General Information

Benlysta (belimumab) is a human IgG 1 À monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS). Elevated levels of BLyS are seen in the blood or joint fluid of patients with autoimmune and inflammatory disorders.

Benlysta is specifically indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus who are receiving standard therapy. Benlysta intravenous (IV) infusion is also indicated for use in pediatrics 5 years of age and older with systemic lupus erythematosus.

Benlysta is supplied as a solution for intravenous infusion. It must be reconstituted and diluted prior to intravenous administration The recommended initial dose is 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter. It should be administered as an intravenous infusion over a period of 1 hour. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction.

Clinical Results

FDA Approval
The FDA approval of Benlysta was based on three randomized, double-blind, placebo-controlled studies involving 2,133 patients with SLE.
Trial 1: Benlysta 1 mg/kg, 4 mg/kg, 10 mg/kg
Trial 1 enrolled 449 subjects and evaluated doses of 1, 4, and 10 mg/kg Benlysta plus standard of care compared with placebo plus standard of care over 52 weeks. The co-primary endpoints were percent change in SELENA-SLEDAI score at Week 24 and time to first flare over 52 weeks. No significant differences between any of the Benlysta groups and the placebo group were observed. Exploratory analysis of this study identified a subgroup of subjects (72%), who were autoantibody positive, in whom Benlysta appeared to offer benefit. The results of this study informed the design of Trials 2 and 3 and led to the selection of a target population and indication that is limited to autoantibody-positive SLE patients.
Trials 2 and 3: Benlysta 1 mg/kg and 10 mg/kg
Trials 2 and 3 were randomized, double-blind, placebo-controlled trials in patients with SLE that were similar in design except - Trial 2 was 76 weeks duration and was conducted in North America and Europe.and Trial 3 was 52 weeks duration and was conducted in South America, Eastern Europe, Asia, and Australia. At screening, subjects were stratified by disease severity based on their SELENA-SLEDAI score, proteinuria level and race (African or Indigenous-American descent vs. other), and then randomly assigned to receive Benlysta 1 mg/kg, 10 mg/kg, or placebo in addition to standard of care. Treatment was administered intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days for 48 weeks in Trial 3 and for 72 weeks in Trial 2. The primary efficacy endpoint was a composite endpoint (SLE Responder Index or SRI) that defined response as meeting each of the following criteria at Week 52 compared with baseline:
≥4-point reduction in the SELENA-SLEDAI score, and
no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores, and
no worsening (<0.30-point increase) in Physician’s Global Assessment (PGA) score
In both Trials 2 and 3, the proportion of SLE patients achieving an SRI response, as defined for the primary endpoint, was significantly higher in the Benlysta 10 mg/kg group than in the placebo group. The trends in comparisons between the treatment groups for the rates of response for the individual components of the endpoint were generally consistent with that of the SRI. At Week 76 in Trial 2, the SRI response rate with Benlysta 10 mg/kg was not significantly different from that of placebo (39% and 32%, respectively).

The efficacy of Benlysta IV for the treatment of SLE in pediatric patients was studied over 52 weeks in 93 pediatric patients with SLE. The proportion of pediatric patients achieving the composite primary endpoint, the SLE response index (SRI-4), was higher in pediatric patients receiving Benlysta IV plus standard therapy compared to placebo plus standard therapy. Pediatric patients who received Benlysta IV plus standard therapy also had a lower risk of experiencing a severe flare, as well as longer duration of time until a severe flare (160 days versus 82 days). The drug's safety and pharmacokinetic profiles in pediatric patients were consistent with those in adults with SLE.

Mechanism of Action

Benlysta (belimumab) is a human IgG 1 À monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS). It blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells. Benlysta does not bind B cells directly, but by binding BLyS, it inhibits the survival of B cells, including auto reactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.

Literature References

Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK, Thomas M, Kim HY, León MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA; BLISS-52 Study Group Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011 Feb 26;377(9767):721-31

Jacobi AM, Huang W, Wang T, Freimuth W, Sanz I, Furie R, Mackay M, Aranow C, Diamond B, Davidson A. Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis and Rheumatism 2010 Jan;62(1):201-10

Wallace DJ, Stohl W, Furie RA, Lisse JR, McKay JD, Merrill JT, Petri MA, Ginzler EM, Chatham WW, McCune WJ, Fernandez V, Chevrier MR, Zhong ZJ, Freimuth WW A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis and Rheumatism 2009 Sep 15;61(9):1168-78

Furie R, Stohl W, Ginzler EM, Becker M, Mishra N, Chatham W, Merrill JT, Weinstein A, McCune WJ, Zhong J, Cai W, Freimuth W; Belimumab Study Group Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Arthritis Research and Therapy 2008;10(5):R109. Epub 2008 Sep 11.