After its reintroduction to the market, natalizumab was reserved for carefully selected patients under strict surveillance and for a limited period of time. Immunomodulators are well tolerated for years, but their efficacy is relatively modest. Immunosuppressants are more effective, but their toxicity prevents long-term treatments. Numerous clinical trials investigate new molecules in order to improve the efficacy of immunomodulators and reduce the toxicity of immunosuppressants. This short review will be limited to the most promising new therapeutic approaches.

Approved Therapies

Immunomodulators

Interferons-beta
IFNβ downregulates T-cell proliferation and pro-inflammatory cytokine production. Their most evident anti-inflammatory effect concerns active brain lesions, demonstrated by a ~80–90% decrease of gadoliniumenhancing (Gd+) lesions. The clinical benefit on relapses is definitely less marked (~30%), and the long-term effect on disability progression is modest (~20%) and remains a matter of debate.

Three formulations of IFNβ are available: IFNβ 1b (Betaferon®), IFNβ 1a im (Avonex®) and IFNβ 1a sc (Rebif®). So far, a marked superiority of their respective clinical benefit has not been demonstrated. The main difference concerns their immunogenicity leading to the production of neutralising antibodies (NAbs).^1,2 Interferonβ 1a im is less immunogenic, in part because of a less frequent administration (once a week) and/or the mode of injection (intramuscular). NAbs inhibit IFNβ biological activity and are associated with a decreased radiological and clinical benefit, apparent 6–12 months after their detection. Their clinical relevance, however, is not clearly defined as their titres vary over time and do not persist in some patients. The detection of NAbs titres of at least 20 at several-month intervals could identify ‘non-reverter’ patients.

Several attempts to improve IFNβ efficacy are in progress. A benefit of higher doses has been found with IFNβ 1b (500 versus 250μg) and IFNβ 1a sc (44 versus 22μg).³ In contrast, a higher dose of IFNβ 1a im (60 versus 30μg) did not improve the benefit and led to a greater incidence of NAbs.⁴ An increased formulation purity of IFNβ 1a sc is currently being tested. Preliminary data demonstrate a much lower persistence of NAbs and a three-fold reduction of adverse events.⁵ A potential increased clinical benefit remains to be assessed.