Tolebrutinib

Tolebrutinib is part of a new class of drugs called Bruton’s tyrosine kinase (BTK) inhibitors. BTK is a molecule that affects the activity of some immune cells. Stopping BTK working properly reduces the activity of those immune cells.

These cells have been linked to MS relapses and progression. Researchers believe reducing their activity could reduce damage caused to nerves.

As a tablet, once daily.

Phase 2b trial

In February 2020, Sanofi shared the results of a phase 2b clinical trial. The trial involved 130 people with relapsing MS. Participants took tolebrutinib for 12 weeks either before or after taking a placebo (dummy drug) for four weeks.

The results showed that compared to the placebo, treatment with the highest doses of tolebrutinib resulted in an 85% reduction in new lesions. 

Phase 3 trials

Following these promising results, Sanofi launched three follow up phase 3 clinical trials.

• The GEMINI 1 and 2 trials aim to recruit 1800 people with relapsing MS. They will compare the efficacy of tolebrutinib with an existing treatment called teriflunomide (Aubagio). The researchers want to know whether tolebrutinib is better at reducing relapses. They’ll also be looking at worsening of disability, lesions visible on MRI scans, cognition and quality of life. The estimated completion date is August 2023. 
• The HERCULES trial aims to recruit 1290 participants with non-relapsing secondary progressive MS. The researchers want to know whether tolebrutinib can slow MS progression. They’ll also be looking at walking speed, manual dexterity, lesions visible on MRI scans, cognition and quality of life. The estimated completion date is October 2024.
• The PERSEUS trial aims to recruit 990 participants with primary progressive MS. Similar to HERCULES, the researchers want to know whether tolebrutinib can slow MS progression. They’ll also be looking at walking speed, manual dexterity, lesions visible on MRI scans, cognition and quality of life. The estimated completion date is August 2024.

In June 2022, the FDA (Food and Drug Administration, a US regulator) placed the Sanofi trials for tolebrutinib on partial clinical hold. This was because a small number of participants experienced liver injury. Their livers returned to normal when they stopped taking the drug.

New participants can’t be enrolled into the trials. And, people who had been taking the drug for 70 days or less had to stop. People who had been taking it for more than 70 days were allowed to complete the treatment.

A phase 1 clinical trial to test the safety profile of tolebrutinib was completed in 2020. Results indicate it is well tolerated and poses no obvious safety concerns.  

The primary side effects reported from the phase 2b clinical trial in 2020 were headaches, chest infections and common cold.

The phase 3 trials showed a small number of participants experienced liver injury. This usually results in bleeding within the liver. Their livers returned to normal when they stopped taking the drug.

Tolebrutinib has not been widely tested in people with MS so it isn’t yet known how it compares to existing MS treatments. Phase 3 clinical trials are hoping to compare the efficacy of tolebrutinib with that of teriflunomide (Aubagio).

Tolebrutinib is currently being investigated in three phase 3 trials, with the results due in 2023 and 2024. If the results are positive, tolebrutinib will be submitted for regulatory approval.

Positive trial results can only make a real difference to people with MS once a regulator like the European Medicines Agency concludes there's sufficient evidence the drug is safe and effective.