Pharmacology and pharmaceutics

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Clinical pharmacology Avonex is indicated for the treatment of relapsing-remitting forms of MS. MS is a chronic inflammatory disorder of the central nervous system (CNS) that results in injury to the myelin and to myelin-producing cells. Two-thirds to three-quarters of affected individuals are women. Clinical onset is usually between the ages of 20 and 40 years. Four different clinical forms of MS have been recognized. The first, relapsing-remitting type of MS (RRMS), accounts for approximately 85% to 90% of MS cases at onset. It is characterized by discrete attacks of neurologic dysfunction. These attacks generally evolve acutely over days to weeks. Over the ensuing several weeks to months, the large majority of patients experience a substantial recovery of function (but not necessarily complete). The specific interferon-induced proteins and mechanisms by which Avonex exerts its effects in multiple sclerosis have not been fully defined. Clinical studies conducted in MS patients showed that inter-leukin 10 (IL-10) levels in cerebrospinal fluid (CSF) were increased in patients treated with Avonex compared to placebo. However, no relationship has been established between absolute levels or changes in levels of IL-10 and clinical outcome in multiple sclerosis.

Pharmacokinetics After completion of phase III clinical trials that supported FDA approval, Biogen developed a new CHO cell line that carried the interferon beta gene and began production of a product referred to as BG9216. These CHO cells were adapted for suspension culture. Data supporting the use of this cell line were submitted to the FDA and showed that the specific activity of BG9216 was greater than the material used in the clinical trials, BG9015. In addition pharmacokinetic bio-equivalence studies in humans showed that BG9216 was not equivalent to BG9015. Based on the biochemical and pharma-cokinetic differences, Biogen was informed that BG9216 was not comparable to BG90 15. Biogen then developed another interferon beta-1a cell line, and the product produced by this cell line was designated BG9418. BG9418 has been extensively characterized and compared in side-by-side analyses with BG9015. Biological, biochemical, and biophysical analyses have shown that the two molecules are comparable. Biological activities of each molecule are similar using several different assays. Finally, pharmacokinetic studies in humans using the two molecules revealed a pattern of clearance from the blood that was determined to be equivalent by rigorous statistical analyses. For these reasons the agency determined that BG9015 and BG9418 are comparable and that clinical data derived from the use of BG9015 can support the approval of the BG9418 molecule.

After an intramuscular dose of Avonex, serum levels of interferon beta-1a peak between 3 and 15 hours and then decline at a rate consistent with a 10-hour elimination half-life. The terminal half-life of interferon beta-1a after intravenous administration has been estimated at between 3 and 4 hours. Serum levels of interferon beta-1a may be sustained after intramuscular administration due to prolonged absorption from the injection site. Systemic exposure, as determined by area under the curve and peak plasma concentration, is greater following intramuscular than subcutaneous administration. According to one report the volume of distribution of interferon beta-1a is about 62 liters, and its total body clearance is 334ml/h per kg.

Disposition No information available

Drug interactions No drug interaction studies have been conducted with Avonex. Other interferons have been found to reduce cytochrome P-450-mediated drug metabolism. Hepatic microsomes isolated from Avonex-treated rhesus monkeys showed no influence on hepatic P-450 enzyme metabolism activity.

E. Therapeutic response The primary outcome assessment for the pivotal clinical trial supporting the approval of Avonex was time to progression in disability, measured as an increase in the Expanded Disability Status Scale (EDSS) of at least 1.0 point that was sustained for at least 6 months. An increase in EDSS score reflects accumulation of disability. This end point was used to ensure that progression reflected a permanent increase in disability rather than a transient effect due to an exacerbation. Time to onset of sustained progression in disability was significantly longer in patients treated with Avonex than in patients receiving placebo. The KaplanMeier estimate of the percentage of MS patients progressing by the end of 2 years was 34.9% for placebo-treated patients and 21.9% for Avonex-treated patients, indicating a slowing of the disease process.

F. Place in therapy Avonex has shown significant advantages over interferon beta-1b (Betaseron) in the treatment of multiple sclerosis. It is administered once a week rather than every other day, and it is not associated with the high incidence of injection site skin necrosis reported with interferon beta-1b in some studies. It appears (based on indirect comparison) at least as effective as interferon beta-1b in reducing the signs of physical disability, and in decreasing the frequency of exacerbations and increasing the periods of stability between exacerbations of the disease.

G. Other considerations In 1993 the FDA approved an interferon beta (interferon beta-1b, Betaseron) and granted the product orphan drug status in the treatment of MS. A clinical trial with Betaseron showed efficacy in reducing the rate of exacerbations by approximately one third. The side effects, however, were considerable. Betaseron differs structurally from natural human interferon-beta; it lacks the amino terminus methionine, the cysteine at position 17 is replaced by a serine, and it is not glycosylated. The Biogen product, Avonex (interferon beta-1a), retains the terminal methionine, has no substitutions, and is glycosylated. Under the regulations of the Orphan Drug Act, Avonex was determined to be a different product from Betaseron, because of a difference in safety profile involving the occurrence of injection site skin necrosis. Analyses of safety data submitted in the Avonex Product License Application (PLA) showed that no injection site necrosis was reported in 158 patients treated with interferon beta-1a. In contrast, the incidence of injection site necrosis reported in the Betaseron PLA was 5% in 124 patients treated with interferon beta-lb. Further supportive evidence for a difference in skin necrosis incidence is suggested by the 85% incidence of injection site reactions in the Betaseron phase III study versus only 4% in the Avonex phase III study.

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