Gonsette.qxp 18/7/07 15:42 Page 18
Multiple Sclerosis
Advances in Treating Multiple Sclerosis
a report by
Richard E Gonsette
Honorary Medical Director, National Centre for Multiple Sclerosis
The approval of three interferons-beta (IFNβ) and of glatiramer acetate (GA) Three formulations of IFNβ are available: IFNβ 1b (Betaferon
®
), IFNβ 1a
by the US Food and Drug Administration (FDA) in the early 1990s was the im (Avonex
®
) and IFNβ 1a sc (Rebif
®
). So far, a marked superiority of
most important recent advance in multiple sclerosis (MS) therapy. These their respective clinical benefit has not been demonstrated. The main
immunomodulators are now a first-line treatment of relapsing-remitting difference concerns their immunogenicity leading to the production of
(RR) and relapsing-progressive (RP) MS. In 2000, mitoxantrone – a cytolytic neutralising antibodies (NAbs).
1,2
Interferonβ 1a im is less immunogenic,
immunosuppressant – was approved for the treatment of patients with a in part because of a less frequent administration (once a week) and/or
rapidly progressive disease. A second immunosuppressant – natalizumab the mode of injection (intramuscular). NAbs inhibit IFNβ biological
(Tysabri
®
) – was approved in November 2004. Given its remarkable efficacy, activity and are associated with a decreased radiological and clinical
natalizumab appeared a promising candidate for the long-term treatment benefit, apparent 6–12 months after their detection. Their clinical
of RR MS. However, severe adverse events led to a temporary suspension of relevance, however, is not clearly defined as their titres vary over time
the drug (February 2005 to June 2006). After its reintroduction to the and do not persist in some patients. The detection of NAbs titres of at
market, natalizumab was reserved for carefully selected patients under strict least 20 at several-month intervals could identify ‘non-reverter’ patients.
surveillance and for a limited period of time. Immunomodulators are well
tolerated for years, but their efficacy is relatively modest. Immuno- Several attempts to improve IFNβ efficacy are in progress. A benefit of
suppressants are more effective, but their toxicity prevents long-term higher doses has been found with IFNβ 1b (500 versus 250µg) and
treatments. Numerous clinical trials investigate new molecules in order to IFNβ 1a sc (44 versus 22µg).
3
In contrast, a higher dose of IFNβ 1a im
improve the efficacy of immunomodulators and reduce the toxicity of (60 versus 30µg) did not improve the benefit and led to a greater
immunosuppressants. This short review will be limited to the most incidence of NAbs.
4
An increased formulation purity of IFNβ 1a sc is
promising new therapeutic approaches. currently being tested. Preliminary data demonstrate a much lower
persistence of NAbs and a three-fold reduction of adverse events.
5
A
Approved Therapies potential increased clinical benefit remains to be assessed.
Immunomodulators Glatiramer Acetate (Copaxon
®
)
GA is a mixture of four synthetic polypeptides participating in the structure
Interferons-beta of myelin basic protein (MBP), which plays a major role in the development
IFNβ downregulates T-cell proliferation and pro-inflammatory cytokine of allergic experimental encephalomyelitis (EAE). The most likely
production. Their most evident anti-inflammatory effect concerns active mechanisms of action are competition with MBP in binding to the major
brain lesions, demonstrated by a ~80–90% decrease of gadolinium- histocompatibility complex (MHC) molecule – acting as an altered peptide
enhancing (Gd+) lesions. The clinical benefit on relapses is definitely less ligand – and the induction of GA-reactive T regulatory cells producing
marked (~30%), and the long-term effect on disability progression is brain-derived neurotrophic factor. GA exerts beneficial effects on relapse
modest (~20%) and remains a matter of debate. rate and disability progression at a magnitude comparable to that of IFNβ.
The first magnetic resonance imaging (MRI) studies demonstrated a
reduction in Gd+ lesions by 33% – less than that with IFNβ. Tolerance is
Richard E Gonsette is Honorary Medical Director of the
National Centre for Multiple Sclerosis in Melsbroek, Belgium.
acceptable, but some patients present systemic reactions specific to GA
His main topics for research are the blood–brain barrier and
characterised by flushing, chest pain, anxiety, dyspnoea and constriction
the prevention of experimental allergic encephalomyelitis.
of the throat, usually resolving within half an hour. To improve the efficacy
Most of his publications concern immune treatments in
multiple sclerosis: myelin basic protein, levamisole, of GA, higher doses have recently been tested (40 versus 20mg).
cyclophosphamide, mitoxantrone, pixantrone and inosine.
Preliminary data suggest that a double dose may be more effective in
Dr Gonsette is Chairman of the Fondation-Charcot-Stichting
(Belgium) and the Belgian Research Group for Multiple
reducing MRI activity and relapse rate, with a similar tolerance.
6
Sclerosis, a Board Member of the European Charcot
Foundation, Past President of the European Committee for
Immunosuppressors
Treatment and Research in Multiple Sclerosis and Past
President and Honorary Member of the Belgian Neurological
Society. He received his medical degree from the Catholic
Mitoxantrone (Novantrone
®
)
University of Louvain before becoming a Research Associate
in the Department of Neuropathology at the same institution.
Approved in 2000 by the FDA, mitoxantrone (MX) is a rescue therapy for
patients with aggressive MS characterised by frequent and/or severely
E: rgonsette@skynet.be.
disabling relapses leading to rapidly progressive disability, who failed to
respond to approved immunomodulators. MX is a cytolytic immuno-
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