Add-on obinutuzumab shows promise for proliferative lupus nephritis
medwireNews: Findings from the phase 2 NOBILITY trial suggest that the addition of the type II anti-CD20 antibody obinutuzumab to standard therapy may improve renal outcomes for patients with proliferative lupus nephritis (LN).
Richard Furie (Northwell Health, Great Neck, New York, USA) and co-investigators say that “B cells are recognised as key mediators of SLE [systemic lupus erythematosus] pathogenesis,” but previous studies of two type I anti-CD20 antibodies – rituximab and ocrelizumab – did not show improved rates of complete renal response (CRR) when added to standard therapy in patients with LN.
They note, however, that obinutuzumab “has a distinct mode of binding to the CD20 antigen compared with type I anti-CD20 antibodies,” and hypothesized that enhanced B-cell depletion with the agent in addition to standard care would improve CRR rates.
The NOBILITY trial included 125 participants (mean age 33 years, 85% women) on standard treatment with mycophenolate and corticosteroids who were randomly assigned to receive infusions of obinutuzumab 1000 mg on day 1 and weeks 2, 24, and 26, following premedication with methylprednisolone 80 mg, or to receive placebo.
At the 1-year follow-up, 35% of patients in the obinutuzumab arm and 23% of those in the placebo arm achieved the composite primary endpoint of CRR, defined as urine protein-to-creatinine ratio (UPCR) of less than 0.5, normal renal function without worsening of baseline serum creatinine by more than 15%, and inactive urinary sediment.
The between-group difference of 12 percentage points had a p value of 0.115, which fell below the prespecified alpha threshold for statistical significance of 0.2, said Furie and colleagues.
“Though all four doses of obinutuzumab were completed by 6 months, there was increasing clinical benefit through 24 months, implying that prolonged time may be required for healing of the kidney and achievement of CRR,” they report. At the 2-year follow-up, CRR rates were significantly higher among patients treated with obinutuzumab versus placebo with a 19 percentage point difference (41 vs 23%; p=0.026).
The team notes that obinutuzumab seemed to confer the greatest benefit at 104 weeks in patients with high levels of proteinuria (UPCR ≥3) at baseline and in those with class IV versus class III LN.
Furie and colleagues say that treatment with obinutuzumab led to “rapid and sustained depletion of peripheral CD19+ B cells to ≤5 cells/μL,” with 98% of participants experiencing depletion by the 2-week follow-up. Comparison with previously published results from the LUNAR trial of rituximab suggested that “obinutuzumab results in more rapid, deep, and durable peripheral B-cell depletion than rituximab,” they say.
In all, 91% of obinutuzumab-treated patients and 89% of those given placebo experienced adverse events during 2 years of follow-up, most commonly urinary tract infections in both groups (23 vs 21%). There were five deaths in the study, including one due to gastrointestinal perforation in the obinutuzumab group and four (one each due to gastrointestinal hemorrhage, refractory SLE, progressive multifocal leukoencephalopathy, and respiratory infection) in the placebo arm.
Together, these 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,” write Furie and team in the Annals of the Rheumatic Diseases.
However, they caution that the study was limited by small patient numbers and use of a prespecified alpha of 0.2, and therefore the results need further confirmation in a larger study.
“The use of obinutuzumab in proliferative LN is being further evaluated in a global phase 3 study (NCT04221477),” they add.
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