Obinutuzumab Shows Efficacy in Systemic Lupus and Primary Membranous Nephropathy Trials

Obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody, demonstrated superior efficacy compared to placebo in treating active systemic lupus erythematosus (SLE) and showed statistically significant benefits over tacrolimus in primary membranous nephropathy, according to results from two separate phase 3 trials. The drug is approved under the brand name Gazyva for the treatment of chronic lymphocytic leukemia, follicular lymphoma, and lupus nephritis.

In the phase 3, multicenter, double-blind, placebo-controlled ALLEGORY trial (ClinicalTrials.gov number, NCT04963296), 303 adults with active SLE but without proliferative or membranous lupus nephritis were randomly assigned in a 1:1 ratio to receive obinutuzumab (1000 mg) or placebo on day 1 and weeks 2, 24, and 26. All patients were receiving standard therapy. At week 52, an SRI-4 response was observed in 76.7% of the patients in the obinutuzumab group and in 53.5% of those in the placebo group (adjusted difference, 23.1 percentage points; 95% confidence interval [CI], 12.5 to 33.6; P<0.001).

The primary end point at week 52 was a response on the SLE Responder Index 4 (SRI-4), defined by a reduction from baseline of at least 4 points in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, no worsening of disease as assessed by the British Isles Lupus Assessment Group (BILAG) 2004 index and Physician's Global Assessment, and no intercurrent events. In an additional analysis whereby nonfatal intercurrent events did not affect response status, the respective percentages were 85.4% and 68.5% (adjusted difference, 16.8 percentage points; 95% CI, 7.1 to 26.4).

Obinutuzumab was superior to placebo with respect to all key secondary end points: BILAG-based Composite Lupus Assessment response, sustained reduction in glucocorticoid dose, sustained SRI-4 response, SRI-6 response, and time to first BILAG-defined flare. Adverse events were reported in 88.7% of the patients in the obinutuzumab group and in 81.5% of those in the placebo group, and serious adverse events in 15.9% and 11.9%, respectively. One patient in the obinutuzumab group and 3 in the placebo group died during the double-blind period.

In a separate randomized, open-label phase 3 MAJESTY trial (ClinicalTrials.gov Identifier: NCT04629248), obinutuzumab was evaluated in 142 enrolled patients with primary membranous nephropathy, a chronic autoimmune kidney disease. Study participants were randomly assigned 1:1 to receive obinutuzumab or tacrolimus. The primary endpoint was the percentage of participants who achieve a complete remission (CR) at week 104.

Findings showed a statistically significantly greater percentage of patients achieved CR with obinutuzumab compared with tacrolimus at week 104. Obinutuzumab also demonstrated statistically significant and clinically meaningful benefit vs tacrolimus in key secondary endpoints, including overall remission at week 104 and complete remission at week 76. The safety profile of obinutuzumab was consistent with previously reported data. No new safety signals were identified.

Obinutuzumab is a humanized monoclonal antibody that targets the CD20 antigen on the surface of B lymphocytes. The ALLEGORY trial was funded by F. Hoffmann–La Roche, and the article was published on March 6, 2026, at NEJM.org. Full results from the MAJESTY trial will be presented at an upcoming medical meeting.