In 2016, the National Institute for Health and Care Excellence ( NICE ) approved the use of Belimumab ( Benlysta ) for the treatment of autoantibody-positive systemic lupus erythematosus ( SLE ).
In 2011, Belimumab became the first drug in over 50 years to be approved by the Federal Drug Administration ( FDA ) in the USA for the treatment of systemic lupus erythematosus.
It is available in the USA for autoantibody positive lupus patients with active, skin or joint disease who have inadequate response to standard therapy. It is not, however, approved for the treatment of renal disease or severe central nervous system ( CNS ) involvement in systemic lupus erythematosus.
Belimumab is a recombinant, fully human IgG1λ mAb, which binds to soluble B-lymphocyte stimulator ( BAFF ).
Given that BAFF inhibits B-cell apoptosis, stimulates the differentiation of B cells into immunoglobulin producing cells and BAFF serum levels correlate with disease activity, it was hypothesized that it might be a target in treatment of systemic lupus erythematosus.
A phase I trial of Belimumab in 70 SLE patients with stable disease for 2 months indicated an abnormal rate of adverse events, but there was a significant reduction in percentages of CD20+ B cells and anti-dsDNA autoantibody titres after one or two doses of Belimumab, without any changes in disease activity.
A 52-week phase II trial included 449 SLE patients with active disease.
Belimumab was administered to 336 and placebo to 113 patients.
The inclusion criteria required a Safety of Oestrogen in Lupus Erythematosus National Assessment SLE Disease Activity Index ( SELENA-SLEDAI ) score greater than or equal to 4, history of measurable antibodies ( not necessarily present at screening ) and a stable therapeutic regimen for greater than or equal to 60 days.
Patients with active lupus nephritis or CNS disease were excluded.
Patients were randomized to receive 1, 4, or 10 mg/kg of Belimumab or placebo on days 0, 14, 28, and subsequently every 28 days for 52 weeks plus standard of care.
The primary clinical endpoints ( change in SELENA–SLEDAI score at week 24 and time to first flare ) were not met, as the mean percent changes in SELENA–SLEDAI were -19.5% for the Belimumab groups versus -17.2% for the placebo group at 24 weeks, and -27.2% versus -20.6% at 52 weeks.
Similarly, there were no differences between the four groups in the rate of flares ( mild / moderate or severe ) or time to first flare over 52 weeks, but time to first flare starting at week 24 through week 52 showed a median time of 154 days in the Belimumab groups and 108 days in the placebo group ( p = 0.0361 ), suggesting that Belimumab might stabilize the disease.
However, almost 30% of the patients were antinuclear antibody ( ANA ) negative, which lead to concerns about the veracity of the diagnosis. But a study has reported that in a 10-year period 17% of strongly ANA positive lupus patients become ANA negative.
A subgroup analysis in the Belimumab study demonstrated that serologically active patients ANA greater than or equal to 1:80 or levels of anti-dsDNA autoantibody greater than or equal to 30 IU/ml ) treated with Belimumab had a significantly greater reduction in SELENA–SLEDAI scores from baseline to week 52.
Based on the phase II trial results, a new SLE responder index ( SRI ) was developed for use in clinical trials. This tries to capture an improvement in disease activity without worsening of the overall condition or the development of significant disease activity in new organ systems.
A responder is defined as a greater than or equal to 4-point reduction in SELENA–SLEDAI score, no new British Isles Lupus Assessment Group ( BILAG ) A or no more than 1 new BILAG B domain score and no deterioration from baseline in the Physician’s Global Assessment ( PGA ) by greater than or equal to 0.3 points.
Two phase III trials were designed: BLISS-52 and BLISS-76 were conducted. The BLISS-52 trial recruited 865 patients from South America, Asia and Eastern Europe. BLISS-76 assessed 819 patients from North America, Europe and Israel, leading to two different ethnic origin distributions. They had a similar design. The inclusion criteria were SLE patients aged greater than or equal to 18 years, SELENA–SLEDAI greater than or equal to 6 and stable treatment regimen for at least 30 days.
Both trials included only serologically active SLE patients.
The exclusion criteria were severe active lupus nephritis or CNS involvement; pregnancy; previous treatment with any B-lymphocyte-targeted drug, intravenous Cyclophosphamide in the previous 6 months, and IVIg or Prednisone more than 100 mg/day within 3 months.
The patients were randomized in a 1:1:1 ratio to receive 1 mg/kg Belimumab, 10 mg/kg Belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days until 48 weeks in the BLISS-52 trial and for 72 weeks in the BLISS-76 trial.
The standard of care regimen and limitations on steroid use are described elsewhere.
The primary endpoint in both trials was the SRI response rate at week 52. The secondary endpoints were the percentage of patients with a four-point reduction from baseline in SELENA–SLEDAI score at week 52, change in PGA score at week 24, change in Short Form 36 version 2 ( SF36 ) at week 24 and percentage of patients in which the mean Prednisone dose was decreased 25% from baseline to 7.5 mg/day or less during weeks 40–52.
In the BLISS-76 trial, SRI response rate at week 76 was also a secondary endpoint.
In the BLISS-52 trial, Belimumab resulted in a significantly higher response rate [ 1 mg/kg: 148 ( 51% ); p = 0.0129 and 10 mg/kg: 167 ( 58% ); p =0.0006 ] compared to placebo [ 125 ( 44% ) ] at week 52 as assessed by SRI.
This revealed a dose response pattern, as Belimumab 10 mg/kg had a significantly greater response than placebo in all three SRI components, though Belimumab 1 mg/kg showed a greater response than placebo in SELENA–SLEDAI and PGA.
In the BLISS-76 trial, there were more SRI responders in the 10 mg/kg Belimumab group than in the placebo group ( 43.2% versus 33.5%; p = 0.017 ) at 52 weeks.
However, the percentage of SRI responders in the 1 mg/kg Belimumab group ( 40.6% ), while numerically greater than that in the placebo group, was not statistically significant ( p = 0.089 ).
Similarly, at week 76 the SRI response rates were numerically greater in the Belimumab groups than in the placebo group, but not significant.
Significantly greater and sustained reductions were noted in anti-dsDNA antibody levels in the belimumab groups in both trials when compared to placebo.
In the BLISS-52 trial, the patients with baseline Prednisone doses more than 7.5 mg/day showed that sustained dose reduction ( greater than or equal to 12 weeks until week 52 ) was more likely with Belimumab 1 mg/kg and 10 mg/kg than with placebo.
In the BLISS-72 trial, more patients in the Belimumab groups were able to reduce corticosteroids by 25% and to 7.5 mg/day between weeks 40 and 52 compared with patients receiving placebo, but this was not significant.
The rates of adverse effects were similar between all three groups in both trials.( Xagena )
Guerreiro Castro A, Isenberg DA, Ther Adv Musculoskelet Dis 2017; 9: 75–85