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General

Interferons (IFNs) are a family of naturally occurring proteins, produced by eukaryotic cells in response to viral infection and other biologic agents. Three major groups of interferons have been distinguished: alpha, beta, and gamma. Interferons alpha and beta comprise the Type I interferons and interferon gamma is a Type II interferon. Type I interferons have considerably overlapping but also distinct biologic activities. The bioactivi-ties of IFNs are mediated by their interactions with specific receptors found on the surfaces of human cells. Differences in bioactivites induced by IFNs likely reflect divergences in the signal transduction process induced by IFN-receptor binding.

Biologic Activities

The mechanism of action of Interferon beta-1b in patients with multiple sclerosis is unknown. 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 (interferon beta-1b) -treated patients and Betaseron (interferon beta-1b) -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 (interferon beta-1b) in multiple sclerosis (MS).

Pharmacokinetics

Because serum concentrations of Interferon beta-1b are low or not detectable following subcutaneous administration of 0.25 mg or less of Betaseron (interferon beta-1b) , pharmacokinetic information in patients with MS receiving the recommended dose of Betaseron (interferon beta-1b) 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 (interferon beta-1b) given as two subcutaneous injections at different sites, was approximately 50%.

After intravenous administration of Betaseron (interferon beta-1b) (0.006 mg to 2.0 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 2.0 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 8.0 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 (interferon beta-1b) were comparable.

Following every other day subcutaneous administration of 0.25 mg Betaseron (interferon beta-1b) 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 (interferon beta-1b) 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.

Clinical Studies

The clinical effects of Betaseron (interferon beta-1b) were studied in four randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis.

The effectiveness of Betaseron (interferon beta-1b) in relapsing-remitting MS (Study 1) was evaluated in a double blind, multiclinic, randomized, parallel, placebo controlled clinical investigation of two years duration. The study enrolled MS patients, aged 18 to 50, who were ambulatory (EDSS of < 5.5), exhibited a relapsing-remitting clinical course, met Poser's criteria¹ 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. Patients who had received prior immuno-suppressant 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 (interferon beta-1b) (N=125), or 0.25 mg of Betaseron (interferon beta-1b) (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 1.

TABLE 1: Two Year RRMS Study Results Primary and Secondary Clinical Outcomes

Of the 372 RRMS patients randomized, 72 (19%) failed to complete two full years on their assigned treatments.

Over the two-year period, there were 25 MS-related hospitalizations in the 0.25 mg Betaseron (interferon beta-1b) -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 (interferon beta-1b) 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 (interferon beta-1b) 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 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).

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.

Studies 2 and 3 were multicenter, randomized, double-blind, placebo controlled trials conducted to assess the effect of Betaseron (interferon beta-1b) in patients with SPMS. Study 2was 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 6.5². Patients in Study 2 were randomized to receive Betaseron (interferon beta-1b) 0.25 mg (n=360) or placebo (n=358). Patients in Study 3 were randomized to Betaseron (interferon beta-1b) 0.25 mg (n=317), Betaseron (interferon beta-1b) 0.16 mg/m²of body surface area (n=314, mean assigned dose 0.30 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 (interferon beta-1b) treatment group (p=0.005), with estimated annualized rates of progression of 16% and 19% in the Betaseron (interferon beta-1b) 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 (interferon beta-1b) 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 (interferon beta-1b) 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 (interferon beta-1b) treatment was demonstrated. In Study 2, the mean annual relapse rates were 0.42 and 0.63 in the Betaseron (interferon beta-1b) 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 Betaseron (interferon beta-1b) groups. 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.

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 (interferon beta-1b) (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 (interferon beta-1b) 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 (interferon beta-1b) compared to 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 (interferon beta-1b) group (Figure 2). The risk for developing a second exacerbation in the Betaseron (interferon beta-1b) 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 on Study (Kaplan-Meier Methodology)

Patients treated with Betaseron (interferon beta-1b) demonstrated a lower number of newly active lesions during the course of the study. A significant difference between Betaseron (interferon beta-1b) 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 (interferon beta-1b) beyond three years are not known.

REFERENCES

¹ Poser CM, et al. Ann Neurol 1983; 13(3): 227-231

² Kurtzke JF. Neurology 1983; 33(11): 1444-1452

Last reviewed on RxList: 6/26/2008
This monograph has been modified to include the generic and brand name in many instances.