Two forms of IFN beta-1a were subject to investigation in large clinical trials: Avonex® and Rebif®. Avonex® was initially tested in a trial involving 301 patients with relapsing MS and mild to moderate neurologic impairment (baseline disability score on the EDSS 1.0–3.5). Treatment consisted of weekly intramuscular (IM) injections (6 million units, or 30 mcg) or placebo for up to two years, the dose and timing of administration being based on the serum level of beta2-microglobulin and the occurrence of side-effects. The principal outcome measure was the length of time to progression of disability, defined as a worsening from baseline of at least one point on the EDSS that persisted for at least six months.

The study was terminated when it was recognised that the drop-out rate was less than anticipated. At the time the trial was stopped, 57 percent of enrolled patients had completed two years, and 77 percent had been followed up for 18 months. Despite this early termination, the IFN beta-1a–treated patients were significantly less likely to reach the primary outcome, the probability being about 21 percent in the treatment group, and 33 percent in the placebo group for those who completed two years of therapy. An 18 percent reduction in exacerbations was noted for the treated group, and those patients who completed two years had one-third fewer exacerbations. The treatment effect was supported by a reduction of gadolinium enhancement and new or enlarging lesions on annual MRIs. A significant difference between the treatment groups, however, was not found for the total brain lesion load.

The clinical significance of the beneficial effect of IFN beta-1a on disease progression at the lower EDSS scores has been endorsed by the findings of a post hoc statistical analysis of the disability outcomes data obtained in this study. Sensitivity calculations indicated that the primary outcome parameter was robust to changes in definitions of EDSS progression and that the proportion of patients progressing to EDSS milestones of 4.0 and 6.0 was significantly lower in the IFN-treated patients. This study was pivotal in the decision of the FDA to license this agent for clinical use.

In a recent placebo-controlled study involving 383 individuals with a first episode suggestive for MS and specific MRI features that are prognostically unfavourable, Avonex® significantly prolonged the time to a second episode. Early use of IFN reduced MRI indicators of subclinical disease activity, but the trial was too short to provide insights about any possible benefits in delaying or reducing disability. Subsequent analyses showed that half of the treated patients continued to show MRI evidence of probable disease activity during the first 18 months of treatment, suggesting that even early treatment did not completely suppress the illness. This study was influential in North American and European regulatory authorities approving this agent for use in this subset of patients at risk of MS, after their first attack.

A large study investigating the effects of Avonex® on disease progression in patients with secondary progressive MS (“IMPACT”) failed to demonstrate a favourable effect on disability progression as measured by the EDSS, but did suggest possible slowing of worsening using an allegedly more sensitive outcome measure (the MS Functional Composite Measure). An additional phase-three study in RRMS suggested that 30 and 60 mg doses of IFN beta-1a (once-weekly IM) are comparable.

Rebif® was investigated in a number of studies, including one in which 560 patients with active relapsing-remitting disease and mild to moderate disability (EDSS 0–5) were randomized to treatment with IFN beta-1a 6 MIU (22 mcg), 12 MIU (44 mcg), or placebo, given subcutaneously three times a week (tiw) for two years. The primary end point for this study was the relapse rate. At the end of the study, 95 percent of the patient data was available for analysis. The results showed that, compared with placebo, IFN beta-1a significantly decreased the number (by 27 percent and 33 percent, with 22 mcg and 44 mcg, respectively) and severity of exacerbations, and increased the time to the first and second relapses. It also increased the percentage of patients who were relapse-free during the study.

In addition, IFN beta-1a prolonged the time to confirmed progression as measured with EDSS scores (1.0 point confirmed at three months). Furthermore, there was a significant reduction in the disease activity on MRI (gadolinium-enhancing lesions, new lesions, or enlarging T2 lesions) as well as on total T2 lesion load in patients receiving active treatment compared with those given placebo. The placebo group showed an accumulation of approximately 11 percent in lesion load over the two years, whereas there was a decrease of about one percent among patients receiving 6 MIU and a decrease of almost four percent in the 12 MIU group.

After two years, patients initially receiving placebo were randomised to blinded IFN beta-1a 22 mcg or 44 mcg three tiw, whereas all other patients continued blinded treatment with their originally assigned dose of IFN beta-1a. Clinical and MRI benefit continued for both doses up to four years, with 44 mcg tiw being superior to 22 mcg tiw for some of the outcome measures applied. Outcomes also were consistently better for patients who were treated for four years than for patients in the crossover groups, who only received active treatment during years three and four.

Another study with Rebif® compared three different doses of IFN beta-1a administered once weekly with placebo, showing increasing treatment effect with increasing dose.

A large placebo-controlled trial in secondary progressive MS (SPMS) reported that Rebif® given three times weekly failed to have a significant effect on disease progression, as defined by the time to confirmed neurologic deterioration (1-point increase) on the EDSS present for at least three months. This study demonstrated, however, that this drug reduced both clinical relapses and MRI evidence of worsening, suggesting continued biological activity in this patient cohort. The lack of benefit on clinical disability, however, suggests that the benefit of Rebif® in this patient group is low. A low dose (22 mcg sc once weekly) reduced the likelihood of a second episode in the subsequent two years in patients with a first episode suggestive of MS who have prognostically unfavourable MRI features. This finding was similar to that reported earlier for weekly IM IFN beta-1a (Avonex ®) despite the very low dose of the drug.

One recent study (“Evidence”) reported that three times weekly 44 mcg sc IFN beta-1a (Rebif®) more effectively reduced relapse rate, compared with once weekly IM (Avonex®) administration, although it was associated with a greater frequency of neutralising antibody formation (see below). This study was too brief to provide disability information.