BENLYSTA is an investigational human monoclonal antibody drug and the first in a new class of drugs called BLyS-specific inhibitors. It is being developed for the treatment of seropositive patients with systemic lupus erythematosus (SLE) by HGS and GlaxoSmithKline (GSK) under a co-development and commercialization agreement entered into in 2006 [1-2]. BENLYSTA has successfully met its primary endpoint in two pivotal Phase 3 trials in systemic lupus [3-16]. In June 2010, HGS and GSK submitted regulatory applications seeking approval to market BENLYSTA in the United States and Europe [17-18]. The FDA has granted BENLYSTA a priority review designation with a Prescription Drug User Fee Act (PDUFA) target date of December 9, 2010 – so it is possible that BENLYSTA could receive regulatory approval in the United States before the end of 2010 [19]. It could become the first new approved drug for people living with lupus in more than 50 years.

How BENLYSTA Works

BENLYSTA inhibits the biological activity of B-lymphocyte stimulator, or BLyS. BLyS is a naturally occurring protein discovered by HGS [20-21], which is required for the survival and development of B-lymphocyte cells into mature plasma B cells. Plasma B cells produce antibodies, the body’s first line of defense against infection. In lupus and certain other autoimmune diseases, elevated levels of BLyS are believed to contribute to the production of autoantibodies – antibodies that attack and destroy the body’s own healthy tissues. The results of prospective observational studies show a significant correlation of elevated levels of BLyS with SLE disease activity [22-32].

BENLYSTA acts by: (1) specifically recognizing and binding to BLyS, (2) inhibiting BLyS’s stimulation of B-cell development, and (3) restoring the potential for autoantibody-producing B cells to undergo the normal process of apoptosis (programmed cell death). Clinical and nonclinical studies show that BLyS antagonists such as BENLYSTA can reduce autoantibody levels in SLE [3-16, 22-32]. The results of two pivotal Phase 3 trials, BLISS-52 and BLISS-76, suggest that belimumab can reduce SLE disease activity [3-16].

BENLYSTA Inhibits the Biological Activity of BLyS

Figure 1. BENLYSTA (belimumab) specifically binds to and inhibits the biological activity of BLyS. Preclinical and clinical results to date show that BENLYSTA can reduce the levels of circulating B cells, including precursor cells to the plasma B cells that produce the body’s normal and abnormal antibodies. This suggests that BENLYSTA may prove useful in the treatment of lupus and certain other autoimmune diseases.

Collaboration with GlaxoSmithKline

In August 2006, HGS and GSK entered into a co-development and commercialization agreement under which HGS has conducted the BENLYSTA Phase 3 trials, with assistance from GSK. The companies will share equally in Phase 3/4 development costs, sales and marketing expenses, and profits of any product commercialized under the agreement. [1-2]

Potential Treatment Settings

HGS and GSK are working closely together to develop BENLYSTA (belimumab) as a potential new treatment for systemic lupus erythematosus (SLE) and other autoimmune diseases. SLE is a chronic, life-threatening autoimmune disease. Approximately five million people worldwide, including approximately 1.5 million in the United States, suffer from various forms of lupus, including SLE.

Lupus can occur at any age, but appears mostly in young people ages 15 to 45. About 90 percent of those diagnosed with lupus are women. African-American women are about three times more likely to develop lupus, and it is also more common in Hispanic, Asian and American Indian women. Symptoms may include extreme fatigue, painful and swollen joints, unexplained fever, skin rash and kidney problems. Lupus can lead to arthritis, kidney failure, heart and lung inflammation, central nervous system abnormalities, inflammation of the blood vessels and blood disorders. For more information on lupus, visit the Lupus Foundation of America at www.lupus.org, the Lupus Research Institute at www.lupusresearchinstitute.org, the National Institute of Arthritis and Musculoskeletal and Skin Diseases at www.niams.nih.gov, or Lupus Europe at www.lupus-europe.org.

HGS and GSK are in the process of examining a range of potential additional indications for BENLYSTA that might be explored in Phase 2 clinical trials, including multiple sclerosis, vasculitis, post-renal transplant and rheumatoid arthritis. In addition, a number of small proof-of-concept studies are already ongoing or imminent in Sjögren’s syndrome, Waldenstrom’s disease and pre-transplant.

BLyS in Patients with Autoimmune Disease

Figure 2. In healthy people, the body signals autoantibody-producing B cells to kill themselves through apoptosis. In patients with autoimmune diseases, such as lupus, the BLyS protein stimulates B-cell hyperactivity and inhibits apoptosis. This allows autoantibody-producing B cells to mature and release autoantibodies into the body. Autoantibodies then attack the body’s own tissues, causing autoimmune diseases like lupus.

Phase 3 Clinical Development Program

The Phase 3 development program for belimumab included two double-blind, placebo-controlled, multi-center Phase 3 superiority trials – BLISS-52 and BLISS-76 – to evaluate the efficacy and safety of belimumab plus standard of care, versus placebo plus standard of care, in seropositive (HEp-2 ANA > 1:80 and/or anti-dsDNA > 30 IU/mL) patients with SLE [33-38]. Both BLISS-52 and BLISS-76 have now been completed. This is the largest clinical trial program ever conducted in lupus patients. BLISS-52 randomized and treated 865 patients at 90 clinical sites in 13 countries, primarily in Asia, South America and Eastern Europe. BLISS-76 randomized and treated 819 patients at 136 clinical sites in 19 countries, primarily in North America and Europe.

The design of the two trials was similar, but the duration of therapy in the two studies was different – 52 weeks for BLISS-52 and 76 weeks for BLISS-76. The data from the BLISS-76 Phase 3 study were analyzed after 52 weeks in accord with the study protocol, in support of the BLA and MAA submissions. The BLISS-76 study then continued for an additional 24 weeks through the full 76-week treatment period, with the objective of generating additional information about belimumab based on a variety of secondary endpoints. HGS designed the Phase 3 program for belimumab in collaboration with GSK and leading international SLE experts, and the program is being conducted under a Special Protocol Assessment agreement with FDA [36].

Clinical Progress to Date

BENLYSTA (belimumab) has met the primary efficacy endpoint in two pivotal Phase 3 trials, as specified by Special Protocol Assessment agreement with FDA [3-16, 36]. The efficacy of treatment with BENLYSTA plus standard of care was superior to placebo plus standard of care in both BLISS-52 and BLISS-76, with overall adverse event rates comparable to placebo plus standard of care. In June 2010, HGS and GSK submitted regulatory applications seeking approval to market BENLYSTA in the United States and Europe. The FDA has granted BENLYSTA a priority review designation with a Prescription Drug User Fee Act (PDUFA) target date of December 9, 2010 – so it is possible that BENLYSTA could receive regulatory approval in the United States before the end of 2010 [19].

BLISS-52

In July 2009, HGS and GSK announced that BENLYSTA met the primary endpoint in BLISS-52, the first of two pivotal Phase 3 trials in seropositive patients with SLE [16]. The results of BLISS-52 were presented in full in October 2009 at the 73rd Annual Scientific Meeting of the American College of Rheumatology (ACR), and additional data were presented in June 2010 at the 2010 Congress of the European League Against Rheumatism (EULAR) and the 9th International Congress on SLE [5, 7-8, 10-12, 14-16].

BLISS-52 Patient Response Rates (SRI)

Belimumab plus standard of care achieved a clinically and statistically significant improvement in patient response rate in the BLISS-52 study as measured by the SLE Responder Index (SRI) at Week 52, compared with placebo plus standard of care. Study results also showed that belimumab was generally well tolerated, with adverse event rates comparable between belimumab and placebo treatment groups.

• The SRI defines patient response by an improvement in SELENA SLEDAI score of 4 points or greater, with no clinically significant BILAG worsening, and no clinically significant worsening in Physician’s Global Assessment. 
• A clinically and statistically significant improvement was shown in SRI response rates for belimumab plus standard of care vs. placebo plus standard of care: 57.6% for 10 mg/kg belimumab, 51.4% for 1 mg/kg belimumab, and 43.6% for placebo (p=0.0006 and p=0.013 for 10 mg/kg and 1 mg/kg belimumab, respectively). 
• There were more responders in the 10 mg/kg belimumab group compared to the placebo group between Weeks 4 and 8 of the study and this difference was statistically significant at Week 16 (p<0.05 for 10 mg/kg belimumab vs. placebo). The improvement was statistically significant and sustained for 10 mg/kg and 1 mg/kg belimumab from Week 24 and Week 28, respectively, through 52 weeks (p<0.05 for both belimumab treatment groups). 
• Post hoc exploratory analyses presented at EULAR evaluated SRI response in BLISS-52 using greater SELENA SLEDAI reductions (-5, -6, or -7 or more points) than the 4-point reduction used for the primary endpoint. These results along with the pre-specified 4-point reduction are provided below. Using these higher SELENA SLEDAI thresholds, a greater treatment effect was observed, with significant improvements in SRI response for both belimumab treatment groups at Week 52.

Key findings of the BLISS-52 study also included the following:

FLARES 

• Belimumab significantly delayed time to first SLE disease flare versus placebo (SLE Flare Index/SFI): median = 119 days for 10 mg/kg belimumab, 126 days for 1 mg/kg belimumab, and 84 days for placebo (p=0.0036 and p=0.0026 for 10 mg/kg and 1 mg/kg belimumab, respectively vs. placebo). 
• The risk of having severe SLE disease flares (SFI) was reduced over 52 weeks by 43% in the 10 mg/kg belimumab treatment group and by 24% in the 1 mg/kg belimumab treatment group vs. placebo (p=0.0055 and p=0.1342 for 10 mg/kg and 1 mg/kg belimumab, respectively). 
• The risk of having 1 BILAG A (severe flare) or more than 1 BILAG B (moderate flare) organ domain score was reduced by 42% in the 10 mg/kg belimumab treatment group and by 13% in the 1 mg/kg treatment group vs. placebo (p=0.0016 and p=0.3722 for 10 mg/kg and 1 mg/kg belimumab, respectively).

DISEASE ACTIVITY

• A significantly greater percentage of patients receiving belimumab achieved a reduction in SELENA SLEDAI score of at least 4 points by Week 52 (p=0.0024 and p=0.019 for 10 mg/kg and 1 mg/kg belimumab, respectively, vs. placebo), with improvement observed for 10 mg/kg belimumab within 4-8 weeks and reaching statistical significance at Week 16 and Weeks 24-52 (p<0.05 vs. placebo). 
• A significantly greater improvement in Physician’s Global Assessment (PGA) at Week 52 was observed in the belimumab treatment groups, with a mean percentage change from baseline of 45.7% for 10 mg/kg belimumab, 39.3% for 1 mg/kg belimumab, and 27.8% for placebo (p<0.0001 and p=0.004 for 10 mg/kg and 1 mg/kg belimumab, respectively, vs. placebo). The improvement in PGA was observed within 4-8 weeks and was sustained through 52 weeks (p<0.05 for both belimumab treatment groups).

STEROID USE 

• In patients who were receiving >7.5 mg per day of prednisone at baseline, a significantly higher percentage of patients in the 1 mg/kg belimumab treatment group vs. the placebo group had their average prednisone dose reduced by at least 25% from baseline to 7.5 mg per day or less during the last 12 weeks of study (p=0.025). A higher percentage of patients in the 10 mg/kg belimumab treatment group vs. the placebo group also had their average prednisone dose reduced by at least 25% from baseline to 7.5 mg per day or less during the last 12 weeks of study, but the difference did not reach a level of statistical significance (p=0.053). 
• In patients who were receiving <7.5 mg per day of prednisone at baseline, significantly fewer patients in the 10 mg/kg belimumab treatment group vs. the placebo group increased their prednisone use to >7.5 mg per day during the last 20 weeks of study (p<0.05). Fewer increases in prednisone use also were observed in the 1 mg/kg belimumab treatment group vs. the placebo group during the last 20 weeks of study, but the difference did not reach a level of statistical significance. 
• In patients who were receiving prednisone at baseline, a significantly higher percentage of patients in the 10 mg/kg belimumab treatment group vs. the placebo group had their average prednisone dose reduced by at least 50% from Weeks 24-52 (all p<0.05). A higher percentage of patients in the 1 mg/kg belimumab treatment group vs. the placebo group also had their average prednisone dose reduced by at least 50% after Week 24, but the difference reached a level of statistical significance only at Week 32 (p=0.036).  

FATIGUE AND QUALITY OF LIFE

• Improved fatigue scores were observed in the 10 mg/kg belimumab treatment group vs. the placebo group within 4-8 weeks, and both belimumab treatment groups achieved statistically significant improvement of fatigue by Week 52 (FACIT-Fatigue Scale; p<0.05 for both belimumab groups vs. the placebo group). 
• Improvement in health-related quality of life (HRQOL) as measured by the SF-36 Physical Component Summary (PCS) score at Week 24, a prespecified major secondary endpoint, was not significantly different among treatment groups. HRQOL improvement as measured by the SF-36 PCS score at Week 52 was significantly greater in both belimumab treatment groups vs. the placebo group (p=0.025 for 10 mg/kg and p=0.027 for 1 mg/kg belimumab, respectively).

BIOMARKER DATA

• Among patients who were positive for autoantibodies at baseline, significantly greater median percent reductions in autoantibodies were observed in the belimumab treatment groups by Week 52 vs. placebo, including: reductions in anti-dsDNA of 37.6% for belimumab 10 mg/kg, 35.1% for belimumab 1 mg/kg, and 12.3% for placebo (p<0.001 for both doses); reductions in anti-Smith of 56.3% for belimumab 10 mg/kg, 47.0% for belimumab 1 mg/kg, and 29.6% for placebo (p=0.0001 and p=0.0042 for belimumab 10 mg/kg and 1 mg/kg, respectively); and anti-ribosomal P of 55.6% for belimumab 10 mg/kg, 35.7% for belimumab 1 mg/kg, and 5.0% for placebo (p<0.0001 and p=0.019 for belimumab 10 mg/kg and 1 mg/kg, respectively). 
• A significantly greater percentage of belimumab-treated patients with hypergammaglobulinemia at baseline achieved normalization of IgG at Week 52 (p<0.05). Significantly greater median percent reductions in immunoglobulins were observed in the belimumab treatment groups by Week 52 (with p<0.0001 for both belimumab doses, vs. placebo), including: reductions in IgG of 15.6% for belimumab 10 mg/kg, 14.1% for belimumab 1 mg/kg, and 3.6% for placebo; reductions in IgM of 30.0% for belimumab 10 mg/kg, 28.5% for belimumab 1 mg/kg, and 3.2%% for placebo; and reductions in IgA of 16.0% for belimumab 10 mg/kg, 16.8% for belimumab 1 mg/kg, and 2.7% for placebo.
• Among patients with low C3 and C4 complement at baseline, significantly greater median percent increases were observed among patients in the belimumab treatment groups vs. the placebo group, with increases observed by Weeks 4-8 that were sustained or increased through Week 52. At Week 52, the median percent increase from baseline in C3 complement was 16.3% for belimumab 10 mg/kg, 10.1% for belimumab 1 mg/kg, and 2.1% for placebo (p<0.0001 and p=0.0061 for belimumab 10 mg/kg and 1 mg/kg, respectively, vs. placebo). At Week 52, the median percent increase from baseline in C4 complement was 50.0% for belimumab 10 mg/kg, 42.9% for belimumab 1 mg/kg, and 12.5% for placebo (p<0.0001 for both belimumab doses, vs. placebo).

SAFETY 

• In BLISS-52, belimumab was generally well tolerated, with rates of adverse events overall, serious and/or severe adverse events, all infections, serious and/or severe infections, and discontinuations due to adverse events comparable between treatment groups receiving belimumab plus standard of care and the treatment group receiving placebo plus standard of care. Serious and/or severe adverse events were reported in 18.5% of patients on belimumab and 16.7% of patients on placebo. Infections were reported in 67.6% of patients on belimumab and 63.8%% of patients on placebo. Serious and/or severe infections were reported in 6.2% of patients on belimumab and 6.3% of patients on placebo. Serious and/or severe infusion reactions were reported in 1.6% of patients on belimumab and 0.3% of patients on placebo. Discontinuations due to adverse events were 5.4% in the belimumab treatment groups and 6.6% in the placebo treatment group. No malignancies were reported. A total of 9 deaths were reported in the study: 4, 2, and 3 in the belimumab 10 mg/kg, belimumab 1 mg/kg and placebo groups, respectively.

BLISS-76

In November 2009, HGS and GSK announced that BENLYSTA met the primary endpoint in BLISS-76, the second of two pivotal Phase 3 trials in seropositive patients with SLE [13]. Study results also showed that belimumab was generally well tolerated, as demonstrated by a similar rate of discontinuations due to adverse events across treatment groups, with overall adverse event rates comparable between belimumab and placebo groups. The results of BLISS-76 were presented in full in June 2010 at the 2010 Congress of the European League Against Rheumatism (EULAR), and additional data from the study were presented later the same month at the 9th International Congress on SLE [3-4, 6, 9, 13].

The data from the BLISS-76 study were analyzed after 52 weeks, in accord with the study protocol, in support of regulatory applications in the United States and Europe. The BLISS-76 study then continued for an additional 24 weeks through the full 76-week treatment period, with the objective of generating additional information based on a number of secondary endpoints.

BLISS-76 Patient Response Rates (SRI) 
 

• Week 52 (Primary Endpoint). Based on intention-to-treat (ITT) analysis, belimumab 10 mg/kg met its primary endpoint of superiority versus placebo at Week 52. A statistically significant improvement was shown in patient response rate for belimumab 10 mg/kg plus standard of care, vs. placebo plus standard of care, as measured by SRI at Week 52: 43.2% for 10 mg/kg belimumab, 40.6% for 1 mg/kg belimumab, and 33.5% for placebo (p=0.017 and p=0.089 for 10 mg/kg and 1 mg/kg belimumab, respectively vs. placebo). 
• Week 76 (Major Secondary Endpoint). At Week 76, belimumab plus standard of care showed higher response rates compared with placebo plus standard of care as measured by SRI; however, this major secondary endpoint did not reach statistical significance: 38.5% for 10 mg/kg belimumab, 39.1% for 1 mg/kg belimumab, and 32.4% for placebo (p=0.13 and p=0.11 for 10 mg/kg and 1 mg/kg belimumab, respectively vs. placebo). 
• Post hoc exploratory analyses of BLISS-76 data at Weeks 52 and 76 evaluated SRI response using greater SELENA SLEDAI reductions (-5, -6, -7, -8, -9 and -10 points) than the 4-point reduction used for the primary endpoint. Using these higher SELENA SLEDAI thresholds, a greater treatment effect was observed, with significant improvements in SRI response for the 10 mg/kg treatment group at both Week 52 and Week 76 (p<0.05 vs. placebo).

Key findings of the BLISS-76 study also included the following:

DISEASE ACTIVITY 

• At Week 52, the mean percent improvement in SELENA SLEDAI score was 36.0% for belimumab 10 mg/kg, 33.9% for belimumab 1 mg/kg, and 26% for placebo (p=0.0077 and p=0.040 for 10 mg/kg and 1 mg/kg belimumab, respectively vs. placebo). At Week 76, the mean percent improvement in SELENA SLEDAI score was 37.0% for belimumab 10 mg/kg, 36.1% for belimumab 1 mg/kg, and 27.8% for placebo (p=0.014 and p=0.027 for 10mg/kg belimumab and 1 mg/kg belimumab, respectively vs. placebo). 
• The proportion of patients with a reduction in SELENA SLEDAI score of at least 4 points by Week 52, a major secondary endpoint, was 46.9% for belimumab 10 mg/kg, 42.8% for belimumab 1 mg/kg, and 35.6% for placebo (p=0.0062 and p=0.087 for belimumab 10 mg/kg and 1 mg/kg, respectively vs. placebo). At Week 76, the proportion of patients with a reduction in SELENA SLEDAI score from baseline of at least 4 points was 41.4% for belimumab 10 mg/kg, 42.1% for belimumab 1 mg/kg, and 33.8% for placebo (p=0.066 and p=0.049 for belimumab 10 mg/kg and 1 mg/kg, respectively vs. placebo). 
• The risk of severe SLE disease flares (SFI) was reduced over 76 weeks by 23% in the 10 mg/kg belimumab treatment group and by 34% in the 1 mg/kg belimumab treatment group vs. placebo (p=0.13 and p=0.023 for 10 mg/kg and 1 mg/kg belimumab, respectively). From Weeks 24-76, the risk of severe SLE disease flares was reduced by 30% in the 10 mg/kg belimumab treatment group and by 45% in the 1 mg/kg belimumab treatment group vs. placebo (p=0.10 and p=0.009 for 10 mg/kg and 1 mg/kg belimumab, respectively). 
• From Weeks 24-76, the risk of all SLE disease flares was significantly reduced in the belimumab 10 mg/kg treatment group, with risk reduction of 22% for 10 mg/kg belimumab and 16% for 1 mg/kg belimumab (p=0.016 and p=0.098 for 10 mg/kg and 1 mg/kg belimumab, respectively). Over 76 weeks from study initiation, however, the risk of all SLE disease flares (SFI) was not statistically different between the belimumab and placebo treatment groups.

STEROID USE 

• At entry into the BLISS-76 study, approximately 46% of patients were receiving steroids at a prednisone-equivalent dose of at least 7.5 mg per day. Among these patients, the percentage of patients who had their average steroid dose reduced from baseline to 7.5 mg per day or less by Week 76 was 25.8% for belimumab 10 mg/kg, 27.7% for belimumab 1 mg/kg, and 17.5%% for placebo (p=0.15 and p=0.046 for belimumab 10 mg/kg and 1 mg/kg, respectively, vs. placebo). One of the BLISS-76 study’s major secondary endpoints was the percentage of these patients who – during Weeks 40-52 – had their average steroid dose reduced by at least 25% from baseline to 7.5 mg per day or less. These percentages were: 16.7% for belimumab 10 mg/kg, 19.2% for belimumab 1 mg/kg, and 12.7% for placebo, and were not statistically significant vs. placebo. 
• Among patients who were receiving <7.5 mg per day of prednisone at baseline (N=443), the percentage of patients who had their average steroid dose increased to >7.5 mg per day by Week 76 was 11.8% for belimumab 10 mg/kg, 13.5% for belimumab 1 mg/kg, and 18.1% for placebo (p=0.17 and p=0.33 for belimumab 10 mg/kg and 1 mg/kg, respectively, vs. placebo).

FATIGUE

• Numerically improved fatigue scores were observed in the belimumab treatment groups vs. the placebo group within 8-12 weeks, and the 1 mg/kg belimumab treatment group achieved statistically significant improvement of fatigue by Week 52, which was maintained at Week 76 (FACIT-Fatigue Scale; p<0.05 vs. the placebo group). Mean absolute FACIT-Fatigue improvement from baseline at Week 76 was 5.0 for belimumab 10 mg/kg, 5.2 for belimumab 1 mg/kg, and 3.2 for placebo (p=0.12 and p=0.036 for belimumab 10 mg/kg and 1 mg/kg, respectively, vs. placebo).

BIOMARKER DATA

• Among patients who were positive for anti-double-stranded DNA autoantibodies (anti-dsDNA) at baseline, a significantly greater median percent reduction in anti-dsDNA was observed among patients in the belimumab treatment groups vs. the placebo group, with reductions observed by Week 8 that were sustained or increased through Week 76. At Week 76, the median percent reduction in anti-dsDNA was 49.5% for belimumab 10 mg/kg, 43.3% for belimumab 1 mg/kg, and 9.7% for placebo (p<0.0001 for belimumab 10 mg/kg and 1 mg/kg, vs. placebo). 
• Among patients with low C4 complement at baseline, a significantly greater median percent increase was observed among patients in the belimumab treatment groups vs. the placebo group, with increases observed by Weeks 4-8 that were sustained or increased through Week 76. At Week 76, the median percent increase in C4 complement was 51.9% for belimumab 10 mg/kg, 38.5% for belimumab 1 mg/kg, and 16.7% for placebo (p<0.0001 and p=0.0002 for belimumab 10 mg/kg and 1 mg/kg, respectively, vs. placebo).

B-CELL SUBSETS

Belimumab acts by specifically recognizing, binding to, and inhibiting the biological activity of the naturally occurring protein BLyS (B-lymphocyte stimulator). In lupus and certain other autoimmune diseases, elevated levels of BLyS are believed to contribute to the production of autoantibodies – antibodies that attack and destroy the body’s own cells. The presence of autoantibodies appears to correlate with disease severity. In the BLISS-76 study, belimumab treatment resulted in selective and, vs. placebo, significantly greater median percent reductions in levels of B-cell and plasma B-cell subsets, with preservation of memory B-cells. The median percent changes from baseline included the following:

• Greater reductions in CD20+ cells were observed at Week 8 in both belimumab treatment groups, reached statistical significance by Week 24 and increased through Week 52 and Week 76 (all p<0.0001 for both belimumab doses vs. placebo). 
• Significantly greater reductions in CD20+/CD27- naïve cells were observed at Week 8 in both belimumab treatment groups and increased through Weeks 24, 52 and 76 (all p<0.0001 for both belimumab doses vs. placebo). 
• Greater reductions in CD20+/CD69+ activated cells were observed at Week 24 in both belimumab treatment groups, reached statistical significance for belimumab 10 mg/kg by Week 52 which was maintained through Week 76, and reached significance for belimumab 1 mg/kg by Week 76 (all p<0.05 vs. placebo). 
• Greater reductions in CD20+/CD138+ plasmacytoid cells were observed at Week 8 in both belimumab treatment groups, reached statistical significance by Week 24 (p<0.05, vs. placebo), and increased or were maintained through Weeks 52 (p<0.001 vs. placebo) and 76 (p<0.001 and p<0.01 for belimumab 10 mg/kg and 1 mg/kg respectively vs. placebo). 
• A significantly greater reduction in CD20-/CD138+ plasma cells was observed at Week 8 in the belimumab 10 mg/kg group, which was maintained through Weeks 24, 52 and 76 (all p<0.01 vs. placebo). In the belimumab 1 mg/kg group, the greater reduction reached statistical significance by Week 24 (p<0.05 vs. placebo); however, statistical significance for the lower dose was not maintained through Weeks 52 and 76). 
• A significantly greater reduction in CD20-/CD27BR short-lived plasma cells was observed at Week 8 in the belimumab 10 mg/kg group, which was maintained through Weeks 24, 52 and 76 (all p<0.01 vs. placebo). Greater reductions were also observed In the belimumab 1 mg/kg group, but the difference did not reach statistical significance. 
• A significantly greater reduction in CD19+/CD27 BR/CD38BR SLE subset cells was observed at Week 8 in the belimumab 10 mg/kg group (p<0.01 vs. placebo), which was maintained through Weeks 24, 52 and 76 (all p<0.001 vs. placebo). Greater reductions were also observed In the belimumab 1 mg/kg group, but the difference did not reach statistical significance. 
• Significantly greater increases in CD20+/CD27+ memory cells were observed at Week 8 in both belimumab treatment groups and increased through Weeks 24, 52 and 76 (p<0.0001 at Weeks 8, 24 and 52, and p<0.05 at Week 76 for belimumab 10 mg/kg vs. placebo).

EFFECT ON PROTECTIVE IMMUNE RESPONSE 

• Belimumab did not significantly affect the ability of SLE patients to maintain a protective response to pneumococcal, tetanus and influenza vaccines, which is consistent with the preservation of memory B-cells.

SAFETY 

• In BLISS-76 through 76 weeks, belimumab was generally well tolerated, with rates of adverse events overall, serious and/or severe adverse events, all infections, serious and/or severe infections, and discontinuations due to adverse events comparable between treatment groups receiving belimumab plus standard of care and the treatment group receiving placebo plus standard of care. Serious and/or severe adverse events were reported in 29.0% of patients on belimumab and 26.2% of patients on placebo. Infections were reported in 74.3% of patients on belimumab and 69.1% of patients on placebo. Serious and/or severe infections were reported in 7.7% of patients on belimumab and 8.4% of patients on placebo. Serious and/or severe infusion reactions were reported in 1.1% of patients on belimumab and 0.7% of patients on placebo. Discontinuations due to adverse events were 7.5% in the belimumab treatment groups and 8.4% in the placebo treatment group. A total of seven malignancies were reported in BLISS-76: 2, 4, and 1 in the belimumab 10 mg/kg, belimumab 1 mg/kg and placebo groups, respectively. A total of three deaths were reported in the study: 1, 2, and 0 in the belimumab 10 mg/kg, belimumab 1 mg/kg and placebo groups, respectively.

LONG-TERM PHASE 2 CONTINUATION STUDY RESULTS

Results through five years of the long-term Phase 2 continuation study of belimumab were presented in June 2010 at the 2010 Congress of the European League Against Rheumatism (EULAR) [39]. The results showed that belimumab was associated with sustained improvement in disease activity across multiple clinical measures, decreased frequency of disease flares, and sustained reductions in autoantibody levels in seropositive patients with SLE. (All patients remaining on study after Week 52 received belimumab.) The data presented from Week 52 to Week 256 in seropositive patients with SLE who were treated with belimumab from initiation of the Phase 2 study include the following trends:

• An increase from 46% to 59% in the SRI response rate ultimately selected as the primary efficacy endpoint of the Phase 3 trials (post hoc; intention-to-treat analysis). 
• A decrease from 62% to 22% in the overall frequency of SLE disease flares, as measured by the SELENA SLEDAI Flare Index. 
• A decrease from 23% to 11% in the frequency of patients experiencing a new BILAG A flare (which would indicate a severe flare of lupus disease activity) or more than one new BILAG B flare (which would indicate a moderate flare of disease activity). 
• An increase from 33% to 41% from Weeks 52-76 in mean percent improvement in PGA score, which was sustained from Weeks 76-256.

The biomarker data presented at EULAR from the Phase 2 continuation study through five years included sustained reductions in a number of autoantibodies from Week 52 to Week 256 in seropositive patients who were treated with belimumab from initiation of the Phase 2 study. The median percent reductions from baseline among patients who were positive for the autoantibodies at baseline included:

• Reduction in anti-dsDNA of 29.4% at Week 52 and 63.0% at Week 256. 
• Reduction in anti-Smith of 29.0% at Week 52 and 51.5% at Week 256. 
• Reduction in anti-cardiolipin IgG of 13.8% at Week 52 and 37.3% at Week 256.

The five-year Phase 2 continuation data also showed that belimumab was generally well tolerated in patients with SLE. By Week 256, overall belimumab exposure was 1,394 patient years. The incidence rates per 100 patients in all adverse event categories, including serious adverse events, overall adverse events, and serious infections, were similar for belimumab and placebo during the 52-week double-blind period, and remained the same or decreased over five years of continuous treatment. The overall incidence of adverse events (in general and by system organ class), serious adverse events, infections, malignancies and laboratory abnormalities decreased or stabilized over time from Week 52 to Week 256.  

How BENLYSTA Was Discovered

HGS first discovered the naturally occurring protein, BLyS or B-lymphocyte stimulator, in 1997 and published a preliminary description of its activity in the journal, Science, in July 1999 [20-21]. Following that discovery, HGS initiated a program to develop human monoclonal antibodies that would specifically recognize and inhibit the biological activity of BLyS. BENLYSTA is a human monoclonal antibody that HGS generated through a collaboration with Cambridge Antibody Technology [40].

For More Information about BENLYSTA Clinical Trials

Health professionals and patients interested in BENLYSTA (belimumab) clinical trials or other studies involving HGS products may inquire via email to This e-mail address is being protected from spam bots, you need JavaScript enabled to view it or by calling HGS at (877) 822-8472. Information about HGS clinical trials may also be found at www.clinicaltrials.gov.

Footnotes

1. (HGSI Press Release) GlaxoSmithKline Exercises Option to LymphoStat-B. July 7, 2005.
2. (HGSI Press Release) Human Genome Sciences Completes Enrollment in First of Two Phase 3 LymphoStat-B Trials. April 22, 2008. 
3. (HGSI Press Release) Human Genome Sciences Announces Presentation of Additional Phase 3 SLE Study Results for BENLYSTA (belimumab) at International Congress on SLE. June 25, 2010. 
4. (HGSI and GSK Joint Press Release) Human Genome Sciences and GlaxoSmithKline Announce Full Presentation at EULAR of BLISS-76 Phase 3 Study Results for BENLYSTA in Systemic Lupus Erythematosus. June 17, 2010. 
5. (HGSI and GSK Joint Press Release) Human Genome Sciences and GlaxoSmithKline Announce Presentation at EULAR of BLISS-52 Phase 3 Study Results for BENLYSTA (belimumab). June 17, 2010. 
6. Furie RA, Gladman DD, D’Cruz D, Petri M, et al. Belimumab, a BLyS-specific inhibitor, reduced disease activity and severe flares in patients with seropositive SLE: BLISS-76 study. 9th International Congress on SLE. June 25, 2010. Oral presentation. 
7. Navarra S, Bae S-C, Hall S, Petri M, et al. Belimumab, a BLyS-specific inhibitor, reduced disease activity, flares, and steroid use in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. 9th International Congress on SLE. June 25, 2010. Oral presentation. 
8. Gladman D, Kang YM, Tsai S-T, Freimuth W, et al. Belimumab, a BLyS-specific inhibitor, significantly improved physical functioning, fatigue, and other health-related quality of life (HRQOL) measures in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. 9th International Congress on SLE. June 26, 2010. Poster presentation. 
9. Van Vollenhoven RF, Zamani O, Wallace D, Cervera R, et al. Belimumab, a BLyS-specific inhibitor, reduces disease activity and severe flares in seropositive SLE patients: BLISS-76 study. EULAR 2010: Annual European Congress of Rheumatology. June 17, 2010. Oral presentation. 
10. Navarra S, Illivanova E, Bae S-C, Petri M, et al. Belimumab, a BLyS-specific inhibitor, reduced disease activity, flares, and steroid use in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. EULAR 2010: Annual European Congress of Rheumatology. June 19, 2010. Poster presentation. 
11. Levy RA, Illinova E, Ionescu R, Freimuth W, et al. Belimumab, a BLyS-specific inhibitor, significantly reduced antibodies and normalized low complement in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. EULAR 2010: Annual European Congress of Rheumatology. June 19, 2010. Poster presentation. 
12. Tanasescu C, Gallacher A, Garcia M, Freimuth W, et al. Belimumab, a BLyS-specific inhibitor, significantly improved physical functioning, fatigue, and other health-related quality of life (HRQOL) measures in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. EULAR 2010: Annual European Congress of Rheumatology. June 19, 2010. Poster presentation. 
13. (HGSI Press Release) Human Genome Sciences and GlaxoSmithKline Announce Positive Results in Second of Two Phase 3 Trials of BENLYSTA in Systemic Lupus Erythematosus. November 2, 2009. 
14. (HGSI and GSK Joint Press Release) Human Genome Sciences and GlaxoSmithKline Announce Full Presentation at ACR of Positive Phase 3 Study Results for BENLYSTA in Systemic Lupus Erythematosus. October 20, 2009. 
15. Navarra S, Guzman R, Gallacher A, et al. Belimumab, a BLyS-specific inhibitor, reduced disease activity, flares and prednisone use in patients with active SLE: efficacy and safety results from the Phase 3 BLISS-52 study. 73rd Annual Scientific Meeting of the American College of Rheumatology. October 20, 2009. Oral Presentation. 
16. (HGSI and GSK Joint Press Release) Human Genome Sciences and GlaxoSmithKline Announce Positive Phase 3 Study Results for BENLYSTA in Systemic Lupus Erythematosus. July 20, 2009. 
17. (HGSI Press Release) Human Genome Sciences Announces Submission of Biologics License Application to FDA for BENLYSTA (Belimumab). June 10, 2010. 
18. (HGSI Press Release) Human Genome Sciences Announces Submission of Marketing Authorization Application to EMA for BENLYSTA (Belimumab). June 7, 2010. 
19. (HGSI Press Release) Human Genome Sciences and GlaxoSmithKline Announce FDA Priority Review Designation for BENLYSTA (Belimumab) as a Potential Treatment for Systemic Lupus Erythematosus. August 19, 2010. 
20. Moore PA, Belvedere O, Orr A, et al. BLyS: member of the tumor necrosis factor family and B-lymphocyte stimulator. Science. 1999; 285: 260-263. 
21. (HGSI Press Release) Human Genome Sciences Announces the Discovery of a Novel Immune Stimulant. July 8, 1999. 
22. Petri M, Stohl W, Chatham W, et al. BLyS plasma concentrations correlate with disease activity and levels of anti-dsDNA autoantibodies and immunoglobulins (IgG) in an SLE patient observational study. 67th Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals. October 27, 2003. Abstract #1712. 
23. Carter RH. A role for BLyS in tissue inflammation? Arthritis & Rheumatism April 2003; 48(4): 882-885. 
24. Tan S, Roschke V, Perry JW, Arkfeld DG, Ehresmann GR, Migone T, Hilbert DM, and Stohl W. Local production of B lymphocyte stimulator and APRIL in arthritic joints of patients with inflammatory arthritis. Arthritis & Rheumatism April 2003; 48(4): 982-992.
25. Petri M. Biomarkers in SLE: The Hopkins lupus cohort. Lupus Foundation of America biomarkers for the assessment of systemic lupus erythematosus meeting. March 2003. 
26. Zhang J, Roschke V, Baker K, Kimberly R, et al. Cutting edge: A role for B lymphocyte stimulator in systemic lupus erythematosus. J Immuno. 2001; 166:6-10. 
27. Cheema GS, Roschke V, Hilbert DM and Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis & Rheumatism June 2001; 44(6): 1313-1319. 
28. Wang H, Marsters SA, Baker T, et al. TACI-ligand interactions are required for T cell activation and collagen-induced arthritis in mice. Nature Immunol. 2001; 2: 632-637. 
29. (HGSI Press Release) High Levels of BLyS Implicated in Lupus and Rheumatoid Arthritis Patients. October 30, 2000. 
30. Gross JA, Johnston J, Mudri S, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000; 404: 995-999. 
31. Khare SD, Saarosi I, Xia XZ, et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci USA. 2000; 97: 3370-3375. 
32. MacKay F, Woodcock SA, Lawton P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 1999; 190: 1697-1710. 
33. (HGSI Press Release) Human Genome Sciences Announces Phase 3 Clinical Development Program for LymphoStat-B in Systemic Lupus Erythematosus. August 9, 2006. 
34. (HGSI Press Release) Human Genome Sciences and GlaxoSmithKline Initiate Second Phase 3 Clinical Trial of LymphoStat-B in Systemic Lupus Erythematosus. May 30, 2007. 
35. (HGSI Press Release) Human Genome Sciences and GlaxoSmithKline Announce Initiation of Phase 3 Clinical Trial of LymphoStat-B in Systemic Lupus Erythematosus. February 13, 2007. 
36. (HGSI Press Release) Human Genome Sciences Announces Special Protocol Assessment and Agreement from FDA for Phase 3 Clinical Trials of LymphoStat-B in Systemic Lupus Erythematosus. October 26, 2006. 
37. (HGSI Press Release) Novel Evidence-Based Systemic Lupus Erythematosus (SLE) Responder Index Described in Peer Reviewed Publication as Potentially Significant Advance in Lupus Drug Development. September 4, 2009. 
38. Furie RA, Petrie MA, Wallace DJ, Freimuth WW, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Care & Research. September 15, 2009. 
39. Chatham W, Weinstein A, Petri M, Freimuth W, et al. Five-year safety and efficacy experience with belimumab, a BLyS-specific inhibitor, in patients with systemic lupus erythematosus (SLE). EULAR 2010: Annual European Congress of Rheumatology. June 19, 2010. Oral presentation. 
40. (HGSI Press Release) Human Genome Sciences and Cambridge Antibody Technology Commit to Exclusive Development of Anti-BLyS Antibodies. October 30, 2000. 

Bibliography

HGS and Collaborators

Baker K, Edwards B, Main S, et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes BLyS bioactivities. Arthritis & Rheumatism Nov 2003; 48: 3253-3265.

Carter RH. A role for BLyS in tissue inflammation? Arthritis & Rheumatism April 2003; 48(4): 882-885.

Chatham W, Weinstein A, Petri M, Freimuth W, et al. Five-year safety and efficacy experience with belimumab, a BLyS-specific inhibitor, in patients with systemic lupus erythematosus (SLE). EULAR 2010: Annual European Congress of Rheumatology. June 19, 2010. Oral presentation.

Chatham W, Stohl W, Merrill JT, et al. Changes in circulating B cell subtype counts, antibody levels and immunoglobulins that associate with therapeutic responsiveness in SLE to BLyS protein antagonism by belimumab. Annual Congress of the European League Against Rheumatism (EULAR 2007). June 16, 2007. Poster presentation.

Chatham W, Aranow C, Furie R, Freimuth W, et al. Progressive normalization of autoantibody, immunoglobulin, and complement levels over 3 years of belimumab (fully human monoclonal antibody to BLyS) therapy in systemic lupus erythematosus (SLE) patients. Annual Congress of the European League Against Rheumatism (EULAR 2008). June 12, 2008. Poster presentation.

Cheema GS, Roschke V, Hilbert DM, Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis & Rheumatism June 2001; 44(6): 1313-1319.

Furie RA, Gladman DD, D’Cruz D, Petri M, et al. Belimumab, a BLyS-specific inhibitor, reduced disease activity and severe flares in patients with seropositive SLE: BLISS-76 study. 9th International Congress on SLE. June 25, 2010. Oral presentation.

Furie RA, Petrie MA, Wallace DJ, Freimuth WW, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Care & Research. September 15, 2009.

Furie R, Stohl W, Ginzler E, et al. Safety, pharmacokinetic and pharmacodynamic results of a Phase 1 single and double dose-escalation study of LymphoStat-B (human monoclonal antibody to BLyS) in SLE patients. 67th Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals. October 26, 2003. Abstract 922.

Furie R, Lisse J, Merrill JT, Petri M, et al. Multiple SLE disease activity measures in a multi-center Phase 2 SLE trial demonstrate belimumab improves or stabilizes SLE activity in serologically active SLE patients. Annual Congress of the European League Against Rheumatism (EULAR 2006). June 22, 2006. Oral Presentation #0030.

Furie R, Lisse J, Merrill JT, Petri M, Ginzler E, Freimuth W, et al. Belimumab (fully human monoclonal antibody to B-lymphocyte stimulator [BLyS]) improves or stabilizes SLE activity in a multi-center Phase 2 trial. 70th Annual Scientific Meeting of the American College of Rheumatology. November 12, 2006. 

Furie R, Petri M, Weisman MH, Freimuth W, et al. Belimumab improved or stabilized SLE disease activity and reduced flare rates during 3 years of therapy. Annual Congress of the European League Against Rheumatism (EULAR 2008). June 12, 2008. Oral presentation.

Gladman D, Kang YM, Tsai S-T, Freimuth W, et al. Belimumab, a BLyS-specific inhibitor, significantly improved physical functioning, fatigue, and other health-related quality of life (HRQOL) measures in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. 9th International Congress on SLE. June 26, 2010. Poster presentation.

Ginzler G, Furie R, Wallace DJ, et al. Novel combined response endpoint shows that belimumab (fully human monoclonal antibody to B-lymphocyte stimulator [BLyS]) improves or stabilizes SLE disease activity in a Phase 2 trial. Annual Congress of the European League Against Rheumatism (EULAR 2007). June 14, 2007. Oral presentation.

Ginzler EM, Wallace DJ, Chatham W, Freimuth W, et al. Belimumab (fully human monoclonal antibody to BLyS) reduced steroid use in systemic lupus erythematosus (SLE) patients during 3 years of therapy. Annual Congress of the European League Against Rheumatism (EULAR 2008). June 12, 2008. Poster presentation.

Halpern W, Lappin P, Zanardi T, et al. Effects of LymphoStat-B, a BLyS antagonist, when administered intravenously to cynomolgus monkeys. 67th Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals. October 27, 2003. Abstract # 1537.

Huizinga, TW, Boling E, Valente R, et al. Genetic and environmental risk factors, disease outcome and responses to anti B-cell therapy belimumab indicate anti-CCP positive RA is a distinct disease entity. 70th Annual Scientific Meeting of the American College of Rheumatology. November 13, 2006.

Levy RA, Illinova E, Ionescu R, Freimuth W, et al. Belimumab, a BLyS-specific inhibitor, significantly reduced antibodies and normalized low complement in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. EULAR 2010: Annual European Congress of Rheumatology. June 19, 2010. Poster presentation.

McKay J, Chwalinska-Sadowska H, Boling E, et al. Belimumab, a fully human monoclonal antibody to B-lymphocyte stimulator (BLyS), combined with standard of care therapy reduces the signs and symptoms of rheumatoid arthritis in a heterogeneous subject population. 69th Annual Scientific Meeting of the American College of Rheumatology. November 16, 2005. Oral Presentation #1920.

Merrill JT, Furie R, Wallace DJ, Freimuth W, et al. 4 year experience of belimumab, a fully human monoclonal antibody, in the treatment of systemic lupus erythematosus (SLE). Annual Congress of the European League Against Rheumatism (EULAR 2009). June 11, 2009. Poster presentation.

Merrill JT, Wallace DJ, Stohl W, Freimuth W, et al. Safety profile of belimumab (fully human monoclonal antibody to BLyS) in patients with systemic lupus erythematosus (SLE) treated during a placebo-controlled trial and in a long-term continuation study. 71st Annual Scientific Meeting of the American College of Rheumatology. November 8, 2007. Poster presentation.

Merrill JT, Wallace DJ, McKay J, Freimuth W, et al. Long-term safety profile belimumab (fully human monoclonal antibody to BLyS) in patients with systemic lupus erythematosus (SLE). Annual Congress of the European League Against Rheumatism (EULAR 2008). June 12, 2008. Poster presentation.

Moore PA, Belvedere O, Orr A, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999; 285: 260-263.

Nardelli B, Belvedere O, Roschke V, Moore PA, Olsen HS, Migone TS, Sosnovtseva S, Carrell JA, Feng P, Giri JG, Hilbert DM. Synthesis and release of B-lymphocyte stimulator from myeloid cells. Blood 2001 Jan 1; 97(1):198-204.

Navarra S, Bae S-C, Hall S, Petri M, et al. Belimumab, a BLyS-specific inhibitor, reduced disease activity, flares, and steroid use in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. 9th International Congress on SLE. June 25, 2010. Oral presentation.

Navarra S, Illivanova E, Bae S-C, Petri M, et al. Belimumab, a BLyS-specific inhibitor, reduced disease activity, flares, and steroid use in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. EULAR 2010: Annual European Congress of Rheumatology. June 19, 2010. Poster presentation.

Navarra S, Guzman R, Gallacher A, et al. Belimumab, a BLyS-specific inhibitor, reduced disease activity, flares and prednisone use in patients with active SLE: efficacy and safety results from the Phase 3 BLISS-52 study. 73rd Annual Scientific Meeting of the American College of Rheumatology. October 20, 2009. Oral Presentation.

Petrie MA, Furie RA, Merrill JT, Freimuth WW, et al. Four-year experience of belimumab, a BlyS-specific inhibitor, in systemic lupus erythematosus. 73rd Annual Scientific Meeting of the American College of Rheumatology. October 21, 2009. Oral Presentation. 

Petri M. Biomarkers in SLE : The Hopkins lupus cohort. Lupus Foundation of America Biomarkers for the Assessment of Systemic Lupus Erythematosus Meeting. March 2003.  

Petri M, Stohl W, Chatham W, et al. BLyS plasma concentrations correlate with disease activity and levels of anti-dsDNA autoantibodies and immunoglobulins (IgG) in a SLE patient observational study. 67th Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals. October 27, 2003. Abstract #1712.

Petri M, Wallace DJ, Stohl W, McKay J, et al. SLE patients with active production of anti-nuclear autoantibodies (ANA positive) have distinct patterns of lupus activity and peripheral B-cell biomarkers compared to ANA negative patients. Annual Congress of the European League Against Rheumatism (EULAR 2006). June 23, 2006. Abstract #FRI0231.

Petri M, Furie R, Ginzler E, Freimuth W, et al. Belimumab improved or stabilized SLE disease activity and reduced flare rate over 2.5 years of therapy. 71st Annual Scientific Meeting of the American College of Rheumatology. November 9, 2007. Oral presentation.

Sekut L, Sturm B, Poortman C, Wager R, Zhang C, Abramian D, Riccobene T, Sosnovtseva S, Sung C, Roschke V, Baker KP, Hilbert DM. Characterization of a human monoclonal antibody that antagonizes B-lymphocyte stimulator bioactivities. American College of Rheumatology 2001 Annual Meeting, Abstract 1377.

Stohl W, Wallace DJ, Merrill JT, et al. Changes in circulating B-cell counts, autoantibody levels and immunoglobulins that associate with therapeutic responsiveness in SLE to BLyS protein antagonism by belimumab. 70th Annual Scientific Meeting of the American College of Rheumatology. November 14, 2006.

Stohl W, Chatham W, McKay J, Freimuth W, et al. Progressive normalization of autoantibody, immunoglobulin, and complement levels over 2.5 years of belimumab (fully human monoclonal antibody to BLyS) therapy in systemic lupus erythematosus (SLE) patients. 71st Annual Scientific Meeting of the American College of Rheumatology. November 8, 2007. Poster presentation.

Strand V, Crawford, B, Petri M, et al. Patients with active systemic lupus erythematosus (SLE) treated with belimumab improve health-related quality of life (HRQOL) in a randomized controlled trial (RCT). 70th Annual Scientific Meeting of the American College of Rheumatology. November 12, 2006.

Strand V, Crawford, B, Petri M, et al. Therapeutic responses reflecting a reduction in SELENA SLEDAI score are associated with a stabilization or improvement in health-related quality of life (HRQOL). 70th Annual Scientific Meeting of the American College of Rheumatology. November 12, 2006.

Strand V, Petri M, Buyon J, et al. Baseline data from five controlled trials (RCTs) demonstrate that systemic lupus erythematosus (SLE) impacts all domains of health-related quality of life (HRQOL). 70th Annual Scientific Meeting of the American College of Rheumatology. November 12, 2006.

Strand V, Petri M, Buyon J, et al. Systemic lupus erythematosus (SLE) impacts all domains of health-related quality of life (HRQOL): baseline results from five randomized controlled trials (RCTS). Annual Congress of the European League Against Rheumatism (EULAR 2007). June 16, 2007. Poster presentation.

Strand V, Crawford B, Petri M, et al. Responders defined by SELENA SLEDAI, BILAG and Physicians Global Assessment of disease activity report stabilization and/or improvement in health-related quality of life (HRQOL) following treatment with belimumab. Annual Congress of the European League Against Rheumatism (EULAR 2007). June 16, 2007. Poster presentation.

Tanasescu C, Gallacher A, Garcia M, Freimuth W, et al. Belimumab, a BLyS-specific inhibitor, significantly improved physical functioning, fatigue, and other health-related quality of life (HRQOL) measures in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. EULAR 2010: Annual European Congress of Rheumatology. June 19, 2010. Poster presentation.

Tan S, Roschke V, Perry JW, Arkfeld DG, Ehresmann GR, Migone T, Hilbert DM, Stohl W. Local production of B lymphocyte stimulator and APRIL in arthritic joints of patients with inflammatory arthritis. Arthritis & Rheumatism April 2003; 48(4): 982-992.

Van Vollenhoven RF, Zamani O, Wallace D, Cervera R, et al. Belimumab, a BLyS-specific inhibitor, reduces disease activity and severe flares in seropositive SLE patients: BLISS-76 study. EULAR 2010: Annual European Congress of Rheumatology. June 17, 2010. Oral presentation.

Wallace DJ, Lisse J, Stohl W, Freimuth W, et al. Belimumab reduces SLE disease activity and demonstrates durable bioactivity at 76 weeks. 70th Annual Scientific Meeting of the American College of Rheumatology. November 14, 2006.

Wallace DJ, Lisse J, Stohl W, McKay J, et al. Belimumab (LymphoStat-B) shows bioactivity and reduces SLE disease activity. Annual Congress of the European League Against Rheumatism (EULAR 2006). June 22, 2006. Oral Presentation #0029.

Wu Y, Bressette D, Carrell JA et al. Tumor necrosis factor (TNF) receptor superfamily member TACI Is a high affinity receptor for TNF family members APRIL and BLyS. J. Biol. Chem. 2000; 275(45): 35478—35485

Zhang J, Roschke V, Baker K, Kimberly R, et al. Cutting edge: A role for B lymphocyte stimulator in systemic lupus erythematosus. J Immuno. 2001; 166:6-10.

Non-HGS, Non-Collaborators

Bukhari M, et al. Rheumatoid factor is the major predictor of increasing severity of radiographic erosions in rheumatoid arthritis. Arthritis & Rheumatism. 2002; 46(4): 906-912.

Cambridge G, Leandro MJ, Edwards JCW, Ehrenstein MR, Salden M, and Webster D. B lymphocyte depletion in patients with rheumatoid arthritis: Serial studies of immunological parameters. American College of Rheumatology 2002 Annual Meeting, Abstract 1350.

Edwards JCW, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. New England Journal of Medicine. 2004; 350(25): 2572-2581.

Gross JA, Johnston J, Mudri S, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000; 404: 995-999.

Gross J, Dillon S, Mudri S, et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. Impaired B cell maturation in mice lacking BLyS. Immunity 2001 15(2): 289-302.

Khare SD, Saarosi I, Xia XZ, et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci USA. 2000; 97: 3370-3375.

Knijff-Dutmer E, et al. Rheumatoid factor measured by fluoroimmunoassay: a responsive measure of rheumatoid arthritis disease activity that is associated with joint damage. Annals of Rheumatoid Disease. 2002; 61: 603-607.

Leandro MJ, Edwards JCW, Cambridge G. Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum Dis 2002; 61: 883-888.

MacKay F., Woodcock SA, Lawton P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 1999; 190: 1697-1710.

Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, Frew E, Scott ML. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science. 14 September, 2001 ; 293: 2111-2114.

Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, Ambrose C, Lawton P, Bixler S, Acha-Orbea H, Valmori D, Romero P, Werner-Favre C, Zubler RH, Browning JL, Tschopp J. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J. Exp Med 1999 Jun 7; 189(11): 1747-56.

Thompson JS, Bixler SA, Qian F, Vora K, Scott ML, Cachero TG, Hession C, Schneider P, Sizing ID, Mullen C, Strauch K, Zafari M, Benjamin CD, Tschopp J, Browning JL, Ambrose C. BAFF-R, a Novel TNF Receptor That Specifically Interacts with BAFF. Science. 14 September 2001 ; 293: 2108-2111.

Tsokos, G. B-cells, be gone – B-cell depletion in the treatment of rheumatoid arthritis. New England Journal of Medicine. 2004; 350(25): 2546-2548.

Wang H, Marsters SA, Baker T, et al. TACI-ligand interactions are required for T cell activation and collagen-induced arthritis in mice. Nature Immunol. 2001; 2: 632-637.

Xia XZ, Treanor J, Senaldi G, et al. TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. J. Exp. Med. 2000; 192: 137-143.

Yan M, Wang H, Chan B, et al. Activation and accumulation of B cells in TACI-deficient mice. Nature Immunology. 2000; 2: 638-643.

To view announcements on LymphoStat-B and BLyS, click on the following:

Human Genome Sciences and Glaxosmithkline Announce FDA Priority Review Designation for Benlysta® (belimumab) as a Potential Treatment for Systemic Lupus Erythematosus - August 19, 2010

Human Genome Sciences Announces Presentation of Additional Phase 3 SLE Study Results for BENLYSTA® (Belimumab) at International Congress on SLE - June 25, 2010

Human Genome Sciences and GlaxoSmithKline Announce Full Presentation at EULAR of BLISS-76 Phase 3 Study Results for BENLYSTA® in Systemic Lupus Erythematosus - June 17, 2010

Human Genome Sciences and GlaxoSmithKline Announce Presentation at EULAR of BLISS-52 Phase 3 SLE Study Results For BENLYSTA® (Belimumab) - June 17, 2010

Human Genome Sciences Announces Submission of Biologics License Application to FDA for BENLYSTA® (Belimumab) - June 10, 2010

Human Genome Sciences Announces Submission of Marketing Authorization Application to EMA for BENLYSTA® (Belimumab) - June 7, 2010

Human Genome Sciences and Glaxosmithkline Announce Topline 76-Week Results of Phase 3 Trial of BENLYSTA™ in Systemic Lupus Erythematosus - April 20, 2010

Human Genome Sciences and GlaxoSmithKline Announce Positive Results in Second of Two Phase 3 Trials of BENLYSTA in Systemic Lupus Erythematosus - November 2, 2009:

Human Genome Sciences and Glaxosmithkline Announce Full Presentation at ACR of Positive Phase 3 Study Results For BENLYSTA™ in Systemic Lupus Erythematosus - October 20, 2009

Novel Evidence-Based Systemic Lupus Erythematosus (SLE) Responder Index Described in Peer Reviewed Publication as Potentially Significant Advance in Lupus Drug Development - September 4, 2009

Human Genome Sciences And Glaxosmithkline Announce Positive Phase 3 Study Results For Benlysta™ In Systemic Lupus Erythematosus - July 20, 2009

Human Genome Sciences Reports Positive Long-Term Data for BENLYSTA™ (formerly Lymphostat-B®) in Patients with Active Systemic Lupus Erythematosus -June 11, 2008 

Human Genome Sciences Completes Enrollment in Second Phase 3 Lymphostat-B® Trial -August 27, 2008 

Human Genome Sciences Reports Positive Long-Term Data for LymphoStat-B in Patients with Active Systemic Lupus Erythematosus - June 12, 2008

Human Genome Sciences Completes Enrollment in First of Two Phase 3 LymphoStat-B® Trials - April 22, 2008

Human Genome Sciences Reports Positve Data from Long-Term Treatment with LymphoStat-B in Patients with Active Systemic Lupus Erythematosus - November 9. 2007

Human Genome Sciences Reports that a Phase 2 Study of Lymphostat-B® Showed Significant Reductions in Disease Activity in Patients with Active Systemic Lupus Erythematosus - June 14, 2007

Human Genome Sciences and GlaxoSmithKline Initiate Second Phase 3 Clinical Trial of LymphoStat-B® in Systemic Lupus Erythematosus - May 30, 2007

Human Genome Sciences and Glaxosmithkline Announce Initiation of Phase 3 Clinical Trial of Lymphostat-B® in Systemic Lupus Erythematosus - February 13, 2007

Human Genome Sciences Announces Positive Special Protocol Assessment from FDA for Phase 3 Clinical Trials of Lymphostat-B™ in Systemic Lupus Erythematosus - November 14, 2006

Human Genome Sciences Announces Positive Special Protocol Assessment from FDA for Phase 3 Clinical Trials of Lymphostat-B™ in Systemic Lupus Erythematosus - October 26, 2006

Human Genome Sciences Announces Phase 3 Clinical Development Program for Lymphostat-B™ in Systemic Lupus Erythematosus - August 9, 2006

Human Genome Sciences Announces Full Presentation of Results of Phase 2 Clinical Trial of Lymphostat-B™ in Systemic Lupus Erythematosus - June 22, 2006

Human Genome Sciences Reports Phase 2 Results for Lymphostat-B™ (Belimumab) in Patients with Rheumatoid Arthritis - November 17, 2005

Human Genome Sciences Reports Results of a Phase 2 Clinical Trial of LymphoStat-B™ in Patients with Systemic Lupus Erythematosus - October 5, 2005

GlaxoSmithKline Exercises Option to LymphoStat-B™ - July 7, 2005

Human Genome Sciences Reports Results of a Phase 2 Clinical Trial of LymphoStat-B™ in Patients with Rheumatoid Arthritis - April 6, 2005

Human Genome Sciences Completes Patient Enrollment in a Phase 2 Clinical Trial of Lymphostat-B™ for the Treatment of Rheumatoid Arthritis - July 29, 2004

Human Genome Sciences Completes Patient Enrollment in a Phase 2 Clinical Trial of Lymphostat-B™ for the Treatment of Systemic Lupus Erythematosus - July 29, 2004

Human Genome Sciences Announces Selection of Lymphostat-BTM for Participation in FDA's Continuous Marketing Application Pilot 2 Program - March 4, 2004

Human Genome Sciences Initiates Phase 2 Clinical Trial of Lymphostat-BTM for the Treatment of Rheumatoid Arthritis - January 8, 2004

Human Genome Sciences Reports Results of Phase 1 Clinical Trial of Lymphostat-B™ in Patients With Systemic Lupus Erythematosus - October 28, 2003

Human Genome Sciences Initiates Phase 2 Clinical Trial of LymphoStat-B for the Treatment of Systemic Lupus Erythematosus - September 25, 2003

Results of Phase I Clinical Trial Demonstrate That LymphoStat-B is Safe and Biolocically Active in Patients with Systemic Lupus Erythematosus - April 21, 2003

Human Genome Sciences Initiates Trials of a New Drug for Systemic Lupus Erythematosus and Other Autoimmune Diseases - November 1, 2001

Human Genome Sciences Announces Trial For Treatment of Immunoglobulin-A Deficiency - September 19, 2001

Human Genome Sciences Receives Orphan Drug Designation for BLyS Therapeutic Protein for Treatment of Common Variable Immunodeficiency - February 27, 2001

High Levels of BLyS Implicated in Lupus and Rheumatoid Arthritis Patients - October 30, 2000

Human Genome Sciences and Cambridge Antibody Technology Commit to Exclusive Development of Anti-BLyS Antibodies - October 30, 2000

Human Genome Sciences and Dow Agree To Develop HGS' Radiolabeled B-Lymphocyte Stimulator - October 30, 2000

Human Genome Sciences to Initiate Human Clinical Trials of BLyS - June 23, 2000

Human Genome Sciences Announces the Discovery of a Novel Immune Stimulant - July 8, 1999