PRISMS: the story of a pivotal clinical trial series in multiple sclerosis

The PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study was initiated in 1994, at which time there were few disease-modifying drugs for multiple sclerosis (MS). The PRISMS series of studies has since provided up to 8 years of clinical, magnetic resonance imaging (MRI), safety, and immunogenicity data on the use of subcutaneous (sc) interferon (IFN) beta-1a in patients with relapsing-remitting MS. This review is the first collation of all these data in one article, with a look ahead to the next generation of studies involving the new formulation of sc IFN beta-1a. Published efficacy, safety, and immunogenicity data, in terms of prospectively defined endpoints and later post hoc analyses, from years 1-8 of the PRISMS series are summarized and collated for the first time. Some of the studies of sc IFN beta-1a that evolved from the PRISMS studies are also discussed. In the 2-year, double-blind, randomized, placebo-controlled study, IFN beta-1a (22 or 44 mcg three times weekly [tiw]) was associated with significantly lower relapse rates, disability progression, and MRI burden of disease compared with placebo (p < 0.05). Subsequently, in the 2-year extension, patients previously receiving placebo were re-randomized to active treatment, and a further 2 years of open-label treatment confirmed good long-term safety and therapeutic efficacy. Follow-up visits at years 7 or 8 (68.2% of initial population) demonstrated a continued benefit for patients originally randomized to the 44-mcg dose compared with those receiving the 22-mcg dose or whose treatment had been delayed by 2 years. Neutralizing antibodies were more common in patients receiving the 22-mcg dose and attenuated treatment efficacy during years 1-4. Class I and long-term data from PRISMS support the use of sc IFN beta-1a tiw as a first-line treatment for MS, as evidenced by sustained efficacy rates, acceptable safety profiles, and high patient retention rates.