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Avonex (Interferon Beta-1A) - Description and Clinical Pharmacology

 
 



DESCRIPTION

AVONEX® (Interferon beta-1a) is a 166 amino acid glycoprotein with a predicted molecular weight of approximately 22,500 daltons. It is produced by recombinant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been introduced. The amino acid sequence of AVONEX® is identical to that of natural human interferon beta.

Using the World Health Organization (WHO) natural interferon beta standard, Second International Standard for Interferon, Human Fibroblast (Gb-23-902-531), AVONEX® has a specific activity of approximately 200 million international units (IU) of antiviral activity per mg of Interferon beta-1a determined specifically by an in vitro cytopathic effect bioassay using lung carcinoma cells (A549) and Encephalomyocarditis virus (ECM). AVONEX® 30 mcg contains approximately 6 million IU of antiviral activity using this method. The activity against other standards is not known. Comparison of the activity of AVONEX® with other Interferon betas is not appropriate, because of differences in the reference standards and assays used to measure activity.

30 MCG LYOPHILIZED POWDER VIAL

A vial of AVONEX® is formulated as a sterile, white to off-white lyophilized powder for intramuscular injection after reconstitution with supplied diluent (Sterile Water for Injection, USP). Each vial of reconstituted AVONEX® contains 30 mcg of Interferon beta-1a; 15 mg Albumin (Human), USP; 5.8 mg Sodium Chloride, USP; 5.7 mg Dibasic Sodium Phosphate, USP; and 1.2 mg Monobasic Sodium Phosphate, USP, in 1.0 mL at a pH of approximately 7.3.

30 MCG PREFILLED SYRINGE

A prefilled syringe of AVONEX® is formulated as a sterile liquid for intramuscular injection. Each 0.5 mL (30 mcg dose) of AVONEX® in a prefilled glass syringe contains 30 mcg of Interferon beta-1a, 0.79 mg Sodium Acetate Trihydrate, USP; 0.25 mg Glacial Acetic Acid, USP; 15.8 mg Arginine Hydrochloride, USP; and 0.025 mg Polysorbate 20 in Water for Injection, USP at a pH of approximately 4.8.

CLINICAL PHARMACOLOGY

GENERAL

Interferons are a family of naturally occurring proteins and glycoproteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferon beta, one member of this family, is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and Interferon beta-1a are glycosylated, with each containing a single N-linked complex carbohydrate moiety. Glycosylation of other proteins is known to affect their stability, activity, aggregation, biodistribution, and half-life in blood. However, the effects of glycosylation of interferon beta on these properties have not been fully defined.

BIOLOGIC ACTIVITIES

Interferons are cytokines that mediate antiviral, antiproliferative and immunomodulatory activities in response to viral infection and other biological inducers. Three major interferons have been distinguished: alpha, beta, and gamma. Interferons alpha and beta form the Type I class of interferons, and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinct biological activities.

Interferon beta 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 2', 5'-oligoadenylate synthetase, (beta)2-microglobulin, and neopterin. These products have been measured in the serum and cellular fractions of blood collected from patients treated with AVONEX®.

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 multiple sclerosis patients showed that interleukin 10 (IL-10) levels in cerebrospinal fluid were increased in patients treated with AVONEX® compared to placebo. Serum IL-10 levels were increased 48 hours after intramuscular (IM) injection of AVONEX® and remained elevated for 1 week. However, no relationship has been established between absolute levels of IL-10 and clinical outcome in multiple sclerosis.

PHARMACOKINETICS

Pharmacokinetics of AVONEX® in multiple sclerosis patients have not been evaluated. The pharmacokinetic and pharmacodynamic profiles of AVONEX® in healthy subjects following doses of 30 mcg through 75 mcg have been investigated. Serum levels of AVONEX® as measured by antiviral activity are slightly above detectable limits following a 30 mcg IM dose, and increase with higher doses.

After an IM dose, serum levels of AVONEX® typically peak between 3 and 15 hours and then decline at a rate consistent with a 10 hour elimination half-life. Serum levels of AVONEX® may be sustained after IM administration due to prolonged absorption from the IM site. Systemic exposure, as determined by AUC and Cmax values, is greater following IM than subcutaneous (SC) administration.

Subcutaneous administration of AVONEX® should not be substituted for intramuscular administration. Subcutaneous and intramuscular administration have been observed to have non-equivalent pharmacokinetic and pharmacodynamic parameters following administration to healthy volunteers.

Biological response markers (e.g., neopterin and (beta)2-microglobulin) are induced by AVONEX® following parenteral doses of 15 mcg through 75 mcg in healthy subjects and treated patients. Biological response marker levels increase within 12 hours of dosing and remain elevated for at least 4 days. Peak biological response marker levels are typically observed 48 hours after dosing. The relationship of serum AVONEX® levels or levels of these induced biological response markers to the mechanisms by which AVONEX® exerts its effects in multiple sclerosis is unknown.

CLINICAL STUDIES

The clinical effects of AVONEX® in multiple sclerosis were studied in two randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis.1,2 Safety and efficacy of treatment with AVONEX® beyond 3 years is not known.

In Study 1, 301 patients received either 30 mcg of AVONEX® (n=158) or placebo (n=143) by IM injection once weekly. Patients were entered into the trial over a 2 ½ year period, received injections for up to 2 years, and continued to be followed until study completion. Two hundred eighty-two patients completed 1 year on study, and 172 patients completed 2 years on study. There were 144 patients treated with AVONEX® for more than 1 year, 115 patients for more than 18 months and 82 patients for 2 years.

All patients had a definite diagnosis of multiple sclerosis of at least 1 year duration and had at least 2 exacerbations in the 3 years prior to study entry (or 1 per year if the duration of disease was less than 3 years). At entry, study participants were without exacerbation during the prior 2 months and had Kurtzke Expanded Disability Status Scale (EDSS3) scores ranging from 1.0 to 3.5. Patients with chronic progressive multiple sclerosis were excluded from this study.

The primary outcome assessment was time to progression in disability, measured as an increase in the EDSS score of at least 1.0 point that was sustained for at least 6 months. An increase in EDSS score reflects accumulation of disability. This endpoint was used to ensure that progression reflected permanent increase in disability rather than a transient effect due to an exacerbation.

Secondary outcomes included exacerbation frequency and results of magnetic resonance imaging (MRI) scans including gadolinium (Gd)-enhanced lesion number and volume and T2-weighted (proton density) lesion volume. Additional secondary endpoints included 2 upper limb (tested in both arms) and 3 lower limb function tests.

Twenty-three of the 301 patients (8%) discontinued treatment prematurely. Of these, 1 patient treated with placebo (1%) and 6 patients treated with AVONEX® (4%) discontinued treatment due to adverse events. Thirteen of these 23 patients remained on study and were evaluated for clinical endpoints.

Time to onset of sustained progression in disability was significantly longer in patients treated with AVONEX® than in patients receiving placebo (p = 0.02). The Kaplan-Meier plots of these data are presented in Figure 1. The Kaplan-Meier estimate of the percentage of 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. This represents a 37% relative reduction in the risk of accumulating disability in the AVONEX®-treated group compared to the placebo-treated group.

The distribution of confirmed EDSS change from study entry (baseline) to the end of the study is shown in Figure 2. There was a statistically significant difference between treatment groups in confirmed change for patients with at least 2 scheduled visits (136 placebo-treated and 150 AVONEX®-treated patients; p = 0.006; see Table 1).

The rate and frequency of exacerbations were determined as secondary outcomes. For all patients included in the study, irrespective of time on study, the annual exacerbation rate was 0.67 per year in the AVONEX®-treated group and 0.82 per year in the placebo-treated group (p = 0.04).

AVONEX® treatment significantly decreased the frequency of exacerbations in the subset of patients who were enrolled in the study for at least 2 years (87 placebo-treated patients and 85 AVONEX®-treated patients; p = 0.03; see Table 1).

Gd-enhanced and T2-weighted (proton density) MRI scans of the brain were obtained in most patients at baseline and at the end of 1 and 2 years of treatment. Gd-enhancing lesions seen on brain MRI scans represent areas of breakdown of the blood brain barrier thought to be secondary to inflammation. Patients treated with AVONEX® demonstrated significantly lower Gd-enhanced lesion number after 1 and 2 years of treatment (p </= 0.05; see Table 1). The volume of Gd-enhanced lesions was also analyzed, and showed similar treatment effects (p </= 0.03). Percentage change in T2-weighted lesion volume from study entry to Year 1 was significantly lower in AVONEX®-treated than placebo-treated patients (p = 0.02). A significant difference in T2-weighted lesion volume change was not seen between study entry and Year 2.

The exact relationship between MRI findings and the clinical status of patients is unknown. The prognostic significance of MRI findings in these studies has not been evaluated.

Of the limb function tests, only 1 demonstrated a statistically significant difference between treatment groups (favoring AVONEX®). A summary of the effects of AVONEX® on the clinical and MRI endpoints of this study is presented in Table 1.

Table 1
Clinical and MRI Endpoints in Study 1
Endpoint Placebo AVONEX® P-Value
PRIMARY ENDPOINT:      
Time to sustained progression
in disability (N: 143, 158) 1
-See Figure 1- 0.02 2
Percentage of patients progressing
in disability at 2 years
(Kaplan-Meier estimate) 1
34.9% 21.9%  
SECONDARY ENDPOINTS:
DISABILITY
     
Mean confirmed change in EDSS
from study entry to end of study
(N: 136, 150) 1
0.50 0.20 0.006 3
EXACERBATIONS      
Number of exacerbations in subset
completing 2 years (N: 87, 85)
     
     0 26% 38% 0.03 3
     1 30% 31%  
     2 11% 18%  
     3 14%   7%  
    >/=4 18%   7%  
Percentage of patients exacerbation-
free in subset completing 2 years
(N: 87, 85)
26% 38% 0.10 4
Annual exacerbation rate
(N: 143, 158) 1
0.82 0.67 0.04 5
MRI      
Number of Gd-enhanced lesions:
At study entry (N: 132, 141)
     Mean (Median)
2.3 (1.0) 3.2 (1.0)  
     Range 0-23 0-56  
Year 1 (N: 123, 134)
     Mean (Median)
1.6 (0) 1.0 (0) 0.02 3
     Range 0-22 0-28  
Year 2 (N: 82, 83)
     Mean (Median)
1.6 (0) 0.8 (0) 0.05 3
     Range 0-34 0-13  
T2 lesion volume:
Percentage change from study
entry to Year 1 (N: 116, 123)
     Median
-3.3% -13.1% 0.02 3
Percentage change from study
entry to Year 2 (N: 83, 81)
     Median
-6.5% -13.2% 0.36 3
Note: (N:,) denotes the number of evaluable placebo and AVONEX® patients, respectively.
1 Patient data included in this analysis represent variable periods of time on study.
2 Analyzed by Mantel-Cox (logrank) test.
3 Analyzed by Mann-Whitney rank-sum test.
4 Analyzed by Cochran-Mantel-Haenszel test.
5 Analyzed by likelihood ratio test.

In Study 2, 383 patients who had recently experienced an isolated demyelinating event involving the optic nerve, spinal cord, or brainstem/cerebellum, and who had lesions typical of multiple sclerosis on brain MRI, received either 30 mcg AVONEX® (n = 193) or placebo (n = 190) by IM injection once weekly. All patients received intravenous steroid treatment for the initiating clinical exacerbation. Patients were enrolled into the study over a two-year period and followed for up to three years or until they developed a second clinical exacerbation in an anatomically distinct region of the central nervous system. Sixteen percent of subjects on AVONEX® and 14% of subjects on placebo withdrew from the study for a reason other than the development of a second exacerbation2.

The primary outcome measure was time to development of a second exacerbation in an anatomically distinct region of the central nervous system. Secondary outcomes were brain MRI measures, including the cumulative increase in the number of new or enlarging T2 lesions, T2 lesion volume compared to baseline at 18 months, and the number of Gd- enhancing lesions at 6 months.

Time to development of a second exacerbation was significantly delayed in patients treated with AVONEX® compared to placebo (p = 0.002). The Kaplan-Meier estimates of the percentage of patients developing an exacerbation within 24 months were 38.6% in the placebo group and 21.1% in the AVONEX® group (Figure 3). The relative rate of developing a second exacerbation in the AVONEX® group was 0.56 of the rate in the placebo group (95% confidence interval 0.38 to 0.81). The brain MRI findings are described in Table 2.

Table 2
Brain MRI Data According to Treatment Group
  AVONEX® Placebo
CHANGE IN T2 VOLUME @18 MONTHS: N = 119 N = 109
   Actual Change (mm3) 1*
    Median (25th%, 75th%)
28 (-576, 397) 313 (5, 1140)
   Percentage Change 1*
    Median (25th%, 75th%)
1 (-24, 29) 16 (0, 53)
NUMBER OF NEW OR ENLARGING N = 132 N = 119
T2 LESIONS @ 18 MONTHS 1*: N (%) N (%)
   0 62 (47) 22 (18)
   1-3 41 (31) 47 (40)
  >/=4 29 (22) 50 (42)
   Mean (SD) 2.13 (3.19) 4.97 (7.71)
NUMBER OF GD-ENHANCING N = 165 N = 152
LESIONS @ 6 MONTHS 2*: N (%) N (%)
   0 115 (70) 93 (61)
   1 27 (16) 16 (11)
  >1 23 (14) 43 (28)
   Mean (SD) 0.87 (2.28) 1.49 (3.14)
1 P value <0.001
2 P value <0.03
*P value from a Mann-Whitney rank-sum test

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