Background Obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody, induces potent B-cell depletion and is approved for the treatment of active lupus nephritis. Its efficacy and safety in patients with active systemic lupus erythematosus (SLE) are yet to be determined. Methods We conducted a phase 3, multicenter, double-blind, placebo-controlled trial involving adults with active SLE but without proliferative or membranous lupus nephritis who were receiving standard therapy. Patients were randomly assigned in a 1:1 ratio to receive obinutuzumab (1000 mg) or placebo on day 1 and weeks 2, 24, and 26. In the prespecified analysis, 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 (i.e., major concomitant-therapy violation, receipt of rescue medication, or early discontinuation of trial participation due to death, lack of efficacy, or adverse events). Results Of 303 patients who underwent randomization, 151 were assigned to receive obinutuzumab and 152 to receive placebo. 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). 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. Conclusions Among adults with active SLE, treatment with obinutuzumab was superior to placebo with respect to the primary and all key secondary end points.
Furie, R. A., Dall'Era, M., Vital, E. M., Garg, J. P., Irazoque Palazuelos, F., Zuta Santillán, A. E., Ravelo-Hernández, J., Santiago, M. B., Zazueta Montiel, B., Botha, S., Leszczyński, P., De Souza, V. A., Sicsik, S. A., Bellatin, L., Naidoo, A., Amoura, Z., D'Agostino, M. A., Kumar, S., Workeneh, B., Rae, J., Mao, H. A., Erblang, F., Meier, O., Maller, J. C., Askanase, A. D., Efficacy and Safety of Obinutuzumab in Active Systemic Lupus Erythematosus, <<THE NEW ENGLAND JOURNAL OF MEDICINE>>, 2026; (marzo): N/A-N/A. [doi:10.1056/NEJMoa2516150] [https://hdl.handle.net/10807/337136]
Efficacy and Safety of Obinutuzumab in Active Systemic Lupus Erythematosus
D'Agostino, Maria Antonietta;
2026
Abstract
Background Obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody, induces potent B-cell depletion and is approved for the treatment of active lupus nephritis. Its efficacy and safety in patients with active systemic lupus erythematosus (SLE) are yet to be determined. Methods We conducted a phase 3, multicenter, double-blind, placebo-controlled trial involving adults with active SLE but without proliferative or membranous lupus nephritis who were receiving standard therapy. Patients were randomly assigned in a 1:1 ratio to receive obinutuzumab (1000 mg) or placebo on day 1 and weeks 2, 24, and 26. In the prespecified analysis, 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 (i.e., major concomitant-therapy violation, receipt of rescue medication, or early discontinuation of trial participation due to death, lack of efficacy, or adverse events). Results Of 303 patients who underwent randomization, 151 were assigned to receive obinutuzumab and 152 to receive placebo. 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). 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. Conclusions Among adults with active SLE, treatment with obinutuzumab was superior to placebo with respect to the primary and all key secondary end points.
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