Drug PipelinePerspective

Gazyva Receives FDA Breakthrough Therapy Designation for Lupus Nephritis

Jay Garg, MD
Jay Garg

The FDA has granted Gazyva breakthrough therapy designation for the treatment of adult patients with lupus nephritis, according to a Genentech press release.

Originally approved by the FDA in 2013 for the treatment of adults with previously untreated chronic lymphocytic leukemia, Gazyva (obinutuzumab, Genentech) was subsequently approved in 2017 for the treatment of adults with previously untreated advanced follicular lymphoma. For the purpose of treating complications linked to systemic lupus erythematosus, the breakthrough designation pairs Gazyva with standard of care practices, such as mycophenolate mofetil or mycophenolic acid and corticosteroids.

“The FDA’s decision is an important milestone in our over decade-long commitment to researching potential therapies for lupus and lupus nephritis,” Jay Garg, MD, group medical director in product development for immunology, infectious diseases and ophthalmology at Genentech, told Healio Rheumatology. “We are looking forward to meeting with health authorities to discuss how best to bring this therapy to people with lupus nephritis, who currently have no FDA-approved medicines available.”

The FDA based its designation on results from the randomized, double-blind, placebo-controlled phase 2 NOBILITY trial comparing the safety and efficacy of Gazyva plus standard of care — mycophenolate mofetil or mycophenolic acid and corticosteroids — against standard of care plus placebo among adult patients (n = 126) with proliferative lupus nephritis. The primary endpoint was the proportion of patients who attained a complete renal response at 52 weeks.

According to study results, Gazyva plus standard of care demonstrated enhanced efficacy vs. placebo plus standard of care in achieving complete renal response at 1 year. Additionally, Gazyva demonstrated improved overall renal responses and serologic markers of disease activity compared with placebo.

Sandra Horning, MD
Sandra Horning

“New treatment options are needed for lupus nephritis, a potentially life-threatening inflammation of the kidneys that most commonly affects women,” Sandra Horning, MD, chief medical officer and head of global product development at Genentech, said in a press release. “We are committed to developing Gazyva as a potential new therapy for lupus nephritis and plan to begin enrolling patients in a phase 3 trial next year.”

Based on safety trials conducted among patients with relapsed or refractory non-Hodgkin lymphoma, the most common adverse events observed with Gazyva were injection site reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

Jay Garg, MD
Jay Garg

The FDA has granted Gazyva breakthrough therapy designation for the treatment of adult patients with lupus nephritis, according to a Genentech press release.

Originally approved by the FDA in 2013 for the treatment of adults with previously untreated chronic lymphocytic leukemia, Gazyva (obinutuzumab, Genentech) was subsequently approved in 2017 for the treatment of adults with previously untreated advanced follicular lymphoma. For the purpose of treating complications linked to systemic lupus erythematosus, the breakthrough designation pairs Gazyva with standard of care practices, such as mycophenolate mofetil or mycophenolic acid and corticosteroids.

“The FDA’s decision is an important milestone in our over decade-long commitment to researching potential therapies for lupus and lupus nephritis,” Jay Garg, MD, group medical director in product development for immunology, infectious diseases and ophthalmology at Genentech, told Healio Rheumatology. “We are looking forward to meeting with health authorities to discuss how best to bring this therapy to people with lupus nephritis, who currently have no FDA-approved medicines available.”

The FDA based its designation on results from the randomized, double-blind, placebo-controlled phase 2 NOBILITY trial comparing the safety and efficacy of Gazyva plus standard of care — mycophenolate mofetil or mycophenolic acid and corticosteroids — against standard of care plus placebo among adult patients (n = 126) with proliferative lupus nephritis. The primary endpoint was the proportion of patients who attained a complete renal response at 52 weeks.

According to study results, Gazyva plus standard of care demonstrated enhanced efficacy vs. placebo plus standard of care in achieving complete renal response at 1 year. Additionally, Gazyva demonstrated improved overall renal responses and serologic markers of disease activity compared with placebo.

Sandra Horning, MD
Sandra Horning

“New treatment options are needed for lupus nephritis, a potentially life-threatening inflammation of the kidneys that most commonly affects women,” Sandra Horning, MD, chief medical officer and head of global product development at Genentech, said in a press release. “We are committed to developing Gazyva as a potential new therapy for lupus nephritis and plan to begin enrolling patients in a phase 3 trial next year.”

Based on safety trials conducted among patients with relapsed or refractory non-Hodgkin lymphoma, the most common adverse events observed with Gazyva were injection site reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

    Perspective
    Gregg J. Silverman

    Gregg J. Silverman

    This is a rather remarkable development as it has been a very difficult path for patients with lupus nephritis. Obinutuzumab is an agent from the same class of anti-CD20 monoclonal antibodies as rituximab (Rituxan, Genentech), which was approved in 1997 for the treatment of non-Hodgkin lymphoma. However, it was not until 2006 that rituximab was approved for the treatment of rheumatoid arthritis refractory to TNF inhibitors.

    Anti-CD20 therapies have been known to be useful for certain autoimmune rheumatic diseases, but the initial trials and treatment, of lupus in general and lupus nephritis in specific, had very ‘cloudy’ results in which they failed to meet their primary endpoints.

    The difference between those studies and today is that the target is the same B-cells that bear the CD20 antigen but the agent is a reengineered and reconceptualized antibody that is much more effective at killing B-cells in the body’s tissues. Obinutuzumab was initially developed, tested and approved for the treatment of B-cell malignancies; the question is whether it would be effective as a treatment for lupus nephritis, even though the first-generation agent rituximab was not successful.

    It is very difficult to attain target goals in patients with lupus because the disease is very heterogeneous. However, there are many physicians who report tremendous benefit among patients with lupus and lupus nephritis who have been treated off-label with rituximab, so there is some hope that this next generation of anti-CD20 therapies will be successful.

    In the history of clinical development for lupus, there has only been one previous agent approved by the FDA based on the randomized controlled trials — belimumab (Benlysta, GlaxoSmithKline) — and clinical trials specifically excluded patients with serious lupus nephritis.

    As such, it has been unclear what to do for these patients as we have had literally no FDA-approved therapies. The two mainstays for treatment have been either been mycophenolate mofetil, by default, which was repurposed from transplant rejection, or a regimen using cyclophosphamide, a cancer therapy.

    Although more patients will need to be studied as obinutuzumab proceeds to phase 3 trials, it is fantastic that we may be able to finally provide an alternative for our patients that have, at once, the most serious and often life-threatening complication of this disease.

    • Gregg J. Silverman, MD
    • Director of the Laboratory of B Cell Immunobiology
      NYU Langone School of Medicine

    Disclosures: Silverman reports consulting for Lilly, Onyx, Pfizer, Quest and Roche and receiving grant support from the American College of Rheumatology Research Foundation, the Lupus Research Institute, and NIH.