Gazyva significantly boosts complete renal response rates in active lupus nephritis
Key takeaways:
- At 76 weeks, complete renal response rates were 46.4% with obinutuzumab and 33.1% with placebo.
- Serious adverse events were more common with obinutuzumab than placebo.
Adding obinutuzumab to standard therapy for active lupus nephritis led to significantly higher rates of complete renal response, according to data published in The New England Journal of Medicine.
Obinutuzumab (Gazyva, Genentech) is a humanized, glycoengineered type II anti-CD20 monoclonal antibody that leads to B-cell depletion and is currently approved for chronic lymphocytic leukemia and follicular lymphoma.
“Although B-cell depletion with rituximab has become a widely used therapy for the treatment of rheumatic diseases, such as rheumatoid arthritis and vasculitis, studies in systemic lupus and lupus nephritis were unsuccessful,” Richard A. Furie, MD, chief of rheumatology at Northwell Health, in Great Neck, New York, told Healio. “Their failures were attributed to inadequate depletion of the target, B cells, which play an important role in the pathogenesis of systemic lupus.
“Instead of yielding to this strategy, a new antibody was constructed that was capable of greater B-cell depletion than what was observed with rituximab,” he added. “Known as obinutuzumab, it was put to the test in lupus nephritis in the phase 2 NOBILITY study. The hypothesis that more robust B-cell depletion would yield greater clinical responses was confirmed and supported advancing to a pivotal phase 3 study known as REGENCY.”
For the randomized, controlled REGENCY study, Furie and colleagues recruited 271 patients with active proliferative lupus nephritis proven via kidney biopsy. The patients were randomly assigned in a 1:1 ratio to receive either IV infusions of obinutuzumab or placebo, in addition standard therapy of mycophenolate and prednisone.
Those selected for obinutuzumab received a 1,000 mg injection at baseline and week 2, and then again at weeks 24, 26 and 52. To help inform long-term dosing regimens, participants were also randomly assigned to receive either an additional injection of obinutuzumab or placebo at week 50.
The primary endpoint assessed levels of complete renal response at week 76, defined as a urinary protein-to-creatinine ratio of less than 0.5; an estimated glomerular filtration rate of at least 85% of baseline; and no rescue therapy, treatment failure, death, early withdrawal or other intercurrent event.
According to the researchers, 46.4% of patients who used obinutuzumab achieved complete renal response at week 76 vs. 33.1% of those who received placebo. A greater number of those on obinutuzumab also achieved complete renal response while using 7.5 mg of prednisone per day or less between weeks 64 and 76 (42.7%), compared with the placebo group (30.9%). According to Furie, this is a clinically important finding “given the well-recognized toxicities of steroids.”
In addition, urinary protein-to-creatinine ratios lower than 0.8 at week 76 were more common among obinutuzumab-treated patients (55.5%), compared with placebo-treated patients (41.9%). This reduction in proteinuria serves as “a surrogate for enhanced long-term kidney survival,” Furie and colleagues wrote.
Regarding safety, the rate of serious adverse events was higher with obinutuzumab (32.4%) than placebo (18.2%).
“This was largely driven by serious infections, which were mainly related to COVID-19 infections, one of the hazards of performing a study with immunosuppressives at the height of the COVID-19 pandemic,” Furie said.
COVID-19-related serious adverse events were particularly more likely with Obinutuzumab. However, when excluding them, the incidence of serious infections dropped from 16.9% to 11% among obinutuzumab-treated patients, with no change in the placebo group (7.6%).
REGENCY represents the “first positive registrational study” testing this mechanism of action in active lupus nephritis, according to Furie.
“It was not that long ago that we approached B-cell depletion in autoimmune diseases with extreme caution owing to safety concerns,” he said. “However, in addition to the favorable effects observed in our patients with rheumatoid arthritis or vasculitis, we have witnessed a relatively good safety profile.”
Some patients in the study are continuing to be followed, Furie added.
“In addition to further analysis of the existing dataset, data gathered beyond week 76 will be evaluated to gather information regarding durability of response, as well as long-term safety and efficacy,” he said. “There is a study being conducted by the same sponsor to evaluate obinutuzumab in patients with systemic lupus erythematosus whose disease primarily consists of extra-renal manifestations.”
Perspective
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This phase 3 study reported by Furie and colleagues documents improved renal outcomes in patients with class III or IV lupus nephritis, with or without concomitant class V nephritis when using obinutuzumab and standard mycophenolate/prednisone therapy, compared with standard therapy alone.
Results were comparable across geographic regions and race. The obinutuzumab arm also improved C3, C4 and anti-DNA levels compared to standard care. Higher disease activity resulted in a greater difference in outcomes comparing the obinutuzumab vs. standard treatment groups.
Both treatment arms demonstrated minimal improvement in FACIT-F scores.
Treatment choice should take into account the increased incidence of serious infection and neutropenia, including COVID-19 events, as anticipated with the addition of deep B-cell depletion. We welcome this positive phase 3 trial confirming the value of B-cell depletion in the management of proliferative lupus nephritis.
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