Dose response to interferon therapy in multiple sclerosis: an evaluation of the evidence

Interferon beta (IFNbeta) is a disease-modifying therapy for multiple sclerosis (MS). Although clinical benefits have been demonstrated in several large, randomized, double-blind studies, the optimal dosing of IFNbeta is controversial.

A search was conducted using the key words IFNbeta, multiple sclerosis, Avonex, Rebif, Betaseron/Betaferon, efficacy, MRI, and dose-response relationship in MEDLINE, EMBASE, and other databases to locate relevant pivotal clinical trials, other prospective studies, and systematic reviews evaluating the efficacy and tolerability of IFNbeta published between 1985 and 2007. This review summarizes the findings of these studies with regard to defining the value of high-dose, high-frequency (HDHF) IFNbeta regimens.

All IFNbeta formulations and dosages have demonstrated efficacy in well-designed phase 3 trials. Two head-to-head trials suggesting that HDHF regimens result in increased efficacy contained shortfalls in study design that precluded definitive conclusions.

Defining the optimal dose and frequency strategy for IFNbeta in patients with MS is complicated by the differences in dosage, route, and frequency of administration among the various agents. Results of well-controlled pivotal trials do not suggest that HDHF IFNbeta regimens provide better long-term benefits for patients with MS than low-dose or low-frequency regimens. In addition, HDHF therapies may increase the incidence of side-effects and neutralizing antibodies that reduce efficacy over time. Although the two head-to-head comparisons of different IFNbeta therapies found HDHF regimens to be more efficacious than lower-dose/lower-frequency regimens, the design limitations of these studies must be considered when weighing the potential value of the findings for recommending treatment strategies.