Novel Antibody Looks Promising in Lupus Nephritis

Pam Harrison

November 19, 2019

WASHINGTON, DC — A novel antibody, obinutuzumab (Genentech-Roche), enhances renal responses in patients with lupus nephritis, through more complete B-cell depletion, compared with standard immunotherapy, and is well-tolerated, according to results from the phase 2 NOBILITY trial.

"We know from our previous trials with anti-B-cell antibodies that results were mixed and we felt that these variable results were possibly due to variability in B-cell depletion with a type 1 anti-CD20 antibody such as rituximab," Brad Rovin, MD, director, division of nephrology, Ohio State University in Columbus, told a press briefing here at Kidney Week 2019: American Society of Nephrology Annual Meeting. 

"So we hypothesized that if we could deplete B cells more efficiently and completely, we would achieve better results. At week 52, 35% of patients in the obinutuzumab-treated group achieved a complete renal response compared to 23% in the standard-of-care arm."

And by week 76, the difference between obinutuzumab and standard-of-care was actually larger at 40% vs 18%, respectively, "and this was statistically significant at a P value of .01," added Rovin, who presented the full findings of the study at the conference.

Obinutuzumab, a highly engineered anti-CD20 antibody, is already approved under the brand name Gazyva for use in certain leukemias and lymphomas. The NOBILITY study was funded by Genentech-Roche, and Rovin reports being a consultant for the company.

Asked by Medscape Medical News to comment on the study, Duvuru Geetha, MBBS, noted that with standard-of-care mycophenolate mofetil (MMF) plus corticosteroids, "the remissions rates we achieve [for lupus nephritis] are still not great," ranging between 30% to 50%, depending on the patient population.

"This is why there is a need for alternative agents," added Geetha, who is an associate professor of medicine, Johns Hopkins University, Baltimore, Maryland.

With obinutuzumab, "the data look very promising because there is a much more profound and sustained effect on B-cell depletion and the renal response rate is much higher [than with MMF and corticosteroids]," she noted.

Geetha added, however, that she presumes patients were all premedicated with prophylactic agents to prevent infectious events, as they are when treated with rituximab.

"I think what is definitely different about this drug is that it induces direct cell death more efficiently than rituximab and that is probably what's accounting for the higher efficacy seen with it," said Geetha, who discloses having received honoraria from Genentech a number of years ago.

"So yes, I believe the results are clinically meaningful," she concluded.

NOBILITY Study Design

The NOBILITY trial randomized 125 patients with Class III or IV lupus nephritis to either obinutuzumab plus MMF and corticosteroids, or to MMF plus corticosteroids alone, for a treatment interval of 104 weeks.

Patients in the obinutuzumab group received two infusions of the highly engineered anti-CD20 antibody at week 0 and week 2 and another two infusions at 6 months.

"The primary endpoint was complete renal response at week 52," the authors point out, "while key secondary endpoints included overall renal response and modified complete renal response."

Both at week 52 and week 76, more patients in the obinutuzumab group achieved an overall renal response as well as a modified complete renal response, compared with those treated with immunosuppression alone.

"If you look at the complete renal response over time, you can see that the curves separate after about 6 months but the placebo group starts to decline as you go further out, whereas the obinutuzumab group continues to separate, so my prediction is that we are going to see this trend continue because of the mechanism of action of obinutuzumab," Rovin explained.

Outcome Obinutuzumab plus immunosuppression, % Immunosuppression alone, % P value
Week 52      
Overall renal response 56 36 .25
Modified complete renal response 40 26 .09
Week 76      
Overall renal response 51 29 .015
Modified complete renal response 48 23 .003

Phase 3 Trials to Start Early 2020

All of the serologies relevant to lupus and lupus nephritis "including C3 and C4 improved while antidoubled stranded DNA levels declined, as did the urine protein-to-creatinine ratio, although the decline was more rapid and more profound in the obinutuzumab-treated patients," Rovin pointed out.

Importantly as well, despite the profound B-cell depletion produced by obinutuzumab, "the adverse event profile of this drug was very similar to the placebo group," he stressed.

As expected, rates of infusion reactions were slightly higher in the experimental group than the immunosuppression alone group, but rates of serious adverse events were the same between groups, as were adverse infectious events, he noted.

Investigators have now initiated a global phase 3 trial, scheduled to start in early 2020, to evaluate the same treatment protocol in a larger group of patients.

Kidney Week 2019. Abstract #FR-OR136. Presented November 8, 2019.

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