Tolebrutinib is a new drug treatment under investigation for relapsing remitting, secondary progressive and primary progressive multiple sclerosis (MS). It is taken as a tablet once daily.
Tolebrutinib for relapsing remitting, secondary and 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 relapsing remitting MS, tolebrutinib reduced the number of new active lesions on MRI.
- In phase II studies, the most common side effects were headache, chest infections and common colds.
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 and it is thought that this will prevent the MS activity which leads to relapses as well as the longer term damage to nerve cells which causes progression.
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 will recruit 1800 participants with relapsing remitting and active secondary progressive MS. One half will take tolebrutinib and the other half Aubagio (teriflunomide) for up to three years. The main measure of these studies is the number of relapses in a year. Additional measures include worsening of disability which persists for three and six months, lesions visible on MRI scans, cognition and quality of life.
Estimated completion date September 2023.
Further details of GEMINI 1
Further details of GEMINI 2
HERCULES – tolebrutinib compared to placebo, in secondary progressive MS
This phase III study is recruiting 1290 participants with non-relapsing (non-active) secondary 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.
Some cases of tolebrutinib-induced liver damage have been reported in clinical trials. Recruitment to HERCULES has been suspended while the trial is amended to increase monitoring of liver function and exclude recruitment of people with risk factors for liver disease.
Estimated completion date August 2024.
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.
Some cases of tolebrutinib-induced liver damage have been reported in clinical trials. Recruitment to PERSEUS has been suspended while the trial is amended to increase monitoring of liver function and exclude recruitment of people with risk factors for liver disease.
Estimated completion date August 2024.
Further details of PERSEUS
The main side effects reported in the phase II clinical trial were:
- headaches
- chest infections
- common cold.
Some cases of tolebrutinib-induced liver damage have been reported in clinical trials. Those affected appeared to be people at greater risk of liver disease because of other, pre-existing medical conditions. Recruitment to HERCULES and PERSEUS has been suspended while the clinical trials are amended to increase monitoring of liver function and exclude recruitment of people with risk factors for liver disease.
