Recombinant interferon-beta-1a - A review of its therapeutic efficacy in relapsing-remitting multiple sclerosis

This review focuses on Rebif(R), one of 2 available formulations of recombi nant interferon-beta-1a, a molecule with the same molecular weight and prim ary structure as native interferon-beta. The product under review is intend ed for subcutaneous injection and contains 22 or 44 mu g of recombinant int erferon-beta-1a. This molecule has the same antiviral, antiproliferative an d immunomodulatory profile as native interferon-beta. Regulation of excessi ve immune responses in the inflamed lesions of patients with multiple scler osis is thought to be important to its mode of action. In vivo studies indi cate that the biological response to interferon-beta-1a is sustained with 3 -times-weekly, in preference to once-weekly, administration. Subcutaneous interferon-beta-1a 22 and 44 mu g 3 times weekly for 2 years s lowed sustained progression of disability (by 6.6 and 9.4 months; first qua rtile), 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 see n with magnetic resonance imagine (MRI)] and burden (measured as the cumula tive 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 signifi cant versus placebo with both doses. A recent study of once weekly interfer on-beta-1a 22 or 44 mu g has confirmed the dose-dependency of the clinical and MRI effects. Patients with more severe disease appear to require the hi gher dosage regimen. Further studies of long term (>2 years) clinical effic acy, tolerability, and pharmacoeconomic aspects are required. Although injection site disorders and alterations in liver enzymes and lymp hopenia an common, they rarely lead to withdrawal from treatment. As with o ther interferons, an influenza-like syndrome is often seen in patients rece iving interferon-beta-1a.. The sustained lover 2 years) presence of neutral ising antibodies has been noted in 6 to 7% of patients: 16 to 18% of patien ts developed neutralising antibodies at some time during 2 years of treatme nt, This formulation is available as powder for reconstitution, or in liqui d-prefilled syringes or an autoinjector device. Conclusions: Subcutaneous interferon-beta-1a 22 to 44 mu g 3 times weekly d ose-dependently decreases the number and severity of relapses in patients w ith relapsing-remitting multiple sclerosis, slows the progression of disabi lity, 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 treatmen ts for relapsing-remitting multiple sclerosis. Multiple sclerosis is a chronic inflammatory debilitating disease of the ne rvous system that is thought to have both a genetic and environmental aetio logical background. Relapsing-remitting multiple sclerosis, in which the di sease follows a stable course between clearly defined relapses, is one of s everal forms. In multiple sclerosis, damage to myelin and other components of the nervous system is believed to be initiated by an immunologically bas ed process. Recombinant interferon-beta-1a is produced in mammalian cells and has the s ame molecular weight and primary structure as native human interferon-beta. This review focuses on Rebif(R), one of 2 available formulations of recomb inant interferon-beta-1a (the other is Avonex(R)). This molecule has the sa me antiviral, antiproliferative and immunomodulatory profile as native inte rferon-beta. Regulation of excessive immune responses in the inflamed lesio ns of patients with multiple sclerosis is thought to be important to its mo de of action. The stimulated release of many of the cytokines found in the lesions of patients with multiple sclerosis is markedly decreased by interf eron-beta-1a in healthy volunteers. In vivo studies indicate that the biolo gical response to interferon-beta-1a is sustained with 3-times-weekly, in p reference to once-weekly, administration. The 2 available interferon-beta-1a formulations (Rebif(R) and Avonex(R)) ha ve equivalent biological activity in terms of international units per milli gram of protein. Pharmacokinetic parameters were similar after a single dos e given by intramuscular or subcutaneous injection. Disposition follows tri -exponential decay. Accumulation was seen with 3-times-weekly, but not once -weekly administration. The efficacy of subcutaneous interferon-beta-1a 11 to 44 mu g 3 times weekl y 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-beta-1a 22 or 44 mu g once weekly, has not been fully reported y et. The time to sustained progression (increase by at least 1 point in the Kurt zke Expanded Disability Status Scale (EDSS) score, confirmed after at least 3 months) was significantly delayed by 6.6 and 9.3 months (first quartile) compared with placebo in patients receiving 22 and 44 mu g 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-beta-1a 22 and 44 mu g 3 times weekly was associated with signif icant 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 a nd 100%) and time to first relapse. Interferon-beta-1a 22 and 44 mu g 3 tim es weekly was also associated with significant decreases in the mean number of new or enlarging lesions (acute activity) and cumulative area or calcul ated volume of lesions (burden of disease) seen with magnetic resonance ima ging (MRI), A significant decrease in the number of hospital visits was see n with interferon-beta-1a 44 mu g 3 times weekly, and significant decreases in the number of steroid courses were seen with both doses. Overall, interferon-beta-1 is well tolerated. Injection site disorders occu rred in about 61% of interferon-beta-1a-recipients with both dosages and 22 % of placebo recipients in the first 3 months of treatment (p less than or equal to 0.05). Significant differences from placebo in increased ALT level s (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 treat ment in patients receiving 44 mu g 3 times daily. As with other interferons , an influenza-like syndrome is often seen in patients receiving interferon -beta-1a. 3% of patients were withdrawn from treatment because of adverse e vents over 2 years of treatment. The sustained lover 2 years) presence of n eutralising antibodies has been noted in 6 to 7% of patients receiving inte rferon-beta-1a. 16 to 18% of patients developed neutralising antibodies at some time during 2 years of treatment. The optimal dosage of interferon-beta-1a is 22 to 44 mu g (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-beta-1a is given in combination with drugs metabolised by the cytochrome P450 enzyme system . Patients with renal or hepatic failure, myelosuppression or depression sh ould be monitored during therapy.