Clinical relevance of anti-drug antibodies with interferon beta-1b therapy in multiple sclerosis

Interferon beta-1b (IFN beta-lb; Betaferone(R)/Betaseron(R)) is an effective treatment for relapsing forms of multiple sclerosis (MS). It was the first immunomodulatory therapy to receive approval for this indication in 1993 in the USA and in 1995 in Europe. It remains the only high-dose, high-frequency treatment with proven efficacy in patients with a clinical demyelinating event, RRMS and SPMS. Several large controlled studies have been performed, including 16 years follow-up of patients, providing a unique data set to evaluate long-term safety and efficacy. Results obtained from several studies have shown an inconsistent impact of neutralizing antibodies (NAb) to IFN beta-1b, unlike NAb to other IFN beta therapies. Although patient heterogeneity and the use of different NAb assays are involved, this reflects intrinsic differences between the respective IFN beta-1b versus IFN beta-1 a molecules as well as their sensitivity to NAb effects. When evaluating the occurrence and the impact of NAb during different IFN beta therapies, standardization is a necessity. Three phase III trials of IFN beta-1b, in which the same assay methodology was applied, suggest that NAb to IFN beta-1b are transient, mostly of low to moderate titre and have no effect on disability progression with only limited effect on relapse rate. Two controlled studies showed better efficacy of high dose, high frequency beta-interferon treatment even in NAb-positive patients over low dose, low frequency beta-interferon treatment in NAb-negative individuals. Given the overall clinical efficacy of IFN beta-1b, the inconsistent data regarding the effect of NAb to IFN beta-1b on treatment outcome, and the unpredictable course of disease in a given patient, treatment decisions should be based on patient response to therapy, not on NAb status. This position is endorsed by current regulatory and neurology association guidelines and is reflected in the package insert information.