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. They announced results of the GEMINI and HERCULES trials in September 2024.

• The GEMINI 1 and 2 trials aimed to recruit 1800 people with relapsing MS. They compared the efficacy of tolebrutinib with an existing treatment called teriflunomide (Aubagio). Researchers found that tolebrutinib was no better at reducing relapses. But it did slow down how long it took to see disability worsening by 29% compared to teriflunomide.
• The HERCULES trial compared tolebrutinib with a placebo (dummy drug) in people with non-relapsing secondary progressive MS. They aimed to recruit 1290 participants to see whether it could slow MS progression. Results showed tolebrutinib delayed how long it took to see disability to worsening by 31% compared to placebo
• The PERSEUS trial recruited 990 people with primary progressive MS. Similar to HERCULES, the researchers wanted to know whether tolebrutinib can slow MS progression. Unfortunately, the researchers found that tolebrutinib did not slow down disability progression in primary progressive MS.

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.

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. Most participants' livers returned to normal when they stopped taking the drug. But sadly one person died following a liver transplant. More frequent monitoring was added to the trial which reduced how severe the liver issues were. 

The GEMINI 1 and 2 trials compared tolebrutinib to teriflunomide (Aubagio). It found that tolebrutinib was no better at reducing relapses. But results indicated that is was better at slowing disability progression.

Sanofi (the drug company who developed tolebrutinib) submitted their phase 3 trial results to the US Food and Drug Administration (FDA), who are responsible for regulating drugs in the US.  

After reviewing Sanofi’s trial results, the FDA rejected tolebrutinib as a treatment for MS. This was because they were concerned about the risk of severe liver damage associated with tolebrutinib. Even once the company had introduced extra monitoring. And because the medication didn’t appear to provide sufficiently meaningful benefits for people taking it. This decision means that tolebrutinib is unlikely to become available for people with MS in the US. 

The Medicines and Healthcare products Regulatory Agency (MHRA) is responsible for reviewing medications in the UK. We are waiting to hear the outcome of their review.