Organ system improvements in Japanese patients with systemic lupus erythematosus treated with belimumab: A subgroup analysis from a phase 3 randomized placebo-controlled trial

Abstract

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 (<7% both treatments) and in a number of BILAG systems: <11% (placebo) and <8% (belimumab), although the small sample size should be noted.

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.

Keywords:

• Belimumab
• British Isles Lupus Assessment Group (BILAG)
• organ damage
• Safety of Estrogen in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI)
• systemic lupus erythematosus

Introduction

Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disease with highly variable disease manifestations and organ involvement [1–3]. Treatment for SLE typically includes non-steroidal anti-inflammatory drugs, antimalarials, and corticosteroids, although these have been associated with side effects and organ damage accrual [4,5]. The chronic, relapsing-remitting nature of SLE, alongside the susceptibility of patients with SLE to organ damage accrual from both disease manifestation and corticosteroid use marks SLE as a refractory disease with a need for effective therapeutic treatment [6].

Belimumab is a human, immunoglobulin G1λ monoclonal antibody that targets the soluble form of B-lymphocyte stimulator, thought to play a major role in the pathogenesis of SLE [7,8]. Intravenous (IV) belimumab (10 mg/kg) was initially approved in the United States and in Europe for the treatment of adults with active autoantibody-positive SLE [9,10]. In September 2017, IV and subcutaneous (SC) belimumab were approved in Japan for the treatment of adult patients with SLE who are inadequate responders to existing therapies [11]. The incidence of SLE in Japan is reported to range between 0.9 and 2.8 per 100,000 per year, with a prevalence ranging from 3.7 to 37.7 per 100,000 [12,13]. Approval of belimumab in Japan was based on the findings from a Phase 3 randomized, double-blind study (BEL113750; NCT01345253) assessing the efficacy and safety of belimumab as add-on to standard of care (SoC) in North-East Asia (China, Japan, and South Korea), as well as the BLISS-52 and BLISS-76 studies, conducted in Europe and North/Central America, and the global BLISS-SC study [11,14–17]. These studies consistently showed significant improvement in disease activity with belimumab versus placebo [14–17]. A subgroup analysis of the North-East Asia study, conducted to specifically assess the safety and efficacy of belimumab within the Japanese population, also demonstrated improved disease activity, as assessed by the SLE Responder Index (SRI) 4 at Week 52 [18].

The current analysis of the North-East Asia trial continues the focus on Japanese patients, assessing the effects of belimumab on disease activity across multiple organ domains in this subpopulation. Organ damage is prevalent in patients with SLE and its severity and frequency increases over time [19–23]. A number of studies have shown that patients displaying organ damage are at risk of accruing additional damage as their disease progresses [3,24,25]. Moreover, organ damage has been associated with mortality, low health-related quality of life and increased healthcare resource use and associated costs, particularly in patients with renal, cardiovascular, or central nervous system involvement [23,26–29]. As such, further information on the effect of SLE treatments on the improvement and worsening of organ damage will help to support prescribing choices.

Materials and methods

Study design

The primary results of this study (BEL113750; NCT01345253) have previously been published [14]. In brief, the study was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of belimumab in patients with active SLE in North-East Asia (China, Japan, and Korea). Patients completed a screening period of up to 5 weeks and were then randomized 2:1 to receive belimumab 10 mg/kg IV or placebo, respectively, in addition to SoC, on Days 0, 14, and 28, followed by doses every 28 days until Week 48, with a final evaluation at Week 52. At randomization, patients were stratified by Safety of Estrogen in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) and by complement (C) levels (low C3 [<0.9 g/L] and/or C4 [as <0.10 g/L] vs no low C3 or C4), as well as the patient’s country of origin.

This subgroup analysis focuses on patients from Japan only (n = 60/707), to assess the effects of belimumab on disease activity across multiple organ domains. Of the 49 centers participating in the North-East Asia study, 16 were located in Japan.

Patients

All patients provided written informed consent prior to the performance of any study-specific procedures. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, International Council for Harmonisation on Good Clinical Practice, and the applicable country-specific regulatory requirements. Details of inclusion and exclusion criteria have been published previously [14]. Eligible patients were aged ≥18 years, with a diagnosis of SLE according to the American College of Rheumatology (ACR) classification criteria and clinically active disease, defined as a SELENA-SLEDAI score ≥8 at screening. Patients were required to be on a stable SLE treatment regimen for ≥30 days prior to Day 0. Key exclusion criteria included severe lupus kidney disease or active nephritis requiring acute therapy within 90 days prior to baseline, central nervous system lupus requiring therapeutic intervention within 60 days prior to baseline, any new SLE medications other than corticosteroids within 60 days prior to baseline, and B cell targeted therapy at any time.

Endpoints and assessments

SELENA-SLEDAI and British Isles Lupus Assessment Group (BILAG) scores were measured at baseline and every subsequent 4 weeks, with a final evaluation at Week 52. Assessments were: SELENA-SLEDAI organ system improvement (decrease in score) by organ system among patients with organ system involvement at baseline; SELENA-SLEDAI organ system worsening (increase in score) by organ system among patients with no organ system involvement at baseline; BILAG improvement from baseline by organ domain in each patient with an A or B domain score at baseline (reported previously); BILAG worsening by organ domain in patients with no A domain score at baseline. Improvement in BILAG was defined as a shift from an A domain score at baseline to a B, C, or D domain score or a shift from a B domain score at baseline to a C or D domain score. Worsening in BILAG was defined as a shift from a B domain score at baseline to an A domain score, or a shift from a C, D, or E domain score at baseline to an A or B domain score.

Statistical analysis

Within the Japanese cohort, all patients who received ≥1 dose of the study drug were included in the modified intent-to-treat (mITT) population. All data summaries were performed using Statistical Analysis Software (SAS), Version 9.3 (SAS Institute Inc., Cary, NC, USA). The results from the study of the overall North-East Asian population were not powered for subgroup analyses. Furthermore, the study was not stratified by organ involvement; statistical significance of organ involvement effects was assessed using Fisher’s exact test. Continuous variables were summarized with mean, median, and standard deviation, 25th and 75th percentile, minimum and maximum values. Categorical variables were summarized with frequency counts and percentages.

Results

Study population and patient demographics

As previously reported, 707 patients were randomized during the North-East Asian study and the mITT population consisted of 705 patients. Of these, 60 patients (belimumab, n = 39; placebo, n = 21) were enrolled and randomized into Japanese study centers [14]. A total of 48/60 (80.0%) of patients completed the 52-week study. Reasons for withdrawals were adverse events (n = 4; 6.7%), withdrawal by patient (n = 4; 6.7%), lack of efficacy (n = 3; 5%), and withdrawal by investigator decision (n = 1; 1.7%).

Patient baseline demographics and clinical characteristics, which have been published previously [14], were similar between treatment groups (Table 1). Baseline characteristics, including gender, height, weight and body mass index, were similar between patients from Japan, China and Korea. The mean (standard deviation) age of the Japanese patients was 36.6 (10.49) years, which was higher than that of the Chinese (31.6 [9.38]) and Korean (32.1 [8.82]) patients. There were also differences in concomitant medication between patients from Japan, China and Korea, as previously published, including a higher use of antimalarials and traditional Chinese medications in the China cohort [14].

Table 1. Baseline demographics and characteristics, including SELENA-SLEDAI and BILAG involvement by organ domain/system (Japan cohort).

	Placebo (n = 21)	Belimumab 10 mg/kg (n = 39)
Age, mean (SD)	33.7 (10.61)	38.1 (10.23)
Female, n (%)	20 (95.2)	35 (89.7)
Daily prednisone dose (mg/day), mean (SD)	11.5 (6.58)	9.8 (5.23)
Concomitant mediations, n (%)
Steroids	21 (100.0)	39 (100.0)
Anti-malarials	0	0
Other immunosuppressants /immunomodulators	19 (90.5)	27 (69.2)
Traditional Chinese medicine - glycosides of Paeony/Tripterygium	0	0
Low C3 and/or low C4 complement levels, n (%)	17 (81.0)	34 (87.2)
SELENA-SLEDAI organ system involvement, n (%)
Immunologic	21 (100.0)	39 (100.0)
Mucocutaneous	19 (90.5)	33 (84.6)
Musculoskeletal	12 (57.1)	23 (59.0)
Renal	5 (23.8)	5 (12.8)
Vascular	2 (9.5)	5 (12.8)
Hematologic	2 (9.5)	3 (7.7)
Cardiovascular and Respiratory	0	0
CNS	0	0
BILAG organ domain involvement by category (A or B domain scores only), n (%)
Mucocutaneous	11 (52.4)	26 (66.7)
Musculoskeletal	12 (57.1)	22 (56.4)
Vasculitis	2 (9.5)	8 (20.5)
Renal	5 (23.8)	5 (12.8)
General	1 (4.8)	4 (10.3)
Hematology	2 (9.5)	0
Cardiovascular and respiratory	0	0
Neurological	0	0

BILAG: British Isles Lupus Assessment Group; CNS: central nervous system; SD: standard deviation; SELENA-SLEDAI: Safety of Estrogen in Lupus Erythematosus National Assessment-SLE Disease Activity Index; SLE: systemic lupus erythematosus.

SELENA-SLEDAI and BILAG involvement by organ domain/system at baseline for Japanese patients is summarized in Table 1. SELENA-SLEDAI immunologic and mucocutaneous organ system involvement were common in both treatment groups (≥84.6%), and SELENA-SLEDAI musculoskeletal involvement occurred in 57.1% of placebo-treated patients and 59.0% of belimumab-treated patients. Involvement of BILAG mucocutaneous and musculoskeletal organ domain categories also occurred in a high proportion (≥52.4%) of both placebo and belimumab-treated patients. All patients in both groups were taking steroids, whilst none were taking anti-malarials (Table 1).

Change from baseline in SELENA-SLEDAI

In the majority of SELENA-SLEDAI organ system categories, a numerically greater percentage of patients who received belimumab had an improvement, compared with placebo (Figure 1(a)). In particular, the proportion of patients experiencing renal organ system improvement was 60.0% in the belimumab group and 20.0% in the placebo group; between-group differences of a similar magnitude were seen for musculoskeletal (52.2% vs 25.0%), mucocutaneous (54.5% vs 31.6%), and hematologic (33.3% vs 0%) organ systems. The percentage of patients with improvements in the mucocutaneous and musculoskeletal SELENA-SLEDAI organ systems is shown in Supplementary Figure 1.

Figure 1. SELENA-SLEDAI improvement^a from baseline at Week 52 (mITT population).

^aDefined as any reduction in SELENA-SLEDAI score and assessed in patients with impairment in domain at baseline.

CNS: central nervous system; CV: cardiovascular; mITT: modified intent-to-treat; SELENA-SLEDAI: Safety of Estrogen in Lupus Erythematosus National Assessment-SLE Disease Activity Index; SLE: systemic lupus erythematosus.

Note: no statistical significance was observed; N/A indicates no patients with baseline impairment in that domain.

The renal and hematologic organ systems were the only systems to show any worsening at Week 52 among patients without impairment at baseline, with only a low number of patients exhibiting worsening in these categories. In the renal system, 1 (6.3%) patient in the placebo group and 2 (5.9%) patients in the belimumab group showed worsening. In the hematologic system, 1 (5.3%) patient in the placebo group and 2 (5.6%) patients in the belimumab group showed worsening.

Change from baseline in BILAG

In all organ domains in which patients had A or B scores at baseline, a greater percentage of patients who received belimumab experienced an improvement in BILAG, compared with placebo (Figure 2(a)). A significant treatment difference was observed between belimumab and placebo groups within the mucocutaneous organ domain (57.7% vs 18.2%; p = .0365). Similarly, between-group differences favoring belimumab were seen in the musculoskeletal (59.1% vs 33.3%) and vascular (62.5% vs 0%) domains, but these differences were not statistically significant. The percentage of patients with improvements in the mucocutaneous and musculoskeletal BILAG domains at each visit suggest a trend towards an increasing difference between belimumab and placebo, particularly between Weeks 4 and 24 (Figure 3).

Figure 2. BILAG improvement^a (a) and worsening^b (b) from baseline at Week 52 (mITT population).

^aDefined as any shift in patients with an A score at baseline to a B, C, or D score, or a shift in patients with a B at baseline who changed to a C or D; ^bdefined as a shift from a baseline B score to an A score, or a baseline C, D, or E score to an A or B score.

BILAG: British Isles Lupus Assessment Group; CV: cardiovascular; mITT: modified intent-to-treat; *denotes p < .05.

Note: N/A denotes no baseline involvement within this domain.

Figure 3. The percentage of patients^a treated with belimumab 10 mg/kg and placebo demonstrating a BILAG improvement^b in the (A) mucocutaneous and (B) musculoskeletal domains at each visit.

^aData only for patients with a BILAG A or B score at baseline; ^bdefined as any shift in patients with an A score at baseline to a B, C, or D score, or a shift in patients with a B at baseline who changed to a C or D score.

BILAG: British Isles Lupus Assessment Group.

BILAG organ system worsening in patients without an A score at baseline was seen in the mucocutaneous, musculoskeletal, vascular, renal, and hematological organ systems (Figure 2(b)). A greater percentage of belimumab patients compared with placebo (5.1% vs 0%) experienced worsening in the hematological organ domain. However, belimumab patients experienced worsening in the musculoskeletal and vascular organ domains less frequently than those treated with placebo (2.7% vs 10.5% and 0% vs 5%, respectively).

Discussion

This subgroup analysis investigated the effects of treatment with belimumab versus placebo, plus SoC therapy, on disease activity in multiple organ systems in Japanese patients with SLE from the Phase 3 North-East Asia study [14]. The analysis showed that more patients treated with belimumab than with placebo had improvements across several SELENA-SLEDAI and BILAG organ domains, and the number of patients who experienced worsening in SELENA-SLEDAI and BILAG organ domains was similar in both treatment groups. These organ activity outcomes in Japanese patients are consistent with those seen in the parent North-East Asia study [14], and a post hoc analysis of the pivotal Phase 3 BLISS-52 and BLISS-76 studies of IV belimumab [30]. Similarly, recent analyses using data from the long-term extension studies of the BLISS program showed low rates of organ damage accrual with belimumab treatment [31].

Patients with SLE are susceptible to damage across multiple organ systems, caused by both active disease and medication toxicities [5,32]. A previous subgroup analysis of the North-East Asia study showed that belimumab reduced disease activity in Japanese patients and Wada et al. demonstrated that effective disease control can prevent organ damage in Japanese patients with SLE [33]. Therefore, the effect of SLE treatments on organ damage are clinically important.

The current study builds upon previous findings, demonstrating improvements in more belimumab- than placebo-treated patients in five of six SELENA-SLEDAI domains where improvements were seen, and in all five BILAG domains where improvements were seen. These results are in line with those seen in a post hoc analysis of the BLISS-52 and BLISS-76 trials, in which more patients treated with belimumab showed 4-point or greater reduction in the SELENA-SLEDAI score at Week 52 compared with patients treated with placebo, and more patients had no new BILAG A or no more than one new BILAG B score at Week 52 [30]. Moreover, significantly fewer patients treated with belimumab versus placebo had worsening in the BILAG hematological domain and in the SELENA-SLEDAI immunological, hematological, and renal domains [30]. Our study also showed more favorable outcomes in renal domain activity, as assessed by BILAG; however, BILAG hematological domain worsening was more frequent in belimumab- than placebo-treated patients. Nonetheless, the proportion of patients experiencing worsening was low across the range of organ domains. Worsening in SELENA-SLEDAI domains was also low, occurring in just two domains (renal and hematological).

In general, findings in some organ domains were consistent across the SELENA-SLEDAI and BILAG indices. Both indices indicated more improvement in patients treated with belimumab than with placebo in the mucocutaneous and musculoskeletal domains, which, in addition to the immunologic SELENA-SLEDAI domain, were the most commonly affected domains at baseline. Compared with placebo, belimumab treatment was also associated with greater rates of improvement in the SELENA-SLEDAI renal domain and the BILAG vascular domain. Consistent with these findings, a post hoc analysis of the BLISS trials, conducted in patients with stable renal involvement, showed that a higher proportion of patients with SELENA-SLEDAI renal involvement at baseline and treated with belimumab had renal improvement [34]. In Manzi’s post hoc analysis of the BLISS studies, which also assessed individual organ domain activity, significantly more belimumab-treated patients had improvements in the SELENA-SLEDAI musculoskeletal, mucocutaneous, and immunological domains and in the musculoskeletal and mucocutaneous BILAG domains [30]. Importantly, the treatment effect with belimumab remained after removal of the contribution of these three commonly affected organ domains, or both the musculoskeletal and mucocutaneous domains, to SELENA-SLEDAI scoring, demonstrating that the responses were not driven by effects on a single organ domain [30]. Rather, belimumab had effects on multiple organ systems, in line with findings in the current study. It should also be noted that mucocutaneous involvement is common in SLE, allowing a greater power to detect a difference than in some other organ systems such as renal or cardiovascular.

This study has a number of limitations that should be considered when interpreting the results. Only a small number of patients were included (n = 60), with varying proportions exhibiting domain level symptoms at baseline. As the results from the study of the overall North-East Asian population were not powered for subgroup analyses, the results of this analysis lack sufficient statistical power to draw definitive conclusions. Furthermore, the study was not stratified by organ involvement, thus there were some differences between treatment groups in the extent of baseline involvement at the domain level, as shown in Table 1. The study also excluded patients with SLE with active severe lupus nephritis or active central nervous system disease, which may be associated with higher rates of organ damage accrual. As such, the study may have selected patients who are less likely to show improvement with treatment because their baseline organ involvement was relatively low. Indeed, belimumab has been shown to have greater therapeutic benefit in patients with higher disease activity (SELENA-SLEDAI ≥10) [35]. On the other hand, only patients with SELENA-SLEDAI scores ≥8 at screening were included; these patients may have been more likely to respond to belimumab than those excluded based on lower SELENA-SLEDAI scores. Overall, the study population may not be wholly representative of a real-world Japanese SLE population, and further real-world data will be useful to fully assess the effects of belimumab in this group of patients.

In conclusion, this Japanese subgroup analysis of the Phase 3 North-East Asia study in patients with active SLE found that a greater number of patients treated with belimumab experienced improvements in the majority of SELENA-SLEDAI and BILAG organ systems, compared with placebo-treated patients. These results provide further evidence to support the use of belimumab in Japanese patients with SLE.

Conflicts of interest

Damon Bass, Sally Egginton, Beulah Ji, and David Roth are employees of GSK and hold shares in the company. Myron Chu was a GSK employee and held shares in the company at the time of study. Yoshiya Tanaka received consulting fees, speaking fees, and/or honoraria from AbbVie, Chugai, Daiichi-Sankyo, Bristol-Myers Squibb, Mitsubishi-Tanabe, Astellas, Takeda, Pfizer, Asahi-Kasei, YL Biologics, Sanofi, Janssen, Eli Lilly, and GSK, and has received research grants from Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers Squibb, MSD, Astellas, AbbVie, and Eisai.

Acknowledgments

The authors would like to acknowledge the following Japanese study investigators who helped to obtain study data for BEL113750.

Table

Site name	PI	Date of obtained permission from PI
Nagasaki University Hospital	Atsushi Kawakami	Nov 27, 2018
Juntendo University Hospital	Hirofumi Amano	Oct 15, 2018
Ehime University Hospital	Hitoshi Hasegawa	Oct 23, 2018
Dokkyo Medical University Hospital	Kazuhiro Kurasawa	Nov 8, 2018
Kohnan Kakogawa Hospital	Kazuko Shiozawa	Oct 31, 2018
Sapporo City General Hospital	Masaya Mukai	Oct 17, 2018
Higashi-Hiroshima Memorial Hospital	Mitsuhiro Iwahashi	Nov 16, 2018
Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital	Takuya Sawabe	Nov 21, 2018
Hokkaido University Hospital	Tatsuya Atsumi	Oct 15, 2018
Tohoku University Hospital	Tomonori Ishii	Nov 20, 2018
National Hospital Organization Kyushu Medical Center	Tomoya Miyamura	Nov 7, 2018
Kurashiki Medical Clinic	Yasuhiko Yoshinaga	Oct 15, 2018
Chibaken Saiseikai Narashino Hospital	Yasushi Nawata	Nov 13, 2018
Tomishiro Central Hospital	Yoshiki Shiohira	Nov 7, 2018
Hakujyujikai Sasebo Chuo Hospital	Yukitaka Ueki	Oct 19, 2018

Data availability

Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

Additional information

Funding

This study [BEL113750; NCT01345253] was funded by GlaxoSmithKline (GSK). Medical writing support was provided by Emma Hargreaves, MA, and Jennie McLean, PhD, of Fishawack Indicia Ltd, UK, and was funded by GSK.