Initial results from a phase III clinical trial show that tolebrutinib can significantly slow down disability progression in people with secondary progressive MS who no longer experience relapses.
The phase III study, called HERCULES, recruited 1,131 participants with non-relapsing (non-active) secondary progressive MS (SPMS). Participants were randomised with some taking tolebrutinib and others taking placebo (a dummy drug) for up to four years.
The main aim of the study was to assess the effect of tolebrutinib on disability progression. This was measured as worsening of disability which persisted for six months (using the EDSS). The study also assessed the safety of the drug.
Initial results from the study, presented at ECTRIMS 2024, showed that significantly less people on tolebrutinib experienced worsening of disability which persisted for six months than those on placebo (37.2% placebo vs 26.9% tolebrutinib). 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. 10% of participants on tolebrutinib saw improvements in their disability compared to 5% on placebo.
Lastly, tolebrutinib-treated participants saw a 38% reduction in active lesions when compared to placebo. Unfortunately, tolebrutinib wasn’t found to significantly slow down brain volume loss (atrophy).
In terms of side effects, more cases of upper respiratory infections – particularly Covid-19 and the common cold – were reported in the tolebrutinib group.
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.
Overall, these initial study results are very promising. If licensed and approved for use on the NHS, tolebrutinib could become one of the first drugs available to delay disability progression in those who have non-relapsing SPMS. This would be a major step forward for a group of people who face worsening disability, but who currently only have access to symptomatic treatments to manage their daily symptoms.
Further tolebrutinib research
The safety and effectiveness of tolebrutinib was assessed in people with relapsing MS in phase III trials, GEMINI 1 and GEMINI 2. The studies compared tolebrutinib to the established disease modifying drug, Aubagio. They looked at the effect on relapse rate and worsening of disability.
Initial results showed that tolebrutinib was no better than Aubagio at reducing relapse rate. However, the drug did delay disability progression by 29%. This is in line with the results of the HERCULES trial in SPMS discussed above.
Tolebrutinib is currently being assessed in people with primary progressive MS in a phase III trial called PERSEUS. This study is looking at the drug’s effect on disability progression. The trial is ongoing with results expected in 2025.
How does tolebrutinib work?
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. This inflammation is what causes lesions in the brain and spinal cord and leads 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, as well as longer term damage to nerve cells which causes progression.
What happens next?
When a drug shows it’s safe and effective in a phase III clinical trial, the next stage is getting the drug licensed to allow it to be sold. Regulatory authorities, like the Medicines and Healthcare products Regulatory Agency (MHRA), will check the clinical trial data to ensure the drug is safe and effective. If satisfied, a licence will be issued.
Sanofi, the drug manufacturer, currently says they’ll begin submissions to regulatory authorities later in 2024.
Once licensed, tolebrutinib would need to be approved as a cost effective treatment by the relevant drug appraisal bodies before it can become available on the NHS. Realistically, if this drug is licensed and approved for use on the NHS, it would take a couple of years before this process is completed.
