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BioDrugs

, Volume 10, Issue 6, pp 471–494 | Cite as

Recombinant Interferon-β-1a

A Review of its Therapeutic Efficacy in Relapsing-Remitting Multiple Sclerosis
Adis Drug Evaluation

Summary

Abstract

This review focuses on Rebif®, one of 2 available formulations of recombinant interferon-β-1a, a molecule with the same molecular weight and primary structure as native interferon-β. The product under review is intended for subcutaneous injection and contains 22 or 44μg of recombinant interferon-β-1a. This molecule has the same antiviral, antiproliferative and immunomodulatory profile as native interferon-β. Regulation of excessive immune responses in the inflamed lesions of patients with multiple sclerosis is thought to be important to its mode of action. In vivo studies indicate that the biological response to interferon-β-1a is sustained with 3-times-weekly, in preference to once-weekly, administration.

Subcutaneous interferon-β-1a 22 and 44μg 3 times weekly for 2 years slowed sustained progression of disability (by 6.6 and 9.4 months; first quartile), decreased the mean number (by 27 and 33%) and severity of relapses, decreased the number of hospital visits and steroid courses, and decreased the acute activity [measured as the number of new or enlarging lesions seen with magnetic resonance imaging (MRI)] and burden (measured as the cumulative area or calculated volume of the lesions) of disease in patients with relapsing-remitting multiple sclerosis. All changes (except hospital visits: significant results were obtained with the higher dose only) were significant versus placebo with both doses. A recent study of once weekly interferon-β-1a 22 or 44μg has confirmed the dose-dependency of the clinical and MRI effects. Patients with more severe disease appear to require the higher dosage regimen. Further studies of long term (>2 years) clinical efficacy, tolerability, and pharmacoeconomic aspects are required.

Although injection site disorders and alterations in liver enzymes and lymphopenia are common, they rarely lead to withdrawal from treatment. As with other interferons, an influenza-like syndrome is often seen in patients receiving interferon-β-1a. The sustained (over 2 years) presence of neutralising antibodies has been noted in 6 to 7% of patients; 16 to 18% of patients developed neutralising antibodies at some time during 2 years of treatment. This formulation is available as powder for reconstitution, or in liquid-prefilled syringes or an autoinjector device.

Conclusions: bd Subcutaneous interferon-β-1a 22 to 44μg 3 times weekly dose-dependently decreases the number and severity of relapses in patients with relapsing-remitting multiple sclerosis, slows the progression of disability, and decreases lesion activity and burden of disease. This formulation offers ease of dosage adjustment and convenience of administration, and is a valuable well-tolerated and effective addition to the choice of treatments for relapsing-remitting multiple sclerosis.

Multiple Sclerosis

Multiple sclerosis is a chronic inflammatory debilitating disease of the nervous system that is thought to have both a genetic and environmental aetiological background. Relapsing-remitting multiple sclerosis, in which the disease follows a stable course between clearly defined relapses, is one of several forms. In multiple sclerosis, damage to myelin and other components of the nervous system is believed to be initiated by an immunologically based process.

Pharmacodynamic Properties of Interferon-β-1a

Recombinant interferon-β-1a is produced in mammalian cells and has the same molecular weight and primary structure as native human interferon-β. This review focuses on Rebif®, one of 2 available formulations of recombinant interferon-β-1a (the other is Avonex®). This molecule has the same antiviral, antiproliferative and immunomodulatory profile as native interferon-β. Regulation of excessive immune responses in the inflamed lesions of patients with multiple sclerosis is thought to be important to its mode of action. The stimulated release of many of the cytokines found in the lesions of patients with multiple sclerosis is markedly decreased by interferon-β-1a in healthy volunteers. In vivo studies indicate that the biological response to interferon-β-1a is sustained with 3-times-weekly, in preference to once-weekly, administration.

Pharmacokinetic Properties

The 2 available interferon-β-1a formulations (Rebif® and Avonex®) have equivalent biological activity in terms of international units per milligram of protein. Pharmacokinetic parameters were similar after a single dose given by intramuscular or subcutaneous injection. Disposition follows tri-exponential decay. Accumulation was seen with 3-times-weekly, but not once-weekly administration.

Clinical Efficacy

The efficacy of subcutaneous interferon-β-1a 11 to 44μg 3 times weekly in patients with relapsing-remitting multiple sclerosis was investigated in a large placebo-controlled trial, and in a smaller study using baseline comparisons. A second placebo-controlled trial, in which patients received interferon-β-1a 22 or 44μg once weekly, has not been fully reported yet.

The time to sustained progression (increase by at least 1 point in the Kurtzke Expanded Disability Status Scale (EDSS) score, confirmed after at least 3 months) was significantly delayed by 6.6 and 9.4 months (first quartile) compared with placebo in patients receiving 22 and 44μg 3 times weekly. Dose-dependence was especially evident in patients with high baseline EDSS scores (>3.5), who required the higher dosage for slowed progression.

Interferon-β-1a 22 and 44μg 3 times weekly was associated with significant decreases in the mean number (by 27 and 33%) and severity of relapses, and significant increases in the number of relapse-free patients (by 69 and 100%) and time to first relapse. Interferon-β-1a 22 and 44μg 3 times weekly was also associated with significant decreases in the mean number of new or enlarging lesions (acute activity) and cumulative area or calculated volume of lesions (burden of disease) seen with magnetic resonance imaging (MRI). A significant decrease in the number of hospital visits was seen with interferon-β-1a 44μg 3 times weekly, and significant decreases in the number of steroid courses were seen with both doses.

Tolerability

Overall, interferon-β-1a is well tolerated. Injection site disorders occurred in about 61% of interferon-β-1a-recipients with both dosages and 22% of placebo recipients in the first 3 months of treatment (p ≤ 0.05). Significant differences from placebo in increased ALT levels (6.5 vs 1.1%), lymphopenia (13.0 vs 3.7%), leucopenia (8.1 vs 1.6%) and granulocytopenia (8.2 vs 1.1%) were also seen in the first 3 months of treatment in patients receiving 44μg 3 times daily. As with other interferons, an influenza-like syndrome is often seen in patients receiving interferon-β-1a. 3% of patients were withdrawn from treatment because of adverse events over 2 years of treatment. The sustained (over 2 years) presence of neutralising antibodies has been noted in 6 to 7% of patients receiving interferon-β-1a. 16 to 18% of patients developed neutralising antibodies at some time during 2 years of treatment.

Dosage and Administration

The optimal dosage of interferon-β-1a is 22 to 44μg (6 to 12 million international units) 3 times weekly subcutaneously, depending on the degree of disability. The dose should be increased systematically over 4 weeks to reach the full dose. Caution is recommended if interferon-β-1a is given in combination with drugs metabolised by the cytochrome P450 enzyme system. Patients with renal or hepatic failure, myelosuppression or depression should be monitored during therapy.

Keywords

Multiple Sclerosis Adis International Limited Expand Disability Status Scale Expand Disability Status Scale Score Rebif 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© Adis International Limited 1998

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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