FDA approves obinutuzumab (Gazyva) for primary membranous nephropathy after Phase III MAJESTY trial showed higher complete proteinuria remission.
The US Food and Drug Administration (FDA) has approved Gazyva (obinutuzumab) injection for adults with primary membranous nephropathy (pMN) at risk of disease progression, to induce remission of proteinuria. The approval is supported by Phase III MAJESTY trial findings, which demonstrated significantly higher complete proteinuria remission with obinutuzumab than with tacrolimus at Week 104.
FDA Approval Introduces a Disease-Specific Treatment
The approval marks the first FDA authorization of a drug specifically for adults with primary membranous nephropathy, an immune-mediated kidney disease associated with progressive protein loss and potential kidney failure.
Obinutuzumab was previously approved for certain cancers, active lupus nephritis and childhood-onset idiopathic nephrotic syndrome. Its latest indication expands its therapeutic use into primary membranous nephropathy, where tacrolimus and other immunosuppressive treatments have been used despite the absence of a specifically approved treatment.
Primary Membranous Nephropathy and Its Clinical Impact
Primary membranous nephropathy is a rare kidney disease caused by an immune-mediated attack on the glomeruli, the small filtering structures responsible for removing waste products from the blood. Damage to these structures increases protein leakage into the urine, resulting in proteinuria.
The disease can cause high cholesterol, hypertension, severe swelling, fatigue and progressive kidney damage. Some patients eventually develop kidney failure and other complications. Reducing proteinuria and achieving remission are therefore important treatment objectives, as persistent protein loss is associated with an increased risk of disease progression.
Phase III MAJESTY Trial Supported the Approval
The approval was supported by MAJESTY (NCT04629248), a Phase III, randomized, controlled, open-label, multicentre study evaluating the efficacy and safety of obinutuzumab in adults with primary membranous nephropathy.
The trial enrolled 142 adults who were assigned to receive either intravenous obinutuzumab or oral tacrolimus, an immunosuppressive treatment sometimes used off-label for this condition. The main study period extended to 104 weeks.
The primary endpoint was complete remission of proteinuria at Week 104. This required a urine protein-to-creatinine ratio (UPCR) of no more than 0.3 g/g, accompanied by stable estimated glomerular filtration rate (eGFR). Participants also had to remain free from rescue therapy, treatment failure and early study discontinuation to qualify.
Higher Complete Remission with Obinutuzumab
At Week 104, complete proteinuria remission was achieved by 36% of participants receiving obinutuzumab, compared with 6% receiving tacrolimus. The difference was statistically significant, representing an absolute treatment difference of 30 percentage points in the FDA-reported results.
The published MAJESTY trial results in the New England Journal of Medicine reported a corresponding remission rate of 37% versus 6% using multiple imputation for missing data, with an adjusted difference of 31 percentage points (95% CI, 18–44; P<0.001).
These findings establish the superiority of obinutuzumab over tacrolimus for the trial’s primary endpoint of complete proteinuria remission. However, the results also require consideration alongside the study’s kidney-function outcomes.
Safety Profile and Boxed Warnings
Obinutuzumab carries boxed warnings for hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML), a rare and serious brain infection associated with weakened immune function.
The most common adverse reactions reported in the primary membranous nephropathy study were infusion-related reactions and upper respiratory tract infections. The published trial also reported neutropenia among the adverse drug reactions.
Grade 3 or higher adverse events occurred in 22% of participants receiving obinutuzumab compared with 19% receiving tacrolimus. Serious adverse events were reported in 17% and 14%, respectively. These findings highlight the importance of assessing infection risk, monitoring requirements and treatment suitability.
FDA Regulatory Designations
Before approval, obinutuzumab received three FDA regulatory designations for primary membranous nephropathy: Breakthrough Therapy, Orphan Drug and Priority Review. These designations supported the development and regulatory review of the treatment for a rare disease with an unmet medical need.
Clinical Interpretation
The approval introduces the first specifically authorized treatment for adults with primary membranous nephropathy at risk of disease progression. The higher complete proteinuria remission rate compared with tacrolimus provides evidence of improved efficacy against the trial’s primary endpoint.
However, the kidney-function findings warrant a more cautious interpretation. In the published MAJESTY results, obinutuzumab did not demonstrate a statistically significant treatment effect on sustained eGFR reduction of at least 30%. Consequently, subsequent endpoints in the hierarchical testing sequence were not formally tested for statistical significance.
This distinction is clinically important. Although complete proteinuria remission included a requirement for stable eGFR, the trial did not establish that obinutuzumab provides superior long-term preservation of kidney function or prevents kidney failure.
The boxed warnings for HBV reactivation and PML also remain important considerations when selecting patients. Overall, MAJESTY supports obinutuzumab’s efficacy in achieving complete proteinuria remission, while longer-term kidney outcomes and its safety profile remain relevant to treatment decisions.
References
FDA Approves First Drug to Treat Adults with Primary Membranous Nephropathy, US FDA, 13 November 2026
Fervenza FC, et al. Obinutuzumab or Tacrolimus in Primary Membranous Nephropathy. New England Journal of Medicine. 2026;395:959–971. doi:10.1056/NEJMoa2602678.
A Study Evaluating the Efficacy and Safety of Obinutuzumab in Participants with Primary Membranous Nephropathy (MAJESTY), ClinicalTrials.gov ID NCT04629248
