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High B-Cell Depletion Succeeds in Lupus Nephritis

— Obinutuzumab was more effective at depleting B cells than rituximab

MedpageToday

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.

Disclosures

The study was supported by Roche/Genentech.

Furie disclosed relevant relationships with AstraZeneca/MedImmune. Co-authors disclosed relevant relationships with GlaxoSmithKline, Aurinia, AstraZeneca, Novartis, Alexion, Bristol-Myers Squibb, Roche, and Genentech.

Primary Source

American College of Rheumatology

Furie R, et al "Two-year results from a randomized, controlled study of obinutuzumab for proliferative lupus nephritis" ACR virtual annual meeting 2020; Abstract 0988.