Obinutuzumab, a type II anti-CD20 monoclonal antibody, has demonstrated superior efficacy over placebo in achieving complete renal response (CRR) in patients with proliferative lupus nephritis (LN) when added to mycophenolate and corticosteroids, according to results from the Phase 2 NOBILITY trial. The findings, published in the Annals of the Rheumatic Diseases, suggest a potential new therapeutic avenue for this severe manifestation of systemic lupus erythematosus (SLE).
The multicenter, double-blind trial randomized 125 patients with Class III or IV LN to receive either obinutuzumab (1000 mg on day 1 and weeks 2, 24 and 26) or placebo, in addition to standard treatment with mycophenolate mofetil (MMF) and corticosteroids. The primary endpoint was the proportion of patients achieving CRR at week 52, defined as a urine protein-to-creatinine ratio (UPCR) <0.5, normal renal function, and inactive urinary sediment.
Key Findings
At week 52, 35% of patients in the obinutuzumab group achieved CRR compared to 23% in the placebo group (p=0.115). By week 104, the difference became statistically significant, with 41% in the obinutuzumab group achieving CRR versus 23% in the placebo group (p=0.026). Obinutuzumab also led to significant improvements in secondary endpoints, including partial renal response (PRR) and overall renal response (ORR) at weeks 52, 76, and 104.
"Obinutuzumab was superior to placebo for the achievement of CRR and ORR in patients with proliferative LN when added to mycophenolate and corticosteroids," the researchers stated. "Greater improvements in anti-dsDNA antibodies, C3, C4, eGFR and proteinuria were also observed with obinutuzumab."
Impact on B Cells and Renal Function
The study demonstrated that obinutuzumab induced rapid and potent depletion of peripheral CD19+ B cells. Specifically, 98% of patients in the obinutuzumab group experienced B-cell depletion at week 2, and 94% remained depleted at week 52. Furthermore, obinutuzumab was associated with greater improvement in eGFR at week 4 and weeks 24 through 104 (adjusted mean difference, 9.7 mL/min/1.73 m2 (95% CI 1.7 to 18), p=0.017).
Safety Profile
Obinutuzumab's safety profile was comparable to placebo. Through week 104, 91% of patients in the obinutuzumab group and 89% in the placebo group experienced at least one adverse event. Serious adverse events occurred in 25% and 30% of patients, respectively. Infusion-related reactions were more common with obinutuzumab (16%) than placebo (10%), but were generally mild and resolved with supportive care.
Clinical Implications
The study authors noted that the 15-year risk of end-stage kidney disease (ESKD) in patients with LN remains high despite potent immunosuppressive therapies. The NOBILITY trial suggests that obinutuzumab, by providing deeper and more durable B-cell depletion, may offer a more effective approach to preserving kidney function in this patient population.
"Results from the present study indicate that B cells play a key role in LN pathogenesis and demonstrate that obinutuzumab contributes to improved clinical responses without increasing the frequency of serious safety events," the authors concluded. A Phase 3 trial (NCT04221477) is underway to further evaluate obinutuzumab in proliferative LN.
