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General Information

Extavia (interferon Beta-1b) belongs to a family of naturally occurring proteins, produced by eukarotic cells in response to viral infection and other biologic agents. The exact mechanism of action through which Extavia works in multiple sclerosis is unknown. However, the beneficial effects are thought to be due to its modulation of the immune system to reduce inflammatory damage. Specifically, interferon beta limits the activation of immune cells that attack myelin, suppresses the production of inflammatory cytokines - a type of protein that amplifies the inflammatory response causing damage to myelin - and stimulates the production of anti-inflammatory cytokines.

Extavia is specifically indicated for the treatment of relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and in patients who have experienced a first clinical episode of MS.

Extavia is supplied as a lyophilized powder for reconstitution into a solution designed for subcutaneous administration. The recommended initial dose of the drug is 0.25 mg injected subcutaneously ever other day. Generally patients should be started at 0.0625 mg (0.25 mL) subcutaneously ever other day, and increased over a six week period to 0.25 mg (1 mL) every other day.

Clinical Results

FDA Approval
The FDA approval of Extavia was based on four randomized, multicenter, double-blind, placebo-controlled studies.

Study One
This trial enrolled 372 subjects, aged 18 to 50 years, who received either placebo, 0.05 mg of Intereron beta-l b or 0.25 mg of Interferon beta1b, self-administered subcutaneously every other day. The primary protocol-defined outcome measures were 1) frequency of exacerbations per patient and 2) proportion of exacerbation-free patients at two years. The annual exacerbation rates were as follows: placebo: 1.31, Extavia (0.05mg): 1.14 (p-value 0.005 vs. placebo) and Extavia (0.25mg): 0.90 (p-value 0.0001vs. placebo). The proportion of exacerbation- free patients was as follows: placebo: 16%, Extavia (0.05mg): 18% (p-value 0.609), Extavia (0.25mg): 25% (p-value 0.001 vs. placebo). The median percent change in MRI area for the 025 mg group was - 1.1 %, which was significantly smaller than the 16.5% observed for the placebo group (p=0.0001). In an evaluation of frequent MRI scans (every six weeks) on 52 patients at one site, the percent of scans with new or expanding lesions was 29% in the placebo group and 6% in the 0.25 mg treatment group (p=0.006).

Study Two and Three
These trials were designed to assess the effect of Interferon beta- 1b in patients with secondary progressive multiple sclerosis (SPMS). Study 2 was conducted in Europe and Study 3 was conducted in North America. Both studies enrolled patients who had evidence of disability progression (both Study 2 and 3) or two relapses (Study 2 only) within the previous two years. Patients in Study 2 were randomized to receive Interferon beta-lb 0.25mg or placebo while patients in Study 3 were randomized to receive Interferon beta- Ib (0.25 mg), Interferon beta1b (0.16mg/m2 body surface area- mean assigned dose 0.30 mg) or placebo. All agents were administered subcutaneously over 2 years. The primary outcome measure was progression of disability, defined as a 1.0 point increase in the EDSS score, or a 0.5 point increase for patients with baseline EDSS >6.0. In Study 2, time to progression in EDSS was longer in the Interferon beta- 1b treatment group (p=0.005), with estimated annualized rates of progression of 16% and 19% in the Interferon beta-Ib and placebo groups, respectively. In Study 3, the rates of progression did not differ significantly between treatment groups, with estimated annualized rates of progression of 12%, 14%, and 12% in the Interferon beta-Ib fixed dose, surface area-adjusted dose, and placebo groups, respectively. In Study 2, the mean annual relapse rates were 0.42 and 0.63 in the Interferon beta- Ib and placebo groups, respectively (p-<0.001). In Study 3, the mean annual relapse rates were 0.16, 0.20, and 0.28, for the fixed dose, surface area-adjusted dose, and placebo groups, respectively (p-<0.02). MRI endpoints in both Study 2 and Study 3 showed lesser increases in T2 MRI lesion area and decreased number of active MRI lesions in patients in the Interferon beta- 1b groups.

Study Four
Thus trial enrolled 468 patients who had recently (within 60 days) experienced an isolated demyelinating event, and who had lesions typical of multiple sclerosis on brain MRI. The subjects were randomized to receive either 0.25 mg Interferon beta- Ib or placebo subcutaneously ever other day. The primary outcome measure was time to development of a second exacerbation with involvement of at least two distinct anatomical regions. Secondary outcomes were brain MRI measures, including the cumulative number of newly active lesions, and the absolute change in T2 lesion volume. Patients were followed for up to two years or until they fulfilled the primary endpoint. Time to development of a second exacerbation was significantly delayed in patients treated with Interferon beta- 1b compared to placebo (p-<O .000 I). The Interferon beta-Ib Kaplan-Meier estimates of the percentage of patients developing an exacerbation within 24 months were 45% in the placebo group and 28% in the Interferon-beta1b group. The risk for developing a second exacerbation in the Interferon beta-Ib group was 53% of the risk of the placebo group. A significant difference in the absolute change in T2 lesion volume was not significantly different between the two arms.

Side Effects

Adverse events associated with the use of Extavia may include, but are not limited to, the following:

lymphopenia
injection site reaction
asthenia
flu-like symptom complex
headache
pain

Mechanism of Action

Extavia (interferon Beta-1b) belongs to a family of naturally occurrg proteins, produced by eukarotic cells in response to virl infection and other biologic agents. The exact mechanism of action through which Extavia works in multiple sclerosis is unknown. However, the beneficial effects are thought to be due to its modulation of the immune system to reduce inflammatory damage. Specifically, interferon beta limits the activation of immune cells that attack myelin, suppresses the production of inflammatory cytokines - a type of protein that amplifies the inflammatory response causing damage to myelin - and stimulates the production of anti-inflammatory cytokines.

Literature References

Hurwitz BJ, Jeffery D, Arnason B, Bigley K, Coyle P, Goodin D, Kaba S, Kirzinger S, Lynch S, Mandler R, Mikol D, Rammohan K, Sater R, Sriram S, Thrower B, Boateng F, Jakobs P, Wash MB, Bogumil T Tolerability and safety profile of 12- to 28-week treatment with interferon beta-1b 250 and 500 microg QOD in patients with relapsing-remitting multiple sclerosis: a multicenter, randomized, double-blind, parallel-group pilot study. Clinical Therapeutics 2008 Jun;30(6):1102-12

Gaindh D, Jeffries N, Ohayon J, Richert ND, Pellicano C, Frank JA, McFarland H, Bagnato F The effect of interferon beta-1b on size of short-lived enhancing lesions in patients with multiple sclerosis. Expert Opinion on Biological Therapy 2008 Dec;8(12):1823-9

Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Bauer L, Jakobs P, Pohl C, Sandbrink R Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006 Oct 10;67(7):1242-9. Epub 2006 Aug 16

Koch-Henriksen N, Sørensen PS, Christensen T, Frederiksen J, Ravnborg M, Jensen K, Heltberg A, Kristensen O, Stenager E, Petersen T, Hansen T; Danish Multiple Sclerosis Group A randomized study of two interferon-beta treatments in relapsing-remitting multiple sclerosis. Neurology 2006 Apr 11;66(7):1056-60. Epub 2006 Mar 1