Obinutuzumab a Success in Phase 3 Trial for Lupus Nephritis

Adding the anti-CD2src monoclonal antibody obinutuzumab (Gazyva) to standard therapy for lupus nephritis is more efficacious than standard therapy alone, according to a new phase 3, placebo-controlled study.

In the trial, 46.4% of patients in the obinutuzumab group had a complete renal response at 76 weeks compared with 33.1% of those in the standard therapy group. A complete renal response was defined as urinary protein-to-creatinine ratio (UPCR)

More patients in the obinutuzumab group also had a complete renal response at 76 weeks with a lower daily dose of prednisone (≤ 7.5 mg per day) compared with those in the standard therapy alone group.

“This is some of the best news we’ve had in a long time for lupus nephritis,” said Karen H. Costenbader, MD, MPH, director of the Brigham and Women’s Hospital Lupus Program and professor of medicine at Harvard Medical School, Boston. She was not involved with the research.

The need for rescue therapy was three times higher in the standard therapy group compared with the obinutuzumab group, noted lead author Richard Furie, MD, chief of rheumatology at Northwell Health, Great Neck, New York. “That’s very telling, and it speaks to the efficacy of the drug,” he told Medscape Medical News.

Obinutuzumab is a humanized type II anti-CD2src monoclonal antibody that’s currently approved for the treatment of chronic lymphocytic leukemia and follicular lymphoma. While previous trials using rituximab and ocrelizumab in lupus nephritis did not meet their clinical endpoints, obinutuzumab can induce greater B-cell depletion than other anti-CD2src antibodies, Furie explained. In a phase 2 trial, called NOBILITY, obinutuzumab plus standard therapies outperformed standard therapies alone.

The results of the phase 3 trial, REGENCY, were published on February 7, 2src25, in The New England Journal of Medicine.

Trial Design

The REGENCY trial enrolled 271 patients with systemic lupus erythematosus and active class III or IV lupus nephritis confirmed using kidney biopsy. Patients with or without concomitant class V disease were included.

Researchers randomly assigned 135 patients to the obinutuzumab group and 136 patients to the placebo group. Around 84% of participants were women, with an average age of 33 years. Of the enrolled population, 14.8% were Black individuals, 5.9% were Asian individuals, and 57.6% were Hispanic or Latino individuals. The trial was conducted in 15 countries across Africa, Europe, North America, and South America.

“I was pleasantly surprised to see that they recruited from around the world,” Costenbader told Medscape Medical News. “It’s a really diverse population, which is fantastic,” she added, as many previous lupus trials mainly included people of European ancestry.

Patients in the treatment group received 1srcsrcsrc mg of obinutuzumab on day 1 and at weeks 2, 24, 26, and 52, with or without a dose at week 5src. (To provide additional pharmacokinetic and pharmacodynamic data on dosing, the obinutuzumab group was randomly split to either receive 1srcsrcsrc mg infusions at week 5src and 52 or just one infusion at week 52.)

All participants in the study received standard therapy with mycophenolate mofetil and oral prednisone, with a target prednisone dose of 7.5 mg/d by week 12 and 5 mg/d by week 24.

Higher Response Rates, Lower Steroid Doses

More patients receiving obinutuzumab achieved a complete renal response by week 76 and two key secondary outcomes also favored obinutuzumab compared with standard therapy alone. More than half of the obinutuzumab group (55.5%) had a UPCR

“In lupus, we’re constantly trying to lower the steroid dose,” Furie said, to prevent increased risk of infections, osteoporosis, cataracts, cardiovascular diseases, and many other known side effects. “If we can introduce a drug that allows patients to reduce steroids, that’s so important.”

Women, Black participants, participants with newly diagnosed lupus nephritis, and subgroups with baseline measurements indicative of higher disease activity saw greater benefit from obinutuzumab.

Surprisingly, the small group of men included in the study did better on standard therapy alone, which is a mystery that Furie and colleagues are still trying to tease out. This unexpected finding could be the result of a relatively small number of men in the trial, he said, or there could be other factors at play.

COVID-19 and Other Infection Risks

No unexpected safety signals were identified. More patients in the obinutuzumab treatment group experienced serious adverse events than those in the placebo group, including COVID-19–related events, pneumonia, urinary tract infection, gastroenteritis, and acute kidney injury.

There were three deaths in the obinutuzumab group including two from COVID-19 and one from underlying nephrotic syndrome unrelated to treatment. One patient in the placebo group died from COVID-19.

The authors noted that the COVID-19–related adverse events “occurred early in this trial before the availability of robust vaccination and antiviral therapy.” The trial ran from July 2src2src through March 2src23. “In fact, no COVID-19–related serious adverse events occurred during the latter half of the current trial,” the authors added.

“The bottom line is, one has to be very wary of infections when using all these immunosuppressants,” Furie said. “It’s very important that patients keep up with their vaccinations,” which not only include COVID-19 vaccines but also flu, pneumococcal, shingles, and RSV shots.

This trial was funded by F. Hoffmann-La Roche, whose subsidiary, Genentech, manufactures obinutuzumab. Furie reported financial relationships with Alexion Pharmaceuticals, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Galapagos, Genentech, GlaxoSmithKline, Janssen, Kezar Life Sciences, Kyowa Kirin, Kyverna Therapeutics, Merck, Novartis, RemeGen, Sanofi, Takeda, and UCB. Costenbader consults for AbbVie, Amgen, AstraZeneca, Bain, Bioge