Q&A: Obinutuzumab for the Treatment of Proliferative Lupus Nephritis

In patients with proliferative lupus nephritis, obinutuzumab (Gazyva, Genentech), a type II anti-CD20 antibody that induces potent B-cell depletion, on a background of mycophenolate and corticosteroids improved renal responses through 2 years without increasing the frequency of serious adverse events. This is according to results from the phase 2 NOBILITY trial, which were published in Annals of the Rheumatic Diseases.¹

In this Q&A, corresponding author Richard A Furie, MD, chief of rheumatology at Northwell Health in Great Neck, New York, discussed the research and its findings.

In the study, 125 patients with lupus nephritis receiving mycophenolate and corticosteroids were randomized to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint of complete renal response (CRR) at Week 52 was achieved by 35% of those in the obinutuzumab group and 23% of the placebo group; 12% difference (95% CI −3.4% to 28%, p=0.115). At Week 104, CRR was achieved by 41% and 23% of each group, respectively; 19% difference (95% CI 2.7% to 35%, p=0.026). Obinutuzumab was not associated with increased serious adverse events, serious infections or deaths.

Rheumatology Network: Why was the study conducted?

Richard A Furie MD: The study was undertaken to determine if greater B-cell depletion would occur in lupus with obinutuzumab and, if so, whether greater depletion would result in more robust clinical responses than seen previously with either rituximab or ocrelizumab.

RN: How significant are the findings?

RF: A peak effect size of 20% is a robust effect size in lupus nephritis. Couple this with a good safety profile, and the results of this study were quite significant.

Based on the NOBILITY trial results, the use of obinutuzumab in proliferative lupus nephritis is being evaluated in a global phase 3 study.

RN: What is the current practice and how could the results possibly change things?

RF: Lupus nephritis complete response rates in those with proliferative nephritis are attained in the minority of treated patients. Since we know that long-term response is better in those who do well in the short-term, an intervention capable of boosting complete response rates is welcomed.

Assuming the phase 3 trial replicates this phase 2 trial, obinutuzumab would become part of our regimen for the treatment of proliferative nephritis.

RN: What are the takeaway points for clinicians?

RF:Despite the earlier failures of rituximab and ocrelizumab to show statistical benefit over standard of care in lupus nephritis, B-cell depletion remained an appealing strategy. Studies suggested that inadequate responses with rituximab in lupus nephritis, systemic lupus, and rheumatoid arthritis were tied to incomplete B-cell depletion. Obinutuzumab administration results in greater and more sustained B-cell depletion than with rituximab, and thus it was justified to evaluate the clinical and biologic effects of obinutuzumab in lupus nephritis.

The degree of B-cell depletion observed in NOBILITY was, in fact, greater than observed with rituximab in the LUNAR trial. Furthermore, with a peak effect size of 20% at week 76, these results were statistically and clinically significant. There were no significant safety signals.

RN: Is there anything else you would like to add?

RF: Two items:

1) An additional analysis stratified patients who received obinutuzumab into those who were sustained B-cell depleters and those who were not. The group of sustained B-cell depleters had an enhanced effect amounting to about 15% over those who were not sustained depleters.

2) The long-term goal of treatment in kidney disease is the preservation of kidney function as measured by glomerular filtration rate (GFR). In the NOBILITY trial at two years, there was an improvement in GFR compared to the standard of care group where there was a decline in GFR.

Reference:

Furie RA, Aroca G, Cascino MD, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial.Annals of the Rheumatic Diseases 2022;81:100-107. DOI: 10.1136/annrheumdis-2021-220920