History
B-cell activating factor is a naturally occurring protein that was discovered by researchers from National Jewish Health (previously the National Jewish Medical and Research Center) and the University of Colorado, who jointly published a paper detailing their findings in May 1999 and named the protein TALL-1.[14] The same protein was named BAFF in another paper published in June 1999, and in a paper published in July of that year, Human Genome Sciences (HGS) referred to it as BLyS (short for B lymphocyte stimulator).[15] Six years later, research showing the key role of BLyS in B cell differentiation, survival, and activation was published.[16]
In October 2000, HGS and Cambridge Antibody Technology (CAT) agreed to co-develop monoclonal antibodies targeted at BLyS. Under this agreement, CAT would identify antibodies and HGS would select appropriate ones to take into clinical trials.[17] In 2003, CAT researchers reported that, by using phage display technology, they had elicited an array of more than 1,000 distinct antibodies, half of which inhibited binding of BLyS to its receptor.[18] Later that year, one of these antibodies was isolated and characterized. It was named LymphoStat-B and subsequently called belimumab.[19]
In August 2006, HGS and GlaxoSmithKline (GSK) entered into a co-development and commercialization agreement under which HGS would conduct Phase III trials for belimumab with assistance from GSK. The companies would share equally in Phase III/IV development costs, sales and marketing expenses, and profits of any product commercialized under the agreement.[17] On 13 February 2007, HGS and GSK announced the initiation of the first of two Phase III clinical trials of belimumab in patients with active lupus erythematosus.[20]
Two Phase III clinical studies were conducted, involving a total of 1,684 patients with scores of ≥6 on the SELENA-SLEDAI assessment of lupus activity. The primary end point was a reduction of ≥4 on the SELENA-SLEDAI assessment, and several other factors, after 52 weeks. Belimumab significantly improved the response rate, reduced disease activity and severe flares, and was well tolerated. Among patients treated with belimumab (10mg/kg) in addition to standard therapy, 58% had SELENA-SLEDAI scores reduced by ≥4 points over 52 weeks, compared with 46% of patients treated with placebo. However, patients of African-American or African descent did not respond significantly to belimumab.[21][22]
These trials did not include patients with the most severe forms of systemic lupus erythematosus, which involve active damage to the kidneys or central nervous system. Subjects with active kidney disease were included in Phase II trials.[23]
Clinical trials found belimumab to be safe in treating systemic lupus erythematosus,[24][25][26] but the magnitude of benefit was small,[27] and Phase III trials excluded the most severe cases of systemic lupus erythematosus, involving kidney and brain damage. Reviewers at the US Food and Drug Administration (FDA) expressed concern that the drug was only "marginally" effective, and that there were more deaths in the treatment group. Defenders said that in addition to its modest efficiency, belimumab allowed patients to significantly reduce their use of corticosteroids.[28]
Belimumab was not effective in Phase II clinical trials for rheumatoid arthritis.[29] It was moderately effective in Phase II trials for Sjögren syndrome.[30]
In December 2020, belimumab was approved by the FDA as a treatment for lupus nephritis in combination with standard treatment.[31]
