Combination therapy in multiple sclerosis

Introduction Since 1993, the field of multiple sclerosis (MS) therapeutics has changed dramatically with the approval by North American and European regulatory agencies of interferon beta-1b (IFNβ-1b, Betaseron), IFNβ-1a by intramuscular injection, (IFNβ-1a (IM), Avonex), IFNβ-1a by subcutaneous injection (IFNβ-1a (SC), Rebif), glatiramer acetate (GA, Copaxone), natalizumab (Tysabri), and most recently in the United States, fingolimod (Gilenya), for the treatment of relapsing–remitting MS (RRMS). In Europe, IFNβ-1b has also been approved for use in secondary progressive MS (SPMS), and in the US Mitoxantrone (mitox, Novantrone) has this indication. Although these agents are clearly beneficial, efficacy is only partial. In the pivotal trials that led to approval, all produced only an approximately 30%–68% reduction in relapse rate and approximately 10% absolute reduction of the proportion of patients with sustained worsening of disability. Experience in clinical practice corroborates this observation: a sizable proportion of patients have continued relapses or worsening disability despite these therapies. A variety of factors probably contribute to this incomplete response: Pharmacogenomic and pathogenic heterogeneity leading to responders and non-responders. Non-compliance because of route of administration and/or side effects. Emergence of biological resistance. Development of neutralizing antibodies (NAbs) vs. IFNβ or natalizumab. Thus, there is a clear need for more effective and better tolerated therapies. Several approaches have been considered for future experimental therapeutics in MS: Trials to define the optimal use of currently available agents For example, multiple prospective therapeutic trials using either IFNβ or GA have now shown that the initiation of a disease-modifying agent at the time of a clinically isolated syndrome (CIS) results in a delay of the occurrence of the second neurological episode. There is a suggestion that starting therapy at an early stage of the disease improves efficacy of the drug as well. Another example of this approach would be trials that utilize an increased understanding of disease pathogenesis and biomarkers. These trials would hopefully provide evidence that will allow the physician to choose from established therapies on an individualized basis, according to a patient's unique disease characteristics. […].