Alexion complement inhibitor shows efficacy in animal models of Lupus Nephritis; results presented at the American College of Rheumatology.

Pharmaceuticals, Inc. announced today that its complement inhibitor was effective in two different animal models of glomerulonephritis, a form of kidney inflammation associated with Lupus.

In a report entitled "Treatment of immune-complex mediated glomerulonephritis with C5 specific monoclonal antibody," presented today at the National Scientific Meeting of the American College of Rheumatology, Yi Wang, Ph.D., and his collaborators at Alexion demonstrated that administration of an antibody that selectively inhibits the cleavage of a pivotal complement component, C5, markedly reduces inflammation and kidney damage and substantially improved survival in two different animal models of glomerulonephritis. The complement inhibitor places a therapeutic road block in the inflammation cascade selectively at complement component C5, arresting the disease process, while leaving the vital immunoprotective parts of the complement system intact.

The complement system is comprised of a group of approximately twenty proteins circulating in the blood that are critical components of the body's immune system. Under normal circumstances, these proteins, in concert with antibodies and white blood cells, act beneficially to protect the body by removing pathogenic microorganisms and disease-causing immune complexes. However, any of a number of stimuli including antibodies, pathogenic microorganisms, injured or normal tissue, proteases (inflammatory enzymes) and artificial surfaces can locally activate the complement cascade causing several of the circulating complement proteins to cleave into active byproducts that can cause a variety of inflammatory diseases. For example, many clinical studies have demonstrated the presence of systemic complement activation in lupus patients undergoing flares and abundant deposition of activated complement proteins in kidney biopsies from lupus patients with active nephritis.

Systematic lupus erythematosus is a devastating disease characterized by severe and disabling nephritis, inflammation of the kidney, and arthritis, as well as inflammatory disorders of many other organ systems. Lupus effects an estimated 1,000,000 Americans.

The C5 inhibitor was administered in both an acute and rapid progressive nephritis (RPGN) model that normally leads to crescentic glomerulonephritis, the most common histologic lesion observed in patients with lupus nephritis, and also in the chronic and lethal NZB/NZW F1 lupus-prone mouse model. C5 inhibitor administration and subsequent complement inhibition prevented histologic and clinical development of nephritis in the RPGN model. C5 inhibitor administration in the lupus-prone mouse model also substantially reduced histologic and biochemical evidence of kidney damage. More importantly, survival at 10 months was markedly improved, from 5 percent in control-treated lupus-prone mice to 85 percent in C5 inhibitor-treated lupus-prone mice.

According to Dr. Louis Matis, vice president of research -- Immunobiology, at Alexion, "this study demonstrates that cleavage of complement component C5 is a critical step in the development of kidney disease, mediated by immune mechanisms. By selectively blocking only this step with a specific therapeutic antibody, clinical and pathologic signs of disease are dramatically ameliorated and survival, in an otherwise lethal disease model, is markedly improved.

Administration of our C5 inhibitor was quite effective at preserving normal kidney function without the general immunosuppressive and toxic side-effects often associated with cytotoxic therapies. We have now completed the humanization of a high affinity mAb called h5G1.1, which prevents the cleavage of human C5 into its pro-inflammatory complement products. Development of h5G1.1 will be targeted at lupus nephritis, rheumatoid arthritis, and selected other inflammatory diseases for which we have established substantial preclinical efficacy."

In a separate presentation at the Rheumatology Meetings, Dr. Wang also reported updated results from Alexion's previous report, entitled "Anti-C5 Monoclonal Antibody Therapy Prevents Collagen-Induced Arthritis and Ameliorates Established Disease," published last month in the Proceedings of the National Academy of Sciences. Dr. Wang and his colleagues demonstrated that prophylactic administration of the C5 inhibitor nearly eliminates the incidence of arthritis and that administration of the C5 inhibitor after onset of arthritis quickly and substantially ameliorated inflammation, reduced swelling, and prevented the spread of disease to additional joints.

Alexion has filed numerous patent applications wordlwide covering both novel compositions of matter directed at the inhibition of C5 cleavage and methods of treatment of various inflammatory diseases with proprietary complement inhibitors. In preclinical studies, C5 inhibition has been observed to be effective in diverse inflammatory targets including lupus, glomerulonephritis, arthritis, stroke, myocardial infarction, and surgical trauma. Alexion is currently in discussions with several healthcare firms regarding joint development of certain of these proprietary compositions.

Leonard Bell, M.D., President and Chief Executive Officer of Alexion, said, "We are very encouraged by the demonstrations of therapeutic efficacy of our complement inhibitors in inflammatory disease targets where current treatments are either ineffective or nonexistent. Importantly, the therapeutic efficacy demonstrated in these two different models of kidney disease was achieved without observable toxicity or negative side effects in the treated subjects over treatment periods as long as six months. We intend to develop h5G1.1-MAb and h5G1.1.-SC for the treatment of chronic and acute inflammatory diseases, respectively."

Alexion Pharmaceuticals, Inc., founded in 1992, is a private, research-based biopharmaceuticals company headquartered in New Haven, focused on developing novel immunoregulatory biotherapeutics targeting severe autoimmune and cardiovascular disorders and organ transplantation.

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