ROCKVILLE, Md., Nov. 17 /PRNewswire-FirstCall/ -- Human Genome Sciences, Inc. today announced that the results of a Phase 2 clinical trial of LymphoStat-B(TM) (belimumab) in patients with rheumatoid arthritis show that LymphoStat-B met the primary efficacy and safety endpoints, and demonstrate that it is safe and well tolerated, biologically active, and reduces rheumatoid arthritis disease activity at a level of statistical significance. The results were reported in San Diego at the 69th Annual Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP).
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An oral presentation entitled “Belimumab, a Fully Human Monoclonal Antibody to B-Lymphocyte Stimulator (BLyS(TM)), Combined with Standard of Care Therapy Reduces the Signs and Symptoms of Rheumatoid Arthritis in a Heterogeneous Subject Population” presented data on 283 patients who participated in the Phase 2 study.(1) The double-blind, placebo-controlled, multi-center clinical trial was designed to evaluate the safety, optimal dosing and efficacy of LymphoStat-B in patients with active moderate-to-severe rheumatoid arthritis who had failed prior treatment(s).(2-3) Study participants had failed an average (mean) of more than 2.2 disease-modifying anti-rheumatic drugs (DMARDS). Approximately 38% of study participants had failed at least one TNF-alpha inhibitor. The study was conducted in the United States and Poland. Patients were randomized to receive one of three different doses (1, 4 or 10 mg/kg) of LymphoStat-B or placebo administered intravenously over a 24-week treatment period, in addition to standard-of-care therapy. All patients in the study were dosed on Days 0, 14 and 28, and then every 28 days for the remainder of the 24 weeks. All patients received concurrent standard-of-care therapy, including up to two DMARDS and less than or up to 10 mg/day of prednisone. Approximately 73% of study participants were receiving background methotrexate therapy. Efficacy was 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 study was the rate of ACR 20(4) response at Week 24 (i.e., the percentage of patients who achieved at least 20% improvement on the ACR-specified measures of disease activity).(5) Secondary biological endpoints, as well as safety, were also evaluated.
Patients treated with LymphoStat-B showed statistically significant improvement in the primary efficacy endpoint versus the placebo group. The rate of improvement in ACR 20 response at Week 24 was 35% in the 1-mg/kg active-treatment group, and 29% in all active-treatment groups combined -- significantly higher than the 16% rate of improvement observed for the placebo group (p=0.0097 and p=0.021, respectively).(6) In addition, trends toward a drug benefit were observed in the 4-mg/kg treatment group (25% ACR 20 response, p=0.17) and in the 10-mg/kg treatment group (28% ACR 20 response, p=0.08). Results show that LymphoStat-B was well tolerated with no clinically significant differences from placebo in adverse events, serious adverse events or laboratory abnormalities. Clinically significant infusion reactions were rare. Human Genome Sciences will continue to collect data from the current Phase 2 trial of LymphoStat-B in patients with rheumatoid arthritis through an ongoing optional extension protocol.
An oral presentation entitled “Belimumab, a Novel Fully Human Monoclonal Antibody to B-Lymphocyte Stimulator (BLyS), Selectively Modulates B-Cell Subpopulations and Immunoglobulins in a Heterogeneous Rheumatoid Arthritis Subject Population” described the correlation of circulating BLyS levels with rheumatoid arthritis (RA) disease activity at baseline, and the effect of LymphoStat-B (belimumab) on B-cell subpopulations in subjects with moderate- to-severe RA in a 24-week Phase 2, double-blind, placebo-controlled, multi- center clinical trial.(7) The results demonstrate that LymphoStat-B produced statistically significant reductions (all active-treatment groups combined versus placebo) of 20% or more in the following B cell subsets: CD 20+ B cells (p=0.0001), CD19+ B cells (p=0.0001), naive B cells (p<0.0001), and activated B cells (p<0.0001). No reductions were observed in plasma B cells. An increase in memory B cells was observed by Day 28, which persisted through Week 24, with modest correlation with improvement in DAS28(8). No dose response was observed with these changes in B-cell levels. Statistically significant median reductions in immunoglobulins were observed (all active- treatment groups combined versus placebo): IgG (10% vs. 4%), IgM (20% vs. 4%), IgA (11% vs. 1%), and IgE (31% vs. 6%). These results show that LymphoStat-B administration was associated with selective reduction in B-cell subpopulations, preservation of plasma B cells and an increase in memory B cells, with a modest reduction in immunoglobulins. Elevated serum BLyS levels at baseline modestly, but significantly, correlated with severity of disease activity, as indicated by an increased DAS28 score (p=0.0098) and elevated levels of rheumatoid factor (p=0.012), c-reactive protein (CRP, p less than or equal to 0.0001) and erythrocyte sedimentation rate (ESR, p=0.0015), suggesting a role for BLyS in the pathogenesis of rheumatoid arthritis.
An oral presentation entitled “Differential Responsiveness to Belimumab in Combination with Standard of Care Therapy in RF+, TNF-alpha-Inhibitor and Methotrexate Partial Responder Subgroups of Subjects with Moderate-Severe Rheumatoid Arthritis” described subgroup analyses of the responsiveness to LymphoStat-B (belimumab) in patients with moderate-to-severe rheumatoid arthritis (RA) in a 24-week Phase 2, double-blind, placebo-controlled, multi- center clinical trial.(9) The study enrolled a heterogeneous patient population, allowing exploration of different potential treatment effects based on treatment history and baseline inflammatory biomarkers. Pre- specified subgroups analyzed included: DAS28, RA duration (years), anti-TNF- alpha experience, and RF+. Exploratory subgroups analyzed included: Prior/failed DMARD experience, CRP, region, and current DMARD. The effect of LymphoStat-B on ACR20 response at Week 24 was analyzed by subgroups and by a multiple logistic regression model.
The subgroup analysis indicated that a statistically significant improvement versus placebo in the 24-week ACR 20 response was observed at the 1-mg/kg dose of LymphoStat-B in the following subgroups: patients who were RF+ at baseline (32% vs. 12%, p<0.01); patients with a baseline DAS28 score >5.1 (36% vs. 15%, p<0.01); anti-TNF-alpha naive patients (40% vs. 13%, p<0.01); patients who had previously failed methotrexate therapy (39% vs. 11%, p<0.05); and patients receiving concomitant methotrexate therapy during the Phase 2 study (38% vs. 16%, p<0.05). A statistically significant improvement versus placebo in the 24-week ACR 20 response also was observed in LymphoStat- B all active-treatment groups combined in the following subgroups: patients who were RF+ at baseline (29% vs. 12%, p<0.05); anti-TNF-alpha naive patients (36% vs. 13%, p<0.01); patients who had previously failed methotrexate therapy (31% vs. 11%, p<0.05); and patients receiving concomitant methotrexate therapy during the Phase 2 study (31% vs. 16%, p<0.05). No improvement was observed in RF- subjects. No improvement was observed in anti-TNF-alpha experienced subjects. Logistic regression analysis in all subjects (adjusting for baseline characteristics) showed that LymphoStat-B treatment was a strong predictor of ACR20 response at Week 24 with an Adjusted Odds Ratio (AOR) of 2.2 (i.e., patients who received treatment with LymphoStat-B were 2.2 times more likely to achieve ACR20 response at Week 24 than patients who did not receive treatment with LymphoStat-B, p=0.03). Logistic regression analysis in patients who were RF+ at baseline showed that LymphoStat-B improved ACR20 response with an AOR of 3.4 (p=0.01).
James D. McKay, D.O, F.A.C.R., F.A.C.O.I, Clinical Associate Professor of Medicine, Oklahoma State University Center for Health Science (Tulsa), said, “The Phase 2 results presented at the ACR/ARHP annual meeting demonstrate that LymphoStat-B is well tolerated, biologically active, and able to reduce significantly the signs and symptoms of rheumatoid arthritis. LymphoStat-B achieved its primary efficacy endpoint in the Phase 2 trial in the context of a protocol design that included heterogeneous background standard-of-care therapy for all study subjects. The improvement in ACR 20 response at Week 24 was significantly greater than placebo in both the 1-mg/kg active-treatment group and in all active-treatment groups combined. A significant drug effect or positive trends were seen with all doses, although there was no evidence of a dose-response relationship. As anticipated based on preclinical and clinical research to date(10-14), selective and statistically significant reductions versus placebo were observed in LymphoStat-B active-treatment groups in B-cell subpopulations including CD 20+ and other subsets, without a reduction in plasma B cells and with an increase in memory B cells. These data support additional studies of LymphoStat-B in rheumatoid arthritis.”
David C. Stump, M.D., Executive Vice President, Drug Development, said, “LymphoStat-B achieved its primary efficacy endpoint in the context of a protocol design for the Phase 2 study in rheumatoid arthritis that included heterogeneous background standard-of-care therapy for all patients enrolled in the trial. The relatively low placebo response rate suggests that this was a somewhat refractory population to treat. The results add substantively to the evidence of LymphoStat-B’s biological activity, as demonstrated by statistically significant and selective reductions in levels of circulating CD 20+ and other B-cell subsets. These data show that LymphoStat-B administration was associated with selective reduction in B-cell subpopulations, preservation of plasma B cells and an increase in memory B cells, along with a modest reduction in immunoglobulins. Elevated serum BLyS levels at baseline significantly correlated with severity of disease activity and with elevated levels of rheumatoid factor and inflammatory markers, suggesting a role for BLyS in the pathogenesis of rheumatoid arthritis. Analysis of major pre- specified subgroups showed statistically significant improvement in the LymphoStat-B 1-mg/kg active treatment arm versus placebo in the 24-week ACR 20 response in a number of subgroups, including patients who were naive to treatment with TNF-alpha inhibitors, patients with more severe disease as assessed by the DAS28 disease activity score at baseline, and patients who were positive for rheumatoid factor at baseline. Very importantly, the data also show that LymphoStat-B was safe and well tolerated during this 24-week exposure period. We look forward to continuing the evaluation of LymphoStat-B in additional clinical studies to determine its appropriate role in the treatment of patients afflicted by rheumatoid arthritis, lupus and other autoimmune diseases.”
LymphoStat-B is a Human Genome Sciences drug, created through a collaboration with Cambridge Antibody Technology.(15) GlaxoSmithKline has exercised its option under a June 1996 agreement to develop and commercialize LymphoStat-B jointly with Human Genome Sciences.(16) Under the terms of the agreement, GSK and Human Genome Sciences will share equally in Phase 3/4 development costs, and will share equally in sales and marketing expenses and profits of any product that is commercialized under the agreement, under a co- development and co-promotion agreement, the remaining terms of which are being negotiated by the parties.
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.(18-19) Plasma B cells produce antibodies, the body’s first line of defense against infection. Retrospective and prospective studies have shown elevated levels of BLyS in the blood of many patients with systemic lupus erythematosus, and in the blood and joint fluid of patients with rheumatoid arthritis. In lupus, rheumatoid arthritis, 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.(20-25) The presence of autoantibodies, especially rheumatoid factor, appears to correlate with disease severity.(26-27) Preclinical and clinical studies demonstrate that B-cell antagonists can reduce autoantibody levels and help control autoimmune disease activity.(1-2, 7, 9-14, 17-33)
Several million people worldwide have rheumatoid arthritis. It is a systemic, chronic autoimmune disease characterized by inflammation of the membrane lining the joint. Symptoms typically appear during middle age and may include swelling of the joints, difficulty moving, and daily joint pain that frequently interferes with a person’s ability to conduct normal activities.
For more information on LymphoStat-B, see http://www.hgsi.com/products/LSB.html. For more information on rheumatoid arthritis and other autoimmune diseases including lupus, visit the Arthritis Foundation at http://www.arthritis.org, the National Institute of Arthritis and Musculoskeletal and Skin Diseases at http://www.niams.nih.gov, or the Lupus Foundation of America at http://www.lupus.org. For additional information on Human Genome Sciences, please visit our web site at http://www.hgsi.com.
Health professionals or patients interested in inquiring about LymphoStat- B trials or any other study involving Human Genome Sciences products are encouraged to inquire via the Contact Us section of the company’s web site, http://www.hgsi.com/products/request.html, or by calling us at (301) 610-5790, extension 3550.
HGS, Human Genome Sciences, BLyS and LymphoStat-B are trademarks of Human Genome Sciences, Inc.
This announcement contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. The forward-looking statements are based on Human Genome Sciences’ current intent, belief and expectations. These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Actual results may differ materially from these forward-looking statements because of the Company’s unproven business model, its dependence on new technologies, the uncertainty and timing of clinical trials, the Company’s ability to develop and commercialize products, its dependence on collaborators for services and revenue, its substantial indebtedness and lease obligations, its changing requirements and costs associated with planned facilities, intense competition, the uncertainty of patent and intellectual property protection, the Company’s dependence on key management and key suppliers, the uncertainty of regulation of products, the impact of future alliances or transactions and other risks described in the Company’s filings with the Securities and Exchange Commission. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of today’s date. Human Genome Sciences undertakes no obligation to update or revise the information contained in this announcement whether as a result of new information, future events or circumstances or otherwise.
Footnotes: 1. 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/Association of Rheumatology Health Professionals. November 16, 2005. Oral Presentation #1920. 2. (HGSI Press Release) Human Genome Sciences Reports Results of a Phase 2 Clinical Trial of LymphoStat-B in Patients with Rheumatoid Arthritis. April 6, 2006. 3. (HGSI Press Release) Human Genome Sciences Completes Patient Enrollment in a Phase 2 Clinical Trial of LymphoStat-B for the Treatment of Rheumatoid Arthritis. July 29, 2004. 4. The ACR 20 is an index developed by the American College of Rheumatology (ACR) to assess patient response to treatment for rheumatoid arthritis. An ACR 20 response is defined as at least a 20% reduction in tender joint count and swollen joint count, in addition to an improvement of at least 20% on three of five other assessments of symptoms or disease manifestations (i.e., patient pain assessment, patient global assessment, physician global assessment, patient self- assessed disability, acute-phase reactant [ESR or CRP]). 5. American College of Rheumatology (ACR) Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis & Rheumatism 2002; 46(2):328-346. 6. ACR20 Response was determined using ESR (erythrocyte sedimentation rate) as the acute phase reactant, with all p values determined using the likelihood ratio test. 7. Stohl W, Chatham W, Weisman M, Furie R, Weinstein A, et al. Belimumab, a novel fully human monoclonal antibody to B-lymphocyte stimulator (BLyS), selectively modulates B-cell subpopulations and immunoglobulins in a heterogeneous rheumatoid arthritis subject population. 69th Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals. November 15, 2005. Oral Presentation #1160. 8. DAS28 is a rheumatoid arthritis Disease Activity Score that measures response by the number of tender and swollen joints among 28 relevant joints, in addition to assessing general health status and erythrocyte sedimentation rate (ESR). 9. Genovese M, Filipowicz-Sosnowska A, Merrill J, et al. Differential responsiveness to belimumab in combination with standard of care therapy in RF+, TNF-alpha-inhibitor and methotrexate partial responder subgroups of subjects with moderate-severe rheumatoid arthritis. 69th Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals. November 15, 2005. Oral Presentation #1989. 10. (HGSI Press Release) Human Genome Sciences Reports Results of a Phase 2 Clinical Trial of LymphoStat-B in Patients with Systemic Lupus Erythematosus. October 5, 2005. 11. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 1 Clinical Trial of LymphoStat-B in Patients with Systemic Lupus Erythematosus. October 28, 2003. 12. 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. 13. 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. 14. 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. 15. (HGSI Press Release) Human Genome Sciences and Cambridge Antibody Commit to Exclusive Development of Anti-BLyS Antibodies. October 30, 2000. 16. (HGSI Press Release) GlaxoSmithKline Exercises Option to LymphoStat-B. July 7, 2005. 17. (HGSI Press Release) Human Genome Sciences Announces the Discovery of a Novel Immune Stimulant. July 8, 1999. 18. 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. 19. 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. 20. Carter RH. A role for BLyS in tissue inflammation? Arthritis & Rheumatism April 2003; 48(4): 882-885. 21. 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. 22. 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. 23. 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. 24. (HGSI Press Release) High Levels of BLyS Implicated in Lupus and Rheumatoid Arthritis Patients. October 30, 2000. 25. 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. 26. Petri M. Biomarkers in SLE: The Hopkins lupus cohort. Lupus Foundation of America Biomarkers for the Assessment of Systemic Lupus Erythematosus Meeting. March 2003. 27. 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. 28. 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. 29. 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. 30. 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. 31. 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. 32. 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. 33. 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.
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