EXTAVIA (Page 4 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Interferon beta-1b has not been tested for its carcinogenic potential in animals.

Mutagenesis

Interferon beta-1b was not genotoxic in the in vitro bacterial reverse mutation assay or the in vitro chromosomal aberration assay in human peripheral blood lymphocytes. Interferon beta-1b treatment of mouse BALBc-3T3 cells did not result in increased transformation frequency in an in vitro model of tumor transformation.

Impairment of Fertility

Administration of interferon beta-1b (doses of up to 0.33 mg/kg/day) to normally cycling female rhesus monkeys had no apparent adverse effects on either menstrual cycle duration or associated hormonal profiles (progesterone and estradiol) when administered over three consecutive menstrual cycles. The highest dose tested is approximately 30 times the recommended human dose of 0.25 mg on a body surface area (mg/m2) basis. The potential for other effects on fertility or reproductive performance was not evaluated.

14 CLINICAL STUDIES

The clinical effects of interferon beta-1b were studied in four randomized, multicenter, double-blind, placebo-controlled studies in patients with MS (Studies 1, 2, 3, and 4).

Patients with Relapsing-Remitting MS

The effectiveness of interferon beta-1b 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 interferon beta-1b (N = 125), or 0.25 mg of 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 3.

Table 3: Two-Year RRMS Study Results of Primary and Secondary Clinical Outcomes (Study 1)
Abbreviations: EDSS, Kurtzke Expanded Disability Status Scale; ND, not done; MRI, magnetic resonance imaging.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.
Efficacy Parameters Treatment groups Statistical comparisons p-value
Primary endpoints Placebo(N = 123)Interferon beta-1b0.05 mg(N = 125)Interferon beta-1b0.25 mg(N = 124)Placebovs0.05 mg0.05 mgvs0.25 mgPlacebovs0.25 mg
Annual exacerbation rate1.311.140.90.0050.1130.0001
Proportion of exacerbation-free patientsa 16%18%25%0.6090.2880.094
Exacerbation frequency per patient0a 1234> 520%32%20%15%15%21%22%31%28%15%7%16%29%39%17%14%9%8%0.1510.0770.001
Secondary endpointsb
Median number of months to first on-study exacerbation5690.2990.0970.01
Rate of moderate or severe exacerbations per year0.470.290.230.020.2570.001
Mean number of moderate or severe exacerbation days per patient4433200.2290.0640.001
Mean change in EDSS scorec at endpoint0.210.21-0.070.9950.1080.144
Mean change in Scripps scored at endpoint-0.53-0.50.660.6410.0510.126
Median duration in days per exacerbation363336ND ND ND
% change in mean MRI lesion area at endpoint21.4%9.8%-0.9%0.0150.0190.0001

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 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 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 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 Patients with RRMS in Study 1

Figure 1
(click image for full-size original)

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).

Patients with Secondary Progressive MS

Studies 2 and 3 were multicenter, randomized, double-blind, placebo-controlled trials conducted to assess the effect of interferon beta-1b 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 EDSS scores ranged from 3.0 to 6.5. Patients in Study 2 were randomized to receive interferon beta-1b 0.25 mg (N = 360) or placebo (N = 358). Patients in Study 3 were randomized to interferon beta-1b 0.25 mg (N = 317), interferon beta-1b 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 interferon beta-1b treatment group (p = 0.005), with estimated annualized rates of progression of 16% and 19% in the 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 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 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 interferon beta-1b treatment was demonstrated. In Study 2, the mean annual relapse rates were 0.42 and 0.63 in the 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 smaller increases in T2 MRI lesion area and decreased number of active MRI lesions in patients in the interferon beta-1b groups compared to the placebo group.

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 MS on brain MRI were randomized to receive either 0.25 mg 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 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 interferon beta-1b 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 interferon beta-1b group (Figure 2). The risk for developing a second exacerbation in the 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 in Patients with Isolated Demyelinating Event with Typical MS Lesions on Brain MRI in Study 4*

Figure 2
(click image for full-size original)

*Kaplan-Meier Methodology

In Study 4, patients treated with interferon beta-1b demonstrated a lower number of newly active lesions during the course of the study. A significant difference between interferon beta-1b and placebo was not seen in the absolute change in T2 lesion volume during the course of the study.

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