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We performed a post hoc analysis of the Belimumab International Study in Lupus Nephritis (BLISS-LN), a Phase 3, multinational, double-blind, 104-week trial, in which 448 patients with lupus nephritis were randomized to receive intravenous belimumab 10 mg/kg or placebo with standard therapy (cyclophosphamide/azathioprine or mycophenolate mofetil). Add-on belimumab was found to be most effective in improving the primary efficacy kidney response and complete kidney response in patients with proliferative lupus nephritis and a baseline urine protein/creatinine ratio under 3 g/g. However, there was no observed improvement in the kidney response with belimumab treatment in patients with lupus nephritis and sub-epithelial deposits or with a baseline protein/creatinine ratio of 3 g/g or more. Belimumab significantly reduced the risk of kidney-related events or death and lupus nephritis flare in the overall population. Belimumab reduced the risk of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) versus standard treatment alone and attenuated the annual rate of eGFR decline in patients who remained on-study. Thus, our data suggest that the addition of belimumab to standard therapy could attenuate the risk of lupus nephritis flare and eGFR decline in a broad spectrum of patients with lupus nephritis.

Objective Enrollment of patients of Black African ancestry with systemic lupus erythematosus (SLE) in Phase 2 and 3 belimumab trials was not reflective of the racial distribution observed in the lupus population. This study assessed efficacy and safety of intravenous (IV) belimumab plus standard therapy in patients of self-identified black race. Methods EMBRACE (GSK Study BEL115471; NCT01632241): 52-week multicenter, double-blind (DB), placebo-controlled trial in adults of self-identified black race with active SLE, receiving monthly belimumab 10 mg/kg IV, or placebo, plus standard therapy. The optional 26-week open-label extension phase included patients who completed the DB phase. The primary endpoint was SLE Responder Index response rate at Week 52 with modified proteinuria scoring adapted from the SLEDAI-2K (SRI-S2K). Key secondary endpoints included: Week 52 SRI response rate, time to first severe flare, and reductions in prednisone dose. Results The modified intention-to-treat population comprised 448 patients (96.9% female; mean [standard deviation] age: 38.8 [11.42] years). The primary endpoint (SRI-S2K response rate at Week 52) was not achieved (belimumab 48.7%, placebo 41.6%; p=0.1068); however, numerical improvements favoring belimumab were observed, especially in patients with high baseline disease activity or renal manifestations. The safety profile of belimumab was generally consistent with previous SLE trials. Adverse events were the primary reason for DB phase withdrawals (belimumab 5.4%; placebo 6.7%). Conclusions The primary endpoint 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.

Summary Background Belimumab is approved for the treatment of active systemic lupus erythematosus (SLE). Although clinical trials showed a favourable benefit–risk profile, numerical differences in the incidence of mortality and adverse events of special interest (AESIs) have been reported. We assessed the frequency of these events in patients with SLE receiving belimumab or placebo plus standard therapy. Methods BASE was a double-blind, randomised, placebo-controlled, phase 4 trial done in 33 countries. Adults with active SLE were randomly assigned (1:1) to receive intravenous belimumab (10 mg/kg) or placebo, plus standard therapy, for 48 weeks. The primary endpoints were incidences of all-cause mortality and AESIs during the on-treatment period (first-to-last study drug dose + 28 days). Safety analyses were done in the as-treated population (patients grouped by actual treatment received >50% of the time). This study was registered with ClinicalTrials.gov ( NCT01705977 ). Findings Between Nov 27, 2012, and July 28, 2017, we randomly assigned 4018 patients. The as-treated population included 2002 patients in the belimumab group versus 2001 in the placebo group. Ten (0·50%) patients in the belimumab group died versus eight (0·40%) in the placebo group (difference 0·10%, 95% CI −0·31 to 0·51). Incidences were similar in the belimumab and placebo groups for serious infections (75 [3·75%] of 2002 vs 82 [4·10%] of 2001; difference −0·35%, 95% CI −1·55 to 0·85), opportunistic infections and other infections of interest (36 [1·80%] vs 50 [2·50%]; −0·70%, −1·60 to 0·20), non-melanoma skin cancers (4 [0·20%] vs 3 [0·15%]; 0·05%, −0·21 to 0·31) and other malignancies (5 [0·25%] vs 5 [0·25%]; 0·00%, −0·31 to 0·31). A higher proportion of patients in the belimumab group than in the placebo group had infusion and hypersensitivity reactions (8 [0·40%] vs 2 [0·10%]; 0·30%, −0·01 to 0·61), serious depression (7 [0·35%] vs 1 [0·05%]; 0·30%, 0·02 to 0·58), treatment-emergent suicidality (28 [1·42%] of 1972 patients vs 23 [1·16%] of 1986; 0·26%, −0·44 to 0·96), and sponsor-adjudicated serious suicide or self-injury (15 [0·75%] of 1972 patients vs 5 [0·25%] of 1986; post hoc difference 0·50%, 0·06 to 0·94). Interpretation In line with previously published data, incidences of all-cause mortality and AESIs were similar in patients given belimumab and placebo, except for serious infusion or hypersensitivity reactions, serious depression, treatment-emergent suicidality, and sponsor-adjudicated serious suicide or self-injury events. Funding GSK.

The phase 2 placebo‐controlled, double‐blind PLUTO trial characterized the pharmacokinetics of belimumab plus standard systemic lupus erythematosus (SLE) therapy in patients with childhood‐onset SLE (cSLE) and demonstrated similar efficacy and safety to that in adult SLE. Patients with active cSLE aged 5‐17 years were randomized to intravenous belimumab 10 mg/kg every 4 weeks (n = 53). A linear 2‐compartment population pharmacokinetics (popPK) model with first‐order elimination was developed, and an exploratory exposure‐response analysis assessed the impact of between‐patient exposure variability on clinical response (SLE Responder Index 4 [SRI4]) in week 52, and occurrence of serious adverse events during the study. The popPK model estimated clearance of 158 mL/day, steady‐state volume of distribution of 3.5 L, terminal half‐life of 16.3 days, and distribution half‐life of 0.8 days in the overall population. Fat‐free mass (FFM) better characterized the pharmacokinetics than total body weight and was more consistent with allometric scaling theory; belimumab pharmacokinetics were largely determined by FFM. Age, sex, disease activity, and concomitant medication had no impact on pediatric belimumab exposure after accounting for body size. Individual and median steady‐state pediatric pharmacokinetic profiles were similar to known adult profiles and pediatric exposure estimates for belimumab 10 mg/kg intravenously were consistent with adult exposures. Exposures were similar between SRI4 responders and nonresponders, and patients who did or did not experience a serious adverse event. There was no clinically relevant correlation between exposure and efficacy or safety, confirming belimumab 10 mg/kg intravenous dose every 4 weeks as appropriate for pediatric patients with cSLE.

ObjectivesThis ongoing Phase-2, randomised, placebo-controlled, double-blind study evaluated the efficacy, safety and pharmacokinetics of intravenous belimumab in childhood-onset systemic lupus erythematosus (cSLE).MethodsPatients (5 to 17 years) were randomised to belimumab 10 mg/kg intravenous or placebo every 4 weeks, plus standard SLE therapy. Primary endpoint: SLE Responder Index (SRI4) response rate (Week 52). Key major secondary endpoints: proportion of patients achieving the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology (PRINTO/ACR) response using 50 and ‘30 alternative’ definitions (Week 52), and sustained response (Weeks 44 to 52) by SRI4 and Parent Global Assessment of well-being (Parent-global). Safety and pharmacokinetics were assessed. Study not powered for statistical testing.ResultsNinety-three patients were randomised (belimumab, n=53; placebo, n=40). At Week 52, there were numerically more SRI4 responders with belimumab versus placebo (52.8% vs 43.6%; OR 1.49 (95% CI 0.64 to 3.46)). PRINTO/ACR 30 alternative (52.8% vs 27.5%; OR 2.92 (95% CI 1.19 to 7.17)) and PRINTO/ACR 50 (60.4% vs 35.0%; OR 2.74 (95% CI 1.15 to 6.54)) responses were more frequent with belimumab than placebo, as were sustained responses for SRI4 (belimumab, 43.4%; placebo, 41.0%; OR 1.08 (95% CI 0.46 to 2.52)) and Parent-global (belimumab, 59.1%; placebo, 33.3%; OR 3.49 (95% CI 1.23 to 9.91)). Serious adverse events were reported in 17.0% of belimumab patients and 35.0% of placebo patients; one death occurred (placebo). Week-52, geometric mean (95% CI) belimumab trough concentration was 56.2 (45.2 to 69.8) µg/mL.ConclusionThe belimumab intravenous pharmacokinetics and benefit–risk profile in cSLE are consistent with adult belimumab studies and the 10 mg/kg every 4 weeks dose is appropriate.Trial registration numberNCT01649765.

Belimumab improved renal outcomes in patients with active lupus nephritis (LN) in BLISS-LN, leading to its approval in the USA and EU. As data on treatment of East Asian patients with LN are limited, we evaluated the efficacy and safety of belimumab in the BLISS-LN East Asian subgroup.Pre-specified subgroup analysis of BLISS-LN, a Phase 3, placebo-controlled, randomized 104-week trial.Adults with biopsy-proven, active LN were randomized (1:1) to belimumab or placebo, plus standard therapy.Patients were administered intravenous belimumab 10 mg/kg, or placebo, plus standard therapy (oral glucocorticoids and either cyclophosphamide for induction followed by azathioprine for maintenance, or mycophenolate mofetil for both induction and maintenance). At the investigator's discretion, 1-3 intravenous pulses of methylprednisolone, 500-1000 mg each, could be administered during induction.The primary endpoint was Primary Efficacy Renal Response (PERR; urine protein:creatinine ratio [uPCR] ≤0.7, eGFR no more than 20% below pre-flare value or ≥60 ml/min/1.73 mPERR and CRR were analyzed using a logistic regression model, and time to a renal-related event or death were analyzed using a multivariable Cox proportional-hazards regression model.142 patients from mainland China, Hong Kong, South Korea, and Taiwan were included (belimumab: n=74; placebo: n=68). At week 104, more belimumab than placebo patients achieved PERR (52.7% vs 36.8%, OR [95% CI] 1.76 [0.88, 3.51]) and CRR (35.1% vs 25.0%, OR [95% CI] 1.73 [0.80, 3.74]). At Week 52, more belimumab than placebo patients achieved PERR (62.2% vs 36.8%; OR [95% CI] 2.74 [1.33, 5.64]). Belimumab reduced the risk of a renal-related event or death compared to placebo at any time (HR [95% CI] 0.37 [0.15, 0.91]). Safety was similar across treatment groups.Small sample size and lack of formal significance testing.Safety and efficacy profiles were consistent with BLISS-LN overall population, supporting benefits of belimumab treatment in the East Asian population with LN.

ObjectiveAssess the safety and efficacy of belimumab in older adults with SLE.MethodsThis post hoc integrated analysis (GSK Study 116559) included safety data from six randomised, placebo-controlled belimumab trials (BLISS-76, BLISS-52, BLISS-SC, North East Asia study, LBSL02, EMBRACE; n=4170). The BASE study provided additional safety data (n=4003). Efficacy data were from five of the trials. Older adults (≥65 years) were compared with the overall populations of patients with SLE. Patients who had received ≥1 treatment dose were included.ResultsSixty-three older adults (1.5%) were included in the pooled safety analysis population and 156 (3.9%) in the BASE study. At baseline, older adults had lower disease activity but more organ damage than the overall populations. In the pooled safety analysis population, five (18.5%) placebo-treated and ten (27.8%) belimumab-treated older adults experienced ≥1 serious adverse event (SAE), as did 230 (17.0%) placebo-treated and 421 (15.0%) belimumab-treated patients overall. In the BASE study, nine (11.0%) placebo-treated and six (8.1%) belimumab-treated older adults experienced ≥1 SAE, as did 222 (11.1%) placebo-treated and 220 (11.0%) belimumab-treated patients overall. No clinically relevant differences in deaths and adverse events of special interest were observed between older adults and the overall populations. Older adults’ SLE Responder Index response rates favoured belimumab versus placebo, consistent with the overall population.ConclusionThe safety and efficacy of belimumab in older adults were generally consistent with the overall populations, suggesting belimumab is a treatment option for older patients with SLE. Due to small numbers of older adults, findings should be interpreted with caution.

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 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).ResultsSRI-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.ConclusionsThese analyses demonstrate consistent efficacy and safety of belimumab plus standard therapy across paediatric and adult patients with SLE.Trial registration numbersPLUTO (NCT01649765); BLISS-52 (NCT00424476); BLISS-76 (NCT00410384); BLISS-NEA (NCT01345253); EMBRACE (NCT01632241); BLISS-SC (NCT01484496); and LBSL02 (NCT00071487).

COPD is heterogeneous, and its presentation varies between countries. The major COPD cohort studies have only been performed in Western populations; the disease is not well characterised in other regions. The COMPASS (Investigation of the Clinical, Radiological and Biological Factors, Humanistic and Healthcare Utilisation Burden Associated with Disease Progression, Phenotypes and Endotypes of COPD in China; NCT04853225) is a prospective, 2.5-year-long, multi-centre, longitudinal, observational study with three aims: 1) to characterise stable and exacerbation phenotypes/endotypes in terms of clinical characteristics, blood and sputum biomarkers, lung microbiome and lung imaging; 2) to understand the relevance of markers of COPD disease progression identified in Western cohorts to Chinese patients; and 3) to characterise treatment pathways and healthcare resource utilisation. COMPASS will recruit 2000 participants, of which 1700 will be in Global Initiative for Chronic Obstructive Lung Disease (GOLD) Grades I–IV (n=700, 700, 200 and 100, respectively), 180 participants with chronic bronchitis without airflow limitation and 120 never-smoker healthy controls. Study visits will be at baseline, 6, 18 and 30 months and at exacerbation. Assessments include lung function, exacerbation frequency, health status, blood biomarkers and, in a sub-cohort of 400 patients, chest high-resolution computed tomography, additional blood and sputum biomarkers, airway micro-, viral- and myco-biome, and physical activity. COMPASS will establish a unique clinical and biological dataset in a well-characterised cohort of individuals with COPD in China, with a particular focus on milder patients. As the first study of its kind attempting to understand the disease in an Asian setting, it will provide valuable insights into regional and ethnic differences in COPD., COMPASS, a prospective, multicentre, observational study of Chinese patients with COPD, will characterise stable and exacerbation phenotypes/endotypes, treatment pathways and HRU, and investigate COPD progression biomarkers' relevance to these patients https://bit.ly/3dyIpf1

ObjectivesTo evaluate the long-term safety and efficacy of belimumab in patients with systemic lupus erythematosus (SLE) from Japan and South Korea.MethodsIn this phase III, open-label continuation study (BEL114333; NCT01597622), eligible completers of BEL113750 (NCT01345253) or BEL112341 (NCT01484496) received intravenous belimumab 10 mg/kg every 28 days for ≤7 years. Primary endpoint was safety. Secondary endpoints: SLE Responder Index (SRI)4 response rate, proportion of patients meeting individual SRI4 criteria, SLE flares and prednisone use. Analyses were based on observed data from the first belimumab exposure (either in parent or current study) through to study end.ResultsOf 142 enrolled patients who received belimumab, 73.2% completed the study. The study population comprised patients with moderate SLE, mean (SD) Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) baseline score of 9.3 (3.9) and 98.6% receiving corticosteroids. Most patients (97.9%) experienced adverse events (AEs); 33.8% experienced serious AEs. Increase in SRI4 (Year 1, Week 24: 47.8%; Year 6, Week 48: 68.2%) and SELENA-SLEDAI responders suggested reductions in disease activity. Proportions of patients with no worsening in Physician Global Assessment/no new organ damage remained stable throughout. Severe SLE flares occurred in 14.8% of patients. Among patients with baseline prednisone-equivalent dose >7.5 mg/day (n=81), the median (min, max) number of days anytime post-baseline that the daily dose was ≤7.5 mg/day or had been reduced by 50% from baseline was 584 (0, 2267).ConclusionsFavourable safety profile and treatment responses were maintained for ≤7 years in patients with SLE from Japan and South Korea.

Objective To investigate the long-term safety and efficacy of intravenous (IV) belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody-positive SLE. Methods The study was designed as a multicenter, open-label, continuation study of IV belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double-blind study. Adverse events (AEs) and laboratory data were monitored from the first belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16-week intervals) and glucocorticoid use (assessed at 4-week intervals). Results Of the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study. Patients received belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260-4,332 days], total belimumab exposure 2,294 patient-years, median number of infusions 115.5 [range 7-155]). The percentage of patients with AEs each year remained stable or decreased. Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12. The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline. Conclusion This study is the longest to date to assess belimumab treatment in patients with SLE in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially exhibited a satisfactory response to belimumab, the treatment continues to be well tolerated and provides long-term disease control.

Background Treatment goals for patients with systemic lupus erythematosus (SLE) include minimising disease activity and reducing the risk of flares. Although belimumab is effective at reducing disease activity and risk of severe flares, it was previously unknown what the clinical effects were upon treatment discontinuation. The objective of this study was to assess the impact of temporary withdrawal of intravenous (IV) belimumab in patients with SLE. Methods This multicentre, open-label, non-randomised, 52-week study (GSK Study BEL116027; NCT02119156) recruited patients with SLE and stable low disease activity, of whom those on belimumab 10 mg/kg IV plus standard therapy either discontinued belimumab for 24 weeks and then restarted belimumab 10 mg/kg IV every 4 weeks (q4w) for 28 weeks (treatment holiday [TH] group), or continued on belimumab 10 mg/kg IV plus standard therapy q4w for 52 weeks (treatment continuation [TC] group). The primary endpoint was median time to first Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) Flare Index flare. Secondary and other endpoints included rate of any flare, time to severe flare, time to renal flare and rebound (SELENA-SLEDAI score exceeding parent study baseline). Data on rebound phenomenon in patients with any disease level of SLE who had permanently withdrawn from further belimumab treatment (long-term discontinuation group [LTD]) were also assessed. Safety was assessed. Results The primary endpoint was not evaluable in the TH (n = 12) and TC (n = 29) groups as fewer than half of patients flared. Unadjusted flare rates per patient-year were 1.0 during treatment discontinuation and 0.3 during treatment restart (0.6 overall) in the TH group and 0.6 in the TC group; there were no severe or renal flares. No TH patients rebounded; 2 (6.9%) TC patients rebounded; 2 (5.1%) patients in the LTD group rebounded. There were no new safety signals. Conclusions Twenty-four-week belimumab discontinuation did not appear to increase the risk of flares or rebound in patients with low SLE disease activity; flare rates were low in both groups. Further studies may help to fully determine the effect of belimumab discontinuation. Trial registration ClinicalTrials.gov, NCT02119156. Registered on April 21, 2014.

Enrollment 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.EMBRACE (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.The 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%).The 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.

BackgroundIn adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or cyclophosphamide-azathioprine), are unknown.MethodsIn a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial conducted at 107 sites in 21 countries, we assigned adults with biopsy-proven, active lupus nephritis in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of = 60 ml per minute per 1.73 m(2) of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of

Background and Aims Belimumab (BEL), an anti-B-cell-activating factor (BAFF) monoclonal antibody, is approved in patients (pts) ≥5 years of age with active systemic lupus erythematosus (SLE). Post hoc analyses of pooled renal outcomes data from two Phase 3 SLE studies showed favourable trends of greater reduction in proteinuria, haematuria, pyuria and lower renal flare rates in BEL-treated pts vs placebo (PBO).1 This is the largest study in acute lupus nephritis (LN) to date that evaluated efficacy and safety of intravenous (IV) BEL plus standard therapy (ST) in pts with active LN. Method BLISS-LN is a Phase 3, randomised, double-blind, placebo-controlled, 104-week study (GSK study BEL114054, NCT01639339); eligible pts (≥18 years) with autoantibody-positive SLE and active, biopsy-proven LN (classes III, IV and/or V) were randomised (1:1) to monthly BEL 10 mg/kg IV or PBO, plus ST. Randomisation was stratified by induction regimen: high dose corticosteroids [HDCS] plus either cyclophosphamide (CyC), followed by azathioprine + low dose corticosteroids (LDCS), or mycophenolate mofetil (MMF), followed by MMF + LDCS. Primary endpoint: primary efficacy renal response (PERR; defined as urine protein creatinine ratio [uPCR] ≤0.7; estimated glomerular filtration rate [eGFR] no more than 20% below pre-flare value or ≥60 ml/min/1.73m2; no rescue therapy) at Week (Wk) 104. Key secondary endpoints: complete renal response (CRR; defined as uPCR Results Overall, 448 pts were randomised (efficacy: 223/treatment group; safety: 224/treatment group); 118 pts received CyC induction and 328 MMF induction; 278 (62.3%) completed the treatment. At Wk 104, 43.0% BEL and 32.3% PBO pts achieved PERR (OR [95% CI] vs PBO 1.55 [1.04, 2.32], p=0.0311); 30.0% BEL and 19.7% PBO pts achieved CRR (OR [95% CI] vs PBO 1.74 [1.11, 2.74], p=0.0167). Over 104 weeks, more BEL than PBO pts achieved CRR at each visit (Figure 1A). PERR at Wk 52 was achieved by 46.6% BEL and 35.4% PBO pts (OR [95% CI] vs PBO 1.59 [1.06, 2.38], p=0.0245). The risk of a renal-related event or death was 49% lower with BEL than PBO (HR [95%CI] 0.51 [0.34, 0.77]; p=0.0014) at any time point during the study. Overall, 15.7% of BEL and 28.3% of PBO pts experienced a renal-related event or death. When analysed by induction regimen, PERR at Wk 104 was achieved by 33.9% BEL and 27.1% PBO CyC-induced pts (OR [95% CI] vs PBO 1.52 [0.66, 3.49], p=0.3272), and by 46.3% BEL and 34.1% PBO MMF-induced pts (OR [95% CI] vs PBO 1.58 [1.00, 2.51], p=0.0501). CRR at Wk 104 was achieved by 18.6% BEL and 18.6% PBO CyC-induced pts (OR [95% CI] vs PBO 1.07 [0.41, 2.78], p=0.8843), and by 34.1% BEL and 20.1% PBO MMF-induced pts (OR [95% CI] vs PBO 2.01 [1.19, 3.38], p=0.0085). Proportions of pts with uPCR shift from ≥0.5 at baseline to Overall, 95.5% BEL and 94.2% PBO pts had ≥1 adverse event (AE); 25.9% BEL and 29.9% PBO pts had ≥1 serious AE; 13.8% BEL and 17.0% PBO pts had serious infections; 12.9% pts in each group had ≥1 AE resulting in study treatment discontinuation; on-treatment fatal AEs were reported in 1.8% BEL and 1.3% PBO pts. Conclusion BEL demonstrated improved renal responses vs PBO in pts with active LN, with a safety profile consistent with previous BEL trials.

Background Elevated B lymphocyte stimulator (BLyS) levels in patients with systemic lupus erythematosus (SLE) correlate positively with disease activity; BLyS expression is directly linked to interferon (IFN) pathway activation. This post hoc meta-analysis of BLISS-52 and BLISS-76 explored the relationship between baseline BLyS mRNA/protein levels and/or type 1 IFN-inducible gene signature (IFN-1) and responses to the BLyS-targeting monoclonal antibody belimumab in SLE. Methods In BLISS-52 and BLISS-76, patients with autoantibody-positive SLE and a SELENA-SLEDAI score ≥ 6 and receiving stable standard SLE therapy were randomised to intravenous belimumab 10 mg/kg or placebo, plus standard of care (SoC), for 52 or 76 weeks. For this post hoc meta-analysis, patients with an appropriate mRNA sample were stratified by BLyS mRNA expression (tertiles: high/medium/low; revised quantiles: high/low), IFN-1 mRNA expression (high/low) and BLyS protein level (high/low). Co-primary endpoints were correlation between baseline BLyS and IFN-1 mRNA levels and SLE Responder Index (SRI)4 response at week 52 within BLyS/IFN-1 subgroups. Secondary endpoints included time to first severe SELENA-SLEDAI Flare Index (SFI) flare. Results Of 554 patients included in this analysis, 281 had received belimumab and 273 had received placebo. Baseline BLyS and IFN-1 mRNA levels were highly correlated (Spearman’s rank correlation coefficient 0.7799; 95% confidence interval [CI] 0.7451, 0.8106; p p = 0.0153), high BLyS mRNA quantile (OR 1.58; 95% CI 1.02, 2.44; p = 0.0402), high IFN-1 mRNA (OR 1.58; 95% CI: 1.08, 2.31; p = 0.0186) and high BLyS protein (OR 3.57; 95% CI 1.63, 7.83; p = 0.0015) subgroups only. The risk of severe SFI flare was significantly lower with belimumab than placebo in the high BLyS mRNA quantile (hazard ratio [HR] 0.59; 95% CI 0.36, 0.97; p = 0.0371) and high BLyS protein (HR 0.39; 95% CI 0.19, 0.79; p = 0.0090) subgroups. Conclusions This post hoc meta-analysis demonstrated a tendency towards improved response to add-on intravenous belimumab 10 mg/kg versus SoC alone in patients with high baseline BLyS protein and IFN-1 mRNA levels and medium/high BLyS mRNA levels.

Background Belimumab is approved as add-on therapy for patients ≥5 years with active, autoantibody-positive systemic lupus erythematosus (SLE).1 The PLUTO trial (NCT01649765) demonstrated safety and efficacy of belimumab in children with SLE2 as generally consistent with adult studies. The current analysis assessed the efficacy of belimumab 10 mg/kg given intravenously (IV) to patient subgroups with baseline markers of high disease activity in PLUTO versus pooled BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) SLE trials. Methods Patients 5–17 years (PLUTO) and ≥18 years (BLISS-52 and BLISS-76) with active SLE were randomised to IV belimumab 10 mg/kg or placebo, plus standard of care (SoC) (PLUTO);2 and IV belimumab 10 mg/kg, or placebo, plus SoC (BLISS trials).3 The primary endpoint was SLE Responder Index 4 (SRI4) at Week 52. This post hoc across-trial comparison (intention-to-treat [ITT] population) investigated the treatment effect of belimumab according to baseline disease activity indicators (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index [SELENA-SLEDAI] score, anti-dsDNA and complement C3/C4 levels) and steroid use; analyses were descriptive. Results In PLUTO, belimumab demonstrated higher SRI4 response versus placebo; this response was similar for patients with baseline SELENA-SLEDAI scores of ≥10 and ≤9, and for and those receiving steroids, but greater in those with scores ≥13, low anti-dsDNA, or normal/high C3/C4 (table 1). Subgroup analyses from the BLISS adult studies demonstrated similar findings with the exception of patients with high anti-dsDNA or low C3/C4 (table 1). Conclusions Subgroup analyses from the PLUTO trial demonstrated favourable belimumab responses in paediatric patients with high SELENA-SLEDAI scores, similar to those observed in adult belimumab studies. However, these results should be interpreted with caution due to the small sample size of PLUTO, the post hoc nature of the analyses and other limitations. Disclosures DLB, MO, AH, BJ, DR and HQ are employees of GSK. BJ and DLB hold stocks and shares in GSK; MO, AH, DR and HQ hold shares in GSK. Acknowledgements This study was funded by GSK. Medical writing support was provided by Gosia Carless, PhD, Fishawack Indicia Ltd, UK, and was funded by GSK. References Benlysta US prescribing information. GlaxoSmithKline; 2018. Available at: https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Benlysta/pdf/BENLYSTA-PI-MG-IFU-COMBINED.PDF Brunner H.I., Abud-Mendoza C., Viola D.I., Calvo I., Levy D.M., Calderon Gallegos J., et al. Efficacy and safety of intravenous belimumab in children with systemic lupus erythematosus. Arthritis Rheumatol 2018;70(59):3224–3225, Abstract 2867. van Vollenhoven R.F., Petri M.A., Cervera R., Roth D.A., Ji B.N., Kleoudis, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis 2012; 71:1343–1349.

Objectives: To assess the efficacy and safety of intravenous (IV) belimumab plus standard systemic lupus erythematosus (SLE) therapy standard of care (SoC) in Japanese patients with SLE. Methods: A Phase 3, multicenter, double-blind, placebo-controlled, 52-week study (BEL 113750; NCT01345253) in patients with SLE, randomized 2:1 to belimumab 10 mg/kg plus SoC or placebo plus SoC to Week 48. Results: Sixty of 707 randomized patients were enrolled from study centers in Japan (belimumab, n = 39; placebo, n = 21). In this cohort, more patients achieved SLE Responder Index 4 response at Week 52 in the belimumab group compared with placebo (46.2% [18/39] vs. 25.0% [5/20]; odds ratio, 2.57 [95% confidence interval: 0.78, 8.47]; p=.1204). Fewer patients receiving belimumab experienced a severe flare through Week 52, with longer median time to flare compared with placebo. More patients with baseline prednisone dose >7.5 mg/d receiving belimumab had a dose reduction of ≥25% from baseline to ≤7.5 mg/d during Weeks 40–52, compared with placebo. No new safety issues were identified within the Japanese cohort. Conclusion: In Japanese patients with SLE, belimumab improved disease activity, with efficacy and safety results similar and consistent to the pivotal Phase 3 trials, suggesting that belimumab is a potential treatment option in this population.

Objective.This observational study was a retrospective analysis of prospectively collected Hopkins Lupus Cohort data to compare longterm renal survival in patients with lupus nephritis (LN) who achieved complete (CR), partial (PR), or no remission following standard-of-care LN induction therapy.Methods.Eligible patients with biopsy-proven LN (revised American College of Rheumatology or Systemic Lupus Collaborating Clinics criteria) were identified and categorized into ordinal (CR, PR, or no remission) or binary (response or no response) renal remission categories at 24 months post-diagnosis [modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Lupus Nephritis Study (mBLISS-LN) criteria]. The primary endpoint was longterm renal survival [without endstage renal disease (ESRD) or death].Results.In total, 176 patients met the inclusion criteria. At Month 24 postbiopsy, more patients met mALMS remission criteria (CR = 59.1%, PR = 30.1%) than mBLISS-LN criteria (CR = 40.9%, PR = 16.5%). During subsequent followup, 18 patients developed ESRD or died. Kaplan–Meier plots suggested patients with no remission at Month 24 were more likely than those with PR or CR to develop the outcome using either mALMS (p = 0.0038) and mBLISS-LN (p = 0.0097) criteria for remission. Based on Cox regression models adjusted for key confounders, those in CR according to the mBLISS-LN (HR 0.254, 95% CI 0.082–0.787; p = 0.0176) and mALMS criteria (HR 0.228, 95% CI 0.063–0.828; p = 0.0246) were significantly less likely to experience ESRD/mortality than those not in remission.Conclusion.Renal remission status at 24 months following LN diagnosis is a significant predictor of longterm renal survival, and a clinically relevant endpoint.

Introduction Le Belimumab (BEL) a montre son efficacite dans les manifestations extra-renales du lupus systemique (LS) dans 4 etudes pivotales. Dans cette etude ont ete evaluees l’efficacite et la tolerance du BEL (IV) + associe au traitement standard (TS) au cours de la glomerulonephrite lupique active (GNL). Patients et methodes Etude de phase 3, en double aveugle ( NCT01639339 ), randomisee (1 :1) incluant des adultes avec un LS et une GNL confirmee par biopsie (classe III, IV et/ou V) qui ont recu chaque mois du BEL 10 mg/kg IV ou placebo (PBO), en sus du TS. La randomisation a ete stratifiee sur l’origine ethnique et sur le traitement (corticoides + soit cyclophosphamide IV en induction suivi par azathioprine en maintien, ou mycophenolate mofetil (MMF) en induction et maintien). Critere principal : Reponse renale primaire (RRP); a la semaine (S) 104 (basee sur ratio proteinurie/creatininurie (RPCU) ≤ 0,7 g/g ; baisse du debit de filtration estime (DFG) Resultats 448 pts randomises (efficacite : 223/groupe ; tolerance : 224/groupe). A S104, RRP : 96 (43,0 %) pts BEL vs 72 (32,3 %) pts PBO (OR [IC95 %] 1,6 [1,0 ; 2,3] ; p = 0,031) ; RRC : 67 (30,0 %) pts BEL vs 44 (19,7 %) pts PBO (OR [IC95 %] 1,7 [1,1 ; 2,7] ; p = 0,017). A S52, plus de pts BEL vs PBO ont atteint une RRP (104 [46,6 %] vs 79 [35,4 %] ; OR [IC95 %] 1,6 [1,1 ; 2,4] ; p = 0,025). Le risque d’evenements renaux ou deces etait plus faible dans le bras BEL (35 (15,7 %)) compare au bras PBO (63 evenements (28,3 %) ; HR [IC95 %] 0,5 [0,3 ; 0,8] ; p = 0,001). Des poussees severes selon le SFI ont ete rapportees chez 42 (18,8 %) pts BEL vs 70 (31,4 %) pts PBO (HR [IC95 %] 0,6 [0,4 ; 0,8] ; p = 0,004). A S104, plus de pts BEL vs PBO ont atteint un score SLEDAI-S2 K Conclusion Dans cette etude a 2 ans, BEL + TS a ameliore la fonction renale, l’activite globale du LS, les taux de biomarqueurs, tout en reduisant l’utilisation des corticoides, avec un profil de securite favorable vs TS seul [1] .

Background: Belimumab (BEL), a monoclonal antibody targeting the B-lymphocyte stimulator, is approved in adults with active systemic lupus erythematosus (SLE). This is the first clinical trial of belimumab in pediatric patients with childhood-onset SLE (cSLE). Objectives: PLUTO, a Phase 2, randomised, double-blind trial (BEL114055; NCT01649765), evaluated the efficacy, safety and pharmacokinetics (PK) of intravenous (IV) BEL vs placebo (PBO), plus standard of care (SoC), in cSLE. Methods: Patients with cSLE 5–17 years of age were randomised to BEL 10 mg/kg IV or PBO every 4 weeks, plus SoC. Primary endpoint: SRI4 at Week 52. Major secondary endpoints: PRINTO/ACR 30 and 50 cSLE evaluation criteria for improvement at Week 52; cSLE core response variables at Week 52; and sustained SRI4 and ParentGA (patient well-being) responses (Weeks 44–52). Other endpoints: components of SRI4 at Week 52; and frequency of severe flares using the modified SELENA-SLEDAI Flare Index. Safety and PK were assessed. Analyses were performed on the intent-to-treat population. The study was not powered to test for differences between groups; p-values were not calculated. Results: 93 patients were included (BEL, n=53; PBO, n=40). Groups (BEL vs PBO) were balanced at baseline for age (mean [standard deviation] 13.5 [2.59] vs 14.8 [2.17] years, respectively) and SELENA-SLEDAI score (10.3 [3.34] vs 10.4 [3.63], respectively). Compared with PBO, there were more SRI4 responders (including all 3 components of SRI4), and PRINTO/ACR 30 and 50 responders in the BEL group (Figure). Likewise, more BEL than PBO recipients had sustained improvement of SRI and patient well-being (ParentGA) (Figure). Changes in cSLE core response variables are shown in the Table. Severe flares were 62% less frequent with BEL vs PBO (hazard ratio 0.38 [95% CI 0.18, 0.82]). PK: BEL exposures in cSLE were similar to adult SLE studies. 9/53 (17%) BEL patients had ≥1 serious adverse event vs 14/40 (35%) PBO patients. One PBO patient died of acute pancreatitis. Conclusion: The benefit:risk profile of BEL IV plus SoC in cSLE is generally consistent with BEL in adult SLE. The 10 mg/kg IV dose used in adults may be an appropriate dose in cSLE. Acknowledgement: The authors would like to acknowledge all investigators (PRINTO, PRCSG and otherwise affiliated) for the PLUTO study. Study funded by GSK. Gosia Carless, PhD, Fishawack Indicia Ltd, UK, provided editorial assistance funded by GSK. Disclosure of Interests: Nicolino Ruperto Grant/research support from: The Gaslini Hospital, where NR works as full-time public employee, has received contributions (> 10.000 USD each) from the following industries in the last 3 years: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Consultant for: Received honoraria for consultancies or speaker bureaus ( I perform consultancy activities on behalf of the Gaslini Institute for the companies listed below: AbbVie, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, Janssen, Novartis, Pfizer, R-Pharm. The money received for these activities are directly transferred to the Gaslini Institute’s bank account. Before March 2016, I was the head of the Pediatric Rheumatology Department at the G. Gaslini Hospital, where the PRINTO Coordinating Centre is located. For the coordination activity of the PRINTO network, the Gaslini Hospital received contributions from the industries listed in this section. This money has been reinvested for the research activities of the hospital in fully independent manners besides any commitment with third parties., Daniel J Lovell Consultant for: Consulting fees and/or honoraria from Astra Zeneca, Wyeth Pharma, Amgen, Abbott, Pfizer, F. Hoffmann-La Roche, Novartis, UBC, Takeda, GSK, Boehringer, and Celgene, Hermine Brunner Grant/research support from: Bristol-Myers Squibb, Pfizer, Consultant for: Pfizer, Bristol-Myers Squibb, Janssen, Novartis, Lilly, Roche, GlaxoSmithKline, Sanofi, Speakers bureau: Novartis, Roche

Background Belimumab (BEL) is approved in adults with active, autoantibody-positive SLE. Phase 2, 3 and long-term extension studies showed a favourable benefit-risk profile. However, numerical differences in the incidence of mortality, infections, hypersensitivity reactions and some psychiatric events warranted a large, focused safety study to assess these events, along with potential for malignancy. Objectives To evaluate all-cause mortality and AESI in patients with SLE receiving intravenous (IV) BEL vs placebo (PBO) over 52 weeks. Methods This study (BASE; BEL115467; NCT01705977) randomised adults with SLE (1:1) to monthly BEL 10 mg/kg IV or PBO, plus standard of care, for 48 weeks. No minimum SELENA-SLEDAI disease activity was required and no exclusions for previous psychiatric conditions were made. Differences in rates (95% CI) of mortality and other pre-specified AESI (malignancies, serious infections, opportunistic infections and other infections of interest, serious depression, suicidality [C-SSRS], and serious infusion/hypersensitivity reactions) on-treatment (first to last dose +28 days) were assessed. For on-treatment serious suicidal ideation/behaviour and self-injury events (per sponsor adjudication), and on-study (first dose to end of Week 52 study follow-up) suicidal ideation/behaviour (C-SSRS), differences (95% CI) vs PBO were calculated post hoc. Results 4003 patients received ≤1 dose. Baseline demographics and disease characteristics were similar between groups. On-treatment mortality and pre-specified AESI rates are shown in the Table 1 below. Overall rates of on-treatment AESIs were similar between groups, except for serious depression and serious infusion/hypersensitivity reactions. On-treatment deaths were most frequently caused by infection (3 [0.15%] PBO vs 9 [0.45%] BEL); on-study deaths occurred in 22 (1.10%) PBO and 13 (0.65%) BEL patients (difference [95% CI]: -0.45 [-1.03, 0.13]). On-treatment serious suicidal ideation/behaviour and self-injury events were reported for 5 (0.25%) PBO and 15 (0.75%) BEL patients (difference [95% CI]: 0.50 [0.06, 0.94]); on-study suicidal ideation/behaviour (C-SSRS) occurred in 39 (1.96%) PBO and 48 (2.43%) BEL patients (difference [95% CI]: 0.47 [-0.44, 1.38]). No suicide-related deaths were reported. Conclusion In this double-blind, placebo-controlled (1:1) safety study, which is the largest SLE clinical study to date with 4003 patients, on-treatment all-cause mortality, infection and malignancy AESI rates were similar between BEL and PBO, with imbalances observed in serious depression, serious suicidal ideation/behaviour and self-injury events, and serious infusion/hypersensitivity reactions. Acknowledgement We acknowledge the BASE Study Group. Study funding: GSK. Disclosure of Interests Saira Sheikh Consultant for: GSK, Morton Scheinberg: None declared, James Cheng-Chung Wei Grant/research support from: TSH Biopharm, Abbvie, BMS, Celgene, Janssen, Novartis, Pfizer and UCB, Consultant for: TSH biopharm, Abbvie, BMS, Celgene, Chugai, Eisai, Janssen, Novartis, Pfizer, Sanofi-Aventis and UCB pharma, Dana Tegzova: None declared, William Stohl Grant/research support from: GSK, Consultant for: Janssen R&D, Tamara Mucenic Grant/research support from: GSK, Janssen, Roche, Eli Lilly, Pfizer, Amgen, Consultant for: Janssen, Roche, UCB, Novartis, Speakers bureau: Janssen, Roche, UCB, Novartis, Abbvie, Pfizer, Roger Levy Shareholder of: GSK, Employee of: GSK, Damon Bass Shareholder of: GSK, Employee of: GSK, Jorge Ross Terres Shareholder of: GSK, Employee of: GSK at the time of study, Rajesh Punwaney Shareholder of: GSK, Employee of: GSK, Julia Harris Shareholder of: GSK, Employee of: GSK, Kevin Thorneloe Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK

Background Black patients have an increased prevalence and severity of systemic lupus erythematosus (SLE), alongside higher mortality rates. The efficacy and safety of intravenous (IV) belimumab has been demonstrated in several Phase 2/3 studies; however, the small number of black patients within these trials, and the conflicting results, have limited conclusions regarding efficacy in this population. The objective of this study was to specifically assess the efficacy and safety of IV belimumab plus standard of care (SoC) in black patients with active, auto antibody-positive SLE. Methods EMBRACE (NCT01632241) is a randomized, multicenter, double-blind, placebo-controlled trial in patients of self identified black race, aged 18 years, with active SLE at screening. Patients were randomized (2:1) to monthly belimumab 10 mg/kg IV or placebo, plus SoC. The primary endpoint was the SLE Responder Index (SRI) response rate with modified SLEDAI-2K (S2K) scoring for proteinuria at Week 52 (SRI-S2K response required a 4 point reduction in the SELENA-SLEDAI (SS)-S2K, no worsening [increase of Results The mITT population comprised 448 patients; 96.9% were female and mean (SD) age was 38.8 (11.42) years. Although the study did not achieve the primary endpoint, numerical trends were observed in favor of belimumab, and significant improvements were observed in subgroups with characteristics of high disease activity (HDA; table). Study withdrawals were similar between groups (belimumab 22.4%; placebo 24.2%) and AEs were the primary reason for withdrawals (belimumab 5.4%; placebo 6.7%). The percentage of patients who experienced an AE (belimumab 83.7%; placebo 87.3%) or serious AE (belimumab 10.9%; placebo 18.8%) was similar between groups. Two deaths occurred within the belimumab group (0.6%; pneumonia and meningitis); neither were established as directly related to belimumab. Conclusions Whilst the primary endpoint of this study in black patients with SLE was not achieved, improvements in favor of belimumab were observed, with significant benefits in patients with HDA. The safety profile was acceptable and consistent with previous studies. Funding Source(s): Study (BEL115471) funded by GSK.

Objectives: To assess the effects of belimumab on disease activity across multiple organ domains in Japanese patients from the Phase 3 randomized, double-blind, North-East Asia study, BEL113750 (NCT01345253). Methods: Patients, aged ≥18 years, with American College of Rheumatology-defined systemic lupus erythematosus (SLE) and a Safety of Estrogen in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score ≥8 at screening, on stable SLE treatment, were randomized 2:1 to receive intravenous belimumab 10 mg/kg or placebo, plus standard of care, on Days 0, 14, and 28, then 4-weekly until Week 48. Patients were assessed for SELENA-SLEDAI and British Isles Lupus Assessment Group (BILAG) organ system improvement/worsening between baseline and Week 52. Results: Sixty patients (belimumab, n = 39; placebo, n = 21) were enrolled in Japan. Improvement was seen in a greater proportion of belimumab patients, compared with placebo, in most SELENA-SLEDAI and BILAG domains (significant for the mucocutaneous domain). Worsening occurred in SELENA-SLEDAI hematologic and renal systems (Conclusion: Organ system improvements were seen in more Japanese belimumab-treated than placebo-treated patients, providing further evidence supporting belimumab use in Japanese patients with SLE.

Background:Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease characterised by persistent B-cell activation. Belimumab (BEL), a monoclonal antibody that inhibits B-lymphocyte stimulator, is approved in patients aged ≥5 years with active autoantibody-positive SLE; however, safety and efficacy data of BEL in older adults are limited.Objectives:Assess the safety and efficacy of BEL in older adults with SLE.Methods:A meta-analysis (GSK study 116559) was performed on the subpopulation of patients aged ≥65 years and compared with the overall population pooled from six controlled, repeat-dose (CRD) BEL trials in adults with SLE (GSK studies: 110752, 110751, LBSL02 [safety only], 112341, 113750, and 115471). Additional safety data were obtained from GSK study 115467.In each trial, patients were randomised to BEL or placebo (PBO) and received ≥1 treatment dose (GSK studies 110752 and 110751: intravenous [IV] BEL 1 or 10 mg/kg; LBSL02: IV BEL 1, 4, or 10 mg/kg; GSK study 112341: subcutaneous BEL 200 mg; GSK studies 113750, 115471, and 115467: IV BEL 10 mg/kg) plus standard therapy. Safety assessments included: incidence of serious adverse events (SAE), mortality and adverse events of special interest (AESI). The primary efficacy analysis for the CRD trials was the SLE Responder Index 4 (SRI4) response rate.Results:Older adults (CRD studies: N=63; study 115467: N=156) had lower disease activity and more organ damage compared with the overall populations, and a greater proportion were of white race compared with the overall population in the CRD studies. There were no clinically relevant differences in the incidence of SAE or death between older adults and the overall populations (Table 1). Rates of AESI (post-infusion/injection systemic reactions [PISR], serious infections of special interest, malignancies, psychiatric events) were generally similar or lower in older adults compared with the overall populations with no imbalances between BEL and PBO in older adults (Table 1). No malignancies were reported in older adults. The SRI4 response rate in older adults favoured BEL vs PBO (OR [95% CI], 1.49 [0.49, 4.58]), consistent with the overall populations of the individual CRD studies (110752 and 110751 pooled [10 mg/kg IV]: 1.68 [1.32, 2.15]; 112341: 1.68 [1.25, 2.25]; 113750: 1.99 [1.40, 2.82]; 115471: 1.42 [0.94, 2.15]).Conclusion:In patients with SLE, the safety and efficacy of BEL in older adults were generally consistent with the overall population and suggest a favourable benefit–risk profile. Due to the small number of older adults analysed, these data should be interpreted with caution.Funding:GSKTable 1.SAE, deaths, and AESIN (%)*Study 115467CRD studies†Older adults(N=156)Overall(N=4003)Older adults(N=63)Overall(N=4170)PBON=82BELN=74PBON=2001BELN=2002PBON=27BELN=36PBON=1355BELN=2815SAE9 (11.0)6 (8.1)222 (11.1)220 (11.0)5 (18.5)10 (27.8)230 (17.0)421 (15.0)Death‡1 (1.2)1 (1.4)11 (0.5)12 (0.6)006 (0.4)16 (0.6)AESI PISR§,‖,¶----02 (5.6)110 (8.1)286 (10.2) Serious PISR002 (8 (0.4)002 (0.1)13 (0.5)Infections of SI (opportunistic, herpes zoster, tuberculosis, sepsis)§02 (2.7)50 (2.5)36 (1.8)1 (3.7)097 (7.2)173 (6.1)Serious infections of SI02 (2.7)17 (0.8)17 (0.8)0017 (1.3)40 (1.4)Malignancies ex. non-melanoma skin cancer§005 (0.2)5 (0.2)002 (0.1)8 (0.3)Depression(inc. mood disorders /anxiety)/suicide/self-injury§,¶,**-‖---3 (11.1)3 (8.3)92 (6.8)210 (7.5)Serious depression/ suicide/self-injury01 (1.4)6 (0.3)18 (0.9)1 (3.7)05 (0.4)9 (0.3)*Patients counted once/category; †Pooled data from all studies except 115467; ‡Study 115467: fatal SAEs that started during on-treatment period; death may have occurred after period end. CRD studies: all deaths during double-blind period; §Per custom MedDRA query; ‖Occurring on/within 3 days of infusion/injection; ¶Study 115467: only serious PISR and serious depression/suicide/self-injury events collected; **Per standard MedDRA query.MedDRA, Medical Dictionary for Regulatory Activities; SI, special interestAcknowledgements:Medical writing assistance was provided by Helen Taylor, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.Disclosure of Interests:David d’cruz Speakers bureau: GSK, Consultant of: GSK, Eli Lilly, Gina Eriksson Shareholder of: GSK, Employee of: GSK, Yulia Green Shareholder of: GSK, Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Paige Meizlik Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK

Background:Belimumab (BEL) is a human monoclonal antibody that specifically inhibits B-cell activating factor (BAFF). PLUTO is an ongoing trial evaluating efficacy and safety of intravenous (IV) BEL in children ≥5 years of age with cSLE. Efficacy, and safety endpoints of PLUTO have been reported;1briefly, numerically more BEL vs PBO pts met the primary and major secondary efficacy endpoints. We present patient (pt) response to BEL over time.Objectives:To evaluate changes in SLE Responder Index (SRI) 4 and SRI6 responses, and disease activity over 52 weeks, in paediatric pts receiving BEL, or placebo (PBO), plus standard SLE therapy (SST).Methods:PLUTO (GSK Study BEL114055,NCT01649765) is a Phase 2, randomised, double-blind, placebo-controlled study. Pts 5–17 years of age with active cSLE were randomised to monthly BEL 10 mg/kg IV, or PBO, plus SST. Endpoints assessed: SRI4 and SRI6 response rate, mean percentage and absolute change from baseline in Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLE Disease Activity Index (SLEDAI) and Physicians’ Global Assessment (PGA) scores, and percentage of pts with no new British Isles Lupus Assessment Group (BILAG) 1A/2B organ domain scores compared with baseline, all by study visit. The last-observation-carried-forward (LOCF) principle (missing values imputed using the last available non-missing value) was applied to pts who withdrew or received protocol-prohibited medication or a dose of allowable medication that resulted in treatment failure prior to the Week (Wk) 52 visit. Descriptive statistics were used.Results:A total of 93 pts (94.6% female, mean [SD] age 14.0 [2.49] years) were randomised for the intention-to-treat (ITT) population: 53 to BEL and 40 to PBO. Mean (SD) BEL and PBO baseline scores were 10.3 (3.34) and 10.4 (3.63) for SELENA-SLEDAI and 1.3 (0.43) and 1.4 (0.42) for PGA, respectively. Pt number with at least BILAG 1A/2B organ domain involvement at baseline was 37 (69.8%) for BEL and 29 (72.5%) for PBO. SRI4 and SRI6 responses over 52 weeks were mostly numerically higher with BEL than PBO; more BEL than PBO pts were SRI4 and SRI6 responders at Wk 52 (Figure 1). Unadjusted mean (SE) percentage changes from baseline over time in SELENA-SLEDAI and PGA scores generally favoured BEL over PBO, as did unadjusted mean (SE) absolute changes (Figure 2). Wk 52 adjusted mean (95% CI) percentage treatment difference vs PBO was -4.0% (-21.8, 13.9) for SELENA-SLEDAI and -6.1% (-23.9, 11.7) for PGA, while Wk 52 adjusted mean (95% CI) treatment difference vs PBO was -0.7 (-2.4, 1.1) for SELENA-SLEDAI and -0.1 (-0.3, 0.1) for PGA. Over the study duration, numerically more BEL than PBO pts had no new BILAG 1A/2B organ domain scores (Figure 2).Figure 1.SRI4 and SRI6 response by study visitFigure 2.SELENA-SLEDAI and PGA score mean percentage and absolute change from baseline, and no new BILAG 1A/2B organ domain scores compared with baseline, all by study visitConclusion:In line with the main analyses performed at Wk 52,1further analyses of responses over time in SRI4, SRI6 and disease activity generally favoured BEL over PBO. Combined, these results continue to support the efficacy profile of IV BEL in the treatment of children with cSLE.References:[1]Brunner HI,et al.Arthritis Rheumatol.2018;70(59): 3224–5, Abst. 2867Acknowledgments:We acknowledge all PLUTO investigators (PRINTO, PRCSG and otherwise affiliated). Study funding: GSK.Disclosure of Interests:Nicolino Ruperto Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, Eli-Lilly, EMD Serono, GSK, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi and Takeda, Liza McCann: None declared, Syuji Takei Grant/research support from: Eisai, Consultant of: Novartis, Bristol-Myers Squibb, Speakers bureau: GSK, Sanofi, Tanabe-Mitsubishi, Novartis, Chugai, Ono, Abbvie, Eli-Lilly, Bristol-Myers Squibb, Clarissa Pilkington: None declared, Damon Bass Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Mohamed Okily Shareholder of: GSK, Employee of: GSK, Gina Eriksson Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK, Hermine Brunner Consultant of: Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Merck Serono, AbbVie, Amgen, Alter, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol-Myers Squibb, Celgene, EMD Serono, Janssen, MedImmune, Novartis, Pfizer, and UCB Biosciences, Speakers bureau: GSK, Roche, and Novartis

Background:Systemic lupus erythematosus (SLE) is an autoimmune disorder more prevalent in the Asian population vs Caucasians. Belimumab (BEL), a monoclonal antibody targeting B-lymphocyte stimulator, is approved in patients (pts) ≥5 years with active, autoantibody-positive SLE.Objectives:Evaluate long-term safety and efficacy of intravenous (IV) BEL + standard SLE therapy (SST) in pts with SLE in Japan/Korea.Methods:In this Phase 3, multicentre, open-label (OL) study (BEL114333;NCT01597622), eligible (≥18 years of age) completers of the double-blind phase of GSK study BEL113750 in Japan and South Korea or the subcutaneous OL phase of GSK Study BEL112341 in Japan, received monthly BEL 10 mg/kg IV plus SST. Primary endpoints: safety assessments. Key secondary endpoints: SRI4 response rate at each scheduled visit (observed data), defined as a ≥4-point reduction from baseline in SELENA-SLEDAI score, no worsening in PGA (Results:Overall, 142 pts were enrolled (Japan n=72; Korea n=70), 104 (73.2%) completed the study, 1 (0.7%) died and 37 (26.1%) withdrew.Overall, 139 (97.9%) pts had ≥1 adverse event (AE) (Table). Most frequent AEs included: nasopharyngitis (60.6%); headache (28.2%); cough, herpes zoster and viral upper respiratory tract infection (18.3% each). Serious AEs (SAEs) occurred in 48 (33.8%) pts. Most common SAEs were infections and infestations, reported in 24 (16.9%) pts (Table). During this study, the annual incidence of AEs, including SAEs and AESI, remained stable or declined, with no trends of clinical concerns regarding the incidence of Grade 3 or 4 values for laboratory parameters. There was 1 transient positive immunogenicity result of no clinical concern.Table.The proportion of SRI4 responders was 47.8% at Year 1 (Week 24) and tended to increase numerically up to 84.6% at Year 7 (Week 48). The proportion of pts with a ≥4-point decrease from baseline in SELENA-SLEDAI score numerically increased from 51.5% at Year 1 (Week 24) to 84.6% at Year 7 (Week 48). Proportion of pts with no PGA worsening was 91.3-100% and the proportion with no new BILAG 1A/2B organ domain scores was 93.3-100% up to Year 7 (Week 48). A total of 21 (14.8%) pts had 24 severe SFI flares.Conclusion:BEL was well tolerated as add-on therapy to SST for ≤7 years in pts with SLE from Japan/Korea. Safety results were consistent with the known BEL safety profile.Study funding: GSK.Disclosure of Interests:Yoshiya Tanaka Grant/research support from: Received research grants from Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Ono, Speakers bureau: Received speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Teijin, Sang-Cheol Bae: None declared, Damon Bass Shareholder of: GSK, Employee of: GSK, Myron Chu Shareholder of: GSK, Employee of: GSK, Paula Curtis Shareholder of: GSK, Employee of: GSK, Kathleen DeRose Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Regina Kurrasch Shareholder of: GSK, Employee of: GSK, Jenny Lowe Shareholder of: GSK, Employee of: GSK, Paige Meizlik Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK

Background:Belimumab (BEL) is the first treatment approved in children ≥5 years of age with cSLE. This recent approval was based on favourable results of the PLUTO trial, evaluating efficacy and safety of intravenous (IV) BEL, plus standard SLE therapy (SST), vs placebo (PBO), in children with cSLE.1Objectives:To evaluate the SLE Responder Index 4 (SRI4) sensitivity of response for the comparison of BEL vs PBO at Week (Wk) 52.Methods:In PLUTO (NCT01649765; GSK study BEL114055), an ongoing Phase 2, randomised, PBO-controlled, double-blind study, patients (pts) 5–17 years of age with active cSLE were randomised to monthly BEL 10 mg/kg IV, or PBO, plus SST, for 52 weeks. The primary efficacy endpoint was the SRI4 response rate at Wk 52. Pre-specified sensitivity analyses supporting the primary efficacy endpoint for the intention-to-treat (ITT) population included unadjusted, last observation carried forward (LOCF), completer responses, and response using SLE Disease Activity Index (SLEDAI) 2K proteinuria scoring rule (4-point score for proteinuria >0.5 g/24 h), all at Wk 52. Completers were pts who completed 52 weeks of treatment. Any pts who withdrew or received protocol-prohibited medication or a dose of allowable medication that resulted in treatment failure prior to the Wk 52 visit had missing data handled using LOCF (missing values imputed using the last previous non-missing value). Statistics are descriptive.Results:Overall, 93 pts were randomised (BEL, n=53; PBO, n=40). Majority (94.6%) of pts were female, mean (standard deviation [SD]) age was 14.0 (2.49) years and mean (SD) disease duration was 2.4 (1.93) years. By Wk 52, numerically more BEL (52.8%) than PBO (43.6%) pts were SRI4 responders; difference vs PBO 9.24; odds ratio (OR; 95% confidence interval [CI]) vs PBO 1.49 (0.64, 3.46). For each sensitivity analysis (unadjusted, LOCF, completer, and SLEDAI 2K responses) the odds of being a responder at Wk 52 were higher for pts receiving BEL vs PBO (Table).Table.Sensitivity analyses: SRI4 response at Wk 52PBO(n=40)BEL(n=53)Unadjusted response (ITT), n*3953 n (%)17 (43.6)28 (52.8) Observed difference vs PBO9.24 OR (95% CI)†vs PBO1.45 (0.63, 3.33)LOCF response (ITT), n*3953 n (%)18 (46.2)30 (56.6) Observed difference vs PBO10.45 OR (95% CI)‡vs PBO1.51 (0.65, 3.52)Completer response (completers), n*3045 n (%)17 (56.7)27 (60.0) Observed difference vs PBO3.33 OR (95% CI)‡vs PBO1.16 (0.44, 3.09)Response using SLEDAI 2K (ITT), n*3953 n (%)17 (43.6)28 (52.8) Observed difference vs PBO9.24 OR (95% CI)‡vs PBO1.49 (0.64, 3.46)*One pt was excluded because they did not have a baseline Safety of Estrogens in Lupus National Assessment (SELENA)-SLEDAI assessment;†calculated from a logistic regression model for the comparison between BEL and PBO without adjustment for any covariates;‡calculated from a logistic regression model for the comparison between BEL and PBO with covariates treatment group, baseline age (5–11 years vs 12–17 years), and baseline SELENA-SLEDAI score (≤12 vs ≥13)Conclusion:The results of the SRI4 primary efficacy endpoint sensitivity analyses further support a favourable effect for BEL vs PBO.References:[1]Brunner HI,et al.Arthritis Rheumatol.2018;70(59): 3224–5, Abst. 2867Acknowledgments:We acknowledge all PLUTO investigators (PRINTO, PRCSG and otherwise affiliated). Study funding: GSK.Disclosure of Interests:Nicolino Ruperto Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, Eli-Lilly, EMD Serono, GSK, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi and Takeda, Hermine Brunner Consultant of: Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Merck Serono, AbbVie, Amgen, Alter, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol-Myers Squibb, Celgene, EMD Serono, Janssen, MedImmune, Novartis, Pfizer, and UCB Biosciences, Speakers bureau: GSK, Roche, and Novartis, Masaaki Mori Grant/research support from: Abbvie Japan, Asahikasei Pharmaceutical, Ayumi Pharmaceutical, CSL Behring, Chugai Pharmaceutical, Japan Blood Products Organization, MSD K.K., Nippon Kayaku, UCB Japan, Consultant of: Daiichi Sankyo, Taisho Pharmaceutical, Jacqueline Clinch Consultant of: Alexion, Speakers bureau: Alexion, Reema Syed: None declared, Naomi Iwata Speakers bureau: Sanofi K.K, Damon Bass Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Mohamed Okily Shareholder of: GSK, Employee of: GSK, Gina Eriksson Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK

Background:Lupus nephritis (LN), a serious manifestation of systemic lupus erythematosus (SLE), affects nearly 70% of patients (pts) in high-risk groups. To preserve renal function, LN requires fast and effective treatment. Despite medical advances, progression rates at 15 years to end-stage renal disease (ESRD) remain >40% for pts with diffuse proliferative LN. Belimumab (BEL), approved in pts aged ≥5 years with active SLE, improved renal parameters in pts with baseline renal involvement in apost hocanalysis of Phase 3 trials data.Objectives:To assess efficacy and safety of intravenous (IV) BEL vs placebo (PBO), plus standard therapy (ST), in pts with active LN.Methods:BLISS-LN is a Phase 3, randomised, double-blind, PBO-controlled, 104-week study (GSK Study BEL114054,NCT01639339). Adults with SLE and biopsy-proven LN (class III, IV, and/or V) were randomised (1:1) to monthly BEL 10 mg/kg IV or PBO, plus ST. Primary endpoint: Primary Efficacy Renal Response (PERR); defined as urine protein creatinine ratio [uPCR] ≤0.7; estimated glomerular filtration rate [eGFR] within 20% of the pre-flare value or ≥60 ml/min/1.73m2; no rescue therapy) at Week (Wk) 104. Key secondary endpoints: Complete Renal Response (CRR; defined as uPCR 2; no rescue therapy) at Wk 104; PERR at Wk 52; time to renal-related event (defined as ESRD/doubling of serum creatinine/renal worsening/renal disease-related treatment failure) or death. Other endpoints: time to PERR/CRR sustained through Wk 104; SLEDAI-S2K score Results:Overall, 448 pts were randomised (efficacy: 223/group; safety: 224/group). Significantly more BEL (43%) than PBO (32.3%) pts achieved PERR at Wk 104 (OR 1.55, 95% CI 1.04, 2.32; p=0.0311). More BEL than PBO pts achieved key secondary and other efficacy endpoints (Table).Overall, 214 (95.5%) BEL and 211 (94.2%) PBO pts had ≥1 adverse event (AE); 58 (25.9%) BEL and 67 (29.9%) PBO pts had ≥1 serious AE; 29 (12.9%) pts in each group had ≥1 AE resulting in study treatment discontinuation; 4 (1.8%) BEL and 3 (1.3%) PBO pts developed on-treatment fatal AEs.Conclusion:In the largest LN study to date, data from BLISS-LN demonstrate that BEL plus ST significantly improves LN renal responses compared with ST alone with a favourable safety profile.Study funding: GSK.Table.Endpoint, n (%)PBO(n=223)BEL(n=223)OR/HR (95% CI) vs PBOp-valueCRR at Wk 104*44 (19.7)67 (30.0)OR 1.74(1.11, 2.74)0.0167PERR at Wk 52*79 (35.4)104 (46.6)OR 1.59(1.06, 2.38)0.0245Time to PERR throughWk 104†72 (32.3)96 (43.0)HR 1.46(1.07, 1.98)0.0157Time to CRR throughWk 104†44 (19.7)67 (30.0)HR 1.58(1.08, 2.31)0.0189Time to renal-related event or death†63 (28.3)35 (15.7)HR 0.51(0.34, 0.77)0.0014SLEDAI-S2K score 41 (18.4)62 (27.8)OR 1.76(1.11, 2.78)0.0164*PBO and BEL columns represent the n (%) responders†Data presented as n (cumulative incidence)Disclosure of Interests:Richard Furie Grant/research support from: GSK, Consultant of: GSK, Brad H Rovin Grant/research support from: GSK, Consultant of: GSK, Frederic Houssiau Grant/research support from: UCB, Consultant of: GSK, Zahir Amoura Grant/research support from: GSK, Roche, Consultant of: GSK, Astra Zeneca, Amgen, Mittermayer Santiago: None declared, Gabriel Contreras Grant/research support from: Genentech, Merck, Consultant of: Genentech, Merck, Ana Malvar Consultant of: GSK and Roche, chi chiu mok: None declared, Amit Saxena Consultant of: GSK, AZ, BMS, Xueqing Yu: None declared, Y.K. Onno Teng Grant/research support from: GSK, Consultant of: GSK, Aurinia Pharmaceuticals, Novartis, Carly Barnett Shareholder of: GSK, Employee of: GSK, Susan Burriss Shareholder of: GSK, Employee of: GSK, Yulia Green Shareholder of: GSK, Employee of: GSK, Beulah Ji Shareholder of: GSK, Employee of: GSK, Christi Kleoudis Shareholder of: GSK, Consultant of: GSK, Employee of: Parexel, David Roth Shareholder of: GSK, Employee of: GSK

Background Non-United States completers of the Phase 3 BLISS-52 (BEL110752) and BLISS-76 (BEL110751) studies could continue treatment with BEL. Objectives To evaluate long-term safety, tolerability and organ damage progression in patients with SLE treated with BEL. Methods In this multicentre, open-label long-term study (BEL112234/NCT00712933), patients received intravenous BEL every 4 weeks, plus standard SLE therapy. Safety was assessed at each visit. Organ damage (Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index [SDI]) was assessed as a safety endpoint every 48 weeks. The study continued until BEL was commercially available in each patient’s country and included an 8 week follow–up period. Results In total, 738 patients entered the long-term study and were treated for up to 9 years (3352 patient-years). Of these, 735 (99.6%) received ≥1 dose of BEL; the mean (SD) number of infusions was 56.4 (27.02). The incidence of adverse events (AEs) remained stable or declined over time (table 1). The most common AEs were headache (n=205, 27.9%), nasopharyngitis (n=155, 21.1%), diarrhoea (n=143, 19.5%), arthralgia (n=136, 18.5%) and influenza (n=134, 18.2%). Sixty-nine patients (9.4%) experienced an AE resulting in discontinuation of BEL or study withdrawal. Eleven deaths occurred, one of which (cardiogenic shock) was possibly related to BEL. Three serious AEs of suicide attempt/ideation (0.4%) occurred. The mean (SD) SDI score was 0.6 (1.02) at baseline (prior to the first dose of BEL). At Year 8 87.7% of patients had no change in SDI score from baseline, indicating low organ damage accrual (figure 1). aNumber of patients; bincluded opportunistic infections, tuberculosis, herpes zoster (recurrent and disseminated) and sepsis; ctwo deaths during post-treatment follow-up. Conclusions BEL displayed a stable safety profile with no new safety signals. There was minimal organ damage progression. Acknowledgements Study funded by GSK. Emma Hargreaves, MA, Fishawack Indicia Ltd, UK, provided editorial assistance funded by GSK. Disclosure of Interest R. Van Vollenhoven Grant/research support from: GSK, Consultant for: GSK, S. Navarra Speakers bureau: GSK, R. Levy Employee of: BLISS-52 investigator and GSK employee since ,Jan 2018 M. Thomas Grant/research support from: GSK, Consultant for: GSK, A. Heath Shareholder of: GSK, Employee of: GSK, T. Lustine Shareholder of: GSK, Employee of: GSK, A. Adamkovic Shareholder of: GSK, Employee of: GSK, J. Fettiplace Shareholder of: GSK, Employee of: GSK (at the time of study), M. L. Wang Shareholder of: GSK, Employee of: GSK, B. Ji Shareholder of: GSK, Employee of: GSK, D. Roth Shareholder of: GSK, Employee of: GSK

Background GPA and MPA (related types of ANCA-associated vasculitis [AAV]) are organ-/life-threatening systemic vasculitides. B cells and increased circulating BLyS (a B cell survival factor) are implicated in AAV pathogenesis, suggesting a role for BLyS in these vasculitides. BEL is an anti-BLyS human immunoglobulin (Ig) G1λ monoclonal antibody. Objectives Examine the effects of BEL plus azathioprine (AZA), on biomarkers in patients with AAV for remission maintenance following standard induction (IND) with glucocorticoids (GC) and CYC or RTX. Methods This double-blind, placebo-controlled, multicentre study (BEL115466/NCT01663623) randomised (1:1) patients (≥18 years) with new/relapsing AAV following IND (oral or IV CYC or RTX), to AZA 2 mg/kg/day and oral GC, plus IV BEL 10 mg/kg or PBO (Days 0, 14, 28 and every 28 days until completion). Remission was defined as Birmingham Vasculitis Activity Score=0, plus GC ≤10 mg/day. The study was truncated after initiation (n~300 to~100) due to revised AAV standard of care (SoC) affecting recruitment. Biomarker endpoints (serum Igs, B cells and ANCA [anti-MPO/PR3]) were measured at baseline (BL) and thereafter. Summaries by IR were post hoc; no analyses were performed. Results At BL, RTX patients had B cell counts≤LLQ. CYC patients had notably low BL B cell counts: the lowest were in oral-CYC patients. Circulating memory B cells (CD20+/CD27+) increased rapidly with BEL, then gradually returned to BL (CYC); no major changes occurred with PBO. BEL had no impact on the proportion of naive CD20 +CD27− B cells vs PBO, post CYC IND. The number of RTX patients with quantifiable data was low; partial reconstitution occurred in a minority of patients (PBO 2/13; BEL 4/14) and did not translate into vasculitis relapses. Overall Ig levels declined more noticeably with BEL vs PBO; suggesting BEL affects antibody-secreting cells. ANCA+patients were similar between groups (PBO 32/50; BEL 30/49). No trends in change in ANCA status over time occurred, regardless of IR. Individual patient data showed no apparent trends between ANCA titres and AAV activity. Conclusions Choice of IR for active AAV affects B cell dynamics. BEL pharmacodynamic effects occurred in patients with AAV receiving SoC. Given the small sample size and high variability, data must be interpreted with caution. Acknowledgements Study funded by GSK. Sam Halliwell, PhD, Fishawack Indicia Ltd, UK, provided editorial assistance funded by GSK. Disclosure of Interest D. Jayne Grant/research support from: GSK, Consultant for: GSK, D. Blockmans: None declared, R. Luqmani Grant/research support from: Arthritis Research UK, GSK, MRC, UCSF/OIF, Canadian Institutes of Health Research and The Vasculitis Foundation, Consultant for: Roche, GSK, Medpace and MedImmune, B. Ji Shareholder of: GSK, Employee of: GSK, Y. Green Shareholder of: GSK, Employee of: GSK, L. Hall Shareholder of: GSK, Employee of: GSK, D. Roth Shareholder of: GSK, Employee of: GSK, R. Henderson Shareholder of: GSK, Employee of: GSK, P. Merkel Grant/research support from: Actelion, Bristol-Myers Squibb, CaridianBCT, Celgene, ChemoCentryx, Genentech/Roche, GSK, Kypha, MedImmune/AstraZeneca, American College of Rheumatology, European League Against Rheumatism, National Institutes of Health (NHLBI, NIAMS, NIAID, NCATS, ORDR), US Food and Drug Administration, The Patient-Centred Outcomes Research Institute and The Vasculitis Foundation, Consultant for: Actelion, Alexion, Boston Pharm., Bristol-Myers Squibb, ChemoCentryx, Genzyme/Sanofi, GSK, Genentech/Roche, InflaRx, PrincipioBio, Proteon and Seattle Genetics

Background Preliminary safety and efficacy data from the Phase II BEL open-label extension study (LBSL02; NCT00071487) have been reported. Objectives Here we present the final 10-year data. Methods This was a multicentre, open-label, continuation trial (BEL112626; NCT00583362) of BEL + SoC in patients with a satisfactory response in the parent study. Patients received intravenous BEL 10 mg/kg every 4 weeks. Baseline was prior to the first ever dose of BEL. Results Of 298 patients in the continuation trial, 131 (44%) remained at Year 10. Total BEL exposure was 2154 patient-years. Adverse events (AEs) remained stable or decreased (Table). Two deaths (pseudomonal lung infection; cytomegaloviral pneumonia) were possibly related to BEL. SLE Responder Index (SRI) response increased (Figure). A British Isles Lupus Assessment Group (BILAG) flare (1 new A/2 new B scores) occurred in 72.6% of patients and 41.9% had a severe flare (SLE Flare Index). Prednisone dose decreased from baseline to Year 10 (Table). Of patients receiving >7.5 mg/day baseline prednisone, 32.6% (14/43) decreased their dose to ≤7.5 mg/day by Year 10; 9.5% (9/95) of patients receiving baseline prednisone ≤7.5 mg/day had a dose increase to >7.5 mg/day. Conclusions Over 10 years BEL + SoC was well tolerated and the rates and nature of AEs were consistent with the known profile of BEL. Efficacy was maintained and prednisone use decreased in those receiving >7.5 mg/day at baseline. Acknowledgements Study funded by GSK. Editorial assistance provided by Katie White, PhD, Fishawack Indicia Ltd, UK; funded by GSK. Disclosure of Interest D. Wallace Grant/research support from: GSK, Consultant for: GSK, E. Ginzler Grant/research support from: GSK, J. Merrill Grant/research support from: GSK, Bristol-Myers Squibb, Consultant for: Anthera Pharmaceuticals, Inc., GSK, EMD Serono, Inc., Lilly, AstraZeneca, Bristol-Myers Squibb, UCB, Celgene, Biogen, R. Furie Grant/research support from: GSK, Consultant for: GSK, W. Stohl Grant/research support from: GSK, Pfizer, Consultant for: Johnson & Johnson, W. Chatham Grant/research support from: GSK, A. Weinstein Grant/research support from: GSK, HGS, Consultant for: GSK, HGS, J. McKay Grant/research support from: GSK, MedImmune, Anthera Pharmaceuticals, Inc., Johnson & Johnson, Lilly, Xencor, Inc., W. McCune Grant/research support from: GSK, Lilly, M. Petri Grant/research support from: GSK, Consultant for: GSK, J. Fettiplace Shareholder of: GSK, Employee of: GSK, D. Roth Shareholder of: GSK, Employee of: GSK, B. Ji Shareholder of: GSK, Employee of: GSK, A. Heath Shareholder of: GSK, Employee of: GSK

Background and aims Steroid reduction is an important treatment goal in systemic lupus erythematosus (SLE). The steroid-sparing effects of belimumab were investigated in subjects in North East Asia. Methods This multicentre, 52 week study (1 13 750/NCT01345253) randomised (2:1) subjects (≥18 years) with SELENA-SLEDAI ³8 to intravenous belimumab 10 mg/kg or placebo every 28 days, plus standard SLE therapy. Multiple measures of steroid use (prednisone equivalent) were made, including a secondary endpoint of reduction in dose over 52 weeks among subjects receiving >7.5 mg/day at baseline (number of days≤7.5 mg/day and/or dose reduced by 50% from baseline). The primary endpoint was SLE Responder Index response rate at Week 52 (reported elsewhere). Results Baseline prednisone doses were similar between groups (Table 1). Across the population, cumulative prednisone dose over 52 weeks was significantly lower in the belimumab group versus placebo (p=0.0005; Table 1. For subjects with baseline dose >7.5 mg/day, the median number of days that prednisone dose was ≤7.5 mg/day and/or reduced by 50% was zero in both groups; however, the 75 th percentile was larger for belimumab (213.5 days) versus placebo (172.0), reflecting the subjects who achieved longer durations of reduced steroid use within the belimumab group (p=0.0288; Figure 1). More subjects in the belimumab group had a dose reduction of ≥25% to ≤7.5 mg/day during Weeks 40–52 (belimumab, 15.6%; placebo, 10.9%: p=0.0721). Adverse event incidences were similar (belimumab, 75.7%; placebo, 74.9%). Conclusions These results suggest belimumab is more effective than placebo in reducing steroid use across 52 weeks in this population. Study funded by GSK.

Background Belimumab, a fully human IgG1λ monoclonal antibody for B Lymphocyte Stimulator protein, was licensed in 2011 by the FDA and EMA for add-on therapy in adult patients with active systemic lupus erythematosus (SLE). As part of a paediatric investigational plan, a study of belimumab in paediatric SLE was designed and commenced in 2012 (BEL114055, ClinicalTrials.gov: NCT01649765). Objectives To outline the study design, study participation and rationale for subject selection. Methods The PLUTO study is a 52-week multi-centre, randomized parallel group, placebo-controlled double-blind study to evaluate the safety, efficacy, and pharmacokinetics (PK) of belimumab plus standard therapy in paediatric patients (5–17 yrs) with SLE. To be eligible to enrol patients need to have a clinical diagnosis of SLE according to the ACR criteria, be autoantibody positive and have a SELENA-SLEDAI score of ≥6. Patients who complete the double-blind phase (Part A), are eligible to join an open-label safety follow-up period of up to ten years (Part B). For subjects who withdraw from Part A or Part B, there is a long-term safety follow up phase (Part C). Part A is divided into 3 Cohorts. Cohort 1 will consist of the first 12 subjects (12–17 yrs). Once the PK and safety profile of Cohort 1 is evaluated and any potential dose adjustments are determined as a result of this analysis, additional subjects 12–17 yrs will then enrol in Cohort 3. Cohort 2 will enrol 12 patients (5–11 yrs) at the dose determined from the PK analysis of Cohort 1. Once the PK and safety profile of Cohort 2 is evaluated and any potential dose adjustments are determined as a result of this analysis, additional subjects 5–11 yrs will then enrol in Cohort 3. Cohorts 1 and 2 will be randomized in a 5:1 ratio, and Cohort 3 subjects will be randomized in a 1:1 ratio to receive belimumab or placebo on a background of standard therapy. An Independent Data monitoring Committee (IDMC) will monitor unblinded safety, efficacy and PK data from the study. Results The study is currently enrolling and is active in the following countries: US, Canada, Argentina, Peru, Mexico, UK, Spain, Netherlands, Poland, Russia and Japan. Subjects selected for study inclusion had active SLE indicated by skin/mucosa, musculoskeletal, haematologic, renal or CNS organ manifestations and were receiving standard concomitant SLE therapies including corticosteroids, anti-malarials and immunosuppressants. The profile of the trial population reflects a patient population who have active SLE but with an inadequate response to standard therapy and who therefore may benefit from an alternative treatment such as belimumab. The ongoing IDMC reviews support the study continuation according to the current protocol. Conclusions The PLUTO study aims to address an area of unmet clinical need in which there are no licensed therapies. Please consider the eligibility of your paediatric SLE patients for this important study. Acknowledgement This study is funded by GSK. Disclosure of Interest J. Fettiplace Shareholder of: GSK, Employee of: GSK, B. Ji Shareholder of: GSK, Employee of: GSK, D. Roth Shareholder of: GSK, Employee of: GSK

Four hundred and eighty Chinese subjects with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were enrolled in a multicenter, double-blind, randomized, placebo-controlled study of adefovir dipivoxil (ADV) 10 mg once daily. There was a significant difference in reduction of serum hepatitis B virus (HBV) DNA after 12 weeks between subjects who received ADV and those who received the placebo (3.4 and 0.1 log10 copies/mL, respectively, P < .001). Further reductions in serum HBV DNA and increases in the proportion of subjects with an HBV DNA level of at most 10(5) copies/mL, with HBV DNA undetectable, and with ALT normalization were observed in ADV-treated subjects at week 52 (median HBV DNA reduction of 4.5 log(10) copies/mL, 67% with HBV DNA