Efficacy and safety of intravenous belimumab in a subgroup of South Korean patients with systemic lupus erythematosus enrolled into a Phase 3, randomized, placebo-controlled trial in North East Asia.

AIM: This post hoc analysis evaluated the efficacy and safety of intravenous belimumab 10 mg/kg in the South Korean subgroup of patients with systemic lupus erythematosus (SLE) enrolled in the North East Asia (NEA) study (GSK Study BEL113750; NCT01345253). METHODS: NEA was a double-blind, placebo-controlled, randomized Phase 3 trial. Patients with active, autoantibody-positive SLE were randomized 2:1 to belimumab or placebo plus standard therapy administered on Days 0, 14, and 28, and then every 28 days up to Week 48. The primary efficacy endpoint in this analysis was SLE Responder Index 4 (SRI-4) response rate at Week 52, defined as the proportion of patients achieving a ≥4-point reduction in Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score, no worsening (<0.3 increase from baseline) in Physician Global Assessment, no new British Isles Lupus Assessment Group (BILAG) A domain and <2 new BILAG B domain scores. RESULTS: Among 100 South Korean patients enrolled in NEA, 54/66 (81.8%) belimumab- and 24/34 (70.6%) placebo-treated patients completed the double-blind phase. Significantly more belimumab- than placebo-treated patients achieved SRI-4 response at Week 52 (n = 35/66, 53.0% vs. n = 8/34, 23.5%; odds ratio [OR; 95% confidence interval (CI)]: 3.67 [1.45, 9.28]; p = .0061). The proportion of patients experiencing ≥1 adverse event was similar between groups (belimumab: n = 60/66, 90.9% vs. placebo: n = 31/34, 91.2%). No new safety signals emerged in this subgroup analysis. CONCLUSION: Belimumab was efficacious for the treatment of SLE and well tolerated among the South Korean subgroup of patients from the NEA study.

Healthcare Costs and Utilization for Patients With Systemic Lupus Erythematosus in China: A National Claims Database Study.

OBJECTIVES: This study aimed to describe the healthcare resource utilization (HCRU) and healthcare costs associated with systemic lupus erythematosus (SLE) management in China from the patient's and the payer's perspective. METHODS: HCRU and medical costs (2017 US dollar [USD]) between January 1 and December 31, 2017, were extracted from the national medical insurance claims database, China Health Insurance Research Association (consisting of claims from all public health insurance schemes in China), for adults with ≥ 1 SLE-related claim. The main analysis group comprised all adults with an SLE diagnosis and claim during 2017 (overall group); the annual subgroup (SLE diagnosis and claim in January 2017) informed annual HCRU and costs. RESULTS: The overall group consisted of 3645 adults with ≥ 1 SLE-related claim. Outpatient visits constituted 86.9% of healthcare visits. SLE-related healthcare outpatient costs were USD 433 per outpatient, and inpatient costs were USD 2072 per inpatient. Medication costs accounted for 75.0% (USD 42/56) of total costs for outpatient visits and 44.3% (USD 456/1030) for inpatient hospitalizations. Notably, 35.4% of patients had a severe SLE flare; mean SLE-related cost per severe flare was USD 1616. HCRU and costs were similar in the annual subgroup. Female sex, SLE flares, tertiary hospitals, renal involvement, and utilization of anti-infective drugs were associated with higher SLE-related patient costs. CONCLUSIONS: SLE in China is associated with considerable HCRU and medical costs, especially for patients experiencing severe SLE flares. Preventing organ involvement, infections, flares, and associated hospitalizations may reduce the burden on patients and healthcare providers in China.

Belimumab use during pregnancy: a summary of birth defects and pregnancy loss from belimumab clinical trials, a pregnancy registry and postmarketing reports.

OBJECTIVE: Describe available data on birth defects and pregnancy loss in women with systemic lupus erythematosus (SLE) exposed to belimumab. METHODS: Data collected from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports up to 8 March 2020 were described. Belimumab exposure timing, concomitant medications and potential confounding factors were summarised descriptively. RESULTS: Among 319 pregnancies with known outcomes (excluding elective terminations), 223 ended in live births from which birth defects were identified in 4/72 (5.6%) in belimumab-exposed pregnancies and 0/9 placebo-exposed pregnancies across 18 clinical trials, 10/46 (21.7%) belimumab-exposed pregnancies in the BPR prospective cohort (enrolled prior to pregnancy outcome) and 0/4 belimumab-exposed pregnancies in the BPR retrospective cohort (enrolled after pregnancy outcome), and 1/92 (1.1%) in belimumab-exposed pregnancies from postmarketing/spontaneous reports. There was no consistent pattern of birth defects across datasets. Out of pregnancies with known outcomes (excluding elective terminations), pregnancy loss occurred in 31.8% (35/110) of belimumab-exposed women and 43.8% (7/16) of placebo-exposed women in clinical trials; 4.2% (2/48) of women in the BPR prospective cohort and 50% (4/8) in the BPR retrospective cohort; and 31.4% (43/137) of belimumab-exposed women from postmarketing/spontaneous reports. All belimumab-exposed women in clinical trials and the BPR received concomitant medications and had confounding factors and/or missing data. CONCLUSIONS: Observations reported here add to limited data published on pregnancy outcomes following belimumab exposure. Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.

Efficacy of belimumab in patients with systemic lupus erythematosus from North East Asia: Results of exploratory subgroup analyses.

OBJECTIVES: To assess belimumab efficacy in patients from North East Asia (NEA) with systemic lupus erythematosus (SLE) in baseline demographic/disease characteristic subgroups. METHODS: This analysis of patient subgroups from BLISS-NEA (GSK Study 113750; NCT01345253) studied adults with SLE randomized to belimumab (10 mg/kg intravenous) or placebo. Primary endpoint, SLE Responder Index 4 (SRI-4) response rate at Week 52, was analysed in subgroups defined by gender, country, prednisone-equivalent dose, concomitant medications, Safety of Estrogens in Lupus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score, complement (C) levels, anti-double-stranded deoxyribonucleic acid (dsDNA) positivity, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score. RESULTS: Patients (overall population: N = 677; belimumab: n = 451, placebo: n = 226) were from China (76.4%), Korea (14.8%), and Japan (8.9%). The mean age was 32.1 years; 92.9% were female. In the overall population, more belimumab (53.8%) than placebo (40.1%) patients were SRI-4 Week 52 responders (p = .0001). SRI-4 response rates by subgroups were generally consistent with the overall population. A greater response with belimumab was seen in patients with a baseline SELENA-SLEDAI score ≥10 versus ≤9 and patients with low C3/C4 levels and anti-dsDNA positive at baseline versus those 'NOT' (low C3 and/or C4 and anti-dsDNA positive). CONCLUSIONS: These findings continue to support the efficacy of belimumab in SLE.

Evaluating disease control following belimumab treatment in patients with SLE enrolled in the US OBSErve study.

OBJECTIVE: To characterise disease control and remission in patients with SLE receiving belimumab for up to 12 months in the real world. METHODS: This post hoc analysis (GSK Study 213502) used data from the US evaluation Of use of Belimumab in clinical practice SEttings (OBSErve) study (GSK Study 117295), an observational cohort study of adults with SLE initiating and continuing belimumab for ≥6 months. Data were collected every 6 months by physician chart review; details of disease activity using the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score were collected if routinely used by physicians. Disease control definitions evaluated were SELENA-SLEDAI score of ≤2 at 12 months, SELENA-SLEDAI score of ≤2 and glucocorticoid (prednisone equivalent) dose of ≤5 mg/day at 12 months, SELENA-SLEDAI score of ≤2 and glucocorticoid dose of ≤5 mg/day at both 6 and 12 months. Disease remission definition was SELENA-SLEDAI score=0 at 12 months. Glucocorticoid dose during follow-up was quantified. RESULTS: US OBSErve enrolled 501 patients, 90 of whom had eligible SELENA-SLEDAI scores for inclusion in this analysis. Mean (SD) SELENA-SLEDAI scores were 13.1 (3.0) at baseline and 4.9 (3.4) at 12 months. Disease control at 12 months was achieved by 31.1% of patients when defined as a SELENA-SLEDAI score of ≤2 (95% CI 21.8 to 41.7); this decreased to 25.6% when requiring a SELENA-SLEDAI score of ≤2 and glucocorticoid dose of ≤5 mg/day (95% CI 16.9 to 35.8) and 17.8% when requiring a SELENA-SLEDAI score of ≤2 and glucocorticoid dose of ≤5 mg/day at both 6 and 12 months (95% CI 10.5 to 27.3). No patient achieved remission at 12 months. Glucocorticoids decreased from a baseline median of 20.0 mg/day (IQR 15.0-30.0) to 5.0 mg/day (IQR 0-10.0) at 12 months. CONCLUSION: Improved disease control and reduced glucocorticoid use was achieved for a proportion of patients following up to 12 months of belimumab treatment in a US real-world setting.

Safety of belimumab in adult patients with systemic lupus erythematosus: Results of a large integrated analysis of controlled clinical trial data.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease that affects multiple organ systems. Belimumab, a targeted human monoclonal antibody, binds to and inhibits soluble B-lymphocyte stimulator. The safety and efficacy of belimumab has consistently been demonstrated in multiple clinical trials for the treatment of patients with active SLE. Integration of these data provides an additional opportunity to explore the safety of belimumab in a larger and more diverse population. This post hoc pooled analysis of clinical studies evaluated the safety profile of belimumab versus placebo in adults with SLE. METHODS: This was a pooled post hoc analysis of 52-week safety data from one Phase 2 and five Phase 3 belimumab trials in adult patients with SLE. Patients received ≥1 dose of placebo or belimumab (1, 4, or 10 mg/kg intravenous or 200 mg subcutaneous), plus standard therapy. Outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), severe AEs, AEs of special interest (AESI), and mortality. RESULTS: Across 4170 patients (placebo: N = 1355; belimumab: N = 2815), baseline demographics, disease characteristics, and treatment exposure were similar for placebo and belimumab. Most patients (placebo: 76.6%; belimumab: 81.0%) completed the protocol Week 52 visit. Overall, incidence of AEs, SAEs, severe AEs, AESI, and mortality were similar between groups. In both groups, the most commonly reported SAEs by system organ class were infections and infestations (placebo: 5.9%; belimumab: 5.4%) and renal and urinary disorders (placebo: 2.2%; belimumab: 1.7%). Additionally, a greater proportion of patients experienced AESI with belimumab versus placebo for post-infusion/injection systemic reactions (placebo: 8.1%; belimumab: 10.2%). Mortality rates were similar between groups (placebo: 0.4%; belimumab: 0.6%). CONCLUSIONS: These results are consistent with those of the individual studies, BASE, BLISS-LN, and long-term extension studies, making belimumab one of the most studied SLE treatments for safety. Collectively, this evidence continues to support a positive benefit-risk profile of belimumab in the treatment of adult patients with SLE.

Impact of Belimumab on Organ Damage in Systemic Lupus Erythematosus.

Organ damage is a key determinant of poor long-term prognosis and early death in patients with systemic lupus erythematosus (SLE). Prevention of damage is a key treatment goal of the 2019 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for SLE management. Belimumab is a monoclonal antibody that inhibits B lymphocyte stimulator (BLyS) and is the only therapy approved for both SLE and lupus nephritis. Here, we review the clinical trial and real-world data on the effects of belimumab on organ damage in adult patients with SLE. Across 4 phase III studies, belimumab in combination with background SLE therapy demonstrated consistent reductions in key drivers of organ damage including disease activity, risk of new severe flares, and glucocorticoid exposure compared to background therapy alone. Long-term belimumab use in SLE also reduced organ damage progression measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, as reported in open-label extension studies, and propensity score-matched comparative analyses to background therapy alone. Results from a clinical trial showed that in patients with active lupus nephritis, belimumab treatment improved renal response, reduced the risk of renal-related events, and impacted features related to kidney damage progression compared to background therapy alone. The decrease of organ damage accumulation observed with belimumab treatment in SLE, including lupus nephritis, suggest a disease-modifying effect.

Conceptual framework for defining disease modification in systemic lupus erythematosus: a call for formal criteria.

Disease modification has become a well-established concept in several therapeutic areas; however, no widely accepted definition of disease modification exists for SLE.We reviewed established definitions of disease modification in other conditions and identified a meaningful effect on 'disease manifestations' (ie, signs, symptoms and patient-reported outcomes) and on 'disease outcomes' (eg, long-term remission or progression of damage) as the key principles of disease modification, indicating a positive effect on the natural course of the disease. Based on these findings and the treatment goals and outcome measures for SLE, including lupus nephritis, we suggest a definition of disease modification based on disease activity indices and organ damage outcomes, with the latter as a key anchor. A set of evaluation criteria is also suggested.Establishing a definition of disease modification in SLE will clarify which treatments can be considered disease modifying, provide an opportunity to harmonise future clinical trial outcomes and enable comparison between therapies, all of which could ultimately help to improve patient outcomes. This publication seeks to catalyse further discussion and provide a framework to develop an accepted definition of disease modification in SLE.

MOONLIGHT study: the design of a comparative study of the effectiveness of belimumab in patients with a history of lupus nephritis from the post-Marketed effectiveness of belimumab cOhOrt and JapaN Lupus NatIonwide reGistry (LUNA) coHorT.

INTRODUCTION: Lupus nephritis (LN) is more prevalent in patients with SLE of Asian ethnicity than in Caucasian patients. Belimumab became available in Japan in 2017 to treat patients with SLE, including those with LN. In the BLISS-LN trial (NCT01639339), belimumab showed a favourable effect on renal outcomes when combined with standard therapy (ST) starting at the induction treatment phase for active LN, but real-world effectiveness of belimumab in LN has not been extensively studied. Here we describe the protocol for the MOONLIGHT (post-Marketed effectiveness of belimumab cOhOrt and JapaN Lupus NatIonwide ReGistry (LUNA) coHorT) study, which will use data from a Japan postmarketing surveillance study and the Lupus Registry of Nationwide Institutions (LUNA) to evaluate the real-world effectiveness of belimumab plus ST versus ST alone in patients with a history of active LN who are not in the induction phase. METHODS AND ANALYSIS: This multicentre, retrospective, observational study (GSK Study 214710) will enrol adults with SLE and a history of active LN, holding ≥3 years of complete follow-up data from the initiation of belimumab (no continuous treatment required). Data for patients with belimumab plus ST treatment (postmarketing registry data, belimumab cohort) will be compared with those for patients with ST only treatment (LUNA data, comparison cohort). Patients who discontinue/initiate belimumab after the start of the follow-up may be included in the comparison/belimumab cohort, respectively. The primary endpoint will be the occurrence of renal flares, for which belimumab's effectiveness will be estimated using a marginal structural model to consider time-dependent treatment and confounding factors. Secondary endpoints will include change in corticosteroid dose, renal disease activity, extrarenal disease activity, disease severity/activity biomarkers, LN class changes, end-stage kidney disease events and hospitalisations. ETHICS AND DISSEMINATION: This study will be conducted according to the Declaration of Helsinki and the local ethical guidelines. Findings will be submitted to peer-reviewed journals and presented at scientific meetings.

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

OBJECTIVE: To assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE). METHODS: We performed across-study comparisons of patients with active SLE who received belimumab or placebo, plus standard therapy, in PLUTO (paediatric phase II) and BLISS-52, BLISS-76, BLISS-NEA and EMBRACE (adult phase III). Analysed efficacy data included Week 52 SLE Responder Index (SRI)-4 response rate (EMBRACE: SRI with modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) proteinuria scoring (SRI-S2K)); SRI-4 response rate (EMBRACE: SRI-S2K) according to baseline disease activity indicators (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score; anti-dsDNA/C3/C4 levels); Week 52 SRI-6 response rate; and time to first severe flare (SELENA-SLEDAI Flare Index) over 52 weeks. Safety data were compared for all aforementioned studies along with adult LBSL02 (phase II) and BLISS-SC (phase III). RESULTS: SRI-4 response rates were similar across the paediatric and adult studies; more belimumab-treated patients achieved SRI-4 responses versus placebo (PLUTO: 52.8% vs 43.6%; BLISS-52: 57.6% vs 43.6%; BLISS-76: 43.2% vs 33.8%; BLISS-NEA: 53.8% vs 40.1%; EMBRACE: 48.7% vs 41.6%). Across all studies, SRI-4 response rates were generally greater in patients with baseline SELENA-SLEDAI scores ≥10 than in patients with baseline SELENA-SLEDAI scores ≤9. A similar proportion of belimumab-treated patients achieved SRI-6 across all studies (PLUTO: 41.2%; BLISS-52: 46.2%; BLISS-76: 33.1%; BLISS-NEA: 43.9%; EMBRACE: 37.5%). Belimumab reduced the risk of severe flare versus placebo in all studies. The incidence of adverse events was similar across all studies. CONCLUSIONS: These analyses demonstrate consistent efficacy and safety of belimumab plus standard therapy across paediatric and adult patients with SLE. TRIAL REGISTRATION NUMBERS: PLUTO (NCT01649765); BLISS-52 (NCT00424476); BLISS-76 (NCT00410384); BLISS-NEA (NCT01345253); EMBRACE (NCT01632241); BLISS-SC (NCT01484496); and LBSL02 (NCT00071487).

Pharmacotherapy and Lung Function Decline in Patients with Chronic Obstructive Pulmonary Disease. A Systematic Review.

Rationale: Whether pharmacological therapy alters decline in FEV1 in chronic obstructive pulmonary disease remains controversial. Because pharmacotherapy improves health status, exacerbation rate, and symptoms, it may be unethical to complete placebo-controlled long-term studies aimed at modifying FEV1 decline.Objectives: We conducted a systematic review of placebo-controlled pharmacological trials lasting ≥1 year to address the question of whether therapy alters FEV1 decline.Methods: A literature search for randomized trials that included repeated spirometry with at least one active and one placebo arm was conducted. Articles were excluded if study duration was <1 year, <3 spirometric measurements, or <100 subjects per arm. Study design was assessed using the Jadad score. To combine studies and find the estimated effect, we used random effects methodology to account for both within-study and between-study variation.Measurements and Main Results: There were 33,051 patients in the analysis (active component, n = 21,941; placebo, n = 11,110 in nine studies). The active treatment arms demonstrated a 5.0 ml/yr reduction (95% confidence interval, 0.8-9.1 ml/yr; P < 0.001) in the rate of FEV1 decline compared with the placebo arms. The relative FEV1 differences between active and placebo arms were within the range of differences reported for health status and for the exacerbation rate in the same studies.Conclusions: In chronic obstructive pulmonary disease, pharmacotherapy ameliorates rate of lung function decline. The relative benefit observed is within the range of those reported for health status and exacerbations in the same studies. Guidelines should be adjusted according to these findings.

InforMing the PAthway of COPD Treatment (IMPACT Trial) Single-Inhaler Triple Therapy (Fluticasone Furoate/Umeclidinium/Vilanterol) Versus Fluticasone Furoate/Vilanterol and Umeclidinium/Vilanterol in Patients With COPD: Analysis of the Western Europe and North America Regions.

BACKGROUND: The InforMing the Pathway of COPD Treatment (IMPACT) trial demonstrated lower moderate/severe exacerbation rates with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI or UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. Since IMPACT was a global study, post-hoc analyses were conducted by geographic region to investigate potential differences in overall findings. METHODS: IMPACT was a 52-week, randomized, double-blind trial. Patients with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25µg, FF/VI 100/25µg, or UMEC/VI 62.5/25µg. Endpoints assessed in the overall, Western Europe and North America populations included on-treatment moderate/severe exacerbation (rates and time-to-first), trough forced expiratory volume in 1 second and St George's Respiratory Questionnaire (SGRQ) total score. Safety was assessed. RESULTS: Overall, 10,355 patients were enrolled, 3164 from Western Europe, 2639 from North America. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in Western Europe (rate ratios 0.82 [95%CI 0.74-0.91], P<.001 and 0.76 [0.67-0.87], P<.001) and in North America (0.87 [0.77-0.97], P=.014 and 0.69 [0.60-0.80], P<.001). FF/UMEC/VI reduced time-to-first moderate/severe exacerbation and improved lung function versus FF/VI and UMEC/VI in both regions, and improved SGRQ total score in Western Europe, but not North America. Safety profiles were generally similar between treatment groups/regions; the inhaled corticosteroid class effect of increased pneumonia incidence was seen in North America but not Western Europe. CONCLUSION: Consistent with intent-to-treat results, FF/UMEC/VI reduced moderate/severe exacerbation rate and risk and improved lung function in Western Europe and North America; however, between-regions differences were seen for SGRQ total score and pneumonia incidence. CLINICAL TRIAL REGISTRATION: NCT02164513.