INTRODUCTION

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs, including skin, joints, heart, lungs, and kidney (1, 2). Black African ancestry is associated with a higher prevalence of SLE, greater disease severity, an increased risk of cardiovascular events, more end-organ damage, and higher mortality rates, compared with a White racial background (3-10).

Belimumab is a human monoclonal antibody that binds to and inhibits the biologic activity of the B lymphocyte stimulator, which plays a key role in B cell selection and differentiation (11, 12). The efficacy and safety of intravenous (IV) and subcutaneous belimumab have been demonstrated in phase II and III studies of SLE (13-16). Due to underrepresentation of patients of Black African ancestry in these trials, underpowered subgroup analyses of this population yielded conflicting efficacy data between the phase II and III studies. Post hoc analysis of the phase II study data demonstrated an improved Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA–SLEDAI) response in patients of Black African ancestry who received belimumab compared with those who received placebo (17). In contrast, post hoc analysis of pooled data from 2 pivotal phase III studies showed that patients of Black African ancestry had a higher SLE Responder Index (SRI) response rate at week 52 with placebo compared with belimumab (18).

The 52-week EMBRACE study investigated the efficacy and safety of belimumab 10 mg/kg IV plus standard therapy compared with placebo plus standard therapy in adults with SLE of self-identified Black race. This report presents results of the efficacy and safety end point analyses from data collected up to the week 52 visit of the double-blind phase, and the subsequent 24-week open-label extension phase of EMBRACE. Additionally, results presented include subgroup analyses.

DISCUSSION

To our knowledge, this is the first randomized, placebo-controlled clinical trial in SLE focusing on patients of self-identified Black race. The response to treatment with belimumab 10 mg/kg IV plus standard therapy did not achieve statistical superiority over placebo plus standard therapy when assessed on the basis of the double-blind phase primary end point; however, SRI–SLEDAI-2K response rates were numerically higher in those who received belimumab. Although the magnitude of the treatment group difference favoring belimumab is lower in this study (response rate 49% with belimumab versus 42% with placebo, odds ratio 1.40 [95% confidence interval 0.93, 2.11]) when compared with that observed in the 2 pivotal phase III studies of IV belimumab (response rate in the Study of Belimumab in Subjects with SLE 52-week trial [BLISS-52], 58% with belimumab versus 44% with placebo, odds ratio 1.83 [95% confidence interval 1.30, 2.59]; response rate in the BLISS 76-week trial [BLISS-76], 43% with belimumab versus 34% with placebo, odds ratio 1.52 [95% confidence interval 1.07, 2.15]), the efficacy results are directionally consistent (13, 14, 24). Our results support the post hoc analysis of the previous phase II study, which showed an improved SELENA–SLEDAI response with belimumab compared with placebo in patients of Black African ancestry (17) and contradicted the post hoc analyses of the pivotal phase III studies (18, 25).

The large difference in SRI–SLEDAI-2K response in the open-label extension phase between the 2 treatment groups may be due to the difference in the length of time that patients received belimumab (>76 weeks in the continuous belimumab group versus 24 weeks in the placebo-to-belimumab group). At open-label extension baseline (start of belimumab treatment), the placebo-to-belimumab group also had lower disease activity compared with the continuous belimumab group, which may have made it more difficult to meet the SLEDAI component of the SRI end point.

The durable SRI–SLEDAI-2K response showed a greater difference between treatment groups relative to that in the primary analysis. The time to first SRI–SLEDAI-2K response that was maintained through week 52 occurred earlier in the belimumab group compared with the placebo group, and the belimumab group had a longer duration of SRI–SLEDAI-2K response compared with the placebo group.

The population recruited in this study had a generally lower disease activity than the overall population in the pivotal phase III studies (13, 14, 16), which may have contributed to the reduced effect size observed. However, subgroup analyses showed higher SRI–SLEDAI-2K responses in the belimumab group compared with the placebo group among patients with high disease activity at baseline (i.e., SELENA–SLEDAI–SLEDAI-2K score ≥10, low complement levels, and low complement levels plus positive anti-dsDNA). This finding is consistent with subgroup analyses of the pivotal phase III trials, in which patients with high disease activity had a greater SRI–SELENA–SLEDAI effect size with belimumab compared with standard therapy (Supplementary Figure 5, http://onlinelibrary.wiley.com/doi/10.1002/art.41900/abstract) (26). These findings add to the growing body of evidence supporting the benefit of belimumab in patients with high disease activity, regardless of race. High disease activity is more common in those of non-White descent, including African descendants (10), and this classification may be useful to practicing clinicians to more easily identify patients who might have an enhanced response to belimumab.

Regional analyses of the primary end point showed that patients in the rest-of-world subgroup compared with the US/Canada subgroup had a higher response to belimumab than to placebo, while those in the US/Canada subgroup had a similar response between treatment groups. A lower proportion of patients in the US/Canada subgroup had low complement levels at baseline than those in the rest-of-world subgroup. Due to this imbalance of baseline disease activity by region, post hoc analyses for response by region and baseline complement level were performed. In patients with low complement levels in both regions, a benefit was observed with belimumab compared with placebo. These regional baseline differences may have contributed to the higher response difference favoring belimumab in the rest-of-world subgroup compared with the US/Canada subgroup.

Renal involvement is more common and severe in patients of Black African ancestry (10, 27-29). Although this study was not powered to determine a treatment difference in renal end points, patients treated with belimumab had an improved SELENA–SLEDAI–SLEDAI-2K renal domain score, decrease in proteinuria, and a downward shift in proteinuria among those with high proteinuria at baseline. In this study, the observation that patients with renal manifestations may benefit from treatment with belimumab is supported by the post hoc analysis performed by Dooley et al and was confirmed in the BLISS in Lupus Nephritis study (ClinicalTrials.gov identifier: NCT01639339), which also included patients of Black African ancestry (30, 31).

Immunoglobulin and SLE biomarker responses from this study were consistent with those in the pivotal belimumab studies (13, 14). The incidences of AEs, and the AE and SAE profile in this study, were consistent with those in the overall SLE population of the BLISS-52, BLISS-76, and BLISS-SC trials (13, 14, 16). Although patients in the open-label extension continuous belimumab group received more exposure to belimumab than those in the placebo-to-belimumab group, no clinically meaningful safety differences were observed.

This study has several limitations. The introduction of the SRI–SLEDAI-2K as a treatment response end point was expected to increase the sensitivity of the study to identify a between-group treatment difference as compared with that assessed using the SRI–SELENA–SLEDAI, and consequently, the sample size was reduced from the original protocol (816 to 501 patients). Unfortunately, the predicted increase in sensitivity was not realized and this, combined with the loss of 48 participants from the modified ITT population due to site noncompliance, resulted in reduced power. Despite stratification at screening, a higher proportion of patients in the belimumab group had a SELENA–SLEDAI–SLEDAI-2K score of ≤9 at baseline, and the mean baseline SELENA–SLEDAI–SLEDAI-2K score was slightly lower compared with the placebo group. It is possible that a 4-point reduction in the score may therefore have been harder to achieve in the belimumab group compared with the placebo group due to disease changes after screening. Furthermore, subgroup analyses across studies have consistently demonstrated that patients with baseline SELENA–SLEDAI scores of ≥10 benefit more from treatment with belimumab compared with those with baseline scores of ≤9 (Supplementary Figure 5, http://onlinelibrary.wiley.com/doi/10.1002/art.41900/abstract). Therefore, this imbalance may have contributed to the reduction in the overall effect size on the primary end point.

This study was initiated as one of the postapproval commitments for belimumab. The decision not to include forced steroid tapering, which was made to ensure the study design was comparable to that of the pivotal BLISS studies, may have contributed to the inability to differentiate between the 2 groups. Although a reduction in steroid use without mandated tapering has been demonstrated following belimumab treatment (32), steroid tapering is an important consideration for the design of future studies in order to ensure that the full treatment effect of a new medicine may be demonstrated. Other than self-identification, no definitions were applied to the inclusion criteria of Black race. This resulted in the inclusion of a proportion of patients who did not identify as being primarily of Black race but considered themselves of mixed race. Although there is variability in the population of patients who self-identified as being of Black race, this study is unique in the SLE field in that it limits the inclusion criteria by race.

Overall, belimumab 10 mg/kg IV plus standard therapy was generally well tolerated; no new safety signals were observed, and findings were consistent with the known safety profile of belimumab. Efficacy and safety appear to be maintained over time. Although statistical significance was not achieved overall, a greater percentage of patients attained the primary end point in the belimumab group compared with the placebo group. Importantly, patients with baseline high disease activity or renal disease benefited from treatment with belimumab, a finding that adds to the growing body of evidence supporting the benefit of belimumab in these groups (13, 14, 16, 30). This study provides clinically meaningful evidence to inform clinicians regarding the management of SLE in patients of Black African ancestry, especially those with high disease activity, a patient population with high unmet needs.

ACKNOWLEDGMENTS

The authors would like to thank Grace Kang (GlaxoSmithKline) for her contribution to this study. They would also like to thank the patients and their families, as well as the investigators and support staff.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Ginzler had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design

Ginzler, Guedes Barbosa, Santiago, Bass, Burriss, Pierce, Roth, Ji.

Acquisition of data

Ginzler, Guedes Barbosa, D'Cruz, Furie, Maksimowicz-McKinnon, Oates, Santiago, Saxena, Sheikh.

Analysis and interpretation of data

Ginzler, Guedes Barbosa, D'Cruz, Furie, Maksimowicz-McKinnon, Oates, Santiago, Saxena, Sheikh, Bass, Burriss, Gilbride, Groark, Miller, Pierce, Roth, Ji.

ROLE OF THE STUDY SPONSOR

GlaxoSmithKline designed, conducted, and funded this study, contributed to collection, analysis, and interpretation of the data, and supported the authors in development of the manuscript. Medical writing support was provided by Casmira Brazaitis, PhD, of Fishawack Indicia Ltd (Knutsford, UK) and funded by GlaxoSmithKline. All authors, including those employed by GlaxoSmithKline, approved the content of the submitted manuscript. GlaxoSmithKline was involved in the decision to submit the manuscript for publication.