Obinutuzumab Induced Decreases of PLA2R Antibodies in Membranous Nephropathy: a Pilot Study
brief summary
Objective: To assess the disappearance rate (half-life) of anti-PLA2R antibodies in high-risk primary membranous nephropathy (pMN) patients treated with obinutuzumab (OBI), and to evaluate immunological and clinical remission, adverse events, and quality of life. Design: Open-label, single-center, prospective pilot intervention study conducted at Radboud University Medical Center. Population: 20 adult patients with high-risk PMN, defined by proteinuria ≥3.5 g/24h despite 6 months of supportive treatment with ACE inhibitors or ARBs. Intervention: OBI 1000 mg on days 1 and 15, with two additional infusions after 6 months if anti-PLA2R antibody levels remain positive and proteinuria exceeds 2 g/24h. Follow-up: Patients were monitored at baseline, and at weeks 1, 2, 4, 8, 12, 24, 37, and 52.
detailed description
Rationale:
Primary membranous nephropathy (PMN) is a leading cause of nephrotic syndrome in adults and is characterized by subepithelial immune complex deposits in the glomerular basement membrane. The disease is associated with circulating auto-antibodies targeting the M-type phospholipase A2 receptor (PLA2R), present in 70-80% of patients.
Despite advances in understanding its pathogenesis, the optimal treatment of PMN remains suboptimal; as the response to immunosuppressive therapy is often limited and slow. When considering treatment in PMN, the overall response rate is important, but in high-risk PMN patients the rapidity of response is even more important. As so, ideally we should be able to identify non-responders and slow-responders before or within a few months after start of therapy. A regimen consisting of rituximab (RTX), cyclophosphamide (CP) and steroids (triple therapy) has proven that a rapid immunological and clinical remission in PMN patients is possible. Obinutuzumab (OBI), a next-generation fully humanized anti-CD20 monoclonal antibody, offers enhanced B cell depletion through greater antibody-dependent cytotoxicity and reduced complement activation when compared to RTX. Retrospective studies suggests that OBI demonstrates superior efficacy in the treatment of treatment-refractory PMN patients compared to RTX, while maintaining a similar safety profile. It has been proven effective in the treatment of proliferative lupus nephritis compared to standard-of-care. These studies not only suggested better overall response, but the data also indicated a more rapid onset of remission.
Objective:
The primary objective of this pilot study is to calculate disappearance rate (half-life) of anti-PLA2R antibodies in PMN patients treated with OBI. We hypothesize that OBI monotherapy might be able to induce a rapid immunological response comparable to triple therapy in high-risk PLA2Rab-associated PMN patients. Secondary outcome measures are immunological remission, complete or partial clinical remission, adverse events and quality of life.
Main trial endpoint:
The main trial endpoint is the disappearance rate (half-life) of anti-PLA2R antibodies in PMN patients after treatment with OBI.
Secondary trial endpoints:
Immunological remission defined as IFT negative. Efficacy on clinical disease activity, defined as either CR or PR at 12 months. Adverse events. Quality of life during OBI treatment.
official title
Obinutuzumab Induced Decreases of PLA2Rab in MN: a Pilot Study