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BENLYSTA™ (belimumab, formerly LymphoStat-B®)

BENLYSTA is an investigational human monoclonal antibody drug for the treatment of systemic lupus erythematosus (SLE), and is being developed by HGS and GlaxoSmithKline (GSK) under a co-development and commercialization agreement entered into in August 2006.[1-2] Two pivotal Phase 3 clinical trials of BENLYSTA are ongoing, with results expected in July and November 2009. Assuming success in Phase 3, HGS believes that BENLYSTA could represent a breakthrough in the treatment of SLE.

How BENLYSTA Works

BENLYSTA inhibits the biological activity of B-lymphocyte stimulator, or BLyS®, which is a naturally occurring protein discovered by HGS.[3-4] 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 systemic lupus erythematosus (SLE) disease activity. [5-15]

Preclinical and clinical studies demonstrate that B-cell antagonists such as BENLYSTA (belimumab) can reduce autoantibody levels and help control autoimmune disease activity. 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). Preclinical and clinical studies show that BLyS antagonists can reduce autoantibody levels and help control autoimmune disease activity. [16-48].

BENLYSTA Inhibits the Biological Activity of BLyS

benlysta_biological_activity.jpg

Figure 1. BENLYSTA 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 GlaxoSmithKline (GSK) entered into a co-development and commercialization agreement under which HGS has responsibility for conducting 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. [49-50]

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. It is estimated that approximately 1.5 million people in the United States and approximately 5 million worldwide suffer from various forms of lupus, including SLE.

Lupus can occur at any age, but appears mostly in young people between the ages of fifteen and forty-five. About 90 percent of the individuals diagnosed with lupus are women. African-American women are about three times more likely, compared with the population as a whole, 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 National Institute of Arthritis and Musculoskeletal and Skin Diseases at www.niams.nih.gov, or the Lupus Europe at www.elef.rheumanet.org.

BLyS in Patients with Autoimmune Disease

 
lsb_clip_image001_0001.jpg

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 BENLYSTA (belimumab) Phase 3 clinical development program includes two double-blind, placebo-controlled, multi-center Phase 3 superiority trials – BLISS-76 and BLISS-52 – to evaluate the efficacy and safety of belimumab plus standard of care, versus placebo plus standard of care, in the treatment of patients with serologically active SLE. [49-53] HGS designed the Phase 3 program for belimumab in collaboration with GSK and leading international SLE experts.

BLISS-52 was initiated in May 2007 and enrolled and randomized 867 patients at 90 clinical sites in 13 countries, primarily in Asia, South America and Eastern Europe. BLISS-76 was initiated in February 2007 and enrolled and randomized 826 patients at 133 clinical sites in 19 countries, primarily in North America and Europe. These are the largest clinical trials ever conducted in lupus patients.

The design of the two trials is similar, but the duration of therapy in the two studies is different, 52 weeks for BLISS-52 and 76 weeks for BLISS-76. The data from BLISS-76 will be analyzed after 52 weeks in support of a potential Biologics License Application (BLA) in the U.S., and Marketing Authorization Applications in Europe and other countries. The results of BLISS-52 are expected in July 2009, and 52-week results from BLISS-76 are expected in November 2009.

In each of the two pivotal Phase 3 trials, patients are randomized to 1 of 3 treatment groups (1 mg/kg BENLYSTA, 10 mg/kg BENLYSTA, or placebo). Patients are dosed intravenously on Days 0, 14 and 28, then every 28 days for the duration of the study. To be eligible for the Phase 3 trials, patients must be serologically active, with unequivocally positive antinuclear antibody (ANA) test results assessed at 2 independent time points (HEp-2 ANA > 1:80 and/or anti-dsDNA > 30 IU/mL). Background SLE medications must be stable for a period of at least 30 days prior to Day 0.

In October 2006, HGS received a Special Protocol Assessment from the Food and Drug Administration (FDA), agreeing that the design of the Phase 3 program and clinical trials is suitable to support regulatory approval. HGS also met with the European Agency for the Evaluation of Medicinal Products (EMEA), and received agreement from EMEA on the major components of the Phase 3 program, including the primary efficacy endpoint measures, target patient population, and dose selection.

Clinical Progress to Date

In June 2006, HGS reported results of the Phase 2 trial through the 52-week placebo-controlled double-blind period of the study – which showed that belimumab significantly reduced disease activity versus placebo in patients with serologically active SLE across multiple clinical measures, exhibited clinically relevant biological activity, and appeared generally safe and well tolerated.[40-43] Frequency and severity of adverse events were similar to placebo. Among the findings at Week 52 was a significantly improved response rate among serologically active patients, as defined by an improvement in SELENA SLEDAI score of 4 points or greater, no new BILAG A flare and no more than one new BILAG B flare, and no worsening in Physician’s Global Assessment. This combination of measures is the primary efficacy endpoint in the ongoing pivotal Phase 3 clinical trials.

The Phase 2 study was designed as a randomized, double-blind, placebo-controlled, dose-ranging superiority trial to evaluate the efficacy and safety of BENLYSTA (belimumab) plus standard of care, versus placebo plus standard of care. A total of 449 patients with active SLE were randomized to receive one of three different doses of BENLYSTA (1, 4 or 10 mg/kg) or placebo administered intravenously over a 52-week treatment period, in addition to standard-of-care therapy. The study began in October 2003 and was conducted in the United States and Canada. The primary efficacy endpoints were the SELENA SLEDAI score at Week 24 and time to first SLE disease flare over 52 weeks (as defined by the SLE Flare Index). Pre-specified secondary efficacy endpoints included the SLENA SLEDAI score at Week 52, BILAG score at Week 52, Physician’s Global Assessment and effect on reduction of prednisone dose, among others.

At the end of the 52-week double-blind period of the Phase 2 trial, 345 patients chose to participate in an optional 24-week extension phase of the study, during which all patients received BENLYSTA. At Week 76, 296 patients chose to remain on BENLYSTA treatment in an open-label long-term continuation phase of the Phase 2 trial, in which all patients are receiving 10 mg/kg BENLYSTA. As of June 11, 2009, 213 patients remained on BENLYSTA treatment in the continuation study.[16-17]

Results through four years of the long-term Phase 2 continuation study of BENLYSTA were presented in June 2009 at the Congress of the European League against Rheumatism (EULAR). [16-17] The data showed that BENLYSTA was associated with sustained improvement in SLE disease activity and patient response rates and with decreased frequency of SLE disease flares in serologically active patients.

Four-year data showed that the percentage of SLE patients who achieved the patient response rate selected as the Phase 3 primary efficacy endpoint rose from 46% at Week 52 to 57% at Week 160, with no increase in overall adverse events, serious adverse events, infections, serious infections, malignancies or laboratory abnormalities.

Significant improvements in SLE disease activity also were observed in serologically active patients at Week 52 of the placebo-controlled double-blind period of the Phase 2 study, as measured by the SELENA SLEDAI and BILAG scales, the Physician’s Global Assessment, and – most importantly – the patient response rate chosen as the primary efficacy endpoint of the Phase 3 trials.

How BENLYSTA Was Discovered

HGS first discovered the naturally occurring protein, BLyS, or B-lymphocyte stimulator, and published a preliminary description of its activity in the journal, Science, in July 1999.[3-4] 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.[54]

For More Information About BENLYSTA Clinical Trials

Health professionals and patients interested in LymphoStat-B 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 (301) 610-5790, extension 3550.


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. 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.
  4. (HGSI Press Release) Human Genome Sciences Announces the Discovery of a Novel Immune Stimulant. July 8, 1999.
  5. 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.
  6. Carter RH.  A role for BLyS in tissue inflammation? Arthritis & Rheumatism April 2003; 48(4): 882-885.
  7. 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.
  8. Petri M.  Biomarkers in SLE: The Hopkins lupus cohort.  Lupus Foundation of America biomarkers for the assessment of systemic lupus erythematosus meeting. March 2003.
  9. 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.
  10. 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.
  11. 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.
  12. (HGSI Press Release) High Levels of BLyS Implicated in Lupus and Rheumatoid Arthritis Patients. October 30, 2000.
  13. 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.
  14. 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.
  15. 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.
  16. (HGSI Press Release) Human Genome Sciences Reports Positive Long-Term Data for BENLYSTA (formerly LymphoStat-B) in Patients with Active Systemic Lupus Erythematosus. June 11, 2009.
  17. 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.
  18. (HGSI Press Release) Human Genome Sciences Reports Sustained Improvement Through Three Years on Treatment with LymphoStat-B in Patients with Active Systemic Lupus Erythematosus. June 12, 2008.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. (HGSI Press Release) Human Genome Sciences Reports Positive Data from Long-Term Treatment with LymphoStat-B in Patients with Active Systemic Lupus Erythematosus.  November 9, 2007.
  24. 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. 
  25. 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. 
  26. 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. 
  27. (HGSI Press Release) 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.
  28. 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.
  29. 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.    
  30. 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.
  31. 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. 
  32. (HGSI Press Release) Human Genome Sciences Announces Positive 76-Week Results of Phase 2 Clinical Trial of LymphoStat-B in Systemic Lupus Erythematosus.  November 14, 2006.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. 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.
  38. 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.
  39. 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.
  40. (HGSI Press Release) Human Genome Sciences Announces Full Presentation of Results of Phase 2 Clinical Trial of LymphoStat-B in Systemic Lupus Erythematosus.  June 22, 2006.
  41. 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. 
  42. 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. 
  43. 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. 
  44. (HGSI Press Release) Human Genome Sciences Reports Phase 2 Results for LymphoStat-B (Belimumab) in Patients with Rheumatoid Arthritis.  November 17, 2005.
  45. 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.
  46. (HGSI Press Release) Results of Phase 1 Clinical Trial Demonstrate that LymphoStat-B Is Safe and Biologically Active in Patients with Systemic Lupus Erythematosus. April 21, 2003
  47. 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. October 27, 2003. Abstract # 1537.
  48. 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.   65th Annual Scientific Meeting of the American College of Rheumatology (2001).  Abstract 1377. 
  49. (HGSI Press Release) Human Genome Sciences and GlaxoSmithKline Initiate Second Phase 3 Clinical Trial of LymphoStat-B in Systemic Lupus Erythematosus. May 30, 2007.
  50. (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.
  51. (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.
  52. (HGSI Press Release) Human Genome Sciences Announces Phase 3 Clinical Development Program for LymphoStat-B in Systemic Lupus Erythematosus. August 9, 2006.
  53. (HGSI Press Release) Human Genome Sciences Announces Selection of LymphoStat-B for Participation in FDA’s Continuous Marketing Application Pilot 2 Program. March 4, 2004.
  54. (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, 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 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.

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.

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.

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.

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.

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 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

 
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