Breaking the ice in systemic lupus erythematosus: belimumab, a promising new therapy.

B lymphocyte stimulator (BLyS), a protein discovered in the 1990s that induces B cell proliferation and differentiation, promotes B cell survival, and is important in immunoglobulin class switching, was the target of a drug development program launched by Human Genome Sciences in the early part of the last decade. Belimumab, a human monoclonal antibody specific for soluble BLyS, was ultimately approved by the United States Food and Drug Administration (FDA) in March 2011 for active autoantibody patients with systemic lupus erythematosus (SLE) despite standard therapy. This program, whose studies spanned approximately 10 years from phase I through phase III, was founded on sound biology and advanced on logic and perseverance. Pre-clinical experimentation in murine models of SLE as well as observational studies in human SLE provided sufficient evidence to support the use of an inhibitor of BLyS as a novel therapy to reduce SLE disease activity. Progressing from phase I through a robust phase III program was no easy task given the complexities of SLE trial design. These challenges were overcome with the implementation of strict study entry requirements, the development of a novel responder index, and rigorous rules regarding background therapies. The success of two phase III studies and the approval of belimumab by the US Food and Drug Administration represent an unprecedented milestone in the history of SLE drug development. Belimumab was the first drug approved in SLE in over 50 years and was the first drug ever approved in SLE through the conventional route of randomized controlled trials. This article reviews the biology of BLyS, clinical trial results, and some of the emerging data from the robust phase II and III datasets.