A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus

Abstract

Objective To assess the efficacy/safety of the B-lymphocyte stimulator inhibitor belimumab/standard-of-care (SOC) versus placebo/SOC in active systemic lupus erythematosus (SLE). Methods In a multicenter, randomized, controlled, phase 3 trial, 819 antinuclear antibody- or anti-dsDNA-positive SLE patients with Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) ≥ 6 were randomized (1:1:1 ratio) to receive intravenous belimumab 1 or 10 mg/kg, or placebo on days 0, 14, and 28, and then every 28 days for 72 weeks. Primary efficacy analyses: SLE Responder Index (SRI) at week 52 (≥ 4-point reduction in SELENA-SLEDAI; no new British Isles Lupus Assessment Group A and < 2 new B organ domain scores; no worsening in Physician’s Global Assessment). Results Belimumab 10 mg/kg plus SOC met the primary efficacy endpoint: significantly greater SRI response at week 52 than placebo (43.2% versus 33.5%; P = 0.017); the rate with belimumab 1 mg/kg was 40.6% (P = 0.089). Week-76 response rates: 32.4%, 39.1%, and 38.5% with placebo, and belimumab 1 and 10 mg/kg, respectively. In post-hoc sensitivity analyses evaluating higher SELENA-SLEDAI thresholds, belimumab 10 mg/kg achieved better discrimination at weeks 52/76. Risk of severe SELENA-SLEDAI flares over 76 weeks was reduced with belimumab 1 mg/kg (34%; P = 0.023) and 10 mg/kg (23%; P = 0.13). Serious and severe adverse events including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups. Conclusion Belimumab plus SOC significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well-tolerated in SLE.

Relative Bioavailability of a Single Dose of Belimumab Administered Subcutaneously by Prefilled Syringe or Autoinjector in Healthy Subjects

“…Safety data were consistent with the known safety profile of belimumab,3, 4 and the majority of subjects (94%) had successful self‐injections, indicating a high level of usability and reliability for the devices.…”

“…Belimumab is a recombinant human immunoglobulin (Ig) G1λ monoclonal antibody that binds and antagonizes the biological activity of soluble B‐lymphocyte stimulator (BLyS), a member of the tumor necrosis factor ligand superfamily, which promotes the survival of B lymphocytes 2. Following completion of 2 large, multicenter, randomized, controlled trials, belimumab was approved for the treatment of adults with active, autoantibody‐positive SLE in combination with standard therapy 3, 4…”

Long‐Term Safety and Efficacy of Belimumab in Patients With Systemic Lupus Erythematosus

“…In the BLISS‐52 and BLISS‐76 studies, rates of severe SFI flare were 14% (40 of 290 patients) and 21% (56 of 273 patients), respectively 13, 14, among patients who received 10 mg/kg belimumab. In this continuation study, the percentage of patients experiencing a new severe SFI flare between the study year 1 and study year 7 midpoints was low; the cumulative count increased from 15 of 267 patients (5.6%) to 55 of 267 patients (20.6%) during this period.…”

“…A placebo‐controlled phase II study showed that intravenous (IV) belimumab plus standard therapy was generally well tolerated 11; a good safety profile was maintained over 7 years 12. Two phase III studies, the Study of Belimumab in Subjects with SLE 52‐week (BLISS‐52) and 76‐week (BLISS‐76) trials, demonstrated the safety and efficacy of belimumab in patients with autoantibody‐positive, active SLE 13, 14. The long‐term safety and efficacy of belimumab were examined in 2 open‐label continuation studies (GlaxoSmithKline [GSK] studies BEL112233 and BEL112234) in patients who completed the BLISS studies.…”

Sensitivity to Change and Minimal Important Differences of the LupusQoL in Patients With Systemic Lupus Erythematosus

“…The BILAG‐2004 category scores A to E are based on intention to treat, where A = severe disease activity, B = moderate disease activity, C = mild, stable disease, D = inactive disease but previously affected system, and E = a system that has never been involved. Changes in overall disease activity between consecutive time points, as measured by the BILAG‐2004 index, were defined as follows: 1) deterioration, with any system changing to A from B/C/D or to B from C/D 21; 2) improvement, with all systems changing from A to B/C/D and B scores changing to C/D 22, with no deterioration in any system (one persistent B score was allowed if there was improvement from A or B in at least 1 other system); 3) persistent inactive disease, with all systems scored as C/D/E at both time points; and 4) persistent active disease, with A or B system scores remaining unchanged but without overall improvement or deterioration. When changes of activity of a single BILAG system were analyzed, the above definitions applied, but only for that system, and no persistent B score was allowable for improvement.…”