Obinutuzumab Shows Promise for Lupus Nephritis in Phase 3 Trial

The REGENCY (NCT04221477) phase 3 trial demonstrated that obinutuzumab paired with standard therapy had greater efficacy than standard therapy alone in treating lupus nephritis. Study results from Richard A. Furie, MD, and colleagues were published in the New England Journal of Medicine.

Obinutuzumab is a humanized type 2 anti-CD20 monoclonal antibody that is approved to treat chronic lymphocytic leukemia and follicular lymphoma. In the previous NOBILITY trial, researchers compared obinutuzumab plus standard therapy (mycophenolate mofetil and glucocorticoids) with standard therapy alone among patients with lupus nephritis.

They found that obinutuzumab use, compared with placebo, resulted in clinically meaningful improvements among patients with a complete renal response at 52, 76, and 104 weeks. In addition, the drug prolonged the time to a lupus nephritis flare and an unfavorable kidney outcome (a composite of treatment failure, doubling of the serum creatinine level, or death). Treatment with obinutuzumab also lessened estimated glomerular filtration rate (eGFR) decline compared with placebo.

Following up on those results, REGENCY assessed the efficacy and safety of obinutuzumab plus standard therapy among a population with active, proliferative lupus nephritis. The randomized, double-blind, placebo-controlled trial was carried out in 15 countries and included 271 adults.

Participants were aged 18 to 75 years; met American College of Rheumatology classification criteria for systemic lupus erythematosus; and had active class 3 or 4 lupus nephritis with or without concomitant class 5 disease (according to the International Society of Nephrology and the Renal Pathology Society), biopsy-confirmed during screening or within 6 months. In addition, participants had 24-hour urine protein to creatine ratio (UPCR) of 1 mg/mg or higher and antinuclear antibody (ANA) positivity (an ANA titer of ≥1:80 on HEp-2 cells or ≥1 equivalent positive ANA test result).

Patients were randomized 1:1 to receive either IV infusions of obinutuzumab (n=135) or placebo (n=136). Obinutuzumab was administered on 1 of 2 dose schedules: 1,000 mg on day 1 and at weeks 2, 24, 26, and 52, with or without an additional dose at week 50.

Of all participants, 14.8% were Black or African American, 5.9% were Asian, and 57.6% were Hispanic or Latino. In the obinutuzumab group, the mean (SD) patient age was 33.0±10.5 years and 84.4% were women. In the placebo group, the mean (SD) patient age was 32.7±10.0 years and 84.6% were women. In the obinutuzumab group, the mean eGFR was 102.8±29.3 mL/min/1.73 m² and mean UPCR was 3.14±2.99 mg/mg. In the placebo group, the mean eGFR was 101.9±32.2 mL/min/1.73 m² and the mean UPCR was 3.53±2.76 mg/mg.

Among participants with previously diagnosed lupus nephritis (obinutuzumab group: n=81; placebo group: n=76) versus those who were newly diagnosed, the median duration since the first lupus nephritis diagnosis was 36.6 months (range, 0.4-330.4) for the obinutuzumab group and 34.3 months (range, 0.8-217.8) for the placebo group.

The primary end point of the study was a complete renal response at week 76; this was defined as 24-hour UPCR lower than 0.5 mg/mg; eGFR at least 85% of baseline value; and no occurrence of an intercurrent event (rescue therapy, treatment failure, death, or early trial withdrawal). Secondary end points included a complete renal response with a prednisone dose of 7.5 mg/day or lower between weeks 64 and 76 and a UPCR lower than 0.8 mg/mg without an intercurrent event at week 76.

At week 76, a complete renal response was seen in 46.4% of participants in the obinutuzumab group compared with 33.1% in the placebo group (adjusted difference, 13.4 percentage points; 95% CI, 2.0-24.8; P=0.02). The placebo group had a higher percentage of patients with treatment failure (17.6%) compared with the obinutuzumab group (3.7%). Similarly, the placebo group had a higher percentage of patients receiving rescue therapy compared with the obinutuzumab group (17.6% vs 5.9%).

A complete renal response between weeks 64 and 76 with a prednisone dose of 7.5 mg or lower occurred in 42.7% of the patients in the obinutuzumab group and 30.9% in the placebo group (adjusted difference, 11.9 percentage points; 95% CI, 0.6-23.2; P=0.04). At week 76, the percentage of participants with a UPCR lower than 0.8 mg/mg with no intercurrent event was 55.5% in the obinutuzumab group and 41.9% in the placebo group (adjusted difference, 13.7 percentage points; 95% CI, 2.0-25.4; P=0.02).

An exploratory analysis using the primary end point, but with death as the only intercurrent event, yielded results consistent with the primary analysis. Results of prespecified subgroup analyses were mostly consistent across the subgroups, including patients with class 4 lupus nephritis, concomitant class 5 lupus nephritis, a baseline UPCR of 3 mg/mg or higher, or serologic activity.

The percentage of participants who experienced adverse events was comparable in the obinutuzumab (92.6%) and placebo groups (88.6%). More serious adverse events occurred in the obinutuzumab group (32.4%) than in the placebo group (18.2%). The most common serious adverse events among the obinutuzumab group participants were infections.

The authors concluded that, “In this trial involving adults with biopsy-proven active lupus nephritis, the addition of obinutuzumab to standard therapy led to a significantly greater percentage of patients with a complete renal response at week 76 than standard therapy alone.”