Obinutuzumab + SoC improves renal responses in LN patients

The addition of obinutuzumab, a humanized type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, to a background of standard-of-care (SoC) therapy led to improved renal responses in patients with proliferative lupus nephritis (LN) compared with SoC alone, findings from the phase II NOBILITY trial have shown.

“Despite widespread use of immunosuppressive therapies for LN, the risk of end-stage kidney disease has not been substantially reduced in recent decades,” said the researchers. “This underscores the critical need for more efficacious and safer therapies for patients with proliferative LN.”

A total of 125 participants (mean age 33 years, 85 percent female) were randomized 1:1 to receive IV obinutuzumab 1,000 mg or placebo (day 1 and weeks 2, 24, and 26) on top of mycophenolate mofetil* and corticosteroids**. About three-quarters of the cohort (74 percent) had class IV LN and concomitant class V LN was present in 30 percent. [Ann Rheum Dis 2022;81:100-107]

Obinutuzumab was superior to placebo for the achievement of CRR*** (35 percent vs 23 percent; p=0.115) and ORR*** (56 percent vs 36 percent; p=0.025) at week 52, which continued through week 104 (41 percent vs 23 percent; p=0.026 [CRR] and 54 percent vs 29 percent; p=0.005 [ORR]).

The 2-year treatment effect of obinutuzumab compared with placebo appeared greatest among patients with high levels of proteinuria at baseline (UPCR^# ≥3; 31 percent vs 10 percent; p=0.098) and those with class IV LN (47 percent vs 16 percent; p=0.001).

Week 104 also saw greater improvements in mean C3 (29 vs 11), C4 (9.6 vs 0.4), and anti-dsDNA antibodies (–1.1 vs –0.05; p<0.001 for all); UPCR <0.5 (62 percent vs 37 percent; p=0.005); and eGFR^# (adjusted mean difference, 9.7 mL/min/1.73 m²; p=0.017) with obinutuzumab vs placebo, as well as achievement of UPCR <0.8 (71 percent vs 45 percent; p=0.003).

Obinutuzumab also resulted in rapid and potent depletion of peripheral CD19+ B cells to ≤5 cells/μL, with nearly all (98 percent) participants having B-cell depletion as early as week 2, which was sustained (94 percent) through week 52.

Infusion-related reactions

There was a slightly higher percentage of obinutuzumab vs placebo recipients who had infusion-related reactions (IRRs; 16 percent vs 10 percent), which were most common with the first infusion. “[Nonetheless,] none were serious, and all resolved with supportive care,” said the researchers.

The lack of serious IRRs in this setting appear to deviate from that observed with obinutuzumab in CLL^## and NHL^##, wherein serious IRRs are common, the researchers noted. The reduced frequency and severity of IRRs may have been driven by the high-dose background corticosteroids. [Leuk Lymphoma 2020;61:934-939] “Pretreatment quantitative and/or qualitative differences in circulating B cells [may also] provide a potential mechanistic basis for the apparent lower incidence and severity of IRRs and cytopaenias with obinutuzumab in nonmalignant conditions.”

Sustained clinical benefit

While all obinutuzumab doses were completed by 6 months, enhanced clinical benefit was seen continuously for 2 years, suggesting that an extended period might be necessary for the healing of the kidney and the achievement of CRR, the researchers noted. Moreover, evidence suggests that short-term responses are predictive of improved long-term kidney outcomes, and that obinutuzumab was associated with greater eGFR preservation over 2 years. [Arthritis Rheumatol 2015;67:1305-1313; Lupus Sci Med 2015;2:e000123]

“[T]hese observations suggest the addition of obinutuzumab to standard therapy may more effectively prevent damage accrual and thus be more likely to preserve kidney function,” said the researchers.

“[Taken together, our findings] 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,” they concluded.