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

This post hoc analysis evaluated the efficacy and safety of intravenous belimumab 10 mg/kg in the South Korean subgroup of patients with systemic lupus erythematosus (SLE) enrolled in the North East Asia (NEA) study (GSK Study BEL113750; NCT01345253).


| INTRODUC TI ON
Systemic lupus erythematosus (SLE) is a chronic, relapsing-remitting autoimmune disease with heterogeneous clinical manifestations affecting multiple organs. 1,2SLE is characterized by elevated levels of B-lymphocyte stimulator (BLyS), which facilitates B-cell hyperactivity, [3][4][5] and circulating autoantibodies that deposit in tissues and induce a pathogenic inflammatory cascade. 1 The prevalence of SLE is greater in Asian populations than Caucasian populations, and Asian patients with SLE are more likely to experience more frequent and severe clinical manifestations than Caucasian patients. 6In South Korea, the 2015 prevalence rate of SLE was 35.45 per 100 000 person-years, 7 with studies between 2005 and 2015 reporting a trend of increasing prevalence. 7,8The mortality rate among patients with SLE is higher than that of the general population, and non-Caucasian patients with SLE, including Asian patients, have an increased risk of mortality compared with their Caucasian counterparts. 91][12] However, long-term use of glucocorticoids for the management of SLE has been identified as a primary cause of irreversible organ damage accrual, [12][13][14] with high-dose glucocorticoids further increasing the risk of organ damage. 15As such, therapies that modify the course of disease by controlling disease activity and facilitate a reduction in glucocorticoid use limit damage accrual and reduce morbidity and mortality. 12,16The European Alliance of Associations for Rheumatology (EULAR) recommends that glucocorticoid use should be withdrawn where possible or minimized to less than 7.5 mg/day (prednisone-equivalent) when withdrawal is not possible. 10The Asia-Pacific League of Associations for Rheumatology (APLAR) in the 2021 SLE consensus also emphasizes the importance of minimizing glucocorticoid use in SLE management. 179][20][21][22] The APLAR recommends that belimumab is considered for active SLE manifestations that are refractory to standard therapy. 17The international approval of belimumab was supported by several Phase 3 trials demonstrating its efficacy, safety, and steroid-sparing potential, [23][24][25] including the North East Asia trial of patients from China, Japan, and South Korea. 26Despite its approval in South Korea, 27 studies of belimumab's efficacy and safety in this population are limited, 28 and further analyses are warranted to investigate the effect of belimumab in addition to standard therapy for South Korean patients with SLE.This subgroup analysis of South Korean adult patients with SLE from the North East Asia trial aims to evaluate belimumab's efficacy and safety in this population.Given the trend of increasing prevalence of SLE in South Korea 7,8 and the need for glucocorticoid-sparing and disease-modifying therapy options, investigations into biologics such as belimumab are timely and relevant to this specific population.

| Study design
This post hoc analysis used individual patient-level data from South Korean patients enrolled in the North East Asia trial, a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 52-week trial (GSK Study BEL113750; NCT01345253) that investigated the efficacy and safety of intravenous (IV) belimumab 10 mg/kg plus standard therapy in adult patients with SLE, versus placebo plus standard therapy.The North East Asia trial was conducted at 49 centers across China, Japan, and South Korea between May 2011 and September 2015.Its primary findings for the overall population have been published, 26 as well as findings for a subgroup of patients from Japan 29 and open-label continuation studies in Japan, South Korea, 28 and China. 30tails on the North East Asia trial design, patient inclusion/ exclusion criteria, randomization, and endpoints have been published previously. 26Briefly, eligible patients were randomized 2:1 to receive either belimumab 10 mg/kg IV or placebo, in addition to standard therapy, on Days 0, 14, and 28, and then every 28 days up to Week 48.Final double-blind efficacy and safety assessments were conducted at Week 52.All patients in the North East Asia trial provided written informed consent; the study received institutional review board approval and was conducted in accordance with the Declaration of Helsinki.

| Patients
South Korean patients enrolled in the North East Asia trial were included in this subgroup analysis.Inclusion and exclusion criteria are reported in Table S1.Briefly, patients were 18 years or older, had a diagnosis of SLE in accordance with the American College of Rheumatology criteria, had clinically active disease (Safety of Estrogens in Lupus Erythematosus National Assessment -SLE Disease Activity Index [SELENA-SLEDAI] score ≥8) and a positive antinuclear antibody test result at screening, and were taking a stable SLE-treatment regimen for at least 30 days.The main exclusion criteria were active nephritis or central nervous system lupus, or having received B-cell-targeted therapy. 26

| Endpoints and assessments
The primary efficacy endpoint was SLE Responder Index 4 (SRI-4) response rate at Week 52, defined as the proportion of patients achieving a ≥4-point reduction in SELENA-SLEDAI score, no worsening (<0.or B domain score at baseline, changes from baseline over 52 weeks in complement C3 and C4 levels among patients with low levels at baseline (low C3 levels defined as <0.9 g/L and low C4 levels defined as <0.1 g/L), and changes in anti-double-stranded DNA (dsDNA) levels from baseline over 52 weeks among patients who were anti-dsDNA positive at baseline (defined as ≥30 IU/mL).Glucocorticoid use was evaluated by assessing the number of days patients received ≤7.5 mg/day and/or a 50% reduced glucocorticoid dose (prednisoneequivalent) from baseline, among patients receiving >7.5 mg/day at baseline, and by the cumulative glucocorticoid dose over 52 weeks.
Glucocorticoid tapering was permitted after Week 24 at the investigator's discretion for patients with improving disease activity for at least 4 weeks.
Adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs; including malignant neoplasms, post-infusion systemic reactions, all infections, depression/suicide/self-injury, and deaths) were evaluated throughout the study.

| Statistical analysis
Efficacy and safety endpoints were assessed in the South Korean subgroup of the overall modified intent-to-treat (mITT) population of the North East Asia trial, which comprised all randomized patients who received at least one dose of study treatment.
The primary endpoint, SRI-4 response rate at Week 52, was analyzed using a logistic regression model with only the treatment group as an independent variable.Similarly, SRI-7 response rates at Week 52, SRI-4 component responses at Week 52, and SRI-4 response and its components at Week 52 when stratified by baseline SELENA-SLEDAI score were analyzed by a logistic regression model with treatment group as the only independent variable.BILAG improvement by organ domain at Week 52 was analyzed by Fischer's exact test.Changes from baseline in complement C3 and C4 levels over 52 weeks (in patients with low levels at baseline) were assessed using an analysis of covariance (ANCOVA) with treatment group as the only independent variable analyzed, and changes from baseline in anti-dsDNA levels (in patients who were anti-dsDNA positive at baseline) over 52 weeks were analyzed by Wilcoxon test.Time to first severe flare over 52 weeks was analyzed using a Cox proportional hazards model without adjustment for additional independent variables.Difference between groups in the number of days of daily glucocorticoid dose (prednisone-equivalent) ≤7.5 mg/ day and/or reduced glucocorticoid dose (prednisone-equivalent) by 50% from baseline over 52 weeks and difference between groups in cumulative glucocorticoid dose (prednisone-equivalent) over 52 weeks were both analyzed using a rank ANCOVA model with treatment group as the only independent variable.

| Patient population
Of the 707 patients in the North East Asia trial, 100 (14.1%) were from South Korea (Figure S1).Among these patients, 54/66 (81.8%) patients randomized to belimumab, and 24/34 (70.6%) patients randomized to placebo completed the double-blind phase.The most common reason for study withdrawal before Week 52 in the belimumab group was patient request (n = 6/66, 9.1%), with patients citing personal reasons for withdrawal or withdrawing consent without further explanation.Adverse events were the most common reason for withdrawal in the placebo group (n = 5/34, 14.7%).
Baseline demographics and disease characteristics reported for South Korean patients were consistent with those in the overall North East Asia trial (Table 1). 26The mean (SD) age of patients was 32.1 (8.82) years, and 93.0%(n = 93) of patients were female.In general, baseline demographics and disease characteristics were similar across the patient cohorts, with a few differences.

| SRI-4 and its components
Significantly more patients in the belimumab group than in the placebo group met the primary efficacy endpoint, an SRI-4 response at Week 52 (n = 35/66, 53.0% vs. n = 8/34, 23.5%; odds ratio [OR; 95% confidence interval (CI)]: 3.67 [1.45, 9.28]; p = .0061)(Figure 1A).components also showed a numerically favorable response to belimumab versus placebo, but not to the level of statistical significance (Table S2).Similarly, there were numerically more belimumab-treated than placebo-treated patients with a baseline SELENA-SLEDAI score ≤9 who were SRI-4 responders at Week 52 and had favorable responses across the SRI-4 components, but not to the level of statistical significance (Table S2).
In patients with low C3 and C4 levels at baseline, greater in-

| Safety
The most common AEs are reported in Table 2

| DISCUSS ION
This subgroup analysis furthered the work of the North East Asia trial in defining the role of belimumab treatment for North East Asian patients with SLE.Our analysis confirms the efficacy and safety of belimumab in South Korean patients with SLE, with findings consistent with belimumab trials performed in Asia 26,28 and internationally, [23][24][25] thus supporting belimumab 10 mg/kg IV plus standard therapy as an efficacious treatment option for patients with SLE from South Korea.
4][25][26] The higher number of SRI-4 responders in the belimumab group compared with the placebo group was driven by a greater proportion of patients achieving a response in each component of the SRI-4, with significantly more belimumab-treated patients experiencing a ≥4-point reduction in SELENA-SLEDAI and no new BILAG 1A/2B at Week 52 compared with placebo.
In this analysis, patients with higher disease activity (baseline SELENA-SLEDAI score of ≥10) achieved a significant SRI-4    31,32 and this is especially important in the context of SLE treatment for Asian patients, who may have higher disease activity than non-Asian patients. 334][25][26] These findings support belimumab's potential for reducing glucocorticoid usage in patients with SLE, a treatment goal that is in line with recent EULAR recommendations. 10Additionally, belimumab was well tolerated in South Korean patients, with a smaller proportion of patients receiving belimumab withdrawing from the trial before Week 52 compared with placebo.
Incidence of AEs, SAEs, and AESIs was generally consistent with previous Phase 3 trials 23,24,26,28 and did not indicate any new safety concerns in this population.While there was a higher incidence of viral upper respiratory tract infection in the belimumab group compared with placebo (15.2% vs. 2.9%), the incidence with belimumab was generally similar to that reported previously for upper respiratory tract infections. 18,23,24,26,28There was no notable difference in the incidence of any infection of special interest between treatment groups in this analysis, including tuberculosis and herpes zoster, opportunistic infections that are a concern for patients with SLE. 34ditionally, there were no cases of leukopenia or lymphopenia reported in the belimumab group.There was a low incidence of depression/suicide/self-injury in the placebo group, with no AE of this class reported in the belimumab group.[25]

| Summary and conclusions
Consistent with previous clinical trials, belimumab was efficacious and well tolerated in South Korean adult patients with SLE, with no new safety concerns raised and a potential for steroid-sparing benefit.These findings support belimumab's role as an add-on therapy to standard treatment for SLE in South Korea.
of glucocorticoid dose (prednisone-equivalent) ≤7.5 mg/day and/or reduced by 50% from baseline b Patients (%) Placebo (n = 21) Belimumab 10 mg/kg IV (n = 33) Patients with organ system improvement a by BILAG at Week 52, among patients with baseline involvement b .a Improvement was defined as changing from a score of A to B, C, or D, or changing from a score of B to C or D; b patients with A or B score at baseline.Improvements in BILAG domains general (belimumab n = 4/5 vs. placebo n = 1/5; p = .2063)and cardiovascular and respiratory (belimumab n = 1/1 vs. placebo n = 1/1; p value not calculable) not shown in figure due to low patient numbers with baseline involvement.BILAG, British Isles Lupus Assessment Group; IV, intravenous.
Most common adverse events and adverse events of special interest.
this analysis adds value to the existing literature.Withdrawals were relatively high in the belimumab group (10.6%, due to patient's request or loss to follow-up) and in the placebo group (5.9%, due to patient's request only), which was likely due to the small sample size of the South Korean subgroup.In the overall North East Asia trial, the proportions of patients who withdrew TA B L E 2 a Patients counted only once per adverse event.