medwireNews: Adding obinutuzumab to standard therapy significantly improves renal response in adults with active lupus nephritis, shows the phase 3 REGENCY trial, published in The New England Journal of Medicine.
Obinutuzumab is a humanized type II anti-CD20 monoclonal antibody that induces B-cell depletion, and “[g]iven the importance of B cells in the pathogenesis of lupus nephritis, B-cell depletion is considered to be a scientifically sound therapeutic approach,” comment Richard Furie, from Northwell Health in Great Neck, New York, USA, and colleagues.
For the double-blind, placebo-controlled trial, they recruited 271 adults (mean age 33 years, 84.5% women) between 2020 and 2023 from 15 countries. All had biopsy-confirmed active lupus nephritis meeting the American College of Rheumatology classification criteria for systemic lupus erythematosus, with at least active class III or IV lupus nephritis.
The researchers comment that the study population was “deemed to be sufficiently diverse,” including for race and ethnicity with Hispanic or Latino, Black or African–American, and Asian patients representing 47.6%, 14.8%, and 5.9% of the group, respectively.
The patients were randomly assigned to receive intravenous obinutuzumab, at a dose of 1000 mg on day 1 and at weeks 2, 24, 26, and 52, with or without an additional dose at week 50, or placebo. The participants also started or continued to receive standard therapy with mycophenolate mofetil (target dose of 2.0–2.5 g/day by week 4 and maintained) and oral prednisone (target dose or up to 7.5 mg/day by week 12 and 5 mg/day by week 24).
The trial’s primary endpoint was a complete renal response at week 76, defined as a 24-hour urinary protein-to-creatinine ratio below 0.5, an estimated glomerular filtration rate (eGFR) of at least 85% of baseline, and no intercurrent events, such as need for rescue therapy, and treatment failure, death, or early withdrawal from the trial.
At week 76, significantly more patients in the obinutuzumab group achieved a complete renal response than those receiving placebo, at 46.4% versus 33.1%, giving a significant difference of 13.4 percentage points after accounting for geographic region and race.
The patients taking obinutuzumab were also significantly more likely than those taking placebo to achieve a complete renal response at a lower prednisone dose of 7.5 mg/day or below in weeks 64–76 (42.7 vs 30.9%).
Additionally, obinutuzumab treatment was associated with a “significant reduction in proteinuria, a surrogate for enhanced long-term kidney survival,” the investigators report, with a urinary protein-to-creatinine ratio below 0.8 without an intercurrent event achieved at week 76 by 55.5% of obinutuzumab-treated patients versus 41.9% of those taking placebo (adjusted difference, 13.7 percentage points). By contrast, eGFR increased from baseline to week 76 among those given obinutuzumab but decreased in those given placebo and did not differ significantly between the treatment arms.
The benefits of obinutuzumab remained consistent across patient subgroups, including those with class IV lupus nephritis, co-existent class V disease, or a baseline urinary protein-to-creatinine ratio of 3 or higher. However, the authors observe that men in the placebo group had a higher complete renal response rate than women (67% of 21 vs 27% of 115), which may have influenced the overall treatment effect comparison. They attribute this difference "to the relatively small number of men in the trial.”
Although overall adverse event (AE) rates were comparable, serious AEs occurred more frequently with obinutuzumab than placebo (32.4 vs 18.2%). This imbalance was primarily due to infectious AEs, which disproportionately affected the obinutuzumab arm and "appeared to be driven, in part, by Covid-19–related events," the authors state. When these events were excluded, the rate of serious infections dropped from 16.9% to 11.0% in the obinutuzumab group, while remaining at 7.6% in the placebo group.
Other common serious AEs occurring in patients taking obinutuzuamb were urinary tract infection (2.9%), pneumonia (2.9%), and gastroenteritis (2.2%). AEs of special interest occurring more with obinutuzamb than placebo included infusion-related reactions (15.4 vs 11.4%), neutropenia (12.5 vs 3.8%), and grade 3 or more severe infections (15.4 vs 6.8%).
There were four deaths during the study – three among obinutuzumab recipients (two from COVID-19 pneumonia, one from nephrotic syndrome) and one in the placebo arm (due to COVID-19).
The authors note that, bar one case of weight loss, all serious AEs and drug-related neutropenic events in the obinutuzumab-treated patients “had resolved or were resolving by week 76.”
The authors conclude that their study findings “support the hypothesis that deep B-cell depletion with obinutuzumab is an effective treatment for patients with lupus nephritis.”
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