Add-on obinutuzumab yields robust treatment benefit in lupus nephritis

In a post hoc analysis using the phase III REGENCY study dataset, obinutuzumab on top of standard therapy (ST) demonstrates significant superiority to placebo plus ST across numerous renal response definitions in patients with active lupus nephritis (LN).

“Obinutuzumab is an anti-CD20 monoclonal antibody that is a far more potent B-cell-depleting agent than its predecessors … REGENCY is the first positive registrational study of [obinutuzumab in] active LN,” said Dr Richard Furie from Northwell Health, Great Neck, New York, US, at EULAR 2025. “REGENCY met its primary endpoint of complete renal response (CRR) at week (W) 76.”

A total of 271 participants were randomized 1:1 to receive obinutuzumab (five or six doses) or placebo. All patients receive background ST comprising mycophenolate mofetil (target dose 2–2.5 g/day) plus glucocorticoids. At least one dose of IV methylprednisolone (250–1,000 mg) was administered prior to the first infusion, while prednisone 0.5 mg/kg/day was given until day 15, which was tapered to 5 mg/day by W24 and maintained until W80.

Nearly half (46.4 percent) of the participants receiving obinutuzumab plus ST achieved CRR, as opposed to only a third in the placebo plus ST arm. A comparison between arms yielded a treatment difference of 13.4 percent (p=0.02). [EULAR 2025, abstract OP0006]

According to Furie, CRR includes urine protein-to-creatinine ratio (UPCR) <0.5 g/g, estimated glomerular filtration rate (eGFR) ≥85 percent of baseline, and the absence of rescue therapy, treatment failure, death, and/or early study withdrawal.

More patients on the obinutuzumab vs placebo regimen achieved the key secondary endpoints of CRR at W76 with prednisone taper (42.7 percent vs 30.9 percent; treatment difference, 11.88 percent; p=0.0421) and proteinuric response at W76 (55.5 percent vs 41.9 percent; treatment difference, 13.68 percent; p=0.0227).

Exploratory analysis

The obinutuzumab arm had fewer participants who experienced an LN flare than the placebo arm (11.1 percent vs 23.5 percent; hazard ratio [HR], 0.44; p=0.0074). An LN flare was defined as a ≥20-percent reduction in eGFR vs W24 in patients with UPCR >1 g/g and/or cellular casts, a UPCR increase*, and receipt of rescue therapy except for glucocorticoid-only rescue.

There were also significantly fewer obinutuzumab vs placebo recipients who experienced an unfavourable kidney-related outcome, which includes death, doubling of serum creatinine, or treatment failure (8.1 percent vs 21.3 percent; HR, 0.37; p=0.0039).

Consistent benefit

“The intent of this analysis was not to compare trial results across the three major LN trials; rather, it was to borrow metrics from BLISS-LN, a study of belimumab, and AURORA-1, a study of voclosporin, to confirm the benefits that we saw in the REGENCY trial,” Furie explained.

The superiority of obinutuzumab to placebo mirrored the patterns seen in the analyses using the modified BLISS-N primary efficacy RR (51.8 percent vs 39.7 percent; treatment difference, 12.1 percent; p=0.0432) and CRR (48.7 percent vs 33.1 percent; treatment difference, 15.7 percent; p=0.0084) definitions at W76, and the modified AURORA-1 CRR definition at W76 (48.7 percent vs 33.8 percent; treatment difference, 15 percent; p=0.0117).

Furie and colleagues noted that the effect size of the benefit of obinutuzumab over placebo at W76 was consistent (between 13 percent and 16 percent), regardless of the outcome measure composition, as well as the stringency of the individual outcome thresholds.

“Whilst cross-trial comparisons are challenging, a robust treatment benefit of obinutuzumab plus ST appears to be maintained when applying modified response definitions from the BLISS-LN and AURORA-1 trials,” Furie noted.