Obinutuzumab or Tacrolimus in Primary Membranous Nephropathy
In a phase 3 randomized trial (MAJESTY) of 142 adults with primary membranous nephropathy, the type II anti-CD20 antibody obinutuzumab produced complete remission at two years in 37% of patients versus 6% with tacrolimus, with comparable rates of serious adverse events and infections.
Background
Obinutuzumab is a type II anti-CD20 antibody already used in haematologic cancers and autoimmune disease. Its efficacy and safety in primary membranous nephropathy had not previously been evaluated against an active comparator in a phase 3 setting.
Study design
Adults with primary membranous nephropathy were randomly assigned 1:1 to intravenous obinutuzumab or oral tacrolimus. The primary endpoint was complete remission at week 104, defined as a urinary protein-to-creatinine ratio of 0.3 or lower together with a stable estimated glomerular filtration rate. Key secondary endpoints included complete or partial remission at week 104, complete remission at week 76, a sustained eGFR reduction of at least 30%, duration of complete remission, and change in PROMIS Fatigue T score. Endpoints were tested in a fixed-sequence hierarchy.
Key findings
142 patients underwent randomization. At week 104, complete remission occurred in 26 of 71 patients on obinutuzumab and 4 of 70 on tacrolimus (37% vs. 6% with multiple imputation; adjusted difference 31 percentage points, 95% CI 18 to 44; P<0.001). Complete or partial remission at week 104 and complete remission at week 76 also favoured obinutuzumab. The analysis of sustained eGFR reduction did not show a significant treatment effect, so subsequent endpoints in the hierarchy were not formally tested.
Safety
Grade 3 or higher adverse events were reported in 16 patients (22%) on obinutuzumab and 13 (19%) on tacrolimus; serious adverse events occurred in 12 (17%) and 10 (14%) respectively. Infection rates were 61 and 57 per 100 patient-years, with 3 and 4 serious infections 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.
Clinical implications
For patients with primary membranous nephropathy at risk of progression, obinutuzumab offers a substantially higher chance of complete remission than tacrolimus with a broadly similar short-term safety profile. Because the trial did not demonstrate a significant effect on sustained eGFR decline, longer follow-up is needed before claiming preservation of kidney function, and CNI therapy remains relevant where anti-CD20 agents are unavailable or contraindicated.
Category
News
Source
The New England Journal of Medicine
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