age adjustment in patients with renal impairment is not recommended.
Hepatic Impairment: No formal studies were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. Belimumab has not been studied in patients with severe hepatic impairment. Baseline ALT and AST levels did not significantly influence belimumab pharmacokinetics.
13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, and Impairment of FertilityLong-term animal studies have not been performed to eva luate the carcinogenic potential of belimumab. The mutagenic potential of belimumab was not eva luated.
Effects on male and female fertility have not been directly eva luated in animal studies.
14 CLINICAL STUDIESThe safety and effectiveness of BENLYSTA were eva luated in three randomized, double-blind, placebo-controlled studies involving 2133 patients with SLE according to the American College of Rheumatology criteria (Trial 1, 2, and 3). Patients with severe active lupus nephritis and severe active CNS lupus were excluded. Patients were on a stable standard of care SLE treatment regimen comprising any of the following (alone or in combination): corticosteroids, antimalarials, NSAIDs, and immunosuppressives. Use of other biologics and intravenous cyclophosphamide were not permitted.
Trial 1: BENLYSTA 1 mg/kg, 4 mg/kg, 10 mg/kg
Trial 1 enrolled 449 patients and eva luated doses of 1, 4, and 10 mg/kg BENLYSTA plus standard of care compared with placebo plus standard of care over 52 weeks in patients with SLE. Patients had to have a SELENA-SLEDAI score of ≥4 at baseline and a history of autoantibodies (anti-nuclear antibody (ANA) and/or anti-double-stranded DNA (anti-dsDNA), but 28% of the population was autoantibody negative at baseline. The co-primary endpoints were percent change in SELENA-SLEDAI score at Week 24 and time to first flare over 52 weeks. No significant differences between any of the BENLYSTA groups and the placebo group were observed. Exploratory analysis of this study identified a subgroup of patients (72%), who were autoantibody positive, in whom BENLYSTA appeared to offer benefit. The results of this study informed the design of Trials 2 and 3 and led to the selection of a target population and indication that is limited to autoantibody-positive SLE patients.
Trials 2 and 3: BENLYSTA 1 mg/kg and 10 mg/kg
Trials 2 and 3 were randomized, double-blind, placebo-controlled trials in patients with SLE that were similar in design except duration — Trial 2 was 76 weeks duration and Trial 3 was 52 weeks duration. Eligible patients had active SLE disease, defined as a SELENA-SLEDAI score ≥6, and positive autoantibody test results at screening. Patients were excluded from the study if they had ever received treatment with a B-cell targeted agent or if they were currently receiving other biologic agents. Intravenous cyclophosphamide was not permitted within the previous 6 months or during study. Trial 2 was conducted primarily in North America and Europe. Trial 3 was conducted in South America, Eastern Europe, Asia, and Australia.
Baseline concomitant medications included corticosteroids (Trial 2: 76%, Trial 3: 96%), immunosuppressives (Trial 2: 56%, Trial 3: 42%; including azathioprine, methotrexate and mycophenolate), and antimalarials (Trial 2: 63%, Trial 3: 67%). Most patients (>70%) were receiving 2 or more classes of SLE medications.
In Trial 2 and Trial 3, more than 50% of patients had 3 or more active org |
