Obinutuzumab significantly reduces disease activity in SLE

medwireNews: Adding obinutuzumab to standard therapy for systemic lupus erythematosus (SLE) significantly reduces disease activity, say ALLEGORY trialists.

The type II anti-CD20 monoclonal antibody “induces potent B-cell depletion,” note the researchers, which growing evidence suggests “is a major contributor to enhanced clinical responses in autoimmune diseases.”

For the phase 3 trial, the team, led by Richard Furie (Northwell, Great Neck, New York, USA), randomly assigned 303 adults with SLE and no proliferative or membranous lupus nephritis to receive obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24, and 26. The use of standard immunosuppressive medications, such as azathioprine, methotrexate, and mycophenolate mofetil,  was comparable in the two groups, with corresponding rates of 70.9% and 67.1%.

The patients had a mean age of 41 years and 90% were women. Their Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores were 8 points or higher (mean 13 points), reflecting moderate to severe disease activity, with 65% of patients in each group scoring at least 12 points.

The study participants also had at least one domain A (severe disease activity) score or at least two domain B (moderate disease activity) scores on the British Isles Lupus Assessment Group (BILAG) 2004 index, and a mean Physician’s Global Assessment (PGA) score of 1.9 points on a 3.0-point visual analog scale, with higher scores indicating greater disease activity.

At week 52 of follow-up, 76.7% of 151 patients given obinutuzumab and 53.5% of 152 individuals given placebo met the criteria for response on the SLE Responder Index 4 (SRI-4), which was a significant difference.

The SRI-4 criteria for response comprised at least a 4-point reduction in SLEDAI-2K score from baseline, no worsening of disease on the BILAG 2004 index and PGA, and no intercurrent events, such as major concomitant-therapy violation, receipt of rescue medication, or early discontinuation from the trial due to death, lack of efficacy or adverse events.

The researchers found that a treatment difference in SLEDAI-2K score with obinutuzumab was evident from week 24 and sustained to week 52.

A significantly superior treatment benefit over placebo was also seen for all the key secondary endpoints – including BICLA response, sustained reduction from weeks 40 to 52 in the prednisone (or equivalent) dose to 7.5 mg/day or less among patients taking at least 10 mg/day at baseline, sustained SRI-4 response, SRI-6 response, and time to first BILAG flare.

Furie and colleagues highlight in The New England Journal of Medicine that a glucocorticoid-sparing effect was seen in 80.0% of patients in the obinutuzumab arm versus 54.1% of those in the placebo, and 33.8% versus 48.7% had a BILAG flare during the study period.

These treatment effects “together address two of the most critical unmet needs in long-term care of patients with SLE,” they say.

The study authors report that “[n]o new or unexpected safety signals were identified in the current trial,” although adverse event (AE) rates were higher in the obinutuzumab group than the placebo group, at 88.7% versus 81.5%.

Grade 3 or higher AEs occurred in a respective 16.6% and 13.9% of patients, and serious AEs in 15.9% and 11.9%. The most common serious AEs with obinutuzumab were pneumonia (2.0%), and upper respiratory tract infections, urinary tract infections, and infusion-related reactions (1.3% each). A total of four patients died: one in the obinutuzumab group due to soft-tissue infection and pneumonia, and three in the placebo group, from pulmonary alveolar hemorrhage, myocarditis with sepsis, and an SLE flare.

Obinutuzumab “resulted in rapid and durable peripheral B-cell depletion,” the researchers observe, with complete B-cell depletion seen by week 2 in 98.5% of patients receiving the drug, compared with 5.6% of those given placebo, and patients sustained more than 92% depletion throughout the 52 weeks.

The team adds, however, that “further investigation is needed to evaluate tissue-level B-cell depletion and correlations with clinical responses.”

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N Engl J Med 2026; doi:10.1056/NEJMoa2516150