"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"...
Mechanism of Action
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 1 (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 bioactivities 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-1b receptor binding induces the expression of proteins that are responsible for the pleiotropic bioactivities of interferon beta-1b. A number of these proteins (including neopterin, β2-microglobulin, MxA protein, and IL-10) have been measured in blood fractions from Betaseron-treated patients and Betaseron-treated healthy volunteers. Immunomodulatory effects of interferon beta-1b include the enhancement of suppressor T cell activity, reduction of pro-inflammatory cytokine production, down-regulation of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system. It is not known if these effects play an important role in the observed clinical activity of Betaseron in multiple sclerosis (MS).
Because serum concentrations of interferon beta-1b are low or not detectable following subcutaneous administration of 0.25 mg or less of Betaseron, pharmacokinetic information in patients with MS receiving the recommended dose of Betaseron is not available.
Following single and multiple daily subcutaneous administrations of 0.5 mg Betaseron to healthy volunteers (N=12), serum interferon beta-1b concentrations were generally below 100 IU/mL. Peak serum interferon beta-1b concentrations occurred between one to eight hours, with a mean peak serum interferon concentration of 40 IU/mL. Bioavailability, based on a total dose of 0.5 mg Betaseron given as two subcutaneous injections at different sites, was approximately 50%.
After intravenous administration of Betaseron (0.006 mg to 2 mg), similar pharmacokinetic profiles were obtained from healthy volunteers (N=12) and from patients with diseases other than MS (N=142). In patients receiving single intravenous doses up to 2 mg, increases in serum concentrations were dose proportional. Mean serum clearance values ranged from 9.4 mL/min•kg-1 to 28.9 mL/min•kg-1 and were independent of dose. Mean terminal elimination half-life values ranged from 8 minutes to 4.3 hours and mean steady-state volume of distribution values ranged from 0.25 L/kg to 2.88 L/kg. Three-times-a-week intravenous dosing for two weeks resulted in no accumulation of interferon beta-1b in sera of patients. Pharmacokinetic parameters after single and multiple intravenous doses of Betaseron were comparable.
Following every other day subcutaneous administration of 0.25 mg Betaseron in healthy volunteers, biologic response marker levels (neopterin, β2-microglobulin, MxA protein, and the immunosuppressive cytokine, IL-10) increased significantly above baseline six-twelve hours after the first Betaseron dose. Biologic response marker levels peaked between 40 and 124 hours and remained elevated above baseline throughout the seven-day (168-hour) study. The relationship between serum interferon beta-1b levels or induced biologic response marker levels and the clinical effects of interferon beta-1b in multiple sclerosis is unknown.
Drug Interaction Studies
No formal drug interaction studies have been conducted with Betaseron.
The clinical effects of Betaseron were studied in four randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis (Studies 1, 2, 3, and 4).
Patients with Relapsing-Remitting Multiple Sclerosis
The effectiveness of Betaseron in relapsing-remitting MS (RRMS) was evaluated in a double blind, multiclinic, randomized, parallel, placebo controlled clinical study of two years duration (Study 1). The study enrolled MS patients, aged 18 to 50, who were ambulatory [Kurtzke Expanded Disability Status Scale (EDSS) of ≤ 5.5 – score 5.5 is ambulatory for 100 meters, disability precludes full daily activities], exhibited a relapsing-remitting clinical course, met Poser's criteria for clinically definite and/or laboratory supported definite MS and had experienced at least two exacerbations over two years preceding the trial without exacerbation in the preceding month. The EDSS score is a method of quantifying disability in patients with MS and ranges from 0 (normal neurologic exam) to 10 (death due to MS). Patients who had received prior immunosuppressant therapy were excluded.
An exacerbation was defined as the appearance of a new clinical sign/symptom or the clinical worsening of a previous sign/symptom (one that had been stable for at least 30 days) that persisted for a minimum of 24 hours.
Patients selected for study were randomized to treatment with either placebo (N=123), 0.05 mg of Betaseron (N=125), or 0.25 mg of Betaseron (N=124) self-administered subcutaneously every other day. Outcome based on the 372 randomized patients was evaluated after two years.
Patients who required more than three 28-day courses of corticosteroids were removed from the study. Minor analgesics (acetaminophen, codeine), antidepressants, and oral baclofen were allowed ad libitum, but chronic nonsteroidal anti-inflammatory drug (NSAID) use was not allowed.
The primary protocol-defined outcome measures were 1) frequency of exacerbations per patient and 2) proportion of exacerbation free patients. A number of secondary clinical and magnetic resonance imaging (MRI) measures were also employed. All patients underwent annual T2 MRI imaging and a subset of 52 patients at one site had MRIs performed every six weeks for assessment of new or expanding lesions.
The study results are shown in Table 3.
Table 3: Two Year RRMS Study Results of Primary
and Secondary Clinical Outcomes (Study 1)
|Efficacy Parameters||Treatment Groups||Statistical Comparisons p-value|
|Primary End Points||Placebo
|Betaseron 0.05 mg
|Betaseron 0.25 mg
|Placebo vs 0.05 mg||0.05 mg vs 0.25 mg||Placebo vs 0.25 mg|
|Annual exacerbation rate||1.31||1.14||0.9||0.005||0.113||0.0001|
|Proportion of exacerbation-free patientsa||16%||18%||25%||0.609||0.288||0.094|
|Exacerbation frequency per patient 2||20%||28%||17%|
|Median number of months to first on-study exacerbation||5||6||9||0.299||0.097||0.01|
|Rate of moderate or severe exacerbations per year||0.47||0.29||0.23||0.02||0.257||0.001|
|Mean number of moderate or severe exacerbation days per patient||44||33||20||0.229||0.064||0.001|
|Mean change in EDSS scorec at endpoint||0.21||0.21||-0.07||0.995||0.108||0.144|
|Mean change in Scripps scored at endpoint||-0.53||-0.5||0.66||0.641||0.051||0.126|
|Median duration in days per exacerbation||36||33||36||NDe||NDe||NDe|
|% change in mean MRI lesion area at endpoint||21.4%||9.8%||-0.9%||0.015||0.019||0.0001|
|a 14 exacerbation free patients (0 from
placebo, six from 0.05 mg, and eight from 0.25 mg) dropped out of the study
before completing six months of therapy. These patients are excluded from this analysis.
b Sequelae and Functional Neurologic Status, both required by protocol, were not analyzed individually but are included as a function of the EDSS.
c EDSS scores range from 1-10, with higher scores reflecting greater disability
d Scripps neurologic rating scores range from 0-100, with smaller scores reflecting greater disability.
e ND = Not done
Of the 372 RRMS patients randomized, 72 (19%) failed to complete two full years on their assigned treatments.
Over the two-year period in Study 1, there were 25 MS-related hospitalizations in the 0.25 mg Betaseron-treated group compared to 48 hospitalizations in the placebo group. In comparison, non-MS hospitalizations were evenly distributed among the groups, with 16 in the 0.25 mg Betaseron group and 15 in the placebo group. The average number of days of MS-related steroid use was 41 days in the 0.25 mg Betaseron group and 55 days in the placebo group (p=0.004).
MRI data were also analyzed for patients in this study. A frequency distribution of the observed percent changes in MRI area at the end of two years was obtained by grouping the percentages in successive intervals of equal width. Figure 1 displays a histogram of the proportions of patients, which fell into each of these intervals. The median percent change in MRI area for the 0.25 mg group was -1.1%, which was significantly smaller than the 16.5% observed for the placebo group (p=0.0001).
Figure 1: Distribution of Change in MRI Area in Patients with RRMS in
In an evaluation of frequent MRI scans (every six weeks) on 52 patients at one site in Study 1, 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).
The exact relationship between MRI findings and clinical status of patients is unknown. Changes in lesion area often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in this study has not been evaluated.
Patients with Secondary Progressive Multiple Sclerosis
Studies 2 and 3 were multicenter, randomized, double-blind, placebo controlled trials conducted to assess the effect of Betaseron in patients with secondary progressive MS (SPMS). Study 2 was conducted in Europe and Study 3 was conducted in North America. Both studies enrolled patients with clinically definite or laboratory-supported MS in the secondary progressive phase, and who had evidence of disability progression (both Study 2 and 3) or two relapses (Study 2 only) within the previous two years. Baseline Kurtzke expanded disability status scale (EDSS) scores ranged from 3.0 to 6.5. Patients in Study 2 were randomized to receive Betaseron 0.25 mg (N=360) or placebo (N=358). Patients in Study 3 were randomized to Betaseron 0.25 mg (N=317), Betaseron 0.16 mg/m² of body surface area (N=314, mean assigned dose 0.3 mg), or placebo (N=308). Test agents were administered subcutaneously, every other day for three 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 Betaseron treatment group (p=0.005), with estimated annualized rates of progression of 16% and 19% in the Betaseron 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 Betaseron fixed dose, surface area-adjusted dose, and placebo groups, respectively.
Multiple analyses, including covariate and subset analyses based on sex, age, disease duration, clinical disease activity prior to study enrollment, MRI measures at baseline and early changes in MRI following treatment were evaluated in order to interpret the discordant study results. No demographic or disease-related factors enabled identification of a patient subset where Betaseron treatment was predictably associated with delayed progression of disability.
In Studies 2 and 3, like Study 1, a statistically significant decrease in the incidence of relapses associated with Betaseron treatment was demonstrated. In Study 2, the mean annual relapse rates were 0.42 and 0.63 in the Betaseron 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 smaller increases in T2 MRI lesion area and decreased number of active MRI lesions in patients in the Betaseron groups compared to the placebo group. The exact relationship between MRI findings and the clinical status of patients is unknown. Changes in MRI findings often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in these studies is not known.
Patients with an Isolated Demyelinating Event and Typical MS Lesions on Brain MRI
In Study 4, 468 patients who had recently (within 60 days) experienced an isolated demyelinating event, and who had lesions typical of multiple sclerosis on brain MRI were randomized to receive either 0.25 mg Betaseron (N=292) or placebo (N=176) subcutaneously every other day (ratio 5:3). 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.
Eight percent of subjects on Betaseron and 6% of subjects on placebo withdrew from the study for a reason other than the development of a second exacerbation. Time to development of a second exacerbation was significantly delayed in patients treated with Betaseron compared to patients treated with placebo (p < 0.0001). The Kaplan-Meier estimates of the percentage of patients developing an exacerbation within 24 months were 45% in the placebo group and 28% of the Betaseron group (Figure 2). The risk for developing a second exacerbation in the Betaseron group was 53% of the risk in the placebo group (Hazard ratio=0.53; 95% confidence interval 0.39 to 0.73).
Figure 2: Onset of Second Exacerbation by Time
in Patients with Isolated Demyelinating Event with Typical MS Lesions on Brain
MRI in Study 4*
In Study 4, patients treated with Betaseron demonstrated a lower number of newly active lesions during the course of the study. A significant difference between Betaseron and placebo was not seen in the absolute change in T2 lesion volume during the course of the study.
Safety and efficacy of treatment with Betaseron beyond three years are not known.
Last reviewed on RxList: 8/6/2013
This monograph has been modified to include the generic and brand name in many instances.
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