Mandy - More on Lymphostat-B

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And here is an article with more technical information in it... The original is at

http://www.hgsi.com/products/LSB.html

Sue

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LymphoStat-B (Human Monoclonal Antibody To B Lymphocyte Stimulator / BLyS)

Background

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 systemic lupus erythematosus and rheumatoid arthritis (see Figures 1 and 3).2, 3, 4, 5 Autoimmune diseases are diseases in which the body is attacked by its own immune system.

Preclinical studies and clinical results to date show that LymphoStat-B significantly reduces the levels of circulating B cells (see Figure 4). Human Genome Sciences is developing LymphoStat-B as a potential treatment for systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases. LymphoStat-B has received a Fast Track Product designation from the U.S. Food and Drug Administration (FDA) for its potential use in treating systemic lupus erythematosus.

Figure 1. Retrospective studies have shown elevated BLyS levels in the blood of patients with systemic lupus erythematosus (SLE), and in the blood and joint fluid of patients with rheumatoid arthritis. Prospective studies have shown a significant correlation of elevated BLyS levels with SLE disease activity.

Clinical Progress

Human Genome Sciences is conducting Phase 2 clinical trials of LymphoStat-B in patients with systemic lupus erythematosus and in patients with rheumatoid arthritis.

We are enrolling and dosing patients in a double-blind, placebo-controlled, multi-center Phase 2 clinical trial designed to evaluate the safety, optimal dosing, and efficacy of LymphoStat-B in adult patients with systemic lupus erythematosus.6 Approximately 350 patients with active systemic lupus erythematosus will be enrolled in the trial and randomized to receive either one of three different doses of LymphoStat-B or placebo. Patients will receive multiple doses of LymphoStat-B or placebo over a 52-week treatment period. Primary endpoints of the trial are safety, optimal dosing, and preliminary efficacy. Efficacy will be measured in the trial according to scores on the SELENA SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) and BILAG (British Isles Lupus Activity Group) disease activity scales. Time to first lupus disease flare also will be recorded.

We are enrolling and dosing patients in a double-blind, placebo-controlled, multi-center Phase 2 clinical trial that will evaluate the safety, optimal dosing, and efficacy of LymphoStat-B in patients with rheumatoid arthritis.7 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.

For more information about clinical trials involving LymphStat-B, visit www.clinicaltrials.gov. In April 2003, the Company announced the results of a Phase 1 clinical trial designed to determine the safety and pharmacology of LymphoStat-B in adult patients with systemic lupus erythematosus who were receiving standard therapies.8,9 These results were presented in October 2003 at the 67th Annual Meeting of the American College of Rheumatology10, 11 Results demonstrate that LymphoStat-B is well tolerated and biologically active in these patients. Seventy patients were enrolled and randomized in the multi-center, double-blind, placebo-controlled, dose-escalation Phase 1 clinical trial. LymphoStat-B or placebo was administered intravenously at 1 milligram (mg)/kilogram (kg), 4 mg/kg, 10 mg/kg, or 20 mg/kg. Patients received a placebo, a single dose of LymphoStat-B, or two doses of LymphoStat-B twenty-one days apart. Safety was the primary endpoint of the study protocol. Pharmacology of LymphoStat-B and biological markers of B-cell function also were evaluated.

Results show that LymphoStat-B is well tolerated with no clinically significant differences from placebo in adverse events or laboratory abnormalities. No drug-related serious adverse events were reported. The half-life of LymphoStat-B was shown to be between 13 and 17 days, which is consistent with that of other human monoclonal antibodies. A dose-proportional pharmacokinetic profile was observed. As expected based on preclinical research and LymphoStat-B's mechanism of action, results show that LymphoStat-B significantly reduced the levels of circulating B cells (CD 20+), the precursor cells to those that produce the body's normal and abnormal antibodies. In addition, significant reductions in anti-dsDNA autoantibody levels were observed in some LymphoStat-B treatment cohorts.

Figure 2. 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. During maturation, autoantibody-producing B cells can evolve. In healthy people, the body signals autoantibody-producing B cells to kill themselves by programmed cell death, or apoptosis.

Figure 3. In patients with autoimmune diseases, such as lupus and rheumatoid arthritis, BLyS stimulates B cell hyperactivity and inhibits apoptosis. Autoantibody-producing B cells mature and release autoantibodies into the body. Autoantibodies bind to tissues, which can result in inflammation of the lungs, heart, joints, and blood vessels, and in kidney failure

How LymphoStat-B Works

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) (see Figure 4). BLyS is a naturally occurring protein that is required for the development of B-lymphocyte cells into mature plasma B cells (see Figure 2.). Plasma B cells produce antibodies, the body's first line of defense against infection.

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. 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.12, 13, 14, 15, 16, 17 The results of prospective studies also now show a significant correlation of elevated levels of BLyS with systemic lupus erythematosus disease activity.17 Interim results of a two-year observational study designed to evaluate longitudinally the relationship between BLyS plasma concentrations and lupus disease activity in patients receiving standard-of-care therapy also were presented at the October 2003 meeting of the American College of Rheumatology.17 Preliminary data demonstrate that BLyS levels are positively and significantly associated with SELENA SLEDAI disease activity scores across all visits (p=0.016), Immunoglobulin-G levels across all visits (p=0.002), and anti-dsDNA autoantibody levels in most visits (p<0.013). Seventy-eight percent of the subjects had a greater than twenty-five percent change from their baseline BLyS levels on at least one visit throughout the study. Of those subjects, thirty-six percent had a greater than fifty percent change from their baseline BLyS levels on at least one visit. Multivariate analysis showed that increases in SELENA SLEDAI score (worsening disease activity) from the previous visit to the current visit were associated with elevated BLyS level in the previous visit (p=0.017). Increases in SELENA SLEDAI score from the previous visit to the current visit also were correlated with increases in BLyS levels during that time period (p=0.0154).

In vitro and in vivo preclinical studies show that LymphoStat-B is well tolerated, biologically active, and capable of reversing the immune stimulatory effects of BLyS.18, 19 Preclinical and clinical study results to date demonstrate that LymphoStat-B significantly reduces the levels of circulating B (CD 20+) cells, the precursor cells to those that produce the body’s normal and abnormal antibodies.11, 19

Figure 4. LymphoStat-B specifically binds to and inhibits the biological activity of BLyS. Preclinical and clinical results to date show that LymphoStat-B can reduce the levels of circulating B (CD-20+) cells, the precursor cells to those that produce the body's normal and abnormal antibodies. This suggests that LymphoStat-B may prove useful in the treatment of lupus, rheumatoid arthritis, and certain other autoimmune diseases.

Potential Treatment Settings

Human Genome Sciences is developing LymphoStat-B as a potential new treatment for systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases.

Systemic lupus erythematosus, commonly referred to as lupus, is a chronic, life-threatening disease. Between 200,000 and 500,000 people are diagnosed with systemic lupus erythematosus in the United States alone. The disease affects between eight and ten times as many women as men. It can occur at any age, but appears mostly in young people between the ages of fifteen and forty-five. 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.

Human Genome Sciences is conducting a Phase 2 clinical trial to evaluate the safety, optimal dosing, and preliminary efficacy of LymphoStat-B in adult patients with systemic lupus erythematosus. Results of a Phase 1 clinical trial of LymphoStat-B in patients with systemic lupus erythematosus show that LymphoStat-B is well tolerated and biologically active in this treatment setting.

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, which is 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 about rheumatoid arthritis, visit the Arthritis Foundation at www.arthritis.org.

Human Genome Sciences and our collaborators have found elevated levels of BLyS in the blood and joint fluid of rheumatoid arthritis patients. In addition, autoantibody levels (especially "rheumatoid factor") appear to correlate with disease severity. This suggests that B cells play a significant role in the pathology of rheumatoid arthritis. LymphoStat-B inhibits BLyS function. It is believed that LymphoStat-B may reduce autoantibody levels and provide a therapeutic benefit to patients with rheumatoid arthritis. Human Genome Sciences plans to initiate Phase 2 clinical trials of LymphoStat-B in patients with rheumatoid arthritis.

How LymphoStat-B Was Discovered

Human Genome Sciences announced the discovery of BLyS and provided a preliminary description of its activity in July 1999.1, 20 Following the discovery of BLyS, Human Genome Sciences initiated a program to identify antibodies that would inhibit BLyS, for development into potential treatments. Human Genome Sciences, in collaboration with Cambridge Antibody Technology (CAT), discovered and optimized the antibody to BLyS, LymphoStat-B, as a drug.

Footnotes

1. (HGSI Press Release) Human Genome Sciences Announces The Discovery Of A Novel Immune Stimulant. July 8, 1999.

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

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

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

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

6. (HGSI Press Release) Human Genome Sciences Initiates Phase 2 Clinical Trial Of LymphoStat-B™ For The Treatment Of Systemic Lupus Erythematosus. September 25, 2003.

7. (HGSI Press Release) Human Genome Sciences Initiates Phase 2 Clinical Trial of LymphoStat-B for the Treatment of Rheumatoid Arthritis. January 8, 2004

8. (HGSI Press Release) Human Genome Sciences Initiates Trials of a New Drug for Systemic Lupus Erythematosus and Other Autoimmune Diseases. November 1, 2001.

9. (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.

10. (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.

11. 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.

12. (HGSI Press Release) High Levels Of BLyS Implicated In Lupus And Rheumatoid Arthritis Patients. October 30, 2000.

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

14. Elevated Serum B Lymphocyte Stimulator Levels in Patients with Systemic Immune-Based Rheumatic Diseases. Cheema GS, Roschke V, Hilbert DM and Stohl W. Arthritis & Rheumatism June 2001; 44(6): 1313-1319.

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

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

17. 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.

18. Characterization of a Human Monoclonal Antibody That Antagonizes B-Lymphocyte Stimulator Bioactivities. Les Sekut, Bonnie Sturm, Carol Poortman, Ruth Wager, Chen Zhang, Donara Abramian, Todd Riccobene, Svetlana Sosnovtseva, Sung, Viktor Roschke, P. Baker, M. Hilbert. American College of Rheumatology 2001 Annual Meeting, Abstract 1377.

19. 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.

20. BLyS: Member of the Tumor Necrosis Factor Family and B Lymphocyte Stimulator. PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, Gentz R, Parmelee D, Li Y, Galperina O, Giri J, Roschke V, Nardelli B, Carrell J, Sosnovtseva S, Greenfield W, SM, Olsen HS, Fikes J, and Hilbert DM. Science July 9, 1999; 285(5425): 260-263.

Bibliography

HGS and collaborators:

Baker K, B, Main S, et al. Generation and Characterization of LymphoStat-B, a Human Monoclonal Antibody that Antagonizes BLyS Bioactivities. Arthritis & Rheumatism Nov 2003; 48. In press.

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

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

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

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

Characterization of a Human Monoclonal Antibody That Antagonizes B-Lymphocyte Stimulator Bioactivities. Les Sekut, Bonnie Sturm, Carol Poortman, Ruth Wager, Chen Zhang, Donara Abramian, Todd Riccobene, Svetlana Sosnovtseva, Sung, Viktor Roschke, P. Baker, M. Hilbert. American College of Rheumatology 2001 Annual Meeting, Abstract 1377.

Elevated Serum B Lymphocyte Stimulator Levels in Patients with Systemic Immune-Based Rheumatic Diseases. Cheema GS, Roschke V, Hilbert DM and Stohl W. Arthritis & Rheumatism June 2001; 44(6): 1313-1319.

Synthesis and release of B-lymphocyte stimulator from myeloid cells. Nardelli B, Belvedere O, Roschke V, PA, Olsen HS, Migone TS, Sosnovtseva S,

Carrell JA, Feng P, Giri JG, Hilbert DM. Blood 2001 Jan 1; 97(1):198-204.

Tumor Necrosis Factor (TNF) Receptor Superfamily Member TACI Is a High Affinity Receptor for TNF Family Members APRIL and BLyS. Wu Y, Bressette D, Carrell JA et al. J. Biol. Chem. 2000; 275(45): 35478Ñ35485

Non-HGS, non-collaborators:

Efficacy and safety of rituximab, a B-cell targeted chimeric monoclonal antibody: A randomized, placebo-controlled trial in patients with rheumatoid arthritis. American College of Rheumatology 2002 Annual Meeting, Abstract 446.

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

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

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

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

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

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

BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell

growth. 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.J. Exp Med 1999 Jun 7; 189(11): 1747-56.

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

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

An Essential Role for BAFF in the Normal Development of B Cells Through a BCMA-Independent Pathway. Schiemann B,* Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, Frew E, ML. Science. 14 September, 2001; 293: 2111-2114.

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

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

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

Background information for LymphoStat-B is available for the following indication:

Systemic Lupus Erythematosus

[Guest guest]

Thanks for all this too!!!

Mandy

-- In LUPIES , " Sue Mechem " wrote:

> And here is an article with more technical information in it...

The original is at

> http://www.hgsi.com/products/LSB.html

>

> Sue

>

>

> ---

> Outgoing mail is certified Virus Free.

> Checked by AVG anti-virus system (http://www.grisoft.com).

> Version: 6.0.712 / Virus Database: 468 - Release Date: 6/27/2004

[Guest guest]

Thanks for all this too!!!

Mandy

-- In LUPIES , " Sue Mechem " wrote:

> And here is an article with more technical information in it...

The original is at

> http://www.hgsi.com/products/LSB.html

>

> Sue

>

>

> ---

> Outgoing mail is certified Virus Free.

> Checked by AVG anti-virus system (http://www.grisoft.com).

> Version: 6.0.712 / Virus Database: 468 - Release Date: 6/27/2004