A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis

Rovin, Brad H.; Furie, Richard; Teng, Y K Onno; Contreras, Gabriel; Malvar, Ana; Yu, Xueqing; Ji, Beulah; Green, Yulia; Gonzalez‐Rivera, Tania; Bass, Damon; Gilbride, Jennifer; Tang, Chun Hang; Roth, David A.

doi:10.1016/j.kint.2021.08.027

Cited by 110 publications

(92 citation statements)

References 34 publications

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“…Similar results were also demonstrated in a recently published secondary analysis of Study BLISS-LN. 9 Due to the limited number of patients with renal biopsy Class V (n = 72), the proteinuria dependent efficacy was inconclusive in this patient population.…”

Section: Approval Of Belimumab In Lupus Nephritis Patients With High ...mentioning

confidence: 97%

Clinical pharmacology considerations for the approval of belimumab for the treatment of adult patients with active lupus nephritis: A regulatory perspective

Liu

Neuner

Thompson

et al. 2022

Lupus

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On 16 December 2020, FDA approved Benlysta® (belimumab) for both the intravenous (IV) and subcutaneous (SC) administration routes for the treatment of adult patients with active lupus nephritis (LN) who are receiving standard therapy. This approval represents the first FDA approved treatment of patients with active LN. The approved IV dosing regimen (10 mg/kg dose Q2W for three doses, then 10 mg/kg Q4W thereafter) was based on a randomized double-blind placebo controlled clinical trial in adult patients with LN. For the approval of the SC dosing regimen (400 mg dose QW for four doses, then 200 mg QW thereafter), efficacy was supported solely by pharmacokinetics (PK) modeling and simulation which estimated a matched steady state average concentration and higher trough concentrations for the SC administration route, for bridging to the efficacy of IV belimumab in adults with LN. The safety and immunogenicity profile of the SC administration route has been assessed in the SLE studies. In a population PK analysis, higher proteinuria was associated with greater belimumab clearance and lower belimumab exposure. In an exposure response analysis, the efficacy of belimumab as evaluated by renal response was mainly driven by patients with lower proteinuria at baseline regardless of other baseline characteristics (e.g. baseline renal function, renal biopsy classification), induction therapies, or belimumab exposure levels (within 10 mg/kg dosing regimen), etc. However, post hoc analyses showed that belimumab had activity in LN patients with higher proteinuria at baseline. There is no adequate information to suggest that a higher dose would provide additional benefit for patients with lower exposure (e.g. higher proteinuria).

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Section: Approval Of Belimumab In Lupus Nephritis Patients With High ...mentioning

confidence: 97%

Clinical pharmacology considerations for the approval of belimumab for the treatment of adult patients with active lupus nephritis: A regulatory perspective

Liu

Neuner

Thompson

et al. 2022

Lupus

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“…Phase 2 studies have encouragingly shown that belimumab can effectively reduce proteinuria and anti-PLA 2 R antibody levels in MN [60]. However, in class V lupus nephritis, a form of secondary MN, belimumab did not improve rates of renal response as compared to standard of care [157]. To settle this question, a randomized controlled study investigating sequential treatment of MN with rituximab followed by belimumab is currently under way (NCT03949855).…”

Section: B Cells and The Treatment Of Membranous Nephropathymentioning

confidence: 99%

B Cells in Primary Membranous Nephropathy: Escape from Immune Tolerance and Implications for Patient Management

Yap

Chan

2021

IJMS

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Membranous nephropathy (MN) is an important cause of nephrotic syndrome and chronic kidney disease (CKD) in adults. The pathogenic significance of B cells in MN is increasingly recognized, especially following the discovery of various autoantibodies that target specific podocytic antigens and the promising treatment responses seen with B cell depleting therapies. The presence of autoreactive B cells and autoantibodies that bind to antigens on podocyte surfaces are characteristic features of MN, and are the result of breaches in central and peripheral tolerance of B lymphocytes. These perturbations in B cell tolerance include altered B lymphocyte subsets, dysregulation of genes that govern immunoglobulin production, aberrant somatic hypermutation and co-stimulatory signalling, abnormal expression of B cell-related cytokines, and increased B cell infiltrates and organized tertiary lymphoid structures within the kidneys. An understanding of the role of B cell tolerance and homeostasis may have important implications for patient management in MN, as conventional immunosuppressive treatments and novel B cell-targeted therapies show distinct effects on proliferation, differentiation and reconstitution in different B cell subsets. Circulating B lymphocytes and related cytokines may serve as potential biomarkers for treatment selection, monitoring of therapeutic response and prediction of disease relapse. These recent advances in the understanding of B cell tolerance in MN have provided greater insight into its immunopathogenesis and potential novel strategies for disease monitoring and treatment.

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“…Several agents which are effective at slowing eGFR decline are already available and might prove particularly useful in high-risk patients with LN. It has already been demonstrated that belimumab can slow eGFR decline in patients with LN as compared with standard therapy alone 26 27. It was also recently shown that dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduces the composite risk of sustained eGFR decline, ESRD, or death from a renal or cardiovascular cause in a general population with CKD, although individuals with LN were excluded 28.…”

Section: Discussionmentioning

confidence: 99%

One-third of patients with lupus nephritis classified as complete responders continue to accrue progressive renal damage despite resolution of proteinuria

et al. 2022

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ObjectiveTreatment response in lupus nephritis (LN) is defined based on proteinuria, yet protocol kidney biopsy studies have shown that patients with lupus can have active nephritis in the absence of proteinuria. Using estimated glomerular filtration rate (eGFR) trajectories, we characterised early chronic kidney disease in LN and examined whether certain patients continue to accrue renal damage despite proteinuric response.MethodsWe conducted a single-centre study of patients diagnosed with their first episode of biopsy-proven class III, IV, and/or V LN (n=37). For each patient, eGFR trajectory was graphed over 5 years following renal biopsy. Participants were divided into those with progressive eGFR loss (eGFR slope <−5 mL/min/1.73 m2/year) versus those with stable eGFR. Participant demographics, renal biopsy features and response status at 1 year (urine protein to creatinine ratio <500 mg/g) were compared between eGFR trajectory groups.ResultsOverall, 30% (n=11) of participants accrued progressive eGFR loss despite standard of care therapy over the first 5 years following renal biopsy. There were no significant differences in baseline renal biopsy features, medication regimens or comorbidities between eGFR trajectory groups. Resolution of proteinuria at 1 year did not differentiate between groups: 6 of 18 (33%) of complete responders continued to accrue renal damage compared with 5 of 17 (29%) of non-responders. Response status could not be assigned for two participants in the stable eGFR group due to missing clinical information at 1 year.ConclusionsWe identified an understudied category of patients with LN who accrue progressive renal damage despite apparent response to standard of care therapy. Better definitions and biomarkers of response are needed to improve renal outcomes and trial design.

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A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis

Cited by 110 publications

References 34 publications

Clinical pharmacology considerations for the approval of belimumab for the treatment of adult patients with active lupus nephritis: A regulatory perspective

Clinical pharmacology considerations for the approval of belimumab for the treatment of adult patients with active lupus nephritis: A regulatory perspective

B Cells in Primary Membranous Nephropathy: Escape from Immune Tolerance and Implications for Patient Management

One-third of patients with lupus nephritis classified as complete responders continue to accrue progressive renal damage despite resolution of proteinuria

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