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Phase II Trial Initiated of LymphoStat-B for the Treatment of Rheumatoid Arthritis

ROCKVILLE, Md., Jan. 8 /PRNewswire-FirstCall/ -- Human Genome Sciences, Inc. (Nasdaq: HGSI - News) announced today that it has begun dosing patients in a Phase 2 clinical trial of LymphoStat-B(TM) (human monoclonal antibody to B- lymphocyte stimulator, BLyS(TM)) for the treatment of rheumatoid arthritis.

The double-blind, placebo-controlled, multi-center Phase 2 clinical trial will evaluate the safety, optimal dosing, and efficacy of LymphoStat-B in patients with rheumatoid arthritis. Approximately 230 patients with active rheumatoid arthritis who have failed prior therapy will be enrolled in the trial and randomized to receive intravenously 1 mg/kg, 4 mg/kg, or 10 mg/kg of LymphoStat-B or placebo every four weeks over a 24-week treatment period. Efficacy will be evaluated according to the American College of Rheumatology (ACR) criteria for defining clinical improvement in rheumatoid arthritis patients. The primary efficacy endpoint for the LymphoStat-B Phase 2 trial will be the rate of response at week 24 (i.e., the percentage of patients who achieve at least 20% improvement on the ACR-specified measures of disease activity). Safety, pharmacokinetics, and changes in quality of life also are being evaluated.

William Stohl, M.D., Ph.D., Professor of Medicine, Division of Rheumatology, University of Southern California, said, "Rheumatoid arthritis is a systemic, chronic autoimmune disease that affects over two million people in the United States alone. The disease is characterized by inflammation of the joints, which is caused by the body's own immune system attacking healthy joint tissue. Preclinical and early clinical data suggest that B cells may have an important contributory role in the pathogenesis of autoimmune diseases such as rheumatoid arthritis. We look forward to evaluating LymphoStat-B's potential to offer a new treatment option to patients suffering from this disease."

David C. Stump, M.D., Executive Vice President, Drug Development, said, "We are pleased to advance LymphoStat-B into Phase 2 clinical trials for the treatment of rheumatoid arthritis. Results of observational studies show that BLyS levels are elevated in the blood and joint fluid of patients with rheumatoid arthritis, and are positively correlated with levels of immunoglobulin-G and of the autoantibody, rheumatoid factor. In rheumatoid arthritis, autoantibody levels -- especially rheumatoid factor -- appear to correlate with rheumatoid arthritis disease severity. Emerging clinical and preclinical evidence suggest that B cell antagonists, such as LymphoStat-B, have the potential to reduce autoantibody levels and help reduce disease progression. Preclinical and clinical results to date indicate that LymphoStat-B is well tolerated and capable of reducing levels of CD20 B cells. The Phase 2 study of LymphoStat-B in patients with rheumatoid arthritis and an ongoing Phase 2 study in patients with systemic lupus erythematosus are designed to provide definitive data on the safety and efficacy of LymphoStat-B in patients suffering from these autoimmune diseases."

William A. Haseltine, Ph.D., Chairman and CEO, said, "Several million people suffer from rheumatoid arthritis worldwide. Emerging research suggests that B cells may play an important role in the pathogenesis of rheumatoid arthritis. We believe that, by inhibiting BLyS's stimulation of B-cell development, LymphoStat-B may be able to help reduce the progression of disease in these patients and improve their quality of life."

LymphoStat-B is a human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS. BLyS is a naturally occurring protein discovered by Human Genome Sciences that is required for the development of B-lymphocyte cells into mature plasma B cells.(1) Plasma B cells produce antibodies, the body's first line of defense against infection. Laboratory studies have indicated that higher than normal levels of BLyS may contribute to the pathogenesis of autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus.(2, 3, 4, 5) Autoimmune diseases are diseases in which the body is attacked by its own immune system.

In rheumatoid arthritis, 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. In rheumatoid arthritis, autoantibody levels -- especially rheumatoid factor -- appear to correlate with disease severity.(6) Retrospective studies have shown elevated levels of BLyS in the blood and joint fluid of patients with rheumatoid arthritis and in the blood of many patients with systemic lupus erythematosus.(6, 7, 8, 9, 10) Preclinical and clinical studies demonstrate that B cell antagonists can reduce autoantibody levels and help control rheumatoid arthritis disease activity.(5, 11, 12)

LymphoStat-B acts by: (1) 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).(13) Clinical and preclinical studies indicate that LymphoStat-B is well tolerated and capable of reducing levels of antibody- producing B cells.(14, 15, 16)

LymphoStat-B was created through a collaboration between Human Genome Sciences and Cambridge Antibody Technology. Human Genome Sciences holds exclusive commercial rights to the drug.

Rheumatoid arthritis is a systemic, chronic autoimmune disease. Rheumatoid arthritis affects approximately 2.1 million Americans, mostly women. Rheumatoid arthritis is characterized by the inflammation of the membrane lining the joint, caused by the body's own immune system attacking healthy joint tissue. Symptoms typically begin during middle age and may include inflammation of joints, swelling, difficulty moving, and pain. Daily joint pain frequently results in limited movement and interferes with a person's ability to carry out normal activities.

For more information on LymphoStat-B, see www.hgsi.com/products/LSB.html. For more information on lupus, rheumatoid arthritis, or autoimmune diseases, visit the Arthritis Foundation at www.arthritis.org, the National Institute of Arthritis and Musculoskeletal and Skin Diseases at www.niams.nih.gov, or The Lupus Foundation of America at www.lupus.org.

For additional information on Human Genome Sciences, please visit our web site at www.hgsi.com.

For more information on the clinical trials evaluating LymphoStat-B, visit www.clinicaltrials.gov. Health professionals or patients interested in inquiring about the LymphoStat-B trials or any other study involving HGSI products are encouraged to inquire via the Contact Us section of the Human Genome Sciences web site, www.hgsi.com/products/request.html, or by calling us at (301) 610-5790, extension 3550.

Footnotes:

1. 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.

2. 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.

3. Khare S.D., 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.

4. 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.

5. 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.

6. 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 2001; 44(6): 1313-1319.

7. 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.

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

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

10. Tan S, Roschke V, Perry JW, et al. Local production of B lymphocyte stimulator and APRIL in arthritic joints of patients with inflammatory arthritis. Arthritis & Rheumatism 2003; 48(4): 982-992.

11. 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.

12. Edwards JCW, Szczepanski L, Szechinski J et al. Efficacy and safety of rituximab, a B-cell targeted chimeric monoclonal antibody: A randomized, placebo-controlled trial in patients with rheumatoid arthritis [abstract]. American College of Rheumatology (ACR) Arthritis & Rheum 46(9) 2002:S197. Abstract # 446.

13. Baker KP, Edwards BM, Main SH et al. Generation and Characterization of LymphoStat-B, a Human Monoclonal Antibody That Antagonizes the Bioactivities of B-Lymphocyte Stimulator. Arthritis & Rheumatism 2003; 48: 3253-3265.

14. (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.

15. 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.

16. 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.

Source: Human Genome Sciences, Inc.

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