Current and future immunomodulatory treatments for progressive forms of MS

First of all, it should be remembered that the mechanisms of MS progression are complex and different from those of acute relapses. These are caused by an invasion of the CNS by immune and inflammatory cells from the bloodstream. The independent progression of relapses is linked to several different mechanisms: - a chronic inflammatory reaction inside the brain, undetectable by gadolinium in MRI, responsible for an increase in volume of pre-existing lesions ("slowly expansive lesions") in which cerebral macrophages (microglia) play a major role; - Wallerian and retrograde axonal neurodegeneration, sometimes trans-synaptic (from one neuron to another); - inflammatory meningeal infiltrates linked to underlying plaques in the cerebral cortex; - focal or diffuse cerebral atrophy; - focal or diffuse atrophy of the spinal cord. Monoclonal antibodies (Tysabri, Ocrevus, Kesimpta, Lemtrada), beta interferons or Copaxone do not penetrate the CNS. The other molecules partially diffuse into the brain (Aubagio, Tecfidera, Gilenya, Zeposia, Ponvory, Mayzent) but it is difficult to measure their possible beneficial local action in addition to their overall action on the immune system.

For the secondary progressive forms of the disease, we now have long-term studies (at least 15 years) showing that the first-line treatment of remittent forms significantly postpones entry into the secondary progressive phase and may even avoid it. We also know that the total number of lesions detected on MRI after 5 years of disease progression is a good predictor of the onset of a secondary progressive phase. If the lesion load becomes significant and severe during the first 5 years of the disease, the risk of a progressive form is much greater than if the lesion load remains low or moderate. The aim of first-line treatments is to prevent the accumulation of lesions and limit the total lesion load. Other studies have shown that there is no point in stopping first-line treatments in people who are entering the secondary progressive phase, as they will progress more slowly and remain better protected from further relapses. According to INAMI [National Institute for Health and Disability Insurance] criteria, Betaferon and Rebif can be prescribed and reimbursed for secondary progressive forms.

Tysabri was studied in secondary progressive forms and did not prove effective in relation to the predetermined objective, i.e. the proportion of patients with increased EDSS in 6 months. The only positive result of this study was that better hand dexterity was maintained. On the other hand, a study with a Gilenya analogue called Mayzent proved positive, slowing the progression of disability by around 25%.

In primary progressive forms, Gilenya was tested in a Phase 3 trial with the primary objective of reducing the proportion of patients worsening over a 3-month interval. This study failed because there was no difference between people receiving the drug and those receiving the placebo. However, Ocrevus was relatively effective, slowing the rate of disability progression by 24% over 3 months. Though significant, these results remain modest. They are best in relatively young people, under 55, with signs of active progressive disease.

Bruton Tyrosine Kinase (BTK) inhibitors have recently given rise to a great deal of hope. This is an enzyme discovered in 1993 by Bruton, located inside B lymphocytes but also present in macrophages and cerebral microglia, which is essential for the maturation of these cells. Inhibitors of this enzyme block the activation of B lymphocytes without destroying them, and they can cross the blood-brain barrier to block B lymphocytes that have already migrated into the CNS. They can also block macrophages and microglia in active and chronically active demyelinating plaques. Three of these inhibitors have already been tested in phase 2 trials in MS: evobrutinib, tolebrutinib and fenebrutinib. Given the encouraging results observed in these studies, numerous phase 3 studies have been launched. Unfortunately, those involving evobrutinib in relapsed forms did not prove superior to Aubagio used as a comparator. In contrast, tolebrutinib is now the first drug to delay disability onset in non-relapsing secondary progressive MS, as reported in 2025. This drug has been shown blocking by 32 % compared with placebo, the progression of the disease due to chronic compartmentalized inflammation within the central nervous system, an unmet medical need so far.

Vidofludimus calcium is like a super-Aubagio, inhibiting the same enzyme (dihydro-orotate dehydrogenase...) in a much more specific way, without having the same side effects. It is taken orally and significantly reduces the appearance of new lesions on MRI. Two phase 3 studies are currently underway.

Anti-CD40L antibodies are currently being tested in MS patients. The CD40 molecule is expressed on the surface of B lymphocytes, but also on other myeloid and brain cells, and is activated by its binding to the CD40-ligand molecule called CD40L or CD154, located on the surface of the T lymphocyte. For a B lymphocyte to activate a pro-inflammatory T lymphocyte, it is necessary for the B lymphocyte to present an antigen (still unknown in MS) to the specific T lymphocyte receptor, and for the CD40 molecule to bind to CD40L. The idea is therefore to make an antibody directed against CD40L to prevent this second binding WITHOUT DISRUPTING the lymphocyte. The intravenous efficacy of Frexalimab in a phase 2 study was remarkable, with 96% of patients with no new active plaques taking gadolinium. Two phase 3 trials are underway, FREXALT for the remittent form and FREVIVA for the progressive form.