Belimumab is a recombinant human IgG-1λ monoclonal antibody. It inhibits the B-cell activating factor (BAFF) and is approved for patients with systemic lupus erythematosus (SLE) older than five years with positive autoantibody. We aimed to evaluate the role of belimumab in the maintenance phase of treatment for lupus nephritis (LN). PubMed, PubMed Central (PMC), Cochrane Library, and Embase were searched using appropriate keywords. The screening of title and abstract was done in Covidence, followed by data extraction of the relevant studies based on inclusion criteria. Review manager (RevMan 5.4) was used for data analysis with random or fixed effects model based on heterogeneities. Two randomized controlled trials were included in the quantitative analysis. There were 1.71 times higher odds of complete renal response in the belimumab group than in the control group (odds ratio (OR), 1.71; 95% confidence interval (CI), 1.12-2.60; I-square (I2) ​​​​= 0%). Similarly, there was 34% lower odds for having no response among the belimumab group (OR, 0.66; 95% CI, 0.45-0.96; I2 = 0%). No significant differences between the two groups were observed for the occurrence of treatment-related adverse events (TRAEs) (OR, 1.07; 95% CI, 0.74-1.56; I2 = 0%), treatment-related serious adverse events (OR, 0.54; 95% CI, 0.15-1.96; I2 = 68%), and treatment-related infections (OR, 0.65; 95% CI, 0.27-1.55; I2 = 21%).Therefore, belimumab and standard treatment were instrumental for beneficial renal response in patients with lupus nephritis and were not associated with increased odds of adverse effect compared with the standard treatment alone.

Belimumab is a fully human recombinant IgG1λ monoclonal antibody that inhibits the binding of soluble B lymphocyte stimulator to B cells and hence prevents the survival and differentiation of selected B-cell subsets. It is available in the US, the EU and Canada for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity despite receiving standard therapy. At 52 weeks, a significantly greater proportion of belimumab 10 mg/kg than placebo recipients experienced a response as assessed by the SLE Responder Index (primary endpoint) in the randomized, double-blind, multinational, phase III BLISS-52 and BLISS-76 trials in patients with active seropositive SLE receiving standard therapy. A significantly greater proportion of belimumab than placebo recipients achieved a ≥4 point reduction in the SELENA-SLEDAI score at week 52 in both BLISS trials. However, the SLE Responder Index response rate was not significantly different between belimumab and placebo at 76 weeks in BLISS-76. Belimumab was generally well tolerated in the BLISS trials. During the double-blind periods of these trials and the phase II trial, twice as many deaths were reported with belimumab than placebo (six vs three). There were no meaningful differences between the incidence of serious infections and malignancies with belimumab or placebo.

The goal of the trial is to evaluate the efficacy and safety of belimumab as a maintenance therapy in adults with refractory Idiopathic inflammatory myositis (IIM) as compared with standard of care. This is a multicentre double-blind, placebo-controlled trial.

OBJECTIVES:

Systemic lupus erythematosus is a heterogeneous, multisystem autoimmune disease. These attributes cause lupus to be a challenging condition to adequately manage, which is further aggravated by the lack of treatment modalities. Belimumab is a full human monoclonal antibody, and its safety and efficacy in lupus management have been demonstrated in a number of randomized clinical trials. However, these gains come at a high cost in an era that is demarcated by soaring pharmaceutical expenditure. Therefore, the objective of this paper is to critically assess the economic evaluations of belimumab.

METHODS:

A systematic review was performed for economic evaluations of belimumab and the retrieved studies were assessed with the quality of health economic studies questionnaire.

RESULTS:

A total of 3 studies and 5 abstracts were retrieved. Belimumab demonstrated a consistent favorable economic profile across Spain, Italy, Portugal, Greece, Hong Kong, Canada, and Greece. The sensitivity analyses revealed that the effectiveness of treatment and the discontinuation rate had the greatest effect on the outcome.

CONCLUSION:

Current data underscore a favorable cost-effectiveness ratio of belimumab in the treatment of systemic lupus erythematosus. Results are consistent across Spain, Italy, Portugal, Greece, Hong Kong, Canada, and Greece, countries for which an economic evaluation was available. Nevertheless, the low number of assessments, along with concerns regarding its long-term effectiveness, underpin areas that necessitate further research.

This study is a prospective, open label, phase I/II pilot study.

This trial is a two‐part study (Part A and Part B) of adults with primary membranous nephropathy (MN), ages 18‐75 inclusive. The study will be conducted at multiple sites in the United States and Canada. Part A: Open‐label Phase Part A is an open‐label, PK study to compare belimumab exposure between participants who have "low" proteinuria (≥ 4 to < 8 g/day) and "high" proteinuria (≥ 8 g/day) at Visit ‐1. Initially Part A planned to enroll 20 individuals with primary MN.: 10 individuals with low proteinuria and 10 individuals with high proteinuria. All Part A participants received 200 mg subcutaneous belimumab weekly, the initially approved dose of belimumab in SLE, for 52 doses (weeks 0‐51). Trough serum belimumab levels would be obtained weekly following the first 4 doses of belimumab. All participants would receive rituximab 1000 mg IV at weeks 4 and 6, and are followed after the 52 week treatment period on no study medication until week 156. Belimumab trough levels were to be analyzed after all 20 participants received the first 4 doses to compare the belimumab exposure between the low and high proteinuria groups. If the belimumab exposure was not comparable between the high and low proteinuria groups, the belimumab dose would be doubled to 400 mg/weekly for participants with high proteinuria in Part B. Dose determination for participants with high proteinuria in Part B would be made by an adjudication committee comprised of the Protocol Chair, NIAID Medical Monitor, ITN Clinical Trial Physician, and Rho Scientist, in consultation with the belimumab PK expert at GSK. Due in part to the observed imbalance in enrollment between the high and low proteinuria groups, an ad hoc PK analysis was conducted. The serum belimumab trough levels of the first 12 participants (8 with high proteinuria and 4 with low proteinuria) who received the first 4 belimumab doses were analyzed to compare belimumab exposure between the low and high proteinuria groups. The results of the PK analysis were reviewed by the adjudication committee, who determined that the results did not support doubling the dose of belimumab in individuals with high proteinuria nor did it identify a new proteinuria threshold that warranted an increased belimumab dose. The belimumab PK expert at GSK concurred. Thus, enrollment into Part A has been suspended, and all participants in Part B are to receive the same dose of belimumab. All participants currently enrolled in Part A continue to receive belimumab and rituximab as previously planned and are undergoing the safety assessments as presented in Appendix A. All enrolled participants in Part A will be followed until week 156 and will be assessed for the same study endpoints as participants in Part B. Part B: Randomized Phase Part B is a prospective, randomized, phase II, double‐blind, placebo‐controlled, multicenter clinical trial in adults with primary MN. Part B is commencing after the completion of the ad hoc PK analysis, which did not support increasing the belimumab dose in participants with high proteinuria. A total of 104 participants will be randomized in a 1:1 fashion into two treatment arms. Randomization will be stratified by low (≥ 4 to < 8 g/day) and high proteinuria (≥ 8 g/day). This stratification will be performed to equally distribute participants at higher risk for progression to renal failure between the two study arms. Participants randomized to the experimental arm will receive subcutaneous belimumab 400 mg (two 200 mg injections) once weekly from weeks 0‐3, and then 200 mg once weekly from weeks 4‐51. This dosing regimen is based on the recommended dosing of subcutaneous belimumab for lupus nephritis. Participants randomized to the comparator arm will receive subcutaneous belimumab placebo according to the same dose and schedule. Participants in both arms will receive rituximab 1000 mg IV at weeks 4 and 6. At week 30, participants will be assessed for a response to study treatment. Participants who meet at least two of the following three criteria at week 30 will be considered to have an inadequate response to study treatment and, defined as fulfilling at least two of the following three criteria at week 30, will receive a second course of rituximab (defined as 1000 mg IV given at weeks 34 and 36): ‐ Anti‐PLA2R levels is ≥ 25% of baseline ‐ Proteinuria is ≥ 50% of baseline ‐ Serum albumin is < 2.8 g/dL After the 52 week treatment period, all participants will be followed on no study medication with assessment of the primary endpoint (complete remission) at week 104. The primary endpoint will be assessed at week 104 because the proteinuric response to treatment is known to lag behind the active treatment period and is recommended to be assessed at least 18 months after the initiation of therapy. There will be a tolerance endpoint at week 156 to determine if treatment with belimumab with rituximab results in a more durable remission compared to rituximab alone, and to assess the rate of relapse after having achieved complete or partial remission.

Systemic lupus erythematosus is a chronic inflammatory autoimmune disease with variable clinical manifestations, mainly affecting women between the ages of 16 and 55 years. It can be life-threatening, especially when renal or neurological involvement occurs. Belimumab (Benlysta", Glaxo-SmithKline) is an immunosuppressant monoclonal antibody that inhibits B cell differentiation into antibody-producing plasma cells. Belimumab is authorised in the European Union for the treatment of adults with autoantibody-positive systemic lupus erythematosus when the disease remains highly active despite "standard" therapy, usually comprising a corticosteroid or another immunosuppressant. In this setting, two double-blind randomised placebo-controlled trials compared two doses of belimumab (1 or 10 mg/kg), given every 2 weeks and then every 4 weeks, in addition to "standard" treatment, in a total of 1684 adult patients. Patients with severe renal or central nervous system involvement were excluded. After 52 weeks the proportion of patients who "responded" to add-on therapy was about 10% higher with belimumab (10 mg/kg) than with placebo, a statistically significant difference. However, this advantage did not persist in one trial that was continued until 76 weeks. Belimumab had no statistically significant benefit in terms of corticosteroid use, time to exacerbations, or quality of life. In a combined analysis of the two trials, the difference in the response rate was greater in the prospectively defined subgroup of patients with "highly active" disease (63.2% with belimumab 10 mg/kg versus 44.3% with placebo; p<0.0001). Adverse reactions can occur during belimumab infusion, including severe and sometimes late-onset hypersensitivity reactions. The risk of infections (particularly opportunistic infections) and cancer is poorly documented. Belimumab also carries a risk of additional immunosuppression when used in combination with other immunosuppressive drugs. In early 2013, given the lack of any proven benefit and the uncertainties surrounding its adverse effects, belimumab add-on therapy simply complicates the treatment of systemic lupus erythematosus and should not be used.

Systemic lupus erythematosus (SLE) is a chronic inflammatory systemic autoimmune disease. Recurrent relapses of disease and development of long-term organ damage are two key unsolved clinical problems. Belimumab is the only FDA-approved biological agent for SLE. Data showed that treatment with belimumab on the background of standard therapy was effective in active SLE patients. However, the efficacy of low-dose belimumab for prevention of disease flares in SLE patients with low disease activity is to be explored.

AIM:

The primary objective of the BeLimumab Antiphospholipid Syndrome Trial (BLAST) is to evaluate the safety and tolerability of belimumab for up to 24 months in patients with persistent aPL positivity and clinical features attributable to aPL that are resistant to warfarin and/or heparin.

This is a phase II, open label, experimental medicine study to evaluate the efficacy, safety and mechanism of action of belimumab in subjects with antiphospholipase A2 receptor (PLA2R) autoantibody positive idiopathic membranous glomerulonephropathy (IMGN), and to profile the relationship between biomarkers, autoantibody status and clinical response. 10 milligrams per kilogram (mg/kg) belimumab intravenous (IV) will be administered at weeks 0, 2, and then every 4 weeks, over a 24-week treatment period in subjects with anti-PLA2R antibody positive IMGN followed by a further long term treatment period until subjects reach remission of proteinuria, up to a maximum of 2 years total treatment. All subjects will receive background supportive therapy throughout the study. The dosing frequency will be adjusted to every 2 weeks if the subject\'s proteinuria as assessed by urinary protein creatinine ratio (PCR) is greater than 1000 milligrams per millimole (mg/mmol) \[greater than 10 grams(g)/24 hours (h)\], to compensate for loss of belimumab in the urine. Effects on mechanistic markers will be measured by the level of proteinuria, levels of anti-PLA2R antibodies, and various other measures of kidney function. These will be compared to historical data. The pharmacokinetics of belimumab will be measured to confirm dosing in heavily proteinuric subjects. Pharmacodynamic (PD) markers, biomarkers and Quality of Life(QoL) in IMGN subjects will also be investigated. Safety will be assessed by adverse events (AE), clinical laboratory evaluations, and vital signs.