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.