- Tolebrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor, a treatment that specifically targets immune cells that have the BTK enzyme. This means it can help control the immune system without wiping out all B cells.
- Two large multi-national clinical trials of people with relapsing MS found tolebrutinib and teriflunomide were similar in their ability to lower the rate of relapses.
- Another large multi-national trial compared tolebrutinib to a placebo (mock treatment) in people with non-relapsing secondary progressive MS and found tolebrutinib lowered the risk of disability progression.
What is tolebrutinib?
Tolebrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that selectively targets B cells (a type of immune cell) that have the BTK enzyme (a biological molecule that speeds up reactions within cells). By doing so, it does not reduce the level of all B cells.
Unlike most available disease-modifying therapies (DMTs), tolebrutinib can cross the blood-brain barrier to target immune cells in the brain and spinal cord. Therefore, it is expected that tolebrutinib may have a greater effect on inflammation in the brain and nerve degeneration than existing DMTs.
What did the researchers do?
In two large multi-national clinical trials (GEMINI 1 and GEMINI 2), researchers gave people with relapsing MS either tolebrutinib or teriflunomide, which are both oral tablets taken daily. They then followed the two groups for an average of two-and-a-half years to assess their rate of relapses and their disability progression.
In another large multi-national clinical trial (HERCULES), researchers gave people with non-relapsing secondary progressive MS either tolebrutinib or placebo (mock treatment) tablets and followed the two groups for up to two-and-a-half years. The researchers assessed the trial participants for their disability progression and new and enlarging lesions.
What did the researchers find for people with relapsing MS?
Published in The New England Journal of Medicine, researchers found people with relapsing MS who were treated with tolebrutinib experienced similar relapse rates as those who were treated with teriflunomide.
On following trial participants for at least the first six months of the trial, the level of disability worsened in 8.3% of people receiving tolebrutinib and in 11.3% of those receiving teriflunomide. Over the same time period, 12.6% of people treated with tolebrutinib and 10.4% of people treated with teriflunomide had confirmed improvement in their disability.
While this study was designed to assess relapse rates and did not proceed with further statistical testing, initial observations suggest that fewer participants on tolebrutinib experienced worsening disability compared to those on teriflunomide, an encouraging trend that warrants further investigation.
Most people in both treatment groups experienced mild side effects. As the clinical trial was conducted during the COVID-19 pandemic, the most common side effect was COVID-19 infection. Other side effects in both groups were inflammation of the nose and throat, headache, hair loss and minor bleeding. A small percentage of people in each group experienced increased liver enzymes, but these resolved without lingering after-effects.
What did they find for people with secondary progressive MS?
Also published in The New England Journal of Medicine, researchers found that people taking tolebrutinib had 31% lower risk of confirmed disability progression (sustained for at least six months) compared to those taking a placebo.
Over the same period, people who took tolebrutinib were nearly twice as likely to experience a lasting improvement in their disability compared to those who took a placebo. People taking tolebrutinib also had lower rates of new or enlarging lesions compared to those taking the placebo.
Most people in this trial also experienced mild side effects. This clinical trial was also conducted during the COVID-19 pandemic and the most common side effect reported was COVID-19, followed by urinary tract infection and falls. People receiving tolebrutinib had more respiratory infections than those in the placebo group.
A higher percentage of people receiving tolebrutinib had raised liver enzymes compared to those who received placebo, but as in the GEMINI trials, these all resolved without lingering after-effects.
One person died from liver failure following a liver transplant, and this was determined to be related to tolebrutinib treatment. However, it is important to remember that adverse events can happen in clinical trials, particularly in people with weakened immune systems. Researchers closely monitor participants for these events and safety measures are in place to protect participants as much as possible.
What does this mean for people living with MS?
While tolebrutinib reduced relapses at a rate similar to teriflunomide in people with relapsing MS, this is the first and only study to show a reduction in disability progression in people with non-relapsing secondary progressive MS, a group with very limited treatment options.
Tolebrutinib has the potential to expand treatment choices and offer hope for people with non-relapsing secondary progressive MS.
