Obinutuzumab reached complete remission in 37% of primary membranous nephropathy against 6% on tacrolimus

Design

phase 3 randomised controlled trial, 1:1 allocation, fixed-sequence hierarchical testing

Population

142 adults with primary membranous nephropathy

Primary outcome

complete remission at week 104 - urine protein-to-creatinine ratio 0.3 or lower with stable eGFR

Effect

37% versus 6%; adjusted difference 31 percentage points (95% CI 18-44, p<0.001); grade 3 or higher adverse events 22% versus 19%

MAJESTY, published in June, randomised 142 adults with primary membranous nephropathy 1:1 to intravenous obinutuzumab or oral tacrolimus in a phase 3 trial. The primary endpoint was complete remission at week 104 - urinary protein-to-creatinine ratio of 0.3 or less with a stable eGFR.

Complete remission occurred in 26 of 71 on obinutuzumab and 4 of 70 on tacrolimus; with multiple imputation for missing data, 37% against 6%, an adjusted difference of 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. Then the hierarchy stopped: sustained eGFR reduction of at least 30% showed no significant treatment effect, so every endpoint below it in the fixed sequence - including duration of remission and fatigue score - was not formally tested. Grade 3 or higher adverse events occurred in 22% versus 19%, serious adverse events in 17% versus 14%, and infection rates were similar at 61 and 57 per 100 patient-years. One patient in each group died during escape therapy.

For a disease where tacrolimus has been a mainstay and relapse on withdrawal is the recurring problem, a six-fold difference in complete remission is a large finding. Two caveats belong in the same breath: 142 patients is modest for a phase 3 trial, and the failure at the eGFR endpoint means this is a proteinuria result, not yet a kidney-survival one. In Indian practice cost will decide most cases, and rituximab - not compared here - remains the anti-CD20 antibody most patients can actually access.

• Confirm PLA2R status and exclude secondary causes before any immunosuppression decision
• Discuss anti-CD20 therapy versus a calcineurin inhibitor explicitly in terms of remission durability
• Note that rituximab was not the comparator - this trial does not rank the two anti-CD20 antibodies
• Set the expectation as proteinuric remission; the eGFR endpoint was not met
• Screen for hepatitis B and latent infection before B-cell depletion, and monitor neutrophils

Why it matters

Membranous nephropathy has been managed with calcineurin inhibitors whose benefit largely disappears on withdrawal, and this is a direct randomised comparison against one.

Don't overread it

The sustained eGFR endpoint was not met - this establishes remission of proteinuria, not preservation of kidney function.

The statistics, in plain English

The hierarchy is the part worth understanding. Fixed-sequence testing means endpoints are tested in a preset order and testing stops at the first failure - so when sustained eGFR reduction showed no effect, everything after it became descriptive rather than statistically supported, however good the numbers look. That is a discipline that protects against false positives, and it means the trial has demonstrated a proteinuria benefit and has not demonstrated preservation of kidney function. With 142 patients and 104 weeks, it was never going to: eGFR decline in membranous nephropathy is slow, and this trial was not sized for it.

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