS score of between 3.0 to 6.5. Participants were randomised with 754 taking tolebrutinib and 377 taking placebo (a dummy drug) for up to four years.

The main aim of the study was to assess whether tolebrutinib affects disability progression that is unrelated to relapse activity (also known as PIRA). This was measured as worsening disability which persisted for at least six months (using the EDSS). The study also assessed the safety of the drug. Other measures included: the number of new or enlarging lesions on MRI, improvement in disability that lasted for at least six months, and percentage change in brain volume.

Results

Results from the study showed that, in non-relapsing SPMS, tolebrutinib significantly reduces the risk of disability progression when compared to placebo. 22.6% of participants in the tolebrutinib group experienced worsening of disability which persisted for at least six months vs 30.7% of participants in the placebo group. Overall, tolebrutinib was found to slow down disability progression by 31% when compared to placebo.

Tolebrutinib was also associated with 38% fewer new or enlarging lesions on MRI. The annual rate of new or enlarging lesions was 1.84 in the tolebrutinib group vs 2.95 for those taking placebo. However, tolebrutinib wasn’t found to slow down brain volume loss (atrophy).

The study also looked at disability improvement that lasted for at least six months. 8.6% of participants on tolebrutinib saw improvements in their disability compared to 4.5% on placebo.

Side effects

The most common side effects in those taking tolebrutinib were respiratory infections – in particular, Covid-19, the common cold and flu – and urinary tract infections.

The main safety concern that arose during the trial was liver damage in some participants. A small number (4%) of those on tolebrutinib experienced a significant increase in liver enzymes. The majority recovered, however one person required a liver transplant and sadly died of post-surgery complications.

In summary

Overall, these initial study results are very promising. If licensed and approved for use on the NHS, tolebrutinib could become one of the first drugs available to slow down disability progression in those with SPMS who no longer experience relapses. This would be a major step forward for a group of people who face worsening disability, but who currently only have access to symptomatic treatments to manage their daily symptoms.

Once a drug is proven to be safe and effective in a phase III clinical trial, the next stage is getting the drug licensed to allow it to be sold.

Regulatory authorities – in the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) – will check the clinical trial data to ensure the drug is safe and effective. If satisfied, a licence (or marketing authorisation) will be issued.

Sanofi, the drug manufacturer, states in their press release that the data is currently under review by the regulatory authorities in Europe and the US. Decisions are expected later in 2025.

Once licensed, tolebrutinib would need to be approved by NICE and the SMC before it can become available on the NHS.

Find out more about the drug development process

The safety and effectiveness of tolebrutinib was assessed in people with relapsing MS in phase III trials, GEMINI 1 and GEMINI 2. The studies compared tolebrutinib to the established disease modifying drug, Aubagio. They looked at the effect on relapse rate and worsening of disability. 

Results showed that tolebrutinib was no better than Aubagio at reducing relapse rate. However, the drug did delay disability progression by 29%. This is in line with the results of the HERCULES trial in SPMS discussed above.

Tolebrutinib is currently being assessed in people with primary progressive MS in a phase III trial called PERSEUS. This study is looking at the drug’s effect on disability progression. The trial is ongoing with results expected in the second half of 2025.

Tolebrutinib belongs to a group of medicines called Bruton's tyrosine kinase (BTK) inhibitors.

Bruton’s tyrosine kinase is an enzyme which is essential for the survival and activation of B-cells. B-cells are a type of white blood cell (lymphocyte) thought to be involved in the inflammation caused by MS. This inflammation is what causes lesions in the brain and spinal cord and leads to relapses. The enzyme also regulates immune cells in the brain called macrophages and microglia which have been linked to MS progression.

Tolebrutinib blocks the actions of the enzyme. It’s thought this will prevent the MS activity which leads to relapses, and slow down the longer-term damage to nerve cells (chronic inflammation and neurodegeneration) that drives disability worsening in progressive MS.

Tolebrutinib is taken as a tablet once a day.