B-Cell Depleting Agent Shows Promise in Lupus Nephritis

WASHINGTON -- Patients with proliferative lupus nephritis appeared to benefit from treatment with obinutuzumab (Gazyva) plus a steroid, according to a phase II trial presented here.

In the NOBIILITY trial, among 125 individuals with lupus nephritis, a significantly higher proportion on 1,000 mg obinutuzumab and methylprednisolone (MMF) achieved a complete renal response compared with those on MMF alone at week 52 (35% vs 23%, P=0.11), reported Brad Rovin, MD, of Ohio State University in Columbus.

Complete renal response was defined as a urine protein-creatinine ratio <0.5; serum creatinine under the upper limit of laboratory normal or within 15% of baseline; and <10 red blood cells per high power field (RBC/HPF).

The effect seemed to increase over time, such that an even greater proportion of patients in the intervention versus placebo group demonstrated a response by week 76 (40% vs 18%), Rovin said at the American Society of Nephrology (ASN) annual meeting. The results also were presented at the 2019 American College of Rheumatology meeting in Atlanta.

Rovin noted that the P-value used for this study was 0.2 because it was an exploratory trial.

"I would anticipate since this affects one of the primary parts of autoimmunity, which is the development of the auto-antibodies, that we may have a very good way to maintain these patients under control," he stated.

Obinutuzumab is a humanized type II anti-CD20 monoclonal antibody that is used in combination with chemotherapy for chronic lymphocytic leukemia and follicular lymphoma. Prior studies have shown mixed results when testing type I anti-CD20 antibodies, like rituximab (Rituxan), versus standard of care. However, obinutuzumab, a type II molecule, is a much stronger B-cell depleting agent, explained Mitchell Rosner, MD, of the University of Virginia in Charlottesville, who was not involved in the study.

"Standard of care has generally been more non-specific immunosuppression with corticosteroids and MMF," Rosner told MedPage Today. "This really represents a paradigm shift in more specific B-cell-directed therapy and a drug that is much more effective in depleting B-cells than rituximab was."

Rovin hypothesized that this may be because obinutuzumab reduces the internalization of antibodies, and is much less reliant on complement to cause B-cell death, which is particularly important in lupus.

"There was quite a bit of variability with cell depletion with type I anti-CD20 molecules, and we hypothesized that ... if we could get better B-cell depletion, we could have a better chance of actually showing improvements over standard of care," Rovin said.

The trial involved patients with class III or IV lupus nephritis, who were required to have urine protein-to-creatinine ratios >1 at the time of a 24-hour urine collection. Excluded were patients with rapid progressive glomerulonephritis, and those who had chronic damage on kidney biopsies, defined as eGFR <30 mL/min/1.73m² or >40% of glomeruli with sclerosis.

Close to 70% of the patient population was Hispanic. The obinutuzumab and standard-of-care groups had good proteinuria levels; about half were positive for double-stranded DNA (49% vs 58%), and many had serum complement (C3) <90 mg/dL at baseline (68% vs 60%).

In addition to a complete renal response, a higher proportion of patients on obinutuzumab also achieved a partial response -- defined as a urine protein creatinine ratio reduction of ≥50% and <50% red blood cells above baseline -- versus placebo at weeks 52 (65% vs 36%, P=0.02) and 76 (51% vs 29%, P=0.02), Rovin reported.

Similar positive results were shown using alternative definitions for response, such as excluding urine sediment or relaxing the serum creatinine requirements, he added.

Complement and other serologies, as well as proteinuria, also improved in the obinutuzumab arm versus standard-of-care arm, indicating a high success rate on the molecular level.

Finally, adverse events (AEs) were similar between groups, with one death in the intervention arm, caused by a gastrointestinal perforation, and four deaths in the placebo group. Serious AEs occurred in 23% and 30% of the obinutuzumab and placebo groups, respectively, the most common of which were due to infection (6% and 18%) and infusion reactions (16% vs 10%).

Rovin said he anticipates a phase III trial investigating obinutuzumab's efficacy in this disease state will begin as early as 2020; follow-up data from week 104 of the trial is also slated for publication. In the phase III trial, researchers will reevaluate the criteria for a complete response used in this trial, which may have been overly stringent, he added.

"About one-third of patients [will have] creatinine that can fluctuate well more than 15%, even if they're in complete response," Rovin said at an ASN press conference. "That criteria might be too rigorous, so we're going to look at that."

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