Elsevier

The Lancet

Volume 377, Issue 9767, 26 February–4 March 2011, Pages 721-731
The Lancet

Articles
Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(10)61354-2Get rights and content

Summary

Background

Systemic lupus erythematosus is a heterogeneous autoimmune disease that is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of B-lymphocyte stimulator (BLyS). The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) was assessed in patients with active systemic lupus erythematosus.

Methods

Patients (aged ≥18 years) who were seropositive with scores of at least 6 on the Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) were enrolled in a multicentre phase 3 study, which was done in Latin America, Asia-Pacific, and eastern Europe. Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, with standard of care. Patients, investigators, study coordinators, and sponsors were masked to treatment assignment. Primary efficacy endpoint was improvement in the Systemic Lupus Erythematosus Responder Index (SRI) at week 52 (reduction ≥4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [<0·3 increase] in Physician's Global Assessment [PGA] score) versus baseline. Method of analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00424476.

Findings

867 patients were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288). 865 were treated and analysed in the belimumab (1 mg/kg, n=288; 10 mg/kg, n=290) and placebo groups (n=287). Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51%], odds ratio 1·55 [95% CI 1·10–2·19]; p=0·0129) and 10 mg/kg (167 [58%], 1·83 [1·30–2·59]; p=0·0006) than with placebo (125 [44%]) at week 52. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53%], 1·51 [1·07–2·14]; p=0·0189) and 10 mg/kg (169 [58%], 1·71 [1·21–2·41]; p=0·0024) than with placebo (132 [46%]). More patients given belimumab 1 mg/kg (226 [78%], 1·38 [0·93–2·04]; p=0·1064) and 10 mg/kg (236 [81%], 1·62 [1·09–2·42]; p=0·0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73%]). No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79%], 1·68 [1·15–2·47]; p=0·0078) and 10 mg/kg (231 [80%], 1·74 [1·18–2·55]; p=0·0048) than with placebo (199 [69%]). Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (<1%), two (<1%), and no patients, respectively. No malignant diseases were reported.

Interpretation

Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease.

Funding

Human Genome Sciences and GlaxoSmithKline.

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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