Belimumab-treated Patients Research Articles

#1133 Kidney characteristics of belimumab-treated patients with SLE pre-lupus nephritis indication: identifying data for future comparative research

Abstract Background and Aims Lupus nephritis (LN) is a severe, renal manifestation occurring in approximately 40% of patients with the chronic autoimmune disease systemic lupus erythematosus (SLE) [1]. Belimumab (BEL), a human immunoglobulin G1λ monoclonal antibody that binds to and inhibits soluble B-lymphocyte stimulator, was indicated for SLE in 2011 and LN in 2020 by the US Food and Drug Administration [2]. BEL has proven efficacy for SLE and LN [2], but there are limited data regarding the effectiveness of BEL to delay LN onset due to lack of sufficient follow-up time. Evaluating the demographic, clinical and kidney characteristics of patients treated with BEL before its regulatory approval for LN allows for a longer follow-up period. This study describes the kidney characteristics of patients with SLE treated with BEL and/or standard therapy (ST) pre-LN indication. The objective was to evaluate whether there are sufficient data from BEL-treated patients with kidney impairment and available laboratory measurements for use in future comparative research regarding effectiveness of BEL to delay LN onset. Method This retrospective, real-world study (GSK Study 217532) used electronic health record (EHR) data to assess adult patients with SLE. Eligible patients received BEL with or without ST (BEL cohort) or ST only (ST cohort) during the study identification period (1 January 2017 to 31 December 2020) and had activity in the EHR 12 months pre-index (baseline period); the index date was the first prescription of BEL or ST. A diagnosis of SLE was defined as presence of International Classification of Diseases, 10th Revision, Clinical Modification codes (M32.1x, M32.8, M32.9) based on either ≥ 2 outpatient medical claims or ≥ 1 inpatient/emergency department claim during the baseline period (or index date). Patients were excluded if they received BEL during the baseline period. LN- and kidney-related characteristics were measured during the baseline period and after 36 months of follow-up. Results This study identified 32 017 patients with SLE: 1318 in the BEL cohort and 30 699 in the ST cohort. The mean (standard deviation) age of the BEL and ST cohorts was 43.9 (12.7) and 51.9 (15.2) years, respectively. Most patients were White (BEL: n = 804 [61.0%]; ST: n = 19,812 [64.5%]) and female (BEL: n = 1247 [94.6%], ST: n = 27 826 [90.6%]). At baseline, 13.1% of the BEL cohort and 10.0% of the ST cohort had an LN diagnosis; chronic kidney disease (CKD) was reported in 22.1% of the BEL cohort and 27.7% of the ST cohort (Table 1). End-stage kidney disease (ESKD) was observed at baseline in 1.0% of the BEL cohort and 4.0% of the ST cohort. Dialysis rate at baseline was 0.7% in the BEL cohort and 3.5% in the ST cohort. A smaller proportion of the BEL cohort had kidney impairment than the ST cohort. Overall, 32.1% of the BEL cohort (n = 423) and 46.1% of the ST cohort (n = 14,162) had 36 months of valid follow-up. The proportion of patients with available kidney laboratory characteristics was generally similar between baseline and 36 months follow-up, and between BEL and ST cohorts (Table 2). However, the proportion of the BEL cohort at baseline and at 36 months’ follow-up with a proteinuria laboratory measurement was >2-fold that of the ST cohort (baseline: BEL = 30.5%, ST = 12.9%; follow-up: BEL = 42.1%, ST = 20.2%). Conclusion This study demonstrates that there are adequate kidney value measurements for BEL and ST patients available to assess kidney outcomes over time in patients with SLE pre-LN indication of BEL. Observationally, the ST cohort displayed more impairment than the BEL cohort, which could indicate more advanced disease in this slightly older cohort. However, future studies should account for baseline differences between ST and BEL cohorts to assess kidney impairment–related outcome measures, by using matching and weighting procedures. Funding GSK.

Longitudinal modeling of efficacy response in patients with lupus nephritis receiving belimumab

Belimumab was approved for active lupus nephritis (LN) in adults in the European Union and patients ≥ 5 years of age in the USA based on a Phase 3, double-blind, placebo-controlled, 104-week study. The study evaluated the efficacy of belimumab plus background standard therapy in adults with active LN using an intravenous (IV) dose of 10 mg/kg. A longitudinal analysis of Primary Efficacy Renal Response (PERR) and Complete Renal Response (CRR) was performed to assess whether patients with high proteinuria at the start of belimumab treatment would benefit from a higher dose. Responder probability was modeled as a logistic regression with probability a function of time and treatment (belimumab or placebo). Dropout risk at each visit was incorporated into a joint model of efficacy response; only efficacy data prior to dropout events (belimumab discontinuation, treatment failure, or withdrawal) were included. Average belimumab concentration over the first 4 and 12 weeks and baseline proteinuria were considered as continuous covariates. In general, renal response (PERR and CRR) over time was higher in patients receiving belimumab than in those receiving placebo. Baseline proteinuria was considered the most relevant predictor of renal response, with reduced efficacy in patients with increased proteinuria for both belimumab or placebo treatment. For belimumab-treated patients, belimumab exposure was not found to be an important predictor of renal response. In conclusion, the 10 mg/kg IV dose was considered appropriate in all patients and there was no evidence to suggest a higher response would be achieved by increasing the dose.

Usefulness of Belimumab in Adult Patients With Systemic Lupus Erythematosus Evaluated Using Single Indexes: A Meta-Analysis and Systematic Review

BackgroundBelimumab is the first antibody drug approved for systemic lupus erythematosus (SLE), and is a fully human monoclonal antibody that inhibits soluble B lymphocyte stimulator protein. In clinical trials, a composite index was used to assess efficacy of belimumab. However, clinical guidelines on SLE treatment currently use single efficacy indexes. ObjectiveThe main objective of this study was to perform a meta-analysis to evaluate the efficacy of belimumab utilizing single indexes used in routine clinical practice, rather than the composite efficacy index used in clinical trials during the development phase. As a secondary endpoint, safety was also evaluated. MethodsSeveral databases were searched to identify reports published up to December 1, 2021 on randomized controlled trials examining the efficacy of belimumab in adult patients with SLE. From the clinical trial data, efficacy was evaluated using single indexes including the SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group Index, and Physician Global Assessment. Safety was also assessed. Data were synthesized and analyzed using Review Manager 5.4. This study protocol was registered in the UMIN Clinical Trials Registry (Registration number: UMIN000052846). ResultsThe search identified 12 reports that met the inclusion criteria. Five reports were included in efficacy evaluation and 9 in safety evaluation. The primary endpoint was SLEDAI. Significantly more belimumab-treated patients achieved a ≥4-point reduction in SLEDAI (relative risk 1.28; 95% confidence interval, 1.16–1.40; P < 0.00001) compared with placebo. Other efficacy endpoints were also improved significantly in the belimumab group. No difference in safety was found between belimumab and placebo. ConclusionsThe present meta-analysis evaluating clinical trial data using various single indexes recommended by clinical guidelines for SLE verifies that addition of belimumab to standard of care is efficacious for moderate-to-severe SLE.

Indirect treatment comparison of anifrolumab efficacy versus belimumab in adults with systemic lupus erythematosus.

Aim: Assess the comparative efficacy of anifrolumab 300mg versus belimumab 10mg/kg in adults with moderate-to-severe systemic lupus erythematosus (SLE) receiving standard therapy. Patients and methods: Population-adjusted simulated treatment comparisons (primary analyses) and matching-adjusted indirect comparisons (supporting analyses) were conducted using individual patient data from TULIP-1/TULIP-2 and summary-level data from BLISS-52/BLISS-76. Results: Compared with belimumab-treated patients, anifrolumab-treated patients were more than twice as likely to achieve a reduction of four or more points in SLE Disease Activity Index 2000 score (simulated treatment comparison odds ratio: 2.47; 95% CI: 1.16-5.25) and SLE Responder Index-4 response (odds ratio: 2.61; 95% CI: 1.22-5.58) at 52weeks. Conclusion: Patients with moderate-to-severe SLE are more likely to achieve an improvement in disease activity with anifrolumab than with belimumab.

What Have We Learnt About the Treatment of Juvenile-Onset Systemic Lupus Erythematous Since Development of the SHARE Recommendations 2012?

IntroductionJuvenile-onset systemic lupus erythematous (JSLE) is a rare multisystem autoimmune disorder. In 2012, the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative developed recommendations for the diagnosis/management of JSLE, lupus nephritis (LN) and childhood-onset anti-phospholipid syndrome (APS). These recommendations were based upon available evidence informing international expert consensus meetings.ObjectiveTo review new evidence published since 2012 relating to the management of JSLE, LN and APS in children, since the original literature searches informing the SHARE recommendations were performed.MethodMEDLINE, EMBASE and CINAHL were systematically searched for relevant literature (2012-2021) using the following criteria: (1) English language studies; (2) original research studies regarding management of JSLE, LN, APS in children; (3) adult studies with 3 or more patients <18-years old, or where the lower limit of age range ≤16-years and the mean/median age is ≤30-years; (4) randomized controlled trials (RCTs), cohort studies, case control studies, observational studies, case-series with >3 patients. Three reviewers independently screened all titles/abstracts against predefined inclusion/exclusion criteria. All relevant manuscripts were reviewed independently by at least two reviewers. Data extraction, assessment of the level of evidence/methodological quality of the manuscripts was undertaken in-line with the original SHARE processes. Specific PUBMED literature searches were also performed to identify new evidence relating to each existing SHARE treatment recommendation.ResultsSix publications met the inclusion/exclusion criteria for JSLE: three RCTs, one feasibility trial, one case series. For LN, 16 publications met the inclusion/exclusion criteria: eight randomized trials, three open label prospective clinical trials, five observational/cohort studies. For APS, no publications met the inclusion criteria. The study with the highest evidence was an RCT comparing belimumab vs. placebo, including 93 JSLE patients. Whilst the primary-endpoint was not met, a significantly higher proportion of belimumab-treated patients met the PRINTO/ACR cSLE response to therapy criteria. New evidence specifically addressing each SHARE recommendation remains limited.ConclusionSince the original SHARE literature searches, undertaken >10-years ago, the main advance in JSLE treatment evidence relates to belimumab. Additional studies are urgently needed to test new/existing agents, and assess their long-term safety profile in JSLE, to facilitate evidence-based practice.

Efficacy and safety of belimumab in paediatric and adult patients with systemic lupus erythematosus: an across-study comparison

ObjectiveTo assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE).MethodsWe performed across-study comparisons of patients with active SLE who received belimumab or...

Biological agents for rheumatic diseases in the outbreak of COVID-19: friend or foe?

BackgroundThe recent outbreak of COVID-19 has raised concerns in the rheumatology community about the management of immunosuppressed patients diagnosed with inflammatory rheumatic diseases. It is not clear whether the use...

Real-World Effectiveness of Belimumab in the Treatment of Systemic Lupus Erythematosus: Pooled Analysis of Multi-Country Data from the OBSErve Studies.

IntroductionThe real-world effectiveness of belimumab for systemic lupus erythematosus (SLE) in six countries was evaluated in the OBSErve program. The aim of this post hoc analysis (GSK study 206351) was to pool individual patient OBSErve data to further evaluate the effectiveness of belimumab in a large sample of patients with SLE.MethodsOBSErve (Argentina, Canada, Germany, Spain, Switzerland, and the USA) enrolled adults ≥ 18 years of age with SLE, who were prescribed belimumab as part of standard therapy (index: date of belimumab initiation). Endpoints (month 6 vs. index) included physician-assessed overall clinical response to belimumab in the overall population (primary) and high disease activity subgroups (secondary; patients with a SLEDAI-2K/SELENA-SLEDAI score ≥ 10 or patients with high anti-dsDNA or low complement at index); other secondary endpoints included changes in glucocorticosteroid (GCS) use and changes in disease activity. Factors associated with physician-assessed overall clinical response were also evaluated.ResultsIn total, 830 patients were included in the overall population (mean [standard deviation (SD)] age: 41.9 [12.57] years; female: 89.3%; 60.4% from the USA). Nearly half (48.1%) of belimumab-treated patients experienced a ≥ 50% physician-assessed improvement in their overall manifestations, and 13% achieved a near normalization of their condition (equal to ≥ 80% improvement). Initiating belimumab while on high-dose (> 7.5 mg/day) GCS use was associated with ≥ 50% clinical improvement at month 6 (OR: 1.9, p = 0.003). Most (78.1%; n = 518/663) patients were able to reduce or discontinue their oral GCS dose after 6 months of belimumab, with a mean (SD) change of − 8.5 (10.74) mg/day prednisone-equivalent. The mean (SD) change from belimumab initiation in disease activity score (SLEDAI-2K/SELENA-SLEDAI) was − 5.7 (4.5; n = 344).ConclusionsBelimumab improves clinical manifestations of SLE and is associated with GCS dose reductions in a real-world clinical setting, supporting the real-world effectiveness of belimumab for SLE.Electronic Supplementary MaterialThe online version of this article (10.1007/s40744-020-00243-2) contains supplementary material, which is available to authorized users.

Comparative analysis of long-term organ damage in patients with systemic lupus erythematosus using belimumab versus standard therapy: a post hoc longitudinal study

ObjectiveLong-term extension (LTE) studies of belimumab in SLE do not include a comparator arm, preventing comparisons between belimumab plus standard therapy and standard therapy alone for organ damage accrual. Propensity...

Pharmacogenetic analysis of belimumab fails to identify robust genetic predictors of efficacy in lupus.

GlaxoSmithKline (GSK) conducted pharmacogenetic (PGx) analyses to determine whether genetic variants influence response to belimumab treatment in patients with systemic lupus erythematosus (SLE). We conducted an exploratory genome-wide meta-analysis (GWAS) of 10.9 million genetic variants and the efficacy data from 816 belimumab-treated SLE patients in three phase 3 belimumab clinical studies. Two highly correlated variants, rs293983 and rs364370, in the ANO3 (anoctamin 3) gene region were significantly associated with efficacy as measured by the SLE Response Index (SRI4) with a per-T-allele odds ratio (OR) of 2.15 [95% confidence interval (CI): 1.66-2.79, P=8.0×10]. In contrast, there was no association with SRI4 response in 577 placebo-treated patients (per-T-allele OR: 0.98; 95% CI: 0.74-1.29, P=0.87). A post-hoc analysis by geographic region revealed a strong SRI4 response signal in 157 belimumab-treated patients from Asia (per-T-allele OR=2.85, 95% CI: 1.41-5.74, P=0.0021). On the basis of this encouraging finding in Asian patients, we conducted a confirmatory analysis of the SRI4 end point in an independent phase 3 study of SLE patients from northeast Asia. We found no evidence of an association between rs293983 and SRI4 response in 204 belimumab-treated patients (per-T-allele OR: 0.90, 95% CI: 0.52-1.57, P=0.64). The inability to replicate the observed GWAS effect suggests this was a false positive result; hence, we failed to identify any genetic variants significantly associated with belimumab efficacy.

Belimumab restores Treg/Th17 balance in patients with refractory systemic lupus erythematosus.

Belimumab, a specific inhibitor of the soluble B lymphocyte stimulator (BlyS), is the first biological drug approved by the United States Food and Drug Administration for the treatment of patients with active systemic lupus erythematosus (SLE) refractory to standard therapy. Given that an imbalance between regulatory T cells (Treg) and interleukin (IL)-17A-secreting T cells (Th17) has been reported in various autoimmune disorders, we assessed the frequency of both Treg and Th17 peripheral blood populations before and after belimumab administration in 20 patients with active SLE refractory to standard therapy. After six months of treatment, the mean SELENA-SLEDAI score as well as the mean anti-double-stranded DNA antibody titers were significantly decreased. In addition, we observed a significant increase in Treg percentages and a parallel, significant decrease in Th17 percentages, accompanied by significantly reduced serum levels of IL-21. In vitro studies showed that Treg purified from belimumab-treated patients were fully functional and displayed a suppressor function similar to that of Treg purified from healthy donors. Belimumab can restore Treg/Th17 balance in SLE patients with uncontrolled disease activity, and this results in decreased flare rate and reduced glucocorticoid dosage.

Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus

To assess the effects of the B lymphocyte stimulator (BLyS)-specific inhibitor belimumab on immunologic biomarkers, including B cell and T cell populations, and maintenance of antibody titers to prior vaccines in autoantibody-positive systemic lupus erythematosus (SLE) patients. Pooled data from 2 phase III trials, the Study of Belimumab in Subjects with SLE 52-week (BLISS-52) and 76-week (BLISS-76) trials, comparing belimumab 1 mg/kg or 10 mg/kg versus placebo (plus standard SLE therapy for each group) were analyzed for changes in autoantibody, immunoglobulin, and complement levels. BLISS-76 patients were also analyzed for changes in B cell and T cell populations and effects on prior vaccine-induced antibody levels. Belimumab-treated patients experienced significant sustained reductions in IgG and autoantibodies and improvement in C3/C4 levels, resulting in greater positive-to-negative conversion rates for IgG anti-double-stranded DNA (anti-dsDNA), anti-Sm, anticardiolipin, and anti-ribosomal P autoantibodies and normalization of hypergammaglobulinemia and low C3/C4 levels. Belimumab-treated patients experienced significant decreases in the numbers of naive and activated B cells, as well as plasma cells, whereas memory B cells and T cell populations did not decrease. Belimumab did not substantially affect preexisting antipneumococcal or anti-tetanus toxoid antibody levels. Post hoc analysis showed greater reductions in SLE disease activity and the risk of severe flares in patients treated with belimumab 10 mg/kg (P≤0.01) who were anti-dsDNA positive and had low C3/C4 levels at baseline. Normalization of the C3 or anti-dsDNA level by 8 weeks, irrespective of therapy, was predictive of a reduced risk of severe flare over 52 weeks. Belimumab appears to promote normalization of serologic activity and reduce BLyS-dependent B cell subsets in serologically and clinically active SLE. Greater serologic activity may predict a better treatment response to belimumab.

New approvals

Azilsartan medoxomil (Edarbi) tablets have been approved by the Food and Drug Administration (FDA) for treating hypertension.1 Compared with olmesartan and valsartan, the 80-mg dose had greater 24-hour blood pressure-lowering effects, in Phase 3 clinical trials.2 It is available in 40-mg and 80-mg tablets. In addition, a new drug application (NDA) was recently filed for a tablet that combines both azilsartan and chlorthalidone. In a clinical trial presented at the American Society of Hypertension's 2010 meeting, the combination of azilsartan/chlorthalidone had better blood pressure-lowering effects than the combination of azilsartan and hydrochlorothiazide (HCTZ). After all this waiting, belimumab (Benlysta) was finally FDA-approved for treating systemic lupus erythematosus (SLE) in March 2011.3 It is a monoclonal antibody that targets B-lymphocyte stimulator protein, also known as BLyS. It is dosed via an intravenous (IV) infusion of 10 mg/kg every 2 weeks for three doses, followed by every 4-week dosing thereafter. Patients in clinical trials only had modest improvement in symptoms with the agent, but its effectiveness was significantly better than placebo. One-year response rates were 43% for belimumab-treated patients and 32% for placebo-treated patients. The drug should not be administered along with live vaccines. A medication guide will be distributed to all patients who receive this agent to inform them of the treatment risks. The last agent to be FDA-approved to treat SLE was hydroxychloroquine, in 1955. For patients with CrCl > 30 mL/min, take 150 mg orally, twice daily For patients with CrCl 15-30 mL/min, take 75 mg orally, twice daily. At a recent guideline committee meeting of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society, the committee recommended that dabigatran be used as an alternative to warfarin in patients with atrial fibrillation who do not have significant heart valve disease, do not have a prosthetic heart valve, and/or do not have advanced hepatic disease, and/or do not have severe renal failure to reduce their clot risk.6 Other similar agents are currently in the FDA pipeline for this and other similar uses.7 The QMS Everolimus Immunoassay was recently FDA-approved as the first test to monitor everolimus blood levels in renal transplant patients.8 Similar blood level tests are already available to monitor transplant patients receiving cyclosporine, tacrolimus, and/or sirolimus. The test is manufactured by Thermo Fisher Scientific (Waltham, Mass.). Voriconazole tablets were FDA-approved as a generic of Vfend in February of 2011.9 The company has 180 days of market exclusivity before other generics will be available. The liquid and IV versions of the drug are covered under a separate patent. Calcitonin, recombinant salmon oral, is currently in Phase 3 clinical trials for the treatment of postmenopausal osteoporosis.10 It was compared with synthetic salmon calcitonin nasal spray and placebo in 565 women, in a Phase 3 clinical trial. At 1 year, the recombinant oral calcitonin product was statistically significantly non-inferior to placebo and nasal calcitonin in increasing bone mineral density. CTAP101 is currently in Phase 2b clinical trials.11 It is an oral, non-hormonal, treatment for vitamin D insufficiency in patients with secondary hyperparathyroidism and stage 3 chronic kidney disease (CKD). It is currently undergoing clinical trials to evaluate its efficacy, safety, pharmacokinetics, pharmacodynamics, and tolerability. Dapagliflozin has had its NDA accepted by the FDA and the European Medicines Agency (EMA) as a new antidiabetic agent in a potentially new medication class.12 The new class is that of sodium-glucose co-transporter-2 (SGLT2) inhibitors, which target a specific location in the kidney, controlling glycemia independent of insulin pathways.12 Presently, there is limited information on using this agent in patients with renal disease. The FDA's Prescription Drug User Fee Act (PDUFA) goal date for this agent is October 28, 2011. Exenatide extended-release (Bydureon) failed to reduce average blood glucose levels in type 2 diabetics compared with liraglutide in a Phase 3 head-to-head trial known as DURATION-6.13 The fate of this agent is not yet known. The FDA declined its approval in October 2010, requesting additional data on its effect on heart rates. It is expected that Eli Lilly/Amylin will respond to the FDA's letter in the second half of this year. Lixisenatide, a once-daily glucagon-like peptide-1 (GLP-1) agonist, was shown to be as effective as twice daily exenatide in lowering HbA1c levels from baseline in type 2 diabetic patients in the 24-week GetGoal-X trial.14, 15 Additionally, lixisenatide-treated patients exhibited fewer symptomatic hypoglycemic reactions compared with exenatide-treated patients (2.5% vs. 7.9%, p < 0.05), and sixfold fewer hypoglycemic events were observed with the investigational agent compared with the FDA-approved agent (8 vs. 48 events). Patients received stepwise dose increases up to a maximum of 20 µm.