The anti-CD20 therapeutic antibody obinutuzumab (Gazyva/Gazyvaro) significantly reduces multiple measures of disease activity when compared with placebo in people with active systemic lupus erythematosus (SLE) who are already receiving standard of care treatment, according to the results of the phase 3 ALLEGORY trial.

Treatment with obinutuzumab led to a significantly higher response rate vs placebo on the primary endpoint of a minimum 4-point improvement in the SLE Responder Index-4 (SRI-4) at 52 weeks (76.7% vs 53.5%). All the trial’s secondary endpoints were significantly in favor of obinutuzumab as well.

“I don’t think we’ve ever had a lupus study that was successful with all key secondary endpoints being positive,” the trial’s principal investigator, Richard Furie, MD, told Medscape Medical News.

Furie, who presented these data last week at the 15th European Lupus meeting, SLEuro 2026, in Lisbon, Portugal, to coincide with their publication in The New England Journal of Medicine, is the chief of the Division of Rheumatology at Northwell Health and professor at the Feinstein Institutes for Medical Research in Manhasset, New York.

Obinutuzumab was approved by the FDA in October 2025 for the treatment of adult patients with lupus nephritis who are receiving standard therapy.

Highlights of the trial’s secondary endpoints in favor of obinutuzumab include:

• Response at 1 year on the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (62.0% vs 40.1%);
• For patients taking ≥ 10 mg/d prednisone (or equivalent) at baseline, reduction of the prednisone dose to ≤ 7.5 mg/d (or equivalent) by week 40 and maintained through week 52 (80.0% vs 54.1%);
• Sustained responses between weeks 40 and 52 in the SRI-4 (72.0% vs 46.4%) and SRI-6 (68.9% vs 38.9%); and
• A lower likelihood of experiencing a first BILAG-defined disease flare by 52 weeks (33.8% vs 48.7%; hazard ratio, 0.58; 95% CI, 0.40-0.82; P = .002). The median time to flare was 52.3 weeks for placebo but could not be determined for obinutuzumab.

From the everyday perspective, Furie said what probably matters most to clinicians and their patients is that more obinutuzumab- than placebo-treated patients at 52 weeks achieved the definition of remission in SLE response (35.1% vs 13.8%) and lupus low disease activity state (57.6% vs 25.0%).

Fellow study investigator Edward Vital, MBChB, PhD, an honorary consultant rheumatologist at Leeds Teaching Hospitals NHS Trust in West Yorkshire, England, told Medscape Medical News separately that the trial “proves the principle that B-cell depletion is an effective strategy, and that developing treatments that are the most efficient at B-cell killing is the secret to getting the best efficacy.”

ALLEGORY: Assessing Obinutuzumab in Active SLE

ALLEGORY had the standard design of a phase 3 trial: it was double-blind, randomized, and placebo-controlled; had a 1-year primary endpoint; and was conducted across multiple sites across North and South America and Europe.

“We were looking for very active patients,” Furie explained. That meant an SLE Disease Activity Index 2000 score of 8 or higher, at least one BILAG domain A score and/or two BILAG domain B scores, and they had to be autoantibody positive. Patients also had to be hypocomplementemic, meaning low C3, C4, or CH50 complement levels.

In total, 303 patients with active SLE were enrolled and randomly assigned 1:1 to obinutuzumab (1000 mg) or matching placebo on top of their existing standard of care. Patients were receiving stable doses of at least one of the following classes of standard therapy: antimalarial agents, nonglucocorticoid immunosuppressants, or glucocorticoids. Obinutuzumab or a matching placebo was given by intravenous infusion 2 weeks apart to start with, with repeat dosing 6 months later. Acetaminophen 650-1000 mg, diphenhydramine 50 mg, and intravenous methylprednisolone 80 mg were given prior to infusions.

“The safety data were fairly similar to other therapies,” Vital observed. The percentage of patients experiencing any adverse event was 88.7% in the Obinutuzumab group and 81.5% in the placebo group, while the percentage experiencing serious adverse events was 15.9% and 11.9%, respectively. There was one death in the obinutuzumab arm due to a soft-tissue infection and pneumonia and three deaths in the placebo arm, which involved patients with a pulmonary alveolar hemorrhage, myocarditis with sepsis, and an SLE flare.

Infection is a risk with having lupus, but that risk is related as much to do the disease itself and the immune system not working properly as it is to its treatment, which involves immunosuppressive therapies such as glucocorticoids that are known to increase the risk for infection, Vital said.

“So, if you get a drug that gets rid of the steroids, gets rid of the disease activity, sometimes your infection risk can actually go down because you become a healthier person with a more normal immune system and less steroid use then,” he observed.

‘Strong Study’ in Extrarenal Lupus

Commenting on the study for Medscape Medical News, Shivani Garg, MD, PhD, an associate professor at Yale School of Medicine in New Haven, Connecticut, said: “Overall, it is a strong study and offers [obinutuzumab] as a good alternative for patients with extrarenal lupus.”

Garg, who directs the Yale Lupus Clinical Research Program and is co-director of the Yale Lupus Program, noted that this “is exciting as patients have more options now, and [it is] promising to see multiple organ responses in severe lupus.”

However, she observed that “more data on organ-specific manifestation responses and head-to-head comparison[s] with existing therapies are needed to guide where this medicine fits in the current therapeutic armamentarium.” 

Moreover, it will be important to understand the benefits and harms, Garg said, “so that patients can feel supported in their decisions and care can be personalized at an individual patient level.”

F. Hoffman-La Roche sponsored the study. Furie and Vital were investigators for the trial and acknowledged receiving research support and other consultancy fees from F. Hoffman-La Roche, among other companies. Garg reported having no relevant financial relationships.

Sara Freeman is a freelance medical journalist based in London, England.