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Rebif (Interferon Beta-1a) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Rebif® (interferon beta-1a) is a purified 166 amino acid glycoprotein with a 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 Rebif® is identical to that of natural fibroblast derived human interferon beta. Natural interferon beta and interferon beta-1a (Rebif® ) are glycosylated with each containing a single N-linked complex carbohydrate moiety.

Using a reference standard calibrated against the World Health Organization natural interferon beta standard (Second International Standard for Interferon, Human Fibroblast GB 23 902 531), Rebif® has a specific activity of approximately 270 million international units (MIU) of antiviral activity per mg of interferon beta-1a determined specifically by an in vitro cytopathic effect bioassay using WISH cells and Vesicular Stomatitis virus. Rebif® 22 mcg and 44 mcg contains approximately 6 MIU or 12 MIU, respectively, of antiviral activity using this method.

Rebif® (interferon beta-1a) is formulated as a sterile solution in a prefilled syringe intended for subcutaneous (sc) injection. Each 0.5 mL (0.5 cc) of Rebif® contain either 22 mcg or 44 mcg of interferon beta-1a, 2 mg or 4 mg albumin (human) USP, 27.3 mg mannitol USP, 0.4 mg sodium acetate, Water for Injection USP.

CLINICAL PHARMACOLOGY

GENERAL

Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons possess immunomodulatory, antiviral and antiproliferative biological activities. They exert their biological effects by binding to specific receptors on the surface of cells. Three major groups of interferons have been distinguished: alpha, beta, and gamma. Interferons alpha and beta form the Type I interferons and interferon gamma is a Type II interferon. Type I interferons have considerably overlapping but also distinct biological activities. Interferon beta is produced naturally by various cell types including fibroblasts and macrophages. Binding of interferon beta to its receptors initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers, including 2', 5'-oligoadenylate synthetase, beta 2-microglobulin and neopterin, which may mediate some of the biological activities. The specific interferon-induced proteins and mechanisms by which interferon beta-1a exerts its effects in multiple sclerosis have not been fully defined.

PHARMACOKINETICS

The pharmacokinetics of Rebif® (interferon beta-1a) in people with multiple sclerosis have not been evaluated. In healthy volunteer subjects, a single subcutaneous (sc) injection of 60 mcg of Rebif® (liquid formulation), resulted in a peak serum concentration (Cmax) of 5.1 ± 1.7 IU/mL (mean ± SD), with a median time of peak serum concentration (Tmax) of 16 hours. The serum elimination half-life (t1/2) was 69 ± 37 hours, and the area under the serum concentration versus time curve (AUC) from zero to 96 hours was 294 ± 81 IU·h/mL. Following every other day sc injections in healthy volunteer subjects, an increase in AUC of approximately 240% was observed, suggesting that accumulation of interferon beta-1a occurs after repeat administration. Total clearance is approximately 33-55 L/hour. There have been no observed gender-related effects on pharmacokinetic parameters. Pharmacokinetics of Rebif® in pediatric and geriatric patients or patients with renal or hepatic insufficiency have not been established.

PHARMACODYNAMICS

Biological response markers (e.g., 2', 5'-OAS activity, neopterin and beta 2-microglobulin) are induced by interferon beta-1a following parenteral doses administered to healthy volunteer subjects and to patients with multiple sclerosis. Following a single sc administration of 60 mcg of Rebif® intracellular 2', 5'-OAS activity peaked between 12 to 24 hours and beta-2-microglobulin and neopterin serum concentrations showed a maximum at approximately 24 to 48 hours. All three markers remained elevated for up to four days. Administration of Rebif 22 mcg three times per week (tiw) inhibited mitogen-induced release of pro-inflammatory cytokines (IFN-(gamma), IL-1, IL-6, TNF-(alpha) and TNF-(beta)) by peripheral blood mononuclear cells that, on average, was near double that observed with Rebif® administered once per week (qw) at either 22 or 66 mcg.

The relationships between serum interferon beta-1a levels and measurable pharmacodynamic activities to the mechanism(s) by which Rebif® exerts its effects in multiple sclerosis are unknown. No gender-related effects on pharmacodynamic parameters have been observed.

CLINICAL STUDIES

Two multicenter studies evaluated the safety and efficacy of Rebif® in patients with relapsing-remitting multiple sclerosis.

Study 1 was a randomized, double-blind, placebo controlled study in patients with multiple sclerosis for at least one year, Kurtzke Expanded Disability Status Scale (EDSS) scores ranging from 0 to 5, and at least 2 acute exacerbations in the previous 2 years. (1)Patients with secondary progressive multiple sclerosis were excluded from the study. Patients received sc injections of either placebo (n = 187), Rebif® 22 mcg (n = 189), or Rebif® 44 mcg (n = 184) administered tiw for two years. Doses of study agents were progressively increased to their target doses during the first 4 to 8 weeks for each patient in the study (see DOSAGE AND ADMINISTRATION).

The primary efficacy endpoint was the number of clinical exacerbations. Numerous secondary efficacy endpoints were also evaluated and included exacerbation-related parameters, effects of treatment on progression of disability and magnetic resonance imaging (MRI)-related parameters. Progression of disability was defined as an increase in the EDSS score of at least 1 point sustained for at least 3 months. Neurological examinations were completed every 3 months, during suspected exacerbations, and coincident with MRI scans. All patients underwent proton density T2-weighted (PD/T2) MRI scans at baseline and every 6 months. A subset of 198 patients underwent PD/T2 and T1-weighted gadolinium-enhanced (Gd)-MRI scans monthly for the first 9 months. Of the 560 patients enrolled, 533 (95%) provided 2 years of data and 502 (90%) received 2 years of study agent.

Study results are shown in Table 1 and Figure 1. Rebif® at doses of 22 mcg and 44 mcg administered sc tiw significantly reduced the number of exacerbations per patient as compared to placebo. Differences between the 22 mcg and 44 mcg groups were not significant (p >0.05).

The exact relationship between MRI findings and the 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 these studies has not been evaluated.

Table 1: Clinical and MRI Endpoints from Study 1

Placebo 22 mcg tiw 44 mcg tiw
n = 187 n = 189 n = 184
Exacerbation-related    Mean number of exacerbations per patient
   over 2 years 1 , 2  (Percent reduction)    Percent (%) of patients exacerbation-free at
   2 years 3

2.56


15%

1.82 **

(29%)
25% *


1.73 ***

(32%)
32% ***

   Median time to first exacerbation
  (months) 1 , 4
4.5 7.6 ** 9.6 ***
MRI    Median percent (%) change of MRI PD-T2
   lesion area at 2 years 5 
  Median number of active lesions per patient
   per scan (PD/T2; 6 monthly) 5
n = 172
11.0


2.25
n = 171
-1.2 ***


0.75 ***
n = 171
-3.8 ***


0.5 ***
* p<0.05 compared to placebo ** p<0.001 compared to placebo *** p<0.0001 compared to placebo (1) Intent-to-treat analysis (2) Poisson regression model adjusted for center and time on study (3) Logistic regression adjusted for center. Patients lost to follow-up prior to an exacerbation were excluded from this analysis (n = 185, 183, and 184 for the placebo, 22 mcg tiw, and 44 mcg tiw groups, respectively) (4) Cox proportional hazard model adjusted for center (5) ANOVA on ranks adjusted for center. Patients with missing scans were excluded from this analysis

The time to onset of progression in disability sustained for three months was significantly longer in patients treated with Rebif® than in placebo-treated patients. The Kaplan-Meier estimates of the proportions of patients with sustained disability are depicted in Figure 1.

The safety and efficacy of treatment with Rebif® beyond 2 years have not been established.

Study 2 was a randomized, open-label, evaluator-blinded, active comparator study.(2)Patients with relapsing-remitting multiple sclerosis with EDSS scores ranging from 0 to 5.5, and at least 2 exacerbations in the previous 2 years were eligible for inclusion. Patients with secondary progressive multiple sclerosis were excluded from the study. Patients were randomized to treatment with Rebif® 44 mcg tiw by sc injection (n=339) or Avonex® 30 mcg qw by intramuscular (im) injection (n=338). Study duration was 48 weeks.

The primary efficacy endpoint was the proportion of patients who remained exacerbation-free at 24 weeks. The principal secondary endpoint was the mean number per patient per scan of combined unique active MRI lesions through 24 weeks, defined as any lesion that was T1 active or T2 active. Neurological examinations were performed every three months by a neurologist blinded to treatment assignment. Patient visits were conducted monthly, and mid-month telephone contacts were made to inquire about potential exacerbations. If an exacerbation was suspected, the patient was evaluated with a neurological examination. MRI scans were performed monthly and analyzed in a treatment-blinded manner.

Patients treated with Rebif® 44 mcg sc tiw were more likely to remain relapse-free at 24 and 48 weeks than were patients treated with Avonex® 30 mcg im qw (Table 2). This study does not support any conclusion regarding effects on the accumulation of physical disability.

Table 2: Clinical and MRI Results from Study 2

Rebif® Avonex® Absolute Difference Risk of relapse on Rebif® relative to Avonex®
Relapses Proportion of patients
relapse-free at 24 weeks 1 Proportion of patients
relapse-free at 48 weeks
N=339
75% *

62% **
N=338
63%

52%

12%
(95% CI: 5%, 19%)
10%
(95% CI: 2%, 17%)

0.68
(95% CI: 0.54, 0.86)
0.81
(95% CI: 0.68, 0.96)
MRI (through 24 weeks) Median of the mean number
of combined unique MRI
lesions per patient per scan 2(25th, 75th percentiles)
N=325


0.17 *
(0.00, 0.67)
N=325


0.33
(0.00, 1.25)
* p <0.001, and ** p = 0.009, Rebif® compared to Avonex®
(1) Logistic regression model adjusted for treatment and center, intent to treat analysis
(2) Nonparametric ANCOVA model adjusted for treatment center, with baseline combined unique lesions as the single covariate.

The adverse reactions over 48 weeks were generally similar between the two treatment groups. Exceptions included injection site disorders (83% of patients on Rebif® vs. 28% of patients on Avonex® ), hepatic function disorders (18% on Rebif® vs. 10% on Avonex® ), and leukopenia (6% on Rebif® vs. <1% on Avonex® ), which were observed with greater frequency in the Rebif® group compared to the Avonex® group.

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