Multiple sclerosis: a new generation of treatments to slow the progression of disability

A disease with multiple forms and evolutions

Multiple sclerosis (MS) affects around 150,000 people in France and is the first cause of non-traumatic disabilityin young adults. This chronic inflammatory disease of the central nervous system most often appears between the ages of 20 and 40, and predominantly affects women.

In almost 85% of cases, the disease begins in a form known as "remittent", characterized by episodes of neurological symptoms: disturbed vision, difficulty walking, loss of sensitivity or severe fatigue... alternating with periods of reduced or partial disappearance of these symptoms. This phrase may last several years, or even a decade, before evolving in a proportion of patients into what is known as a "secondarily progressive" form, marked by a slow, steady worsening of disability, particularly problems with walking, balance or autonomy. In around 15% of patients, this progression of disability appears from the outset, without any clearly identifiable relapses: these are the "primary progressive forms".

Therapeutic advances over the last 20 years have profoundly transformed the management of inflammatory forms of the disease. Immunomodulatory and immunosuppressive treatments currently available now make it possible to reduce inflammatory flare-ups and the appearance of new lesions by around 90%. These include, in particular, monoclonal antibodiessuch as Ocrevus or Kesimpta, which are now widely used.

These advances have also enabled the progression to progressive forms to be sharply limited: historically, between 60% and 70% of patients developed a progressive worsening of disability, compared with around 20% to 30% with current treatments.

Despite these major advances, progressive forms remain the principal challenge of the disease, available treatments having a limited impact on the slow progression of disability as they are less active on the mechanisms involved in neurodegeneration.

Promising advances for progressive forms

In this context, and in view of the persistent therapeutic need in progressive forms of multiple sclerosis, several international clinical trials devoted to BTK inhibitors have recently delivered particularly encouraging results. These trials, in which the French centers of the FCRIN4MS network (labeled F-CRIN) were heavily involved, aim to evaluate a new generation of treatments capable of acting directly within the brain on the chronic inflammatory mechanisms involved in the progression of disability.

Among the most advanced molecules is Tolebrutinib(Sanofi), evaluated in the international phase 3 HERCULES trial, a randomized, double-blind, placebo-controlled multicenter study conducted in over 1,100 patients with secondarily progressive forms known as "non-active", i.e. without recent inflammatory flare-ups.

The aim of this trial was to assess the ability of Tolebrutinib to slow disability progression in patients for whom therapeutic options have so far remained very limited. The results show a 31% reduction in the risk of confirmed disability progression at six months in patients treated with Tolebrutinib versus placebo. The investigators also observed a decrease in new lesions visible on MRI as well as clinical improvement in some patients.

Other BTK inhibitors also showed encouraging results. In the international phase 3 FENtrepid trial, conducted in nearly 1,000 patients with primary progressive MS, Fenebrutinib (Roche) showed efficacy at least comparable to that of Ocrevus, (one of the reference treatments currently used in the disease, to which it was compared) with an additional reduction of around 12% in the risk of disability progression. Certain motor parameters, notably manual function, also appeared particularly preserved.

A major French involvement in international clinical trials

France occupies today a major place in the development of new therapeutic strategies against progressive multiple sclerosis. The réseau FCRIN4MS, a national clinical research network of excellence with F-CRIN accreditation, brings together 35 specialized hospital centers throughout France, almost all of which are currently participating in at least one clinical trial dedicated to BTK inhibitors. In particular, the Strasbourg center is among the world's top recruiters for the study evaluating Fenebrutinib, with around 25 patients included.

All in all, over a dozen studies devoted to BTK inhibitors have already benefited from the support of the network.

A new step in the management of multiple sclerosis

These results mark an important milestone for patients who have until now had very few effective options against the progressive course of the disease. With the emergence of a new generation of treatmentscapable of going beyond the simple control of inflammatory flare-ups, they illustrate the essential role of clinical research networks such as FCRIN4MS in the development of large international trials and in acceleratingpatient access to medical innovations.

Research is now pursuing three major complementary objectives: controlling inflammation, protecting neurons and repairing neurological damage.

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