Published June 5, 2026
N Engl J Med 2026;395:959-971
DOI: 10.1056/NEJMoa2602678
Abstract
Background
Studies of obinutuzumab, a type II anti-CD20 antibody, have shown efficacy in the treatment of hematologic cancers and autoimmune diseases. An evaluation of the efficacy and safety of obinutuzumab in patients with primary membranous nephropathy is needed.
Methods
In a phase 3 trial, we randomly assigned adults with primary membranous nephropathy in a 1:1 ratio to receive intravenous obinutuzumab or oral tacrolimus. The primary end point was complete remission (defined as a urinary protein-to-creatinine ratio of 0.3 or lower and a stable estimated glomerular filtration rate [eGFR]) at week 104. Key secondary end points were complete or partial remission at week 104, complete remission at week 76, a sustained reduction in the eGFR of at least 30%, duration of complete remission, and change in the Patient-Reported Outcomes Measurement Information System Fatigue T score from baseline to week 104. Fixed-sequence hierarchical testing was performed. Safety was assessed.
Results
A total of 142 patients underwent randomization. At week 104, complete remission was observed in 26 of 71 patients in the obinutuzumab group and in 4 of 70 patients in the tacrolimus group (37% vs. 6% with multiple imputation for missing data; adjusted difference, 31 percentage points; 95% CI, 18 to 44; P<0.001). The analyses of complete or partial remission at week 104 and complete remission at week 76 also showed a significant treatment effect. The analysis of a sustained eGFR reduction did not show a significant treatment effect; thus, subsequent end points in the hierarchy were not formally tested for significance. Adverse events of grade 3 or higher were reported in 16 patients (22%) in the obinutuzumab group and in 13 patients (19%) in the tacrolimus group; serious adverse events occurred in 12 (17%) and 10 (14%), respectively. There were 61 and 57 infections per 100 patient-years in the obinutuzumab and tacrolimus groups, respectively; 3 and 4 serious infections per 100 patient-years; and 11 and 14 serious adverse events per 100 patient-years. Adverse drug reactions with obinutuzumab included infusion-related reactions, respiratory tract infections, and neutropenia. One patient in each group died during escape therapy.
Conclusions
Obinutuzumab was superior to tacrolimus in inducing complete remission in patients with primary membranous nephropathy. (Funded by F. Hoffmann–La Roche; MAJESTY ClinicalTrials.gov number, NCT04629248.)
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Notes
This article was published on June 5, 2026, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Supported by F. Hoffmann–La Roche.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the patients and their caregivers, health care providers, and research staff who participated in this trial; the past and current members of the obinutuzumab primary membranous nephropathy team at F. Hoffmann–La Roche and Genentech, including Katherine Vernon, Ed Spinks, Sylvie Prot, Vishal Duggal, Debbie Chen, Julie Ishida, Min Bao, William Riboulet, Nykyta Petrenko, Sunny Pokala, Heather Boston, Jene Meyer, Caroline Greenan, Caroline Kamara, Tom Parsons, Harini Raghu, Jamie Haddon, Imran Hassan, Leena Khatri, Saibah Chohan, Jennifer Pulley, Marco Prunotto, Michael Johnston, Nicolas Frey, Georgina Meneses-Lorente, Mahmut Yilmaz, Mandy Dorsey, and Ann-Christin Hans; and Radhika Das Chakraborty and Danielle Lindley of Nucleus Global for medical-writing assistance with earlier drafts of the manuscript.
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History
Published online: June 5, 2026
Published in issue: September 10, 2026
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Cited by
- A Step Forward — Obinutuzumab for Membranous Nephropathy, New England Journal of Medicine, 395, 10, (1024-1026), (2026)./doi/full/10.1056/NEJMe2609719
- Emerging Immune Cell Biomarkers in Primary Membranous Nephropathy: Immune Cell Profiling During Anti-CD20 B Cell-Targeted Therapy, International Journal of Molecular Sciences, 27, 16, (7233), (2026).https://doi.org/10.3390/ijms27167233
- Ten tips for the diagnosis and management of nephrotic syndrome, Clinical Kidney Journal, 19, 9, (2026).https://doi.org/10.1093/ckj/sfag268
- Obinutuzumab for Rituximab-Intolerant Minimal Change Disease: A Case Report and Review of Recent Literature, Cureus, (2026).https://doi.org/10.7759/cureus.114295
- Efficacy and safety of obinutuzumab in refractory membranous nephropathy: a single-arm meta-analysis, Frontiers in Immunology, 17, (2026).https://doi.org/10.3389/fimmu.2026.1880420
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