Virbagen Omega

Pharmacotherapeutic Group: Interferons, ATC code: L03 AB07. Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons are cytokines that mediate antiviral, antiproliferative, and immunomodulatory activities. Three major forms of interferons have been distinguished: alpha, beta, and gamma. Interferons alpha and beta are classified as Type I interferons, and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinguishable biological activities. They can also differ with respect to their cellular sites of synthesis. Interferon beta is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and AVONEX (interferon beta-1a) are glycosylated and have a single N-linked complex carbohydrate moiety. Glycosylation of other proteins is known to affect their stability, activity, biodistribution, and half-life in blood. However, the effects of interferon beta that are dependent on glycosylation are not fully defined. Mechanism of action AVONEX exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include MHC Class I, Mx protein, 2' / 5'-oligoadenylate synthetase, β 2 -microglobulin, and neopterin. Some of these products have been measured in the serum and cellular fractions of blood collected from patients treated with AVONEX. After a single intramuscular dose of AVONEX, serum levels of these products remain elevated for at least four days and up to one week. Whether the mechanism of action of AVONEX in MS is mediated by the same pathway as the biological effects described above is not known because the pathophysiology of MS is not well established. Clinical efficacy and safety The effects of lyophilised AVONEX in the treatment of MS were demonstrated in a placebo-controlled study of 301 patients (AVONEX n=158, placebo n=143) with relapsing MS characterised by at least 2 exacerbations in the previous 3 years or at least one exacerbation per year prior to entry when the duration of the disease was less than 3 years. Patients with an EDSS of 1.0 to 3.5 at entry were included in the clinical trial. Due to the design of the study, patients were followed for variable lengths of time. 150 AVONEX-treated patients completed one year on study and 85 completed two years on study. In the study, the cumulative percentage of patients who developed disability progression (by Kaplan-Meier life table analysis) by the end of two years was 35% for placebo-treated patients and 22% for AVONEX-treated patients. Disability progression was measured as an increase in the Expanded Disability Status Scale (EDSS) of 1.0 point, sustained for at least six months. It was also shown that there was a one-third reduction in annual relapse rate. This latter clinical effect was observed after more than one year of treatment. A double-blind randomised dose comparison study of 802 relapsing MS patients (AVONEX 30 micrograms n=402, AVONEX 60 micrograms n=400) has shown no statistically significant differences or trends between the 30 micrograms and the 60 micrograms doses of AVONEX in clinical and general MRI parameters. The effects of AVONEX in the treatment of MS were also demonstrated in a randomised double-blind study performed with 383 patients (AVONEX n=193, placebo n=190) with a single demyelinating event associated with at least two compatible brain MRI lesions. A reduction of the risk of experiencing a second event was noted in the AVONEX treatment group. An effect on MRI parameters was also seen. The estimated risk of a second event was 50% in three years and 39% in two years in the placebo group and 35% (three years) and 21% (two years) in the AVONEX group. In a post-hoc analysis, those patients with a baseline MRI with at least one Gd-enhancing lesion and nine T2 lesions had a two-year risk of suffering a second event of 56% in the placebo group and 21% in the AVONEX treatment group. However, the impact of early treatment with AVONEX is unknown even in this high-risk subgroup as the study was mainly designed to assess the time to the second event rather than the long-term evolution of the disease. Furthermore, for the time-being there is no well established definition of a high risk patient although a more conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least three months after the initial scan. In any case, treatment should only be considered for patients classified at high risk. Paediatric population Limited data of the efficacy/safety of AVONEX 15 micrograms IM once per week (n=8) as compared to no treatment (n=8) with follow up for 4 years showed results in line to those seen in adults, although the EDSS scores increased in the treated group over the 4 year follow-up thus indicating disease progression. No direct comparison with the dose currently recommended in adults is available. AVONEX 30 micrograms/0.5 ml solution for injection was studied as an active comparator in 2 controlled clinical trials in paediatric patients aged 10 to less than 18 years with relapsing remitting multiple sclerosis (see section 4.2). In an open-label randomised active controlled trial, 150 participants were randomly assigned in a 1:1 ratio to treatment with dimethyl fumarate, administered orally at a dose of 240 mg twice a day, or AVONEX, administered at a dose of 30 μg once weekly by intramuscular (IM) injection, for 96 weeks. In the ITT population, treatment with dimethyl fumarate resulted in a higher proportion of patients with no new or newly enlarging T2 hyperintense lesions at Week 96 relative to baseline as compared with AVONEX [12.8% versus 2.8% respectively]. In a double-blind, double-dummy, active-controlled study, 215 participants were randomly assigned to receive either oral fingolimod (0.5 mg once daily or 0.25 mg once daily for patients weighing ≤40 kg) or AVONEX 30 μg IM once weekly for up to 24 months. The primary endpoint, the adjusted annualized relapse rate (ARR) at week 96, was significantly lower in patients treated with fingolimod (0.122) compared to patients who received AVONEX (0.675), translating into an 81.9% relative reduction in ARR (p <0.001). Overall, the safety profile in patients receiving AVONEX in the two clinical trials was qualitatively consistent with that previously observed in adult patients.