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American Journal of Kidney Diseases

Efficacy and Safety of Belimumab in Patients With Lupus Nephritis: Subgroup Analyses of a Phase 3 Randomized Trial in the East Asian Population

Published:September 01, 2022DOI:https://doi.org/10.1053/j.ajkd.2022.06.013

      ABSTRACT

      Rationale and Objective

      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.

      Study Design

      Pre-specified subgroup analysis of BLISS-LN, a Phase 3, placebo-controlled, randomized 104-week trial.

      Setting and Participants

      Adults with biopsy-proven, active LN were randomized (1:1) to belimumab or placebo, plus standard therapy.

      Intervention

      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.

      Outcomes

      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 m2, and no treatment failure) at week 104. Key secondary endpoints included: Complete Renal Response (CRR; uPCR <0.5, eGFR no more than 10% below pre-flare value or ≥90 ml/min/1.73 m2, and no treatment failure) at week 104; PERR at week 52; time to renal-related event or death; safety.

      Analytical Approach

      PERR 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.

      Results

      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.

      Limitations

      Small sample size and lack of formal significance testing.

      Conclusion

      Safety and efficacy profiles were consistent with BLISS-LN overall population, supporting benefits of belimumab treatment in the East Asian population with LN.

      Graphical abstract

      Index words

      Plain Language Summary

      Lupus nephritis (LN) is a severe complication of the kidneys in patients with the autoimmune disease systemic lupus erythematosus. Belimumab is used in combination with standard therapy for treatment of patients with LN. As data on belimumab treatment of East Asian patients with LN are limited, we assessed the efficacy and safety of belimumab in a subgroup of East Asian patients from the BLISS-LN, a randomized controlled trial. Patients received monthly belimumab or placebo in addition to standard therapy. After 104 weeks, patients who received belimumab showed earlier and more sustained improvements in kidney outcomes compared with patients who received placebo, while no new safety concerns were raised. These results support the use of belimumab treatment for East Asian patients with LN.

      INTRODUCTION

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      Despite recent advances, approximately 10−20% of patients with LN will develop end-stage kidney disease as a result of persistent disease activity and long-term steroid use, which may lead to premature mortality.
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      Thus, it is critical to achieve early and sustained remission in LN to prevent long-term complications and mortality. However, only a limited number of treatments are approved for the treatment of LN in Asia, with standard therapy consisting of mycophenolate mofetil (MMF) or cyclophosphamide (CYC) combined with corticosteroids.
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      LN continues to have significant unmet medical needs.
      Belimumab is a recombinant, human IgG1λ monoclonal antibody that binds to the soluble B-lymphocyte stimulator protein,
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      and it is approved globally for the treatment of patients with active autoantibody-positive SLE receiving standard therapy.

      GSK. FDA approves GSK's Benlysta as the first medicine for adult patients with active lupus nephritis in the US [Press release]. 17 December. Available at: https://www.gsk.com/en-gb/media/press-releases/fda-approves-gsk-s-benlysta-as-the-first-medicine-for-adult-patients-with-active-lupus-nephritis-in-the-us/# (Accessed December 2020)

      GSK. Prescribing Information 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125370s064,761043s007lbl.pdf (Accessed March 2021).

      GSK. (2019). Benlysta, the world's first biologic therapy for the treatment of systemic lupus erythematosus (SLE), now approved in mainland China [Press release]. 16 July. Available at: https://www.gsk-china.com/en-gb/media/press-releases/2019/benlysta-the-world-s-first-biologic-therapy-for-the-treatment-of-systemic-lupus-erythematosus-sle-now-approved-in-mainland-china/ (Accessed March 2021).

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      GSK. GSK announces positive results in fourth consecutive pivotal trial of Benlysta (belimumab) in SLE [Press release]. 13 November. Available at: https://www.gsk.com/en-gb/media/press-releases/gsk-announces-positive-results-in-fourth-consecutive-pivotal-trial-of-benlysta-belimumab-in-sle/#:∼:text=David%20Roth%2C%20Project%20Lead%20for%20Benlysta%20at%20GSK%2C,the%20region%2C%20this%20study%20result%20is%20extremely%20important (Accessed March 2021).

      The Phase 3 BLISS-LN study was the largest controlled study in active LN to date, which demonstrated that the addition of intravenous (IV) belimumab to standard therapy improves renal outcomes in patients with LN.
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      The results of the study were recently reported
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      and supported the approval of belimumab in the USA and EU for the treatment of adult patients with active LN.

      GSK. FDA approves GSK's Benlysta as the first medicine for adult patients with active lupus nephritis in the US [Press release]. 17 December. Available at: https://www.gsk.com/en-gb/media/press-releases/fda-approves-gsk-s-benlysta-as-the-first-medicine-for-adult-patients-with-active-lupus-nephritis-in-the-us/# (Accessed December 2020)

      ,

      GSK. European Commission approves Benlysta for adult patients with active lupus nephritis [Press release]. 5 May. Available at: https://www.gsk.com/en-gb/media/press-releases/european-commission-approves-benlysta-for-adult-patients-with-active-lupus-nephritis/ (Accessed May 2015).

      As the literature on treatment of East Asian patients with LN is limited, in this study, we evaluated the efficacy and safety of belimumab plus standard therapy in the East Asian subgroup of patients enrolled in the BLISS-LN study.

      METHODS

      Study design and treatments

      BLISS-LN was a Phase 3, double-blind, multicenter, randomized, placebo-controlled, 104-week study (GSK Study BEL114054; NCT01639339) (Figure 1), conducted between July 2012 and July 2019 to assess the efficacy and safety of belimumab plus standard therapy in adult patients with active LN. Eligible patients were randomized 1:1 to belimumab 10 mg/kg IV plus standard therapy or placebo plus standard therapy. Randomization was stratified according to induction regimen (CYC or MMF) and race (Black African ancestry or other).
      Figure thumbnail gr1
      Figure 1Study design. *Standard therapy included induction with HDCS plus CYC followed by AZA maintenance, or induction with HDCS plus MMF followed by MMF. Standard therapy was initiated within 60 days before randomization and first dose of investigational product on Day 1, with most patients receiving the study treatment (belimumab or placebo) within 30 days of standard therapy induction. PERR is defined as uPCR ≤0.7, eGFR no more than 20% below pre-flare value or ≥60 mL/min/1.73 m2, and no treatment failure. CRR is defined as uPCR <0.5, eGFR no more than 10% below pre-flare value or ≥90 mL/min/1.73 m2, and no treatment failure. AZA, azathioprine; CRR, Complete Renal Response; CYC, cyclophosphamide; eGFR, estimated glomerular filtration rate; HDCS, high-dose corticosteroids; IV, intravenous; LN, lupus nephritis; MMF, mycophenolate mofetil; PERR, Primary Efficacy Renal Response; uPCR, urine protein:creatinine ratio
      Patients received treatment on Days 1 (baseline), 15, and 29, and then every 28 days up to Week 100. Final assessments were performed at Week 104. At the end of the 104-week double-blind period of this study, eligible patients enrolled into a 28-week open-label extension period, in which all patients received belimumab 10 mg/kg IV plus standard therapy every 28 days until Week 24, with the final assessment at Week 28.
      Standard induction therapy, chosen by the investigators and initiated within 60 days before Day 1, consisted of IV CYC (500 mg every 2 weeks [±3 days] for 6 infusions) or MMF (target dose 3 g/day). CYC induction therapy was followed by the azathioprine (AZA) maintenance therapy (target: 2 mg/kg/day; ≤200 mg/day) until study end. MMF induction was followed by MMF maintenance therapy (2 g/day for the second week, then 3 g/day from the third week onwards); after 6 months, for tolerability reasons, the dose could be reduced to 1 g/day or the patient switched to AZA (target: 2 mg/kg/day). At the investigator’s discretion, high-dose glucocorticoids (1–3 IV pulses of methylprednisolone; 500–1000 mg each) could be administered during induction, followed by oral prednisone (0.5–1.0 mg/kg/day; with the total daily dose of ≤60 mg). By Week 24, the dose of steroids must have been tapered to ≤10 mg/day or patient was considered treatment failure.
      Full methods of the BLISS-LN study have been previously published.
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.

      Patients

      All patients in BLISS-LN study provided written informed consent. The study was conducted in accordance with the principles of the Declaration of Helsinki, and all the study sites received approval from ethics committees or institutional review boards.
      This study was a pre-specified subgroup analysis of East Asian patients from the BLISS-LN study, which included patients from mainland China, Hong Kong, South Korea, and Taiwan.
      Eligibility criteria for the BLISS-LN study have been published previously.
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
      Briefly, enrolled patients were ≥18 years of age, with active, autoantibody-positive (anti-nuclear antibody ≥1:80; and/or anti-double-stranded deoxyribonucleic acid [dsDNA] ≥30 IU/mL) SLE as per updated American College of Rheumatology classification criteria.
      • Hochberg M.C.
      Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.
      Patients also had a urine protein to creatinine ratio (uPCR) ≥1 and biopsy-proven International Society of Nephrology/Renal Pathology Society proliferative Class III or IV LN with or without coexisting Class V, or pure Class V LN during screening or within the 6 months before screening. Key exclusion criteria included previous failure with both CYC and MMF; receipt of CYC induction therapy in the previous 3 months; treatment with belimumab, any B-cell targeted therapy or a biologic investigational agent in the previous year; severe active central nervous system lupus; estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 at screening (according to the simplified Modification of Diet in Renal Disease equation);
      • Levey A.S.
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      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.
      and acute or chronic infections requiring management.

      Endpoints and assessments

      The primary endpoint was the proportion of patients with Primary Efficacy Renal Response (PERR; defined as uPCR ≤0.7, eGFR no more than 20% below pre-flare value or ≥60 ml/min/1.73 m2, and no treatment failure) at Week 104. Of note, the primary endpoint for BLISS-LN was revised in 2017. The original endpoint was complete, partial, or no renal response, determined according to the level of proteinuria, the calculated glomerular filtration rate from 24-hour urine collections, and microscopic examination of urinary sediment (see the supplementary appendix in Furie et al. 2020).
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
      Key secondary endpoints included the proportion of patients with Complete Renal Response (CRR; defined as a uPCR <0.5, eGFR no more than 10% below pre-flare value or ≥90 ml/min/1.73 m2, and no treatment failure) at Week 104; the proportion of patients with PERR at Week 52; time to renal-related event (defined as end-stage kidney disease/doubling of serum creatinine level from the baseline level; renal worsening as evidenced by increased proteinuria and/or impaired renal function; kidney disease-related treatment failure) or death. Other endpoints included time to PERR and CRR sustained through Week 104; proportion of PERR and CRR responders at Week 104 by induction regimen; time to first severe SLE Flare Index (SFI) flare; proportion of patients with SLEDAI-S2K <4 (defined as Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index [SELENA-SLEDAI] with proteinuria scoring as per SLEDAI-2000 rules score <4 points) at Week 104; proportion of patients receiving average prednisone-equivalent dose ≤5 mg/day and ≤7.5 mg/day at Week 104; and changes in biomarker levels (IgG, anti-dsDNA, anti-C1q, and complement C3/C4).
      Safety was assessed by monitoring of adverse events (AEs), serious AEs, AEs of special interest (AESI: malignancies; infusion, anaphylactic or hypersensitivity reactions; infections of special interest; depression, suicide, and self-injury), eGFR (post hoc analysis), death, and immunogenicity throughout the study.

      Statistical analyses

      Analyses were performed on the modified intention-to-treat (mITT) population that included all randomized patients who received at least one dose of belimumab or placebo.
      PERR, CRR, and SLEDAI-S2K score were analyzed using logistic regression models. Time to a renal-related event or death was analyzed using a Cox proportional-hazards regression model. Data were censored following discontinuation of belimumab or placebo, withdrawal from the study, or having a treatment failure unrelated to a kidney event.
      For the PERR, CRR, and time to renal-related event or death, the model was adjusted for potential confounding factors: induction regimen (CYC vs MMF), baseline uPCR, and baseline eGFR. Additionally, PERR and CRR at Week 104, and time to renal-related event or death were analyzed post hoc in the East Asian population by baseline renal biopsy class (Class III or IV, Class III+V or IV+V, and Class V) and proteinuria (uPCR <3 g/g vs ≥3 g/g). For the SLEDAI-S2K score <4, in the statistical model the covariates were treatment group, baseline SLEDAI-S2K score and induction regimen (CYC vs MMF).
      For PERR and CRR, discontinuation of belimumab or placebo, withdrawal from the study, or treatment failure were considered as a non-response.
      This pre-specified subgroup analysis was not powered to confirm efficacy in subgroups and, therefore, all results are descriptive only and no P values are included.

      RESULTS

      Baseline demographics and clinical characteristics of the East Asian subgroup

      Among the 446 randomized patients who were included in the overall mITT population of the BLISS-LN study, 223 (50%) were of Asian race, of whom 142 were included in these East Asian region subgroup analyses (n=74 in belimumab group and n=68 in placebo group). In the East Asian subgroup, 55.6% of patients were from mainland China, 4.2% were from Hong Kong, 30.3% were from South Korea and 9.9% were from Taiwan. Patient disposition stratified by induction regimen is shown in Figure 2.
      Figure thumbnail gr2
      Figure 2Patient disposition stratified by induction regimen (mITT population). CYC, cyclophosphamide; mITT, modified intention-to-treat; MMF, mycophenolate mofetil
      Baseline patient demographics and disease characteristics are presented in Table 1. Baseline disease characteristics were generally balanced between groups. The median (interquartile range [IQR]) SLE duration was 1.16 (0.13, 6.85) years and LN duration was 0.12 (0.08, 1.48) years. Overall, 52.8% of patients had renal biopsy class III or IV, 29.6% had class III or IV coexisting with class V, and 17.6% had pure class V. Mean (standard deviation, SD) uPCR was 3.39 (3.7) g/g (median [IQR] 2.49 (1.26, 4.60) g/g), eGFR was 110.3 (41.1) mL/min/1.73 m2, and SLEDAI-S2K score was 11.6 (4.5) for the entire cohort. The mean (SD) baseline uPCR by renal biopsy class (post hoc analysis) was: 3.46 (4.29) g/g for Class III or IV patients (median [IQR] 2.68 [1.22, 4.54]); 3.67 (3.21) g/g for Class III + V or Class IV + V (median [IQR] 2.52 [1.26, 4.85]) and 2.70 (1.98) g/g for pure Class V patients (median [IQR] 2.05 [1.53, 3.12]). The baseline average daily prednisone-equivalent dose was lower in patients receiving MMF at baseline than in patients receiving CYC (Table 1).
      Table 1Baseline demographics and clinical characteristics (East Asian subgroup)
      Placebo n=68Belimumab 10 mg/kg IV n=74Total

      N=142
      CYC n=12MMF n=56Total n=68CYC n=16MMF n=58Total n=74
      Female, n (%)10 (83.3)52 (92.9)62 (91.2)12 (75.0)53 (91.4)65 (87.8)127 (89.4)
      Age (years), mean (SD)33.4 (10.8)31.8 (9.7)32.1 (9.8)33.3 (11.2)35.2 (10.8)34.8 (10.9)33.5 (10.4)
      Region and country, n (%)

      Mainland China

      Hong Kong

      South Korea

      Taiwan
      6 (50.0)

      0 (0.0)

      6 (50.0)

      0 (0.0)
      31 (55.4)

      4 (7.1)

      17 (30.4)

      4 (7.1)
      37 (54.4)

      4 (5.9)

      23 (33.8)

      4 (5.9)
      9 (56.3)

      0 (0.0)

      7 (43.8)

      0 (0.0)
      33 (56.9)

      2 (3.4)

      13 (22.4)

      10 (17.2)
      42 (56.8)

      2 (2.7)

      20 (27.0)

      10 (13.5)
      79 (55.6)

      6 (4.2)

      43 (30.3)

      14 (9.9)
      SLE disease duration (years)*, median (IQR)0.52 (0.14, 4.25)3.70 (0.16, 9.91)3.25 (0.16, 8.49)0.43 (0.11, 4.60)0.41 (0.11, 5.68)0.41 (0.11, 5.68)1.16 (0.13, 6.85)
      LN disease duration (years)*, median (IQR)0.09 (0.07, 0.11)0.17 (0.08, 4.51)0.14 (0.08, 3.73)0.08 (0.07, 0.79)0.12 (0.08, 0.64)0.11 (0.08, 0.64)0.12 (0.08, 1.48)
      Renal biopsy class, n (%)
      Class III or IV6 (50.0)31 (55.4)37 (54.4)8 (50.0)30 (51.7)38 (51.4)75 (52.8)
      Class III or IV and V2 (16.7)17 (30.4)19 (27.9)6 (37.5)17 (29.3)23 (31.1)42 (29.6)
      Class V4 (33.3)8 (14.3)12 (17.6)2 (12.5)11 (19.0)13 (17.6)25 (17.6)
      uPCR level (g/g), mean (SD)2.60 (1.4)4.13 (5.0)3.86 (4.6)4.08 (3.0)2.65 (2.2)2.96 (2.5)3.39 (3.7)
      Median (IQR)2.54 (1.39, 3.64)2.71 (1.43, 5.29)2.71 (1.43, 4.86)3.09 (2.03, 5.83)1.89 (1.00, 3.58)2.32 (1.13, 3.68)2.49 (1.26, 4.60)
      uPCR level (g/g), n (%)
      <0.50 (0.0)2 (3.6)2 (2.9)1 (6.3)2 (3.4)3 (4.1)5 (3.5)
      0.5−<37 (58.3)29 (51.8)36 (52.9)7 (43.8)38 (65.5)45 (60.8)81 (57.0)
      ≥35 (41.7)25 (44.6)30 (44.1)8 (50.0)18 (31.0)26 (35.1)56 (39.4)
      eGFR (mL/min/1.73 m2), mean (SD)118.9 (37.7)113.1 (46.7)114.2 (45.1)102.1 (37.5)108.0 (37.2)106.7 (37.1)110.3 (41.1)
      eGFR (mL/min/1.73 m2), n (%)
      eGFR ≥6012 (100.0)51 (91.1)63 (92.6)14 (87.5)53 (91.4)67 (90.5)130 (91.5)
      eGFR ≥9010 (83.3)38 (67.9)48 (70.6)9 (56.3)38 (65.5)47 (63.5)95 (66.9)
      SLEDAI-S2K score, mean (SD)11.6 (5.8)11.8 (4.7)11.7 (4.8)12.2 (4.8)11.3 (4.1)11.5 (4.2)11.6 (4.5)
      Biomarkers
      Anti-dsDNA

      Positive (≥30 IU/mL), n (%)

      Mean (SD)
      9 (75.0)

      289.9 (313.8)
      40 (71.4)

      428.1 (835.7)
      49 (72.1)

      402.7 (766.0)
      12 (75.0)

      125.3 (87.8)
      40 (69.0)

      314.6 (1000.8)
      52 (70.3)

      270.9 (879.8)
      101 (71.1)

      334.9 (825.1)
      Anti-C1q

      Positive (≥22.2 U/mL), n (%)

      Mean (SD)
      10 (83.3)

      392.9 (382.7)
      46 (82.1)

      155.9 (182.3)
      56 (82.4)

      198.2 (244.0)
      15 (93.8)

      209.2 (188.9)
      51 (87.9)

      177.1 (213.3)
      66 (89.2)

      184.4 (207.0)
      122 (85.9)

      190.7 (223.9)
      Complement C3 level
      Mean (SD)

      Low C3 (<90 mg/dL), n (%)
      82.8 (31.8)

      7 (58.3)
      73.4 (26.8)

      45 (80.4)
      75.1 (27.7)

      52 (76.5)
      73.0 (26.3)

      13 (81.3)
      73.1 (27.1)

      40 (69.0)
      73.1 (26.7)

      53 (71.6)
      74.0 (27.1)

      105 (73.9)
      Complement C4 level

      Mean (SD)

      Low C4 (<10 mg/dL), n (%)
      17.3 (12.6)

      4 (33.3)
      14.5 (8.4)

      18 (32.1)
      15.0 (9.2)

      22 (32.4)
      14.8 (8.1)

      5 (31.3)
      15.0 (9.3)

      24 (41.4)
      15.0 (9.0)

      29 (39.2)
      15.0 (9.1)

      51 (35.9)
      Average daily prednisone-equivalent dose (mg/day) at baseline, mean (SD)56.7 (4.4)42.5 (20.4)45.0 (19.3)56.3 (7.0)45.3 (18.0)47.7 (16.9)46.4 (18.1)
      *Duration defined as (treatment start date – diagnosis date + 1)/365.25
      among patients with positive levels at baseline.
      CYC, cyclophosphamide; eGFR, estimated glomerular filtration rate; IQR, interquartile range; IV, intravenous; LN, lupus nephritis; MMF, mycophenolate mofetil; SD, standard deviation; SLE, systemic lupus erythematosus; SLEDAI-S2K, SLE Disease Activity Index -2000; uPCR, urine protein:creatinine ratio

      Efficacy results of the East Asian subgroup

      A higher proportion of belimumab patients in the East Asian subgroup achieved the primary endpoint of PERR at Week 104 compared with placebo-treated patients (52.7% vs 36.8%; odds ratio [OR] [95% confidence interval; CI] 1.76 [0.88, 3.51]; Figure 3). At Week 104, a higher proportion of belimumab patients achieved CRR compared with placebo patients (35.1% vs 25.0%; OR [95% CI] 1.73 [0.80, 3.74]; Figure 3). In addition, a higher proportion of belimumab patients in the East Asian subgroup achieved PERR at Week 52 than placebo patients (62.2% vs 36.8%; OR [95% CI] 2.74 [1.33, 5.64]; Figure 3). A higher proportion of belimumab patients achieved PERR and CRR from as early as Week 24 (Figure S1) compared with placebo patients, both of which were then consistently higher for the study’s duration. The PERR and CRR results of the East Asian population demonstrated a similar trend to the results observed in the overall population of the BLISS-LN study, which favored belimumab over placebo (PERR at Week 104, OR [95% CI] 1.55 [1.04, 2.32]; CRR at Week 104, OR [95% CI] 1.74 [1.11, 2.74]; PERR at Week 52, OR [95% CI] 1.59 [1.06, 2.38]; Figure 3 and Figure S1C and D).
      Figure thumbnail gr3
      Figure 3PERR and CRR at Week 104 and PERR at Week 52 in the East Asian subgroup and the overall population of the BLISS-LN study (mITT population). CI, confidence interval; CRR, Complete Renal Response; IV, intravenous; mITT, modified intention-to-treat; OR, odds ratio; PERR, Primary Efficacy Renal Response
      In the East Asian population, during the 2 years of treatment, there was a 46% increased chance of achieving PERR at any time that would be maintained through Week 104 in the belimumab group compared with placebo group (hazard ratio [HR] [95% CI] 1.46 [0.88, 2.44]) and a 37% increased chance of achieving CRR at any time that would be maintained through Week 104 (HR [95% CI] 1.37 [0.74, 2.56]; Figure 4).
      Figure thumbnail gr4
      Figure 4Time to PERR (A) and CRR (B) that is maintained through Week 104 (East Asian subgroup, mITT population). CRR, Complete Renal Response; IV, intravenous; mITT, modified intention-to-treat; PERR, Primary Efficacy Renal Response
      When analyzed by induction therapy, at Week 104 for the MMF subgroup, a higher proportion of patients who received belimumab achieved PERR than patients who received placebo (OR [95% CI] 2.19 [1.01, 4.74]); however, in the CYC subgroup, the proportion of patients who achieved PERR was higher in the placebo than in the belimumab group although adjusting for baseline uPCR and baseline eGFR in the logistic regression meant the OR was above 1 (OR [95% CI] 1.03 [0.15, 7.34]; Table S1). A similar result was shown for patients who achieved CRR: a higher proportion of patients who received belimumab achieved CRR than patients who received placebo for the MMF subgroup (OR [95% CI] 2.24 [0.94, 5.36]); however, a lower proportion of patients who received belimumab achieved CRR than those who received placebo in the CYC subgroup (OR [95% CI] 0.64 [0.10, 4.17]; Table S1).
      The proportion of patients with a renal-related event or death was 9.5% in the belimumab group and 25.0% in the placebo group. The risk of a renal-related event or death at any time up to Week 104 was reduced by 63% among patients who received belimumab compared with those in the placebo group (HR [95% CI] 0.37 [0.15, 0.91]; Figure 5).
      Figure thumbnail gr5
      Figure 5Time to renal-related event or death through Week 104 (East Asian subgroup, mITT population). IV, intravenous; mITT, modified intention-to-treat
      In the East Asian population, 6.8% (5/74) of belimumab patients and 29.4% (20/68) of placebo patients had ≥1 severe SFI flare, with a 78% lower risk of experiencing first severe flare at any time in patients receiving belimumab (HR [95% CI] 0.22 [0.08, 0.58]). Among patients experiencing a severe flare, the median (IQR) time to first severe SFI flare was 173.0 (72.0, 479.0) days in the belimumab group and 301.0 (197.0, 397.0) days in the placebo group.
      At Week 104, more patients in the belimumab group achieved SLEDAI-S2K score <4 versus those in the placebo group (31.1% vs 23.5%, respectively; OR [95% CI] 1.46 [0.69, 3.08]).
      At Week 104, a higher proportion of belimumab-treated patients compared with placebo-treated patients were receiving lower average daily prednisone-equivalent doses (≤5 mg/day: 23.0% vs 17.6%, respectively, OR [95%CI] 1.56 [0.66, 3.65]; ≤7.5 mg/day: 31.1% vs 19.1%, respectively, OR [95% CI] 2.13 [0.96, 4.77]).
      At Week 104, a greater proportion of PERR responders was observed in belimumab-treated patients with Class III or IV LN compared with placebo-treated patients (Figure S3). For patients with Class III+V or IV+V and Class V LN, PERR rates tended to favor placebo over belimumab (Figure S3). For CRR at Week 104, the results tended to favor belimumab over placebo in patients with Class III or IV and Class III+V or IV+V LN, but not Class V LN (Figure S3). Regardless of the uPCR levels, numerically higher proportions of belimumab-treated patients achieved PERR and CRR at Week 104 than placebo-treated patients, with higher treatment differences observed in patients with uPCR <3 g/g at baseline than in patients with ≥3 g/g (Figure S3). In general, the results of this subgroup analysis observed in the East Asian population were consistent with those of the overall population of the BLISS-LN study (Figure S3). Fewer belimumab-treated patients experienced renal-related events or death than placebo-treated patients across all subgroups (Table S2).

      Biomarkers

      Overall, greater increases from baseline in IgG levels were observed in placebo group compared with belimumab group (Figure S2A). Among patients with positive levels at baseline, a greater reduction from baseline in anti-dsDNA and anti-C1q levels were observed in the belimumab group than in placebo group throughout the treatment period (Figure S2B and S2C). In patients with low complement levels at baseline, belimumab-treated patients exhibited greater increases from baseline in C3 and C4 levels than placebo-treated patients throughout the treatment period (Figure S2D and S2E).

      Safety in the East Asian subgroup

      Safety results in the East Asian subgroup were generally similar across both treatment groups (Table 2). In the East Asian population, 94.6% (70/74) of belimumab and 97.1% (66/68) of placebo patients experienced ≥1 AE, and 24.3% (18/74) belimumab and 27.9% (19/68) placebo patients experienced ≥1 serious AE. AEs leading to treatment discontinuation occurred in 12.2% (9/74) and 7.4% (5/68) patients in the belimumab and placebo groups, respectively (Table 2). These safety results were consistent with those observed in the overall population of the BLISS-LN study (Table 2).
      Table 2Summary of AEs in the East Asian subgroup and the overall population of BLISS-LN study
      East Asian subgroup (N=142)Overall safety population* (N=448)
      AE, n (%)Placebo (n=68)Belimumab (n=74)Placebo (n=224)Belimumab (n=224)
      ≥1 AE66 (97.1)70 (94.6)211 (94.2)214 (95.5)
      ≥1 related AE34 (50.0)36 (48.6)119 (53.1)123 (54.9)
      ≥1 serious AE19 (27.9)18 (24.3)67 (29.9)58 (25.9)
      ≥1 severe AE5 (7.4)10 (13.5)48 (21.4)54 (24.1)
      ≥1 AE resulting in study treatment discontinuation5 (7.4)9 (12.2)29 (12.9)29 (12.9)
      AESI
      Malignancies excluding NMSC†,‡0 (0.0)2 (2.7)0 (0.0)2 (0.9)
      Malignancies including NMSC†,‡0 (0.0)2 (2.7)0 (0.0)3 (1.3)
      Post-infusion systemic reactions§4 (5.9)9 (12.2)29 (12.9)26 (11.6)
      All infections of special interest11 (16.2)7 (9.5)34 (15.2)30 (13.4)
      Serious infections of special interest2 (2.9)3 (4.1)7 (3.1)9 (4.0)
      Active TB0 (0.0)2 (2.7)1 (0.4)3 (1.3)
      Serious active TB0 (0.0)2 (2.7)1 (0.4)2 (0.9)
      All herpes zoster†,ǁ7 (10.3)4 (5.4)19 (8.5)21 (9.4)
      Serious herpes zoster2 (2.9)0 (0.0)2 (0.9)5 (2.2)
      Non-opportunistic herpes zoster5 (7.4)1 (1.4)16 (7.1)12 (5.4)
      Serious non-opportunistic herpes zoster2 (2.9)0 (0.0)2 (0.9)2 (0.9)
      Opportunistic herpes zoster2 (2.9)3 (4.1)3 (1.3)9 (4.0)
      Serious opportunistic herpes zoster0 (0.0)0 (0.0)0 (0.0)3 (1.3)
      Recurrent herpes zoster2 (2.9)3 (4.1)2 (0.9)7 (3.1)
      Sepsis0 (0.0)0 (0.0)2 (0.9)0 (0.0)
      Depression (inc. mood disorders and anxiety)2 (2.9)2 (2.7)15 (6.7)11 (4.9)
      Suicide/self-injury**0 (0.0)1 (1.4)1 (0.4)1 (0.4)
      Deaths††0 (0.0)1 (1.4)3 (1.3)4 (1.8)
      *All randomized patients who received ≥1 dose of belimumab
      †per Custom MedDRA
      ‡includes tumors of unspecified malignancy adjudicated as malignant
      §no serious post-infusion systemic reactions were reported in the East Asian population
      ǁnot all herpes zoster infections were recurrent or disseminated
      ¶per GSK adjudication; **per standard MedDRA query
      ††fatal serious AEs that started on-treatment although death may have occurred anytime thereafter.
      AE, adverse event; AESI, AEs of special interest; MedDRA, Medical Dictionary for Regulatory Activities Terminology; NMSC, non-melanoma skin cancer; TB, tuberculosis
      AESI are shown in Table 2. Overall, 2 cases of malignancies were reported in belimumab patients, 1 papillary thyroid carcinoma and 1 thymoma conservatively adjudicated as malignant. There were no serious post-infusion systemic reactions. Serious cases of tuberculosis were reported in 2.7% (2/74) of belimumab patients. The incidence of herpes zoster was low across both treatment groups, with serious herpes zoster reported in 2.9% (2/68) of placebo patients and none in the belimumab group. Overall, 2.7% (2/74) of belimumab patients and 2.9% (2/68) of placebo patients experienced depression, and suicide/self-injury was reported in 1.4% (1/74) of belimumab patients. One belimumab patient experienced suicidal behavior with an attempt of suicide at Week 44, though there was no completed suicide. One death was reported in the belimumab group that was due to pneumonia. The AESI results of the East Asian population were generally consistent with those observed for the overall population of the BLISS-LN study (Table 2).
      The mean observed on treatment eGFR was relatively stable through Week 104 in the belimumab group but gradually declined from Week 52 in the placebo group (Figure 6; post hoc).
      Figure thumbnail gr6
      Figure 6Observed on-treatment eGFR (from creatinine adjusted for BSA; ml/min/1.73 m2) by visit (East Asian subgroup, safety population; post hoc). BSA, body surface area; eGFR, estimated glomerular filtration rate; SE, standard error
      No immunogenic responses were reported in patients of either treatment group at any visit.

      DISCUSSION

      The BLISS-LN study was the largest study to date to demonstrate the beneficial effect of belimumab on renal responses over standard therapy in patients with LN.
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
      Given the high prevalence of LN among East Asian patients with SLE,
      • Patel M.
      • Clarke A.M.
      • Bruce I.N.
      • Symmons D.P.
      The prevalence and incidence of biopsy-proven lupus nephritis in the UK: Evidence of an ethnic gradient.
      • Feldman C.H.
      • Hiraki L.T.
      • Liu J.
      • et al.
      Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000-2004.
      • Gonzalez L.A.
      • Toloza S.M.
      • McGwin Jr., G.
      • Alarcon G.S.
      Ethnicity in systemic lupus erythematosus (SLE): its influence on susceptibility and outcomes.
      • Li M.
      • Zhang W.
      • Leng X.
      • et al.
      Chinese SLE Treatment and Research group (CSTAR) registry: I. Major clinical characteristics of Chinese patients with systemic lupus erythematosus.
      it is important to assess whether the benefit of belimumab extends specifically to this population. Our subgroup analysis of East Asian patients participating in the BLISS-LN study demonstrated that the addition of belimumab to standard therapy improved kidney responses compared with standard therapy alone. Efficacy results in the East Asian subgroup were consistent with those of the overall population of the BLISS-LN study.
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
      Compared with standard therapy alone, more patients receiving belimumab achieved PERR and CRR at Week 104. At Week 104, the treatment difference versus placebo (OR) for PERR in the East Asian subgroup was higher than for the overall BLISS-LN population. However, the treatment difference versus placebo for CRR at Week 104 was similar between the East Asian subgroup and the overall population. In the East Asian subgroup, patients who received belimumab had a higher chance at any time of maintaining a PERR or CRR to Week 104 compared with standard therapy. In addition, more belimumab-treated patients achieved PERR at Week 52 compared with placebo-treated patients.
      When we evaluated the efficacy of belimumab according to induction regimen, in the MMF subgroup, more belimumab-treated patients achieved PERR and CRR at Week 104 than placebo-treated patients, a finding that was not shown in the CYC subgroup. It should, however, be noted that the CYC subgroup consisted of considerably fewer patients (n=28) than the MMF subgroup (n=114). Additionally, in the belimumab group, the CYC East Asian subgroup had higher baseline uPCR and lower eGFR compared with the placebo group.
      The risk of a renal-related event or death at any time was 63% lower among belimumab-treated patients compared with patients who received standard therapy alone. This risk reduction in the East Asian population was higher than the 49% for the overall population, but consistently, the difference between treatment groups was in favor of belimumab in both populations (HR [95% CI] 0.37 [0.15, 0.91] in the East Asian population and HR [95% CI] 0.51 [95% CI] 0.34, 0.77 in the overall population of BLISS-LN
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
      ).
      Post hoc subgroup analyses of PERR and CRR at Week 104 by baseline renal biopsy class and proteinuria level for the East Asian population were consistent with those of the overall population of the BLISS-LN study,
      • Rovin B.H.
      • Furie R.
      • Teng Y.K.O.
      • et al.
      A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis.
      suggesting that the addition of belimumab was most effective in improving the PERR and CRR in patients with a proliferative histologic component or baseline uPCR <3 g/g; however, definitive conclusions cannot be drawn due to the small size of subgroups.
      Fewer belimumab patients experienced severe SFI flare than placebo patients. The risk of experiencing a first severe flare was 78% lower at any time in belimumab patients than placebo patients. Amongst patients with severe flare, first severe SFI flares occurred earlier in the study in the belimumab group compared with those in the placebo group. The beneficial effect of belimumab on the systemic disease activity was also evident from a higher proportion of patients who attained SLEDAI-S2K scores <4 in the belimumab group compared with the placebo group.
      Belimumab demonstrated increased steroid dose reduction in the East Asian population, consistent with the results of the overall population of the BLISS-LN study.
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
      At Week 104, in both the East Asian and the overall populations, the OR for the prednisone-equivalent dose reduction to ≤5 mg/day and to ≤7.5 mg/day were in favor of belimumab versus placebo (≤5 mg/day: 1.56, 95% CI: 0.66, 3.65 vs 1.51, 95% CI: 1.01, 2.27, respectively; ≤7.5 mg/day: 2.13, 95% CI: 0.96, 4.77 vs 1.65, 95% CI: 1.11, 2.45, respectively). The reduction in disease activity was also evident from serological tests, with increasing improvements over time in anti-dsDNA, anti-C1q, C3, and C4, which is consistent with the results observed in the overall population of the BLISS-LN study.
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
      Consistent with the clinical benefits observed in BLISS-NEA Phase 3 belimumab study conducted in China, Japan, and South Korea, belimumab demonstrated meaningful improvement in disease activity in the Asian patient population in BLISS-LN.
      • Zhang F.
      • Bae S.C.
      • Bass D.
      • et al.
      A pivotal phase III, randomised, placebo-controlled study of belimumab in patients with systemic lupus erythematosus located in China, Japan and South Korea.
      This subgroup analysis showed that belimumab is well tolerated in the East Asian population with LN, with a safety profile consistent with that of the overall population of the BLISS-LN study as well as with other belimumab studies.
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
      ,
      • Furie R.
      • Petri M.
      • Zamani O.
      • et al.
      A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.
      ,
      • Stohl W.
      • Schwarting A.
      • Okada M.
      • et al.
      Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study.
      No new safety concerns specific to the East Asian population were identified. In contrast to the overall BLISS-LN study population where herpes zoster rates were similar (8.5% for placebo and 9.4% for belimumab groups), in the East Asian population, herpes zoster was more frequently reported in patients receiving placebo (10.3%) than in belimumab (5.4%) patients. The incidence of depression was low and similar across both treatment groups. One case of attempted suicide was reported in the belimumab group in a patient with a history of manic depression who had self-discontinued prescribed antidepressant. The patient recovered and completed the belimumab study treatment. One death was reported in the belimumab group, caused by a fatal serious AE that started on-treatment, with death occurring post-treatment. The fatal serious AE of bilateral pneumonia was considered by the investigator to have a reasonable possibility that it was related to study agent.
      The pattern of improvement in renal outcomes in the East Asian population, as measured by changes in eGFR, was consistent with those observed in the overall BLISS-LN population.
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
      However, in the East Asian population, the observed on treatment mean (SD) eGFR values in the belimumab group were less clearly separated from the placebo group by Week 104 (East Asian population: 115.7 [33.50] ml/min/1.73 m2 and 111.1 [23.42] ml/min/1.73 m2, respectively (post hoc); overall population: 111.3 [35.75] ml/min/1.73 m2 and 100.8 [29.18] ml/min/1.73 m2, respectively). This could possibly be explained by the imbalances observed at baseline and possible imbalances in treatment discontinuations during the study. In the East Asian population, the mean baseline eGFR was lower in the belimumab group than in the placebo group, whereas in the overall BLISS-LN population, the mean baseline eGFR was similar between both treatment groups (East Asian population: 106.7 [37.08] mL/min/1.73 m2 and 114.2 [45.07] mL/min/1.73 m2, respectively; overall population: 100.0 [37.71] mL/min/1.73 m2 and 101.0 [42.70] mL/min/1.73 m2, respectively).
      • Furie R.
      • Rovin B.H.
      • Houssiau F.
      • et al.
      Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.
      There are some limitations with this subgroup analyses. As mentioned above, the subgroup analyses were not powered for formal significance testing. Also, although the East Asian population is an important subgroup of the overall BLISS-LN population, constituting about 32%, the sample size of this subgroup analysis was relatively small and did not include patients from Thailand and the Philippines who were included in the overall population of the BLISS-LN study. The lower sample size in the East Asian subgroup may explain the increased variability in the proportion of PERR and CRR responders when compared with the overall population (Figure S1). Despite these limitations, this subgroup analysis provides valuable information on the efficacy and safety of belimumab in the East Asian population of patients with active LN.
      In summary, treatment with belimumab resulted in early and sustained improvements in renal outcomes in the East Asian population, with no new safety concerns. The results of this subgroup analysis were consistent with those of the overall BLISS-LN study population and support the benefits of belimumab treatment across renal and systemic outcomes in SLE.

      Article Information

      Authors’ Contributions: Study conception or design: JAG, YG, BJ, DAR; acquisition of data: XY, NC, JX, CCM, S-CB, AM, XP, WC, HR, XL, KN; data analysis or interpretation: XY, NC, JX, CCM, WC, HR, JAG, YG, BJ, CL, AM, MO, C-HT, DAR. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.
      Support: This study (GSK Study 114054) was funded by GSK. The sponsor (GSK) contributed to the design, collection, analysis and interpretation of the data, and the decision to submit the manuscript for publication, and supported the authors in development of the manuscript. All authors, including those employed by GSK, approved the content of the submitted manuscript. Medical writing support was provided by Olga Conn, PhD, of Fishawack Indicia Ltd, UK, part of Fishawack Health, and was funded by GSK. All authors made the final decision on the relevant data to be reported, and the main points to be communicated in the manuscript.
      Financial Disclosure: XY has received grant/research support from National Natural Science Foundation of China, Baxter, Equipment Grant Program, Wanbang Biopharmaceuticals, AstraZeneca, and GSK; consulting fees from Baxter, Wanbang Biopharmaceuticals, Fresenius, and Fresenius Kabi; is an officer or board member at Baxter, ARB, AstraZeneca, and GSK; royalties from Elsevier, CAN, People’s Medical Publishing House; speaker fees/honoraria from Baxter, Fresenius and Fresenius Kabi, Wanbang Biopharmaceuticals, Kyowa Kirin. NC and JX have received speaker fees/honoraria from GSK. WC has received grant/research support from the National Natural Science Foundation of China, and received speaker fees/honoraria from GSK. HR has received speaker fees/honoraria from GSK. XL has received speaker fees/honoraria from GSK. KN has received grant/research support from Aurinia pharmaceuticals, Boehringer Ingelheim, and GSK; consulting fees from AstraZeneca; speaker fees/honoraria from Fresenius Kabi, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Roche, and Novartis. JAG, YG, BJ, AM, MO, C-HT, and DAR are employees of GSK and hold stocks and shares in the company. CL is an employee of GSK. The remaining authors declare that they have no relevant financial interests.

      Acknowledgments

      The authors would like to thank the participating patients and their families, clinicians, and study investigators.
      Data Sharing: Anonymised individual patient data and study documents can be requested for further research from www.clinicalstudydatarequest.com.
      Peer Review: Received October 3, 2021. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form June 12, 2022.

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