Tolebrutinib is a new drug treatment under investigation for secondary progressive and primary progressive multiple sclerosis (MS). It is taken as a tablet once daily.
Tolebrutinib for secondary progressive MS: Licensing
Tolebrutinib for primary progressive MS: Phase III
- Tolebrutinib interferes with the function of macrophages which have been linked to MS progression and of B cells, a type of white blood cell which is involved in the immune response that damages the myelin coating of nerves.
- In non-relapsing secondary progressive MS, tolebrutinib can significantly slow down disability progression, according results from a phase III trial.
- In phase III studies, the most common side effects were respiratory infections, in particular Covid-19, the common cold and flu.
- In relapsing MS, phase III trials found tolebrutinib was no better at reducing the number of relapses than Aubagio.
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 which causes lesions in the brain and spinal cord and can lead 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.
Other BTK inhibitors in the MS drug pipeline include evobrutinib, fenebrutinib, orelabrutinib and remibrutinib.
Tolebrutinib is taken as a tablet, once daily.
In a phase II study, 130 participants with relapsing remitting MS took one of 4 doses of tolebrutinib for 12 weeks either before or after taking placebo for 4 weeks. Compared to the placebo period, treatment with the highest dose of tolebrutinib resulted in an 85% relative reduction in new T1 lesions, and an 89% relative reduction in T2 lesions. T1 lesions are areas of active, ongoing inflammation; T2 lesions are areas where inflammation has caused damage, regardless of whether there is ongoing inflammation at the time of the scan.
GEMINI I and 2 – tolebrutinib compared to Aubagio (teriflunomide), in relapsing remitting MS
These identical phase III studies recruited 1,873 participants with relapsing remitting and active secondary progressive MS. One half took tolebrutinib and the other half Aubagio (teriflunomide) for up to three years. The main measure of these studies was the number of relapses in a year. Additional measures included worsening of disability which persisted for three and six months, lesions visible on MRI scans, cognition and quality of life.
Results showed that, unfortunately, there was no difference in relapse rate when comparing participants on tolebrutinib vs Aubagio. Although the group generally had very low relapse activity. The results did, however, find that significantly less people on tolebrutinib experienced worsening of disability which persisted for six months than those on Aubagio (8.3% tolebrutinib vs 11.3% teriflunomide). Overall, tolebrutinib was found to slow down disability progression by 29% when compared to Aubagio.
These results suggest that tolebrutinib could have an impact on progression that is independent of relapse activity (PIRA).
The most common side effects in those taking tolebrutinib were Covid-19, the common cold and headache.
Liver damage was the main safety concern arising in the trial. A small number (5.6%) of participants on tolebrutinib experienced significant increases in liver enzymes. All of these participants recovered.
Further details of GEMINI 1
Further details of GEMINI 2
HERCULES – tolebrutinib compared to placebo, in secondary progressive MS
This phase III study recruited 1,131 participants with non-relapsing secondary progressive MS. 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. The participants were randomised at a 2:1 ratio, 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 of disability which persisted for six months (using the EDSS). Other measures included walking speed, manual dexterity, cognitive function, MS activity on MRI scans, improvement in disability and quality of life.
Results showed that significantly less people on tolebrutinib experienced worsening of disability which persisted for six months than those on placebo (22.6% tolebrutinib vs 30.7% placebo). Overall, tolebrutinib was found to slow down disability progression by 31% when compared to placebo.
The study also looked at disability improvement that was sustained for six months. 8.6% of participants on tolebrutinib saw improvements in their disability compared to 4.5% on 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).
In terms of side effects, people taking tolebrutinib reported more cases of respiratory infections – particularly Covid-19, the common cold and flu – and urinary tract infections than those on placebo.
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. Halfway through the trial, liver enzyme monitoring was increased, specifically in the first three months of treatment, to help identify those who might be more at risk of liver damage.
Further details of HERCULES
PERSEUS – tolebrutinib compared to placebo, in primary progressive MS
This phase III study is recruiting 990 participants with primary progressive MS. One half will take tolebrutinib and the other half will take placebo for up to four years. The main aim of the study is to assess the effect of tolebrutinib on disability progression, measured as worsening of disability which persists for six months. Other measures include walking speed, manual dexterity, cognitive function, MS activity on MRI scans, and quality of life.
This trial is ongoing. Results are expected in the second half of 2025.
Further details of PERSEUS
Some cases of tolebrutinib-induced liver damage were reported in clinical trials. Recruitment to HERCULES and PERSEUS was paused while the trials were amended to increase monitoring of liver function and exclude recruitment of people with risk factors for liver disease.
The main side effects reported in the phase II and III clinical trials were:
- respiratory infections (in particular, Covid-19, the common cold and flu)
- urinary tract infections
- headache.
Some cases of tolebrutinib-induced liver damage were reported in clinical trials. Those affected appeared to be people at greater risk of liver disease because of other, pre-existing medical conditions.
