Efficacy and safety of sequential therapy with subcutaneous belimumab and one cycle of rituximab in patients with systemic lupus erythematosus: the phase 3, randomised, placebo-controlled BLISS-BELIEVE study

Abstract

Objectives: Disease activity control in patients with systemic lupus erythematosus (SLE) with corticosteroid and immunosuppressant withdrawal is a treatment goal. We evaluated whether this could be attained with sequential subcutaneous belimumab (BEL) and one cycle of rituximab (RTX).

Methods: In this phase 3, double-blind BLISS-BELIEVE trial (GSK Study 205646), patients with active SLE initiating subcutaneous BEL 200 mg/week for 52 weeks were randomised to intravenous placebo (BEL/PBO) or intravenous RTX 1000 mg (BEL/RTX) at weeks 4 and 6 while stopping concomitant immunosuppressants/tapering corticosteroids; standard therapy for 104 weeks (BEL/ST; reference arm) was included.

Primary endpoint: proportion of patients achieving disease control (SLE Disease Activity Index-2000 (SLEDAI-2K) ≤2; without immunosuppressants; prednisone equivalent ≤5 mg/day) at week 52 with BEL/RTX versus BEL/PBO. Major (alpha-controlled) secondary endpoints: proportion of patients with clinical remission (week 64; clinical SLEDAI-2K=0, without immunosuppressants/corticosteroids); proportion of patients with disease control (week 104). Other assessments: disease control duration, anti-dsDNA antibody, C3/C4 and B cells/B-cell subsets.

Results: The modified intention-to-treat population included 263 patients. Overall, 16.7% (12/72) of BEL/PBO and 19.4% (28/144) of BEL/RTX patients achieved disease control (OR (95% CI) 1.27 (0.60 to 2.71); p=0.5342) at week 52. For major secondary endpoints, differences between BEL/RTX and BEL/PBO were not statistically significant. Anti-dsDNA antibodies and most assessed B cells/B-cell subsets were lower with BEL/RTX versus BEL/PBO. Mean disease control duration through 52 weeks was significantly greater with BEL/RTX versus BEL/PBO.

Conclusions: BEL/RTX showed no superiority over BEL/PBO for most endpoints analysed; however, it led to significant improvements in disease activity markers compared with BEL/PBO. Further investigation of combination treatment is warranted.

Trial registration number: NCT03312907.

Keywords: Autoimmune Diseases; B-Lymphocytes; Biological Therapy; Lupus Erythematosus, Systemic; Rituximab.

Figure 1. Patient disposition summary. mITT population excludes 29 patients from the BEL/ST group, due to IBAs being potentially unblinded. BEL, belimumab; IBA, independent blinded assessor; ITT, intention-to-treat; mITT, modified intention-to-treat; RTX, rituximab; ST, standard therapy.

Figure 2. Disease control* by baseline characteristics subgroups at week 52, based on IBA assessment (mITT population^†; N=263). Note: OR (95% CI) and p value are from a logistic regression model with covariates: baseline SLEDAI-2K, baseline immunosuppressants, baseline prednisone-equivalent dose and treatment group (however, covariates were excluded from the corresponding subgroup models, for example, baseline SLEDAI-2K was not included in analysis by baseline SLEDAI-2K). *Disease control is defined as a SLEDAI-2K score ≤2 achieved without immunosuppressants and with a prednisone-equivalent dose of ≤5 mg/day. ^†mITT population excludes 29 patients from the BEL/ST group, due to IBAs being potentially unblinded. BEL, belimumab; BLyS, B-lymphocyte stimulator; C3/4, complement 3/4; IBA, independent blinded assessor; mITT, modified intention-to-treat; PBO, placebo; RTX, rituximab; SLEDAI-2K, SLE Disease Activity Index-2000; SLE, systemic lupus erythematosus; ST, standard therapy.