Subcutaneous Recombinant Interferon-β-1a (Rebif®)

Summary

Abstract

Subcutaneous recombinant interferon-β-1a (Rebif®) 22 or 44μg three times weekly is a valuable option in the first-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS). It has shown benefits on outcome measures related to relapses, progression of disability and magnetic resonance imaging (MRI) in clinical trials. A significant efficacy advantage for subcutaneous interferon-β-1a three times weekly over intramuscular interferon-β-1a 30μg once weekly was shown at 24 and 48 weeks. The most common adverse events are generally mild and clinically manageable. Considering both direct and indirect comparative clinical trial data, an assessment suggests that subcutaneous interferon-β-1a 44μg three times weekly has the best benefit-to-risk values of the available disease-modifying drugs used to treat RRMS.

Pharmacological Properties

Glycosylated recombinant interferon-β-1a has the same primary structure and biological effects in the body as endogenous human interferon-β. Immunomodulatory activity, the principal pharmacodynamic property of interferon-β-1a, most likely results from interferon-stimulated gene products mediating biological activities. The long-term clinical significance of the development of neutralising antibodies (NABs) to interferon-β-1a is currently unclear; therefore, it is recommended that treatment decisions are based on clinical efficacy and not on the presence of NABs alone.

In healthy volunteers, subcutaneous interferon-β-1a has a long apparent elimination half-life and appears to accumulate after repeated doses.

Therapeutic Efficacy

In a randomised 2-year trial, subcutaneous interferon-β-1a 22 or 44μg three times weekly for 2 years was more effective than placebo as assessed by a number of clinical (e.g. relapse rate per patient, proportion of patients without clinical relapse and changes from baseline in Kurtzke Expanded Disability Status Scale [EDSS] scores) and MRI (total burden of disease and numbers of active lesions per patient per scan) endpoints. Significant dose-response effects in favour of the higher dosage were evident when the study period was extended for another 2 years. Extension data for a total follow-up period of 7–8 years in the original cohort showed sustained clinical benefits with subcutaneous interferon-β-1a therapy.

In a 48-week comparative trial, patients randomised to subcutaneous interferon-β-1a 44μg three times weekly were more likely to remain free of relapses and have significantly more favourable measures of MRI lesion activity at weeks 24 and 48 weeks, and a longer time to first relapse, than those randomised to intramuscular interferon-β-1a 30μg once weekly. In the crossover extension phase (median treatment duration 34 weeks), clinical and MRI outcomes improved in patients who crossed over from treatment with intramuscular interferon-β-1a 30μg once weekly to subcutaneous interferon-β-1a 44μg three times weekly.

Tolerability

In clinical trials of subcutaneous interferon-β-1a, the most commonly reported adverse events (e.g. injection-site reactions, headache and influenza-like symptoms) were generally mild, manageable and reversible. Mild, asymptomatic and reversible haematological disorders and alterations in liver function tests may occur. A few patients experience serious effects on liver function.

Subcutaneous interferon-β-1a 44μg three times weekly was associated with a significantly higher incidence of injection-site disorders and liver function or haematological abnormalities than intramuscular interferon-β-1a 30μg once weekly. No between-group differences were noted regarding the proportions of patients experiencing serious adverse events.

Pharmacoeconomic and Other Considerations

In an assessment that evaluated the four available RRMS disease-modifying treatments based on the numbers of patients needed to treat to obtain benefit or harm, subcutaneous interferon-β-1a 44μg three times weekly had the best benefit-to-risk values. Based on data from pivotal directly comparative trials, subcutaneous interferon-β-1a 44μg three times weekly had favourable benefit-to-risk values relative to subcutaneous interferon-β-1a 22μg three times weekly and intramuscular interferon-β-1a 30μg once weekly. Based on indirect comparative data from published clinical trials, subcutaneous interferon-β-1a appeared to have favourable efficacy values relative to interferon-β-1b every other day, and interferon-β formulations appeared to have favourable benefit-to-risk ratios relative to placebo and also subcutaneous glatiramer acetate 20gmg once daily.

In pharmacoeconomic analyses from a healthcare payer perspective, subcutaneous interferon-β-1a 44μg three times weekly was predicted to be increasingly more cost effective than placebo over the mid-(10 years) and long-(20 years) term with regard to preventing EDSS-months of disability in the UK and France, and cost saving relative to intramuscular interferon-β-1a 30μg once weekly over 48 weeks in the US.