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Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study.

ABSTRACT: To assess the efficacy and safety of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE).Patients with moderate-to-severe SLE (score of ?8 on the Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the SLE Disease Activity Index [SLEDAI]) were randomized 2:1 to receive weekly SC belimumab 200 mg or placebo by prefilled syringe in addition to standard SLE therapy for 52 weeks. The primary end point was the SLE Responder Index (SRI4) at week 52. Secondary end points were reduction in the corticosteroid dosage and time to severe flare. Safety was assessed according to the adverse events (AEs) reported and the laboratory test results.Of 839 patients randomized, 836 (556 in the belimumab group and 280 in the placebo group) received treatment. A total of 159 patients withdrew before the end of the study. At entry, mean SELENA-SLEDAI scores were 10.5 in the belimumab group and 10.3 in the placebo group. More patients who received belimumab were SRI4 responders than those who received placebo (61.4% versus 48.4%; odds ratio [OR] 1.68 [95% confidence interval (95% CI) 1.25-2.25]; P?=?0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171.0 days versus 118.0 days; hazard ratio 0.51 [95% CI 0.35-0.74]; P?=?0.0004), and more patients were able to reduce their corticosteroid dosage by ?25% (to ?7.5 mg/day) during weeks 40-52 (18.2% versus 11.9%; OR 1.65 [95% CI 0.95-2.84]; P?=?0.0732), compared with placebo. AE incidence was comparable between treatment groups; serious AEs were reported by 10.8% of patients taking belimumab and 15.7% of those taking placebo. A worsening of IgG hypoglobulinemia by ?2 grades occurred in 0.9% of patients taking belimumab and 1.4% of those taking placebo.In patients with moderate-to-severe SLE, weekly SC doses of belimumab 200 mg plus standard SLE therapy significantly improved their SRI4 response, decreased severe disease flares as compared with placebo, and had a safety profile similar to placebo plus standard SLE therapy.

SUBMITTER: Stohl W

PROVIDER: S-EPMC5434872 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study.

Stohl William W Schwarting Andreas A Okada Masato M Scheinberg Morton M Doria Andrea A Hammer Anne E AE Kleoudis Christi C Groark James J Bass Damon D Fox Norma Lynn NL Roth David D Gordon David D

Arthritis & rheumatology (Hoboken, N.J.) 20170407 5

<h4>Objective</h4>To assess the efficacy and safety of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE).<h4>Methods</h4>Patients with moderate-to-severe SLE (score of ≥8 on the Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the SLE Disease Activity Index [SLEDAI]) were randomized 2:1 to receive weekly SC belimumab 200 mg or placebo by prefilled syringe in addition to standard SLE therapy for 52 weeks. The primary end point was th ...[more]

PMID: 28118533

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Project description:IntroductionBelimumab, an anti-B-lymphocyte-stimulator antibody, is approved for the treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Rituximab, a B cell-depleting anti-CD20 antibody, remains in the SLE treatment armamentarium despite failed trials in lupus nephritis and extrarenal lupus. These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE. This study aims to evaluate and compare the efficacy, safety and tolerability of subcutaneous (SC) belimumab and a single cycle of rituximab in patients with SLE with belimumab alone.Methods and analysisBLISS-BELIEVE is a three-arm, randomised, double-blind, placebo-controlled, 104-week superiority study. Two hundred adults with SLE will be randomised 1:2:1 to arm A, belimumab SC 200 mg/week for 52 weeks plus placebo at weeks 4 and 6; arm B, belimumab SC 200 mg/week for 52 weeks plus rituximab 1000 mg at weeks 4 and 6; arm C, belimumab SC 200 mg/week plus standard of care for 104 weeks. The 52-week treatment period (arms A and B) is followed by a 52-week observational phase. The primary efficacy endpoint is the proportion of patients with disease control (SLE Disease Activity Index (SLEDAI)-2K≤2, without immunosuppressants and with a prednisone-equivalent dose of ≤5 mg/day) at week 52. Major secondary efficacy endpoints are the proportion of patients in clinical remission (defined as SLEDAI-2K=0, without immunosuppressants and corticosteroids) at week 64, and the proportion of patients with disease control at week 104. Safety endpoints include the incidence of adverse events (AEs), serious AEs and AEs of special interest.Ethics and disseminationWithin 6 months of the study's primary manuscript publication, anonymised individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.Trial registration numberNCT03312907; Pre-results.

Project description:IntroductionFew treatment options exist for patients with systemic lupus erythematosus (SLE) who fail conventional therapy. Although widely used to treat lupus, the efficacy of B cell depletion therapy using rituximab has not been demonstrated in randomised clinical trials. Following rituximab, elevated levels of serum B cell activating factor (BAFF) have been associated with failure to remit or subsequent lupus relapse. The administration of belimumab, a monoclonal antibody specific for BAFF and approved for lupus therapy, could potentiate the efficacy of rituximab and enable longer periods of disease remission. The aim of this trial is to assess the safety and efficacy of belimumab following rituximab in patients with SLE.Methods and analysisBEAT Lupus is a double-blind, randomised, placebo controlled, phase II clinical trial. Patients with SLE commencing a treatment cycle of rituximab (two 1g infusions, 2 weeks apart) as standard of care will be randomised to receive belimumab or placebo, 4 to 8 weeks following the first rituximab infusion. Belimumab or placebo infusions are administered for 52 weeks. The primary outcome measure is anti-double stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes include measures of adverse events, lupus disease activity and cumulative steroid dose. The kinetics of B cell repopulation will be assessed in a subgroup of participants. Belimumab administration after rituximab may provide a novel therapeutic pathway for patients with active lupus if safety is demonstrated in this proof of concept study, and lower anti-dsDNA antibodies levels are achieved in those patients treated with belimumab compared with placebo.Ethics and disseminationThe protocol has been reviewed and approved by the Hampstead Research Ethics Committee - London (reference 16/LO/1024). Trial information is available at https://www.isrctn.com/ISRCTN47873003, and the results of this trial will be submitted for publication in relevant peer-reviewed journals. Key findings will also be presented at national and international conferences.Trial registration numberISRCTN47873; date assigned to the registry: 28 November 2016. The stage is pre-results.

Project description:OBJECTIVE:To investigate the efficacy and safety of belimumab, a human immunoglobulin monoclonal antibody against B lymphocyte stimulator, in a subset of patients with systemic lupus erythematosus (SLE) who were hypocomplementemic (C3 <90 mg/dl and/or C4 <10 mg/dl) and anti-double-stranded DNA (anti-dsDNA) positive (?30 IU/ml) at baseline. METHODS:In this phase III, double-blind, placebo-controlled study (BEL112341; ClinicalTrials.gov identifier: NCT01484496), patients with moderate to severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI] score ?8) were randomized (2:1) to receive weekly subcutaneous (SC) belimumab 200 mg or placebo, plus standard SLE therapy, for 52 weeks. The primary end point was SLE Responder Index 4 (SRI-4) response rate at week 52. Secondary end points were time to severe flare and reduction in corticosteroid dose (weeks 40-52). Safety was assessed throughout. RESULTS:Of the 836 patients in the intent-to-treat (ITT) population, 356 were hypocomplementemic and anti-dsDNA positive at baseline (108 in the placebo group and 248 in the SC belimumab 200 mg group). Compared with placebo, the belimumab group contained more SRI-4 responders (47.2% versus 64.6%; P = 0.0014), had a lower incidence of severe flare according to the SELENA-SLEDAI flare index (31.5% versus 14.1%), and had a greater percentage of patients who reduced corticosteroid dosage by ?25% to ?7.5 mg/day during weeks 40-52 (11.4% versus 20.7%; P = 0.0844). Adverse events (AEs) were similar between treatment groups. CONCLUSION:Our findings indicate that in hypocomplementemic, anti-dsDNA-positive SLE patients, weekly SC belimumab 200 mg significantly improves SRI-4 response, decreases severe flare incidence, and reduces corticosteroid use versus placebo; a trend toward greater benefit compared with the overall ITT population was observed. AEs were consistent with the known safety profile of belimumab.

Project description:ObjectiveEnrollment of patients of Black African ancestry with systemic lupus erythematosus (SLE) in phase II and phase III of the belimumab trials was not reflective of the racial distribution observed in the lupus population. This study was undertaken to assess the efficacy and safety of intravenous (IV) belimumab plus standard therapy in patients of self-identified Black race.MethodsEMBRACE (GSK Study BEL115471; ClinicalTrials.gov identifier: NCT01632241) was a 52-week multicenter, double-blind, placebo-controlled trial in adults of self-identified Black race with active SLE who received monthly belimumab 10 mg/kg IV, or placebo, plus standard therapy. The optional 26-week open-label extension phase included patients who completed the double-blind phase. The primary end point of the study was SLE Responder Index (SRI) response rate at week 52 with modified proteinuria scoring adapted from the SLE Disease Activity Index 2000 (SLEDAI-2K) (SRI-SLEDAI-2K). Key secondary end points included SRI response rate at week 52, time to first severe SLE flare, and reductions in prednisone dose.ResultsThe modified intent-to-treat population comprised 448 patients, of whom 96.9% were women and the mean ± SD age was 38.8 ± 11.42 years. The primary end point (improvement in the SRI-SLEDAI-2K response rate at week 52) was not achieved (belimumab 48.7%, placebo 41.6%; odds ratio 1.40 [95% confidence interval 0.93, 2.11], P = 0.1068); however, numerical improvements favoring belimumab were observed, in which the SRI-SLEDAI-2K response rates were higher in those who received belimumab compared with those who received placebo, especially in patients with SLE who had high disease activity or renal manifestations at baseline. The safety profile of belimumab was generally consistent with that observed in previous SLE trials. Adverse events were the primary reasons for double-blind phase withdrawals (belimumab 5.4%, placebo 6.7%).ConclusionThe primary end point of this study was not achieved, but improvement with belimumab versus placebo was observed, suggesting that belimumab remains a suitable treatment option for SLE management in patients of Black African ancestry.

Project description:Background Belimumab is a recombinant, human, IgG1λ monoclonal antibody that targets B-lymphocyte stimulator. The intravenous formulation is indicated for the treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Belimumab has been formulated for subcutaneous (SC) administration to improve patient convenience. This post-hoc modeling and simulation analysis characterizes the population pharmacokinetics (PK) of SC belimumab, and compares the exposure profiles of the approved belimumab IV dose-10 mg/kg every four weeks-to the 200 mg SC weekly dose in SLE patients, highlighting key pharmacological differences relevant for clinicians. Methods Data from two Phase 1 studies in US American and Japanese healthy subjects were analyzed with a non-linear mixed effects modeling approach. The resulting SC population PK model and a previously developed IV population PK model were used to conduct simulation trials in a Phase 3 IV belimumab SLE patient population, comparing chronic exposure profiles and exposure ranges stratified by body weight tertiles for IV vs SC dosing. Results The PK of belimumab following SC administration was best described by a linear two-comment model. The estimates for clearance, steady-state volume of distribution, and bioavailability were 208 mL/day, 5250 mL, and 76%, respectively. After four weeks of SC dosing, simulated belimumab concentrations exceeded the steady-state trough concentrations of the IV dosing regimen. At steady state simulated serum profiles demonstrated comparable average belimumab concentrations (Cavg,ss) after IV and SC dosing. Simulated belimumab exposures demonstrated largely overlapping concentration ranges following 200 mg SC weekly and 10 mg/kg IV every four weeks dosing. Discussion The predicted Cavg,ss of belimumab in SLE patients was comparable following 200 mg SC weekly and 10 mg/kg IV every four weeks dosing. The simulated belimumab accumulation following SC weekly dosing indicated that administration of a loading dose was not required. Similar Cavg,ss ranges were predicted for fixed dose SC and weight-proportional IV regimens in the simulated SLE population, albeit with a reversed body-size-to-exposure relationship for the SC regimen. These findings provide rheumatologists with a better understanding of expected differences in belimumab exposure when comparing IV and SC dosing regimens.

Dataset Information

Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study.

Publications

Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study.

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