Belimumab with rituximab for the treatment of primary membranous nephropathy

Introduction: B cell depletion with rituximab leads to complete or partial remission (CR/PR) in only ~60% of patients with primary membranous nephropathy (PMN). Adding belimumab to rituximab may result in greater depletion of memory B cells, limit the re-emergence of autoreactive B cells, and improve clinical responses. Methods: REBOOT Part A (NCT03949855) is a single arm, open-label, pharmacokinetic study where all participants had proteinuria [≥] 4g/day and detectable serum anti-phospholipase A2 receptor (anti-PLA2R) antibodies. Participants received belimumab 200 mg subcutaneously weekly for 52 weeks and rituximab 1000 mg intravenously at weeks 4 and 6. Assessments included belimumab exposure at week 4 and CR/PR at week 104. Results: Seventeen participants started belimumab. Belimumab exposure was not significantly reduced in those with high (> 9 g/day) proteinuria at week 4. Among all treated participants, 59% (10/17) achieved CR/PR at week 104, while in per protocol analyses, 91% (10/11) achieved CR/PR at week 104. All participants in per protocol analyses had normal serum albumin and undetectable serum anti-PLA2R by week 104. Circulating memory B cells increased before rituximab and were depleted by rituximab. B cell re-constitution occurred after week 52 with primarily naive and transitional B cells. Belimumab with rituximab was well-tolerated, with one participant discontinuing belimumab due to infection. Conclusion: In this study, a high proportion of participants receiving belimumab with rituximab achieved CR/PR. Thus, a multi-targeted approach to B cell depletion may improve immunologic and clinical outcomes in PMN and is being studied in a larger, randomized, placebo-controlled clinical trial.