Effect of belimumab on proteinuria and anti-phospholipase A2 receptor autoantibody in primary membranous nephropathy

Abstract

Background: Immunosuppressant drugs reduce proteinuria and anti-phospholipase A2 receptor autoantibodies (PLA2R-Ab) in primary membranous nephropathy (PMN) with varying success and associated toxicities. This study aimed to evaluate the effect of belimumab on proteinuria and PLA2R-Ab in participants with PMN.

Methods: In this prospective, open-label, experimental medicine study, 14 participants with PMN and persistent nephrotic-range proteinuria received up to 2 years belimumab monotherapy (10 mg/kg, every 4 weeks). Changes in proteinuria (urinary protein:creatinine ratio), PLA2R-Ab, albumin, cholesterol, B-cell subsets and pharmacokinetics were analysed during treatment and up to 6 months after treatment.

Results: Eleven participants completed to the primary endpoint (Week 28) and nine participants completed the study. In the intention-to-treat population population, baseline proteinuria of 724 mg/mmol [95% confidence interval (CI) 579-906] decreased to 498 mg/mmol (95% CI 383-649) and 130 mg/mmol (95% CI 54-312) at Weeks 28 and 104, respectively, with changes statistically significant from Week 36 (n = 11, P = 0.047). PLA2R-Ab decreased from 174 RU/mL (95% CI 79-384) at baseline to 46 RU/mL (95% CI 16-132) and 4 RU/mL (95% CI 2-6) at Weeks 28 and 104, respectively, becoming statistically significant by Week 12 (n = 13, P = 0.02). Nine participants achieved partial (n = 8) or complete (n = 1) remission. Participants with abnormal albumin and/or cholesterol at baseline gained normal/near normal levels by the last follow-up. Adverse events were consistent with those expected in this population.

Conclusions: Belimumab treatment in participants with PMN can reduce PLA2R-Ab and subsequently proteinuria, important preludes to remission induction.

Keywords: anti-phospholipase A2 receptor antibody; belimumab; pharmacokinetics; primary membranous nephropathy; proteinuria.

FIGURE 1

Schematic of participant flow. Wk, week. ^aParticipant discontinued after 8 weeks of treatment due to intercurrent tubulointerstitial nephritis causing deterioration in renal function while receiving both loop and thiazide diuretics and not considered related to belimumab. ^bParticipant discontinued after 12 weeks of treatment due to investigator assessment of proteinuria without improvement. ^cParticipant discontinued after 6 weeks of treatment due to loss of appetite/depression not considered drug related, as the depression was noted prior to dosing with belimumab.

FIGURE 2

Percent change from baseline for proteinuria and PLA2R-Ab (ITT population) (least squares mean, 95% CI). N FU, numbers of participants at each time point are given below the figure. Sixteen weeks and 6 months after dose follow-up have been nominally assigned to Weeks 116 and 128, but include data from participants withdrawn early and not on rescue therapy.

FIGURE 3

Time course of changes in other clinical outcomes (ITT population). (A) Serum albumin. (B) Serum cholesterol. (C) Serum IgG. (D) eGFR. Wk, week; 6 M PLD, 6 months after the last dose.

FIGURE 4

Percent change from baseline in concentration of B cells (ITT population). (A) B cells (CD19⁺). (B) Naïve B cells (CD19⁺CD27⁻IgD⁺). (C) Memory B cells (CD19⁺CD27⁺). Wk, week; 6 M PLD, 6 months post last dose.