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The B-cell depleting monoclonal antibody obinutuzumab (Gazyva) showed efficacy through 2 years for patients with lupus nephritis, a severe complication of systemic lupus erythematosus that affects some 45% of lupus patients and for which more effective treatments are needed.

At week 104, complete renal responses were seen in 41% of patients randomized to obinutuzumab plus standard of care compared with 23% of those given placebo plus standard of care, which was a difference of 19% (80% CI 8-29, P=0.026), reported Richard Furie, MD, of the Zucker School of Medicine at Hofstra/Northwell in Great Neck, New York.

"Renal responses were not only robust but were sustained through 2 years, 1.5 years after the final exposure to obinutuzumab. I think these data are very impressive," Furie said during a plenary session at the American College of Rheumatology virtual meeting.

Obinutuzumab is a type II anti-CD20 monoclonal antibody that was approved for chronic lymphocytic leukemia in 2013. It is far more potent than rituximab (Rituxan) at depleting B cells, with its 100-fold greater antibody dependent cytotoxicity and less dependence on complement-dependent cytotoxicity. A for lupus nephritis did not find clinical efficacy for the drug at week 52.

In vitro, this agent showed greater B cell depletion than rituximab in samples from lupus patients, and in head-to-head trials for B-cell malignancies it was superior to rituximab.

In the first 18 months of this study, known as , complete B cell depletion and improved renal responses were seen through month 18 in patients with proliferative lupus nephritis.

The study included 125 patients with class III/IV lupus nephritis whose baseline protein-to-creatinine ratio was 1 or greater and whose kidney biopsies demonstrated proliferative nephritis alone or with concomitant membranous nephritis.

They were randomized to receive obinutuzumab, 1,000 mg or placebo on background standard therapy of 2 to 2.5 g mycophebnolate mofetil (CellCept) plus an initial pulse of 1 to 3 g methylprednisolone and oral steroids that were tapered to 7.5 mg/day by week 12.

The treatment consisted of two courses 6 months apart, with each course consisting of two infusions 2 weeks apart.

The endpoint of complete renal response required a reduction in urinary protein-to-creatinine ratio to 0.5 or less and a normal serum creatinine that was no greater than 15% above the baseline value. In addition, patients had to have fewer than 10 red blood cells per high power field and no red cell casts.

Approximately three-quarters of patients had diffuse proliferative nephritis, and the remainder had coexisting proliferative and membranous nephritis.

Approximately 85% had normal baseline creatinine and the average urinary protein value was 3 g. A total of 90% of patients received all four treatments and the vast majority completed their week 104 visits, Furie said.

By week 104, 40% of patients in the placebo group and 22% of those in the obinutuzumab group required an additional rescue therapy.

B-cell depletion to levels below 5 cells/µL persisted through week 52, but repletion was seen in most by week 104. "The clinical effects of treatment were long lasting and in fact persisted to a time point when B cell repletion had occurred," Furie noted.

Complete renal responses at week 52 were seen in 35% and 23% of the obinutuzumab and placebo groups, respectively (P=0.115), but by 40% versus 18% (P=0.007) by week 76.

Other endpoints at week 104 also favored the obinutuzumab group versus placebo:

• Overall (complete plus partial) renal response, 54% vs 29%, for a difference of 25% (80% CI 14-36, P=0.005)
• C3 >90 mg/dL, 76% vs 47%, for a difference of 29% (80% CI 19-40, P=0.008)
• C4 >10 mg/dL, 95% vs 74%, for a difference of 21% (80% CI 13-29, P=0.001)
• Mean change in estimated GFR from baseline +6.5 vs -3.2, for a difference of 9.7 (80% CI 1.7-18, P=0.018)
• Mean change in urinary protein-to-creatinine ratio, -2.3 vs -1.4, for a difference of -0.96 (80% CI -1.4 to -0.57, P=0.002)

Infusion reactions were more common in the obinutuzumab group, while serious infections were more common in the placebo group (8% vs 18%). Four deaths occurred in the placebo group, one from progressive multifocal leukoencephalopathy, and one death occurred in the obinutuzumab group.

, a phase III trial, will provide further safety and efficacy data, and "barring anything catastrophic occurring in the phase III study, we'll have this drug available to us," Furie said.

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