ArticlesEfficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial
Introduction
Systemic lupus erythematosus is a multisystem autoimmune disease that results in morbidity, increased mortality rate, and poor quality of life.1, 2, 3, 4, 5, 6 B-lymphocyte stimulator (BLyS), a key survival cytokine for B lymphocytes,7, 8, 9 is overexpressed in patients with systemic lupus erythematosus and other autoimmune diseases.10, 11, 12, 13, 14 In patients with systemic lupus erythematosus, BLyS concentrations are associated with changes in disease activity and anti-dsDNA antibody titres.10, 12, 13, 14 Belimumab (Benlysta, Human Genome Sciences, Rockville, MD, USA) is a fully human immunoglobulin (Ig) G1-λ monoclonal antibody that binds to soluble human BLyS and inhibits its biological activity.15, 16 It selectively reduces the numbers of subsets of CD20+ B lymphocytes and short-lived plasma cells, and anti-dsDNA antibody titres in patients with systemic lupus erythematosus.17
The results of a phase 2, dose-ranging, placebo-controlled trial of belimumab with standard of care in patients with active systemic lupus erythematosus showed that the monoclonal antibody was biologically active and well tolerated.17 The coprimary endpoints of reduction in Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) at week 24 and prolongation of time to first flare over 52 weeks were not achieved. However, in a large proportion of patients (71·5% of overall study population) with seropositive systemic lupus erythematosus–ie, with titres of antinuclear antibody (ANA) of at least 1:80 or concentrations of anti-dsDNA antibody of at least 30 IU/mL–belimumab reduced and stabilised disease activity.17 The results of an uncontrolled, open-label extension (4 years) of this phase 2 study in patients with systemic lupus erythematosus showed that rates of adverse events, including serious adverse events and infections, stabilised or decreased, and patients who were seropositive had sustained improvement in disease activity, with decreased frequency of flares.18
Evidence-based assessment of this phase 2 trial of belimumab in patients with systemic lupus erythematosus resulted in the creation of a new Systemic Lupus Erythematosus Responder Index (SRI), based on improvement in disease activity without worsening of the overall disorder or development of substantial disease activity in new organ systems.19
Development of new treatments for systemic lupus erythematosus has been challenging because of the heterogeneity of the disease, variety of disease activity scales that are used, and lack of a contemporary regulatory precedent because no drug has specifically been approved for systemic lupus erythematosus in more than 50 years.20, 21, 22, 23, 24 The aim in this trial was to assess the efficacy, safety, and tolerability of belimumab with standard of care in patients with seropositive systemic lupus erythematosus.
Section snippets
Patients
In a phase 3 study done in 90 centres in 13 countries in Latin America (Argentina, Brazil, Chile, Colombia, and Peru), Asia-Pacific (Australia, Hong Kong, India, Korea, Philippines, and Taiwan), and eastern Europe (Romania and Russia), patients (aged ≥18 years) who met the American College of Rheumatology criteria for systemic lupus erythematosus25 and had active disease (score ≥6 at screening on SELENA-SLEDAI)26 were eligible for enrolment. Other inclusion criteria were unequivocally positive
Results
From May 8, 2007, to April 14, 2008, 867 patients with systemic lupus erythematosus were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288) in Latin America (n=429), Asia-Pacific (n=339), and eastern Europe (n=99). Figure 1 shows the trial profile. Two of 867 patients never received any study treatment and were excluded; the modified intention-to-treat population was therefore 865 patients who were randomly assigned and treated during the study, and analysed.
Discussion
Belimumab with standard of care resulted in a significantly higher response rate than did placebo and standard of care at week 52 when assessed with SRI. A dose-response pattern was noted, with belimumab 10 mg/kg resulting in a significantly greater response than did placebo in all three SRI components, whereas belimumab 1 mg/kg resulted in a greater response than did placebo in two components (SELENA-SLEDAI and PGA).
The onset of clinical improvement with belimumab, assessed with SRI and flare
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