Obinutuzumab beats tacrolimus in membranous nephropathy — on proteinuria

Design

Phase 3 randomised open-label trial with fixed-sequence hierarchical testing (MAJESTY)

Population

142 adults with primary membranous nephropathy randomised 1:1

Primary outcome

Complete remission at week 104 (urinary protein-to-creatinine ratio 0.3 or lower with stable eGFR)

Effect

37% vs 6% (26/71 vs 4/70); adjusted difference 31 percentage points (95% CI 18-44), P<0.001. Sustained eGFR reduction of at least 30% did not differ significantly. Grade 3 or higher adverse events 22% vs 19%; serious adverse events 17% vs 14%

Primary membranous nephropathy is the commonest cause of nephrotic syndrome in non-diabetic adults, and the choice between calcineurin inhibition and B-cell depletion has been argued for years. MAJESTY randomised 142 adults to intravenous obinutuzumab, a type II anti-CD20 antibody, or oral tacrolimus.

At week 104, complete remission — urinary protein-to-creatinine ratio of 0.3 or lower with stable eGFR — occurred in 26 of 71 on obinutuzumab against 4 of 70 on tacrolimus: 37% versus 6%, an adjusted difference of 31 percentage points (95% CI 18 to 44). Complete or partial remission at two years, and complete remission at 76 weeks, also favoured obinutuzumab.

The sentence that matters comes next in the hierarchy. The analysis of sustained eGFR reduction of at least 30% did not show a significant treatment effect, and because the testing was fixed-sequence, everything below it — including duration of remission and fatigue — was not formally tested. So the trial establishes superiority for remission of proteinuria and has not demonstrated preservation of kidney function.

Safety was broadly comparable: grade 3 or higher adverse events in 22% versus 19%, serious adverse events 17% versus 14%, and similar infection rates. Obinutuzumab brought infusion reactions, respiratory infections and neutropenia.

• The demonstrated benefit is complete remission of proteinuria at two years
• Kidney function preservation was not demonstrated, and endpoints below it were not tested
• Safety was comparable, with infusion reactions and neutropenia specific to obinutuzumab
• Cost and infusion capacity will decide availability in most Indian settings
• Anti-PLA2R antibody status was not part of the reported endpoints here

Why it matters

It offers a two-dose antibody in place of two years of a calcineurin inhibitor, if the outcome you are treating is proteinuria.

Don't overread it

Remission of proteinuria is a surrogate; this trial did not demonstrate that obinutuzumab preserves kidney function.

The statistics, in plain English

A 31 percentage point absolute difference is large, and the interval (18 to 44) is well clear of zero. The important structural point is the hierarchy: when a prespecified endpoint in a fixed sequence fails, everything after it is exploratory by design, however impressive it looks. Here that means the eGFR result stops the chain, and 142 patients is too few and two years too short to detect a difference in kidney survival anyway.

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