Obinutuzumab Aids Standard Therapy for Lupus Nephritis

Recent research shows that obinu­tuzumab—a monoclonal antibody that depletes B cells and is approved for the treatment of B cell malignancies—may benefit patients with lupus nephritis, a condition that can lead to kidney failure.¹

The phase 3, randomized controlled Study to Evaluate the Efficacy and Safety of Obinutuzumab in Patients with ISN/RPS 2003 Class III or IV Lupus Nephritis (REGENCY) trial in patients with active lupus nephritis showed that obinutuzumab plus standard therapy was more effective than standard therapy alone in achieving a complete renal response in adults with active lupus nephritis.

Almost half of obinutuzumab patients had a complete renal response vs. about one-third of patients who had standard therapy plus placebo.

“These findings really speak to the power of B cell depletion,” says first author Richard Furie, MD, professor at the Feinstein Institutes for Medical Research, Manhasset, N.Y., the Marilyn and Barry Rubenstein Chair in Rheumatology at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell and chief of the Division of Rheumatology at Northwell Health, Hempstead, N.Y.

B Cell Depletion Drugs

Dr. Richard Furie

B cells make protective antibodies. But in autoimmune diseases, they make disease-causing antibodies. Dr. Furie noted that early trials of rituximab led to obinutuzu­mab’s approval for rheumatoid arthritis and vasculitis. Rituximab is a therapeutic monoclonal antibody that binds to a specific protein on B cells and was first approved for the treatment of lymphoma. But early studies of rituximab in systemic lupus, which Dr. Furie calls “the prototypical B cell–driven disease,” and lupus nephritis failed to meet their primary end points.

Further investigation revealed that these trials’ failure to achieve clinical response may have resulted from insufficient B cell depletion as rituximab patients varied in how much they depleted their B cells, Dr. Furie notes. A post-hoc analysis of one of the studies, Lupus Nephritis Assessment with Rituximab (LUNAR), revealed that patients with lupus nephritis who completely depleted B cells had a 3.5-fold higher rate of complete response, compared with those with incomplete B cell depletion.²

Focus on B cell depletion in lupus moved to obinutuzumab, a more potent B cell–depleting antibody. Approved in 2013 for the B cell malignancy chronic lymphocytic leukemia, obinutuzumab outperformed rituximab in head-to-head studies in B cell malignancies, Dr. Furie says. “Since obinutuzumab is a far more potent B cell depleter than rituximab, it made sense to once again study it in lupus nephritis,” Dr. Furie notes.

NOBILITY, a phase 2 trial of 125 patients with lupus nephritis, showed that obinutuzumab plus standard of care led to clinically meaningful improvements in the percentage of patients with a complete renal response at weeks 52, 76 and 104, compared with placebo plus standard of care.³ Post-hoc analyses showed that compared with placebo plus standard of care, obinutuzumab plus standard of care delayed time to lupus nephritis flares and unfavorable kidney outcomes and reduced loss in estimated glomerular filtration rate (eGFR), a surrogate for kidney survival.

The REGENCY Trial

NOBILITY’s success justified the phase 3 REGENCY trial, Dr. Furie says. It included 271 patients with proliferative lupus nephritis. All study patients received the standard therapy, mycophenolate mofetil, plus a target dose of 7.5 mg/day of oral prednisone by week 12, and 5 mg/day by week 24. One-half got 1,000 mg of obinutuzumab on day 1, and at weeks 2, 24, 26 and 52, with or without a dose at week 50.

The study’s primary end point was a complete renal response at week 76, defined as a urine-protein-to-creatinine ratio (UPCR) lower than 0.5 (with protein and creatinine both measured in milligrams), an eGFR at least 85% of baseline value and no intercurrent events. Secondary end points included complete renal response with 7.5 mg/day or less of prednisone during weeks 64–76 and a UPCR less than 0.8, without intercurrent events.

More than 46% of patients who received obinutuzumab achieved the desired response, complete renal response, compared with 33.1% in the placebo group. The complete renal response rate was 42.7% for the patients in the obinutuzumab group, compared with 30.9% for patients who received standard care. The researchers saw UPCR less than 0.8 in 55% of patients in the obinutuzumab group vs. 41.9% of patients in the standard care group.

Patients in the obinutuzumab group had a higher frequency of serious adverse events related to infection, particularly COVID-19. “The REGENCY study was unfortunately the victim of the surprise attack by COVID,” says Dr. Furie. However, once the medical community gained experience with COVID and vaccines were developed, COVID-related adverse events decreased in frequency, he notes.

In March, Roche submitted a supplemental application for obinutuzumab, marketed as Gazyva/Zazyvaro, in lupus nephritis.

Prescribing Obinutuzumab

Vaccines are generally important for all autoimmune disease patients, but current politics and declining public support for vaccination make some patients in Dr. Furie’s practice hesitant to get vaccines that are important prior to starting obinutuzumab and other B cell-depleting drugs. “When you start immunosuppressive medicines, and I don’t care what their mechanism[s] of action are, they attack the immune system and make patients more susceptible [to these illnesses]. The bottom line is anybody going on a B cell depleter should be vaccinated,” says Dr. Furie. At a minimum, patients need influenza, pneumonia and COVID-19 vaccines, he adds.

Dr. Furie also urged rheumatologists to familiarize themselves with the safety profiles of drugs they prescribe so they can explain them to patients.

Having Options

The 2024 ACR Guideline for the Screening, Treatment, and Management of Patients with Lupus Nephritis recommends triple therapy for active proliferative lupus nephritis, Dr. Furie notes.⁴ Triple therapy consists of glucocorticoids and two additional immunosuppressive therapies, which can include mycophenolate or cyclophosphamide and a biologic.

Soon obinutuzumab will be one of the available and recommended biologics that could be added to mycophenolate, in addition to belimumab and voclosporin. “Everyone will have a different opinion about which drug(s) to use, and we’ll need to figure this out,” Dr. Furie notes.

He envisions a future with three approaches for eliminating B cells. They include monoclonal antibodies and two new approaches. The first novel approach, called chimeric antigen receptor T (CAR T) cell therapy, involves engineering immune cells to recognize and kill B cells. CAR T requires collecting patients’ T cells, adding chimeric antigen receptors to them, and then returning the T cells to the patient. The second novel approach is the T cell engaging bispecific antibodies that target both a B cell protein and the CD3 molecule on T cells, he says. This latter approach achieves B cell depletion without the requirement of administering living cells.

“Personalizing medication choices is an important area that research needs to pursue,” Dr. Furie emphasizes. “We have come a long way in the development of drugs for our patients with lupus. No doubt there will be more therapies coming, and all these research activities translate into better outcomes for our patients with lupus.”

Deborah Levenson is a writer and editor based in College Park, Md.

References

1. Furie RA, Rovin BH, Garg JP, et al. Efficacy and safety of obinutuzumab in active lupus nephritis. N Eng J Med. 2025 Apr 17;392(15):1471–1483.
2. Gomez Mendez LM, Cascino MD, Garg J, et al. Peripheral blood B cell depletion after rituximab and complete response in lupus nephritis. Clin J Am Soc Nephrol. 2018 Oct 8;13(10):1502–1509.
3. Furie RA, Aroca G, Cascino MD, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: A randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022 Jan;81(1):100–107.
4. Sammaritano LR, Askanase A, Bermas BL, et al. 2024 American College of Rheumatology (ACR) guideline for the screening, treatment, and management of lupus nephritis. Arthritis Rheumatol. 2025 Sep;77(9):1115–1135.

Acknowledgment

Dr. Furie is an investigator and consultant to Genentech.