B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis

Lupus nephritis (LN) is the most common and severe manifestation of systemic lupus erythematosus (SLE), affecting more than one-third of patients. LN is also an important contributor to morbidity and mortality in SLE patients. Despite advances in immunosuppressive therapies, outcomes have not significantly improved over the last two decades as only a minority of patients achieve the desired end point of complete renal response in clinical trials, underscoring a major therapeutic unmet need. Aberrant B-cell function plays an important role in the pathogenesis of SLE, and therefore, therapies targeting their depletion have been investigated for LN treatment. Among these therapies include the anti-CD20 monoclonal antibodies, rituximab and obinutuzumab. Although LUNAR, the phase III, randomized, placebo-controlled trial of rituximab for the treatment of LN failed to meet its primary end point of renal response when compared with placebo, there were signals from the trial and other studies that suggested a potential role for B-cell depletion in LN treatment. Recent data with obinutuzumab demonstrated that it produces more potent and durable B-cell depletion and is clinically superior to rituximab in the treatment of B-cell malignancies. The NOBILITY trial was a phase II, multicenter, randomized, double-blind trial that compared obinutuzumab to placebo in patients with proliferative LN. NOBILITY met its primary end point of complete renal response, suggesting that more profound B-cell depletion enhances outcomes in those with proliferative LN. Obinutuzumab is currently being studied for the treatment of proliferative LN in a global phase III trial (NCT04221477).