Safety and Efficacy of Belimumab in Patients with Lupus Nephritis: Open-Label Extension of BLISS-LN Study

Abstract

Background and objectives: In the BLISS-LN study, belimumab improved kidney outcomes in adult patients with active lupus nephritis. This 28-week open-label extension of BLISS-LN assessed belimumab's safety and efficacy.

Design, setting, participants, & measurements: Eligible patients completing BLISS-LN received monthly intravenous belimumab 10 mg/kg plus standard therapy. End points included safety, open-label week 28 primary efficacy renal response (urine protein-creatinine ratio [UPCR] ≤0.7, eGFR no more than 20% below open-label baseline value or ≥60 ml/min per 1.73 m², no prohibited medications) and complete renal response (UPCR <0.5, eGFR no more than 10% below open-label baseline value or ≥90 ml/min per 1.73 m², no prohibited medications), and UPCR and eGFR by visit. Responses were also analyzed post hoc using the double-blind phase criteria.

Results: Of 257 enrolled patients, 255 were treated (safety population: n=123 switched from placebo-to-belimumab; n=132 remained on belimumab); 245 (97%) patients completed the study. Adverse events and serious adverse events were experienced by 62% and 4% of placebo-to-belimumab patients, respectively, and by 70% and 8% of belimumab-to-belimumab patients, respectively. One death occurred in the placebo-to-belimumab group. From open-label baseline to week 28, increases occurred in the proportions of patients achieving primary efficacy renal response (placebo-to-belimumab: from 60% to 67%; belimumab-to-belimumab: from 70% to 75%) and complete renal response (placebo-to-belimumab: from 36% to 48%; belimumab-to-belimumab: from 48% to 62%). Based on double-blind phase criteria, changes also occurred in the proportions achieving primary efficacy renal response (placebo-to-belimumab: from 54% to 53%; belimumab-to-belimumab: from 66% to 52%) and complete renal response (placebo-to-belimumab: from 34% to 35%; belimumab-to-belimumab: from 46% to 41%). The seeming decrease in response rates in the belimumab-to-belimumab groups was attributed to discontinuations/administration of glucocorticoids for non-SLE reasons as opposed to nephritis. Median UPCR and eGFR values were similar at open-label baseline and week 28.

Conclusions: No new safety signals were identified, and efficacy was generally maintained throughout the open-label phase.

Clinical trial registry name and registration number: BLISS-LN, NCT01639339.

Keywords: belimumab; clinical trial; glomerular disease; glomerulonephritis; kidney disease; lupus nephritis; proteinuria.

Graphical abstract

Figure 1.

Patient disposition in the open-label phase. *Two patients enrolled in the open-label phase did not receive open-label belimumab. They were inadvertently enrolled in the open-label phase while permanently discontinued from the double-blind investigational product and were thus excluded from analysis populations. ^†Of the 255 patients who received one or more open-label intravenous belimumab 10-mg/kg doses, one patient was not included in the modified intention-to-treat population due to Good Clinical Practice nonadherence issues in the double-blind phases of the study. Open-label data from this patient were excluded from all efficacy analyses, but they were included in the safety analyses for consistency with the double-blind phase reporting. Data are reported for the modified intention-to-treat population from “Received ≥1 open-label intravenous belimumab 10 mg/kg” downward. ^‡Includes all withdrawals for both treatment groups (belimumab-to-belimumab, n=8; placebo-to-belimumab, n=1).

Figure 2.

Probability of (A) primary efficacy renal response and (B) complete renal response maintained through open-label week 28 (using double-blind criteria) in patients enrolled in the open-label phase (open-label modified intention-to-treat population; post hoc analyses). This figure shows the cumulative probability of primary efficacy renal response and complete renal response that were sustained through open-label week 28 estimated using the Kaplan–Meier method. Patients randomized to placebo in the double-blind phase started belimumab in the open-label phase. Week 104 denotes the end of the double-blind phase and the start of the open-label phase. Primary efficacy renal response and complete renal response were defined using double-blind phase criteria. To have a primary efficacy renal response and a complete renal response, the results had to be replicated across two consecutive visits. Patients who discontinued open-label treatment, had treatment failure, or withdrew from the trial were not considered to have had a sustained response. Data on patients who did not have a primary efficacy renal response and a complete renal response at open-label week 28 were censored at the last available visit to open-label week 28. Data from patients who had treatment failure and discontinued open-label treatment, were lost to follow-up, or died were censored. The time to event in days was calculated as the event date minus the treatment start date plus one.

Figure 3.

(A) UPCR (<0.5) and (B) eGFR by visit over double-blind and open-label phases in patients enrolled in the open-label phase (open-label modified intention-to-treat population; observed cases). Patients randomized to placebo in the double-blind phase started belimumab in the open-label phase; double-blind week 104 visit and the open-label baseline visit were the same visit. The UPCR graph denotes the proportion of responders over time. SE, standard error, UPCR, urine protein-creatinine ratio.