On 13 December 2024, America’s Food and Drug Administration (FDA) designated tolebrutinib a “breakthrough therapy” in the treatment of non-relapsing secondary progressive multiple sclerosis further to a successful Phase 3 clinical test.
Tolebrutinib was developed by Sanofi and is a Bruton tyrosine kinase (BTK) inhibitor. These cells were discovered by Bruton in 1993 and are present in B lymphocytes, macrophages and brain microglia. The latter are the macrophages specific to the brain. Tolebrutinib crosses the blood-brain barrier, and by blocking this enzyme prevents the activation of both B lymphocytes and macrophage cells. It so happens that the latter play a major part in lesion progression and therefore the symptoms of multiple sclerosis in the absence of a clinical relapse. They are located on the periphery of chronically active plaques and are responsible for the continuous and insidious destruction of the myelin sheaths, which leads to the gradual expansion of demyelinating lesions (chronic expanding lesions). They are also activated by the degeneration of the nerve fibres (axons).
The HERCULES Phase 3 study was performed on 1131 patients at the progressive stage of their disease, who had not suffered a relapse for at least 2 years prior to the beginning of the study. In fact, on average, these patients had not relapsed for an average of 7 years and had an invalidity (EDSS) score of 3 (significant disability in one functional system) to 6.5 (requires 2 walking aids to walk about 20 m). 60% of the patients required walking aids, which indicated the high degree of disability among the population studied.
The chief result of this study was evidence that tolebrutinib increases the time prior to confirmed progression of the disability by 31% compared with the placebo group. Statistically, this is a highly significant difference. Moreover, the disability of 10% of the patients treated definitely improved, in fact in twice as many cases as in the patients taking the placebo.
This designation as a “breakthrough therapy” shows that tolebrutinib has the potential to slow down the development of disability and thus meet an essential medical requirement of progressive multiple-sclerosis patients.
The main side effect was an increase in liver enzymes up to over three times the upper limit of normal in 4.1% of the participants (and 1.6% of the placebo group). All cases of liver-enzyme increase resolved without any particular medical intervention.
A study of tolebrutinib in primary progressive MS (PERSEUS) is under way, with results expected during the second half of 2025.
What actually differentiates tolebrutinib from other current multiple-sclerosis treatments is that it targets not only adaptive immunity (B lymphocytes), but also the innate immunity conferred by the macrophages and brain microglia. Its other important characteristic is its ability to penetrate the central nervous system and act locally on demyelinating lesions.
The specific targeting of macrophages and microglia ensures that new therapies will become available to treat multiple sclerosis. The future may lie in an association of immunomodulators and anti-inflammatory medications, as well as medications that deactivate macrophages from the inception of the disease. This would enable progression independent of relapse activity (PIRA) to be prevented at a very early stage, and therefore the simultaneous blocking of the two major mechanisms responsible for demyelination: acute demyelination through the invasion of inflammatory blood cells and chronic demyelination through the local activation of macrophages.
Professor Emeritus Christian Sindic