"The U.S. Food and Drug Administration today approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS).
MS is a chronic, inflammatory, autoimmune disease of the central nervous system"...
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Mechanism of Action
The mechanism of action by which AVONEX exerts its effects in patients with multiple sclerosis is unknown.
Interferons (IFNs) are a family of naturally occurring proteins, produced by eukaryotic cells in response to viral infection and other biologic agents. Three major types of interferons have been defined: type I (IFN-alpha, beta, epsilon, kappa and omega), type II (IFN–gamma) and type III (IFN-lambda). Interferon-beta is a member of the type I subset of interferons. The type I interferons have considerably overlapping but also distinct biologic activities. The bioactivities of all IFNs, including IFN-beta, are induced via their binding to specific receptors on the membranes of human cells. Differences in the bioactivites induced by the three major subtypes of IFNs likely reflect differences in the signal transduction pathways induced by signaling through their cognate receptors.
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, β2-microglobulin, and neopterin. These products have been measured in the serum and cellular fractions of blood collected from patients treated with AVONEX.
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 maximally were increased by 48 hours after intramuscular 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 of AVONEX in multiple sclerosis patients have not been evaluated. The pharmacokinetic and pharmacodynamic profiles of AVONEX in healthy subjects following doses of 30 micrograms through 75 micrograms have been investigated. Serum levels of AVONEX as measured by antiviral activity are slightly above detectable limits following a 30 microgram intramuscular dose, and increase with higher doses.
After an intramuscular dose, serum levels of AVONEX generally peak at 15 hours post-dose (range: 6-36 hours) and then decline at a rate consistent with a 19 (range: 8-54) hour elimination half-life.
Subcutaneous administration of AVONEX should not be substituted for intramuscular administration as there is no data establishing that subcutaneous and intramuscular administration of AVONEX result in equivalent pharmacokinetic and pharmacodynamic parameters.
Biological response markers (e.g., neopterin and β2-microglobulin) are induced by AVONEX following parenteral doses of 15 micrograms through 75 micrograms 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.
The clinical effects of AVONEX in patients with relapsing forms of multiple sclerosis (MS) were studied in two randomized, multicenter, double-blind, placebo-controlled studies in patients with MS (Studies 1 and 2). Safety and efficacy of treatment with AVONEX beyond 3 years is not known.
In Study 1, 301 patients received either 30 micrograms of AVONEX (n=158) or placebo (n=143) by intramuscular injection once weekly. Patients 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. The EDSS is a scale that quantifies disability in patients with MS and ranges from 0 (normal neurologic exam) to 10 (death due to MS). 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 point that was sustained for at least 6 months. An increase in EDSS score reflects accumulation of disability. This endpoint was used to help distinguish permanent increase in disability from a transient increase due to an exacerbation.
As shown in Figure 1, the time to onset of sustained progression in disability was significantly longer in AVONEX-treated patients than in placebo-treated patients in Study 1 (p = 0.02). The percentage of patients progressing by the end of 2 years was 35% for placebo-treated patients and 22% for AVONEX-treated patients. This represents a 37% relative reduction in the risk of accumulating disability in the AVONEX-treated group compared to the placebo-treated group.
Figure 1: Time to Onset of Sustained Disability
Progression in Patients with MS in Study 11
1 Kaplan-Meier Methodology; Disability progression was defined as at least a 1 point increase in EDSS score sustained for at least 6 months
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 the AVONEX and placebo groups in confirmed change for patients with at least 2 scheduled visits (p = 0.006).
Figure 2: Confirmed Change in EDSS from Study Entry to
End of Study 1
The rate and frequency of MS exacerbations were 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 3).
Gadolinium (Gd)-enhanced and T2-weighted magnetic resonance imaging (MRI) scans of the brain were obtained in most patients at baseline and at the end of 1 and 2 years of treatment. Secondary outcomes included Gd-enhanced lesion number and volume, and T2-weighted lesion volume. Gd-enhancing lesions seen on brain MRI scans represent areas of breakdown of the blood brain barrier thought to be secondary to inflammation. AVONEX-treated patients demonstrated significantly lower Gd-enhanced lesion number after 1 and 2 years of treatment than placebo-treated patients (p ≤ 0.05; see Table 3). The volume of Gd-enhanced lesions showed similar treatment effects in the AVONEX and placebo groups (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 in the AVONEX and placebo groups.
The exact relationship between MRI findings and the clinical status of MS patients is unknown. The prognostic significance of MRI findings in these studies has not been evaluated.
Summary of Effects of Clinical and MRI Endpoints in Study 1
A summary of the effects of AVONEX on the clinical and MRI endpoints of this study is presented in Table 3.
Table 3: Clinical and MRI Endpoints in Patients with
MS in Study 1
|Time to sustained progression in disability (N: 143, 158)1||--- See Figure 1 ---||0.022|
|Percentage of patients progressing in disability at 2 years (Kaplan-Meier estimate)1||35%||22%|
|SECONDARY ENDPOINTS: DISABILITY|
|Mean confirmed change in EDSS from study entry to end of study (N: 136, 150)1||0.50||0.20||0.0063|
|Number of exacerbations in subset completing 2 years (N: 87, 85)|
|Percentage of patients exacerbation-free in subset completing 2 years (N: 87, 85)||26%||38%||0.104|
|Annual exacerbation rate (N: 143, 158)1||0.82||0.67||0.045|
|Number of Gd-enhanced lesions:|
|At study entry (N: 132, 141)|
|Mean (Median)||2.3 (1.0)||3.2 (1.0)|
|Year 1 (N: 123, 134)|
|Mean (Median)||1.6 (0)||1.0 (0)||0.023|
|Year 2 (N: 82, 83)|
|Mean (Median)||1.6 (0)||0.8 (0)||0.053|
|T2 lesion volume:|
|Percentage change from study entry to Year 1 (N: 116, 123)|
|Percentage change from study entry to Year 2 (N: 83, 81)|
|Note: (N: , ) denotes the number of evaluable placebo and
AVONEX patients, respectively.
1Patient data included in this analysis represent variable periods of time on study.
2Analyzed by Mantel-Cox (logrank) test.
3Analyzed by Mann-Whitney rank-sum test.
4Analyzed by Cochran-Mantel-Haenszel test.
5Analyzed 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 micrograms of AVONEX (n = 193) or placebo (n = 190) by intramuscular injection once weekly. Patients were enrolled into the study over a twoyear 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.
In Study 2, the primary outcome measure was time to development of a second exacerbation in an anatomically distinct region of the central nervous system. Time to development of a second exacerbation was significantly delayed in AVONEX-treated compared to placebo-treated patients (p = 0.002). The Kaplan-Meier estimates of the percentage of patients developing an exacerbation within 24 months were 39% in the placebo group and 21% in the AVONEX group (see 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).
Figure 3: Time to onset of a Second Exacerbation in
1 Kaplan-Meier Methodology
Secondary outcomes were brain MRI measures, including the cumulative increase in the number of new or enlarging T2 lesions, T2 lesion volume at baseline compared to results at 18 months, and the number of Gd-enhancing lesions at 6 months. See Table 4 for the MRI results.
Table 4: Brain MRI Results in Study 2
|CHANGE FROM BASELINE IN T2 VOLUME OF LESIONS AT 18 MONTHS:||N = 119||N = 109|
|Actual Change (mm³)1* Median (25th%, 75th%)||28 (-576, 397)||313 (5, 1140)|
|Percentage Change1* Median (25th%, 75th%)||1 (-24, 29)||16 (0, 53)|
|NUMBER OF NEW OR ENLARGING T2 LESIONS AT 18 MONTHS1*:||N = 132
|N = 119
|0||62 (47)||22 (18)|
|1-3||41 (31)||47 (40)|
|≥ 4||29 (22)||50 (42)|
|Mean (SD)||2.13 (3.2)||4.97 (7.7)|
|NUMBER OF GD-ENHANCING LESIONS AT 6 MONTHS2*:||N = 165
|N = 152
|0||115 (70)||93 (61)|
|1||27 (16)||16 (11)|
|> 1||23 (14)||43 (28)|
|Mean (SD)||0.87 (2.3)||1.49 (3.1)|
|1 P value < 0.001
2 P value < 0.03
* P value from a Mann-Whitney rank-sum test
Last reviewed on RxList: 3/27/2013
This monograph has been modified to include the generic and brand name in many instances.
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