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Proteolix, Inc. Drug Candidate, PR-957, Prevents Disease Progression in Rheumatoid Arthritis Models by Selective Inhibition of the Immunoproteasome

Findings Published in Nature Medicine Suggest Broad Implications for the Treatment of Inflammatory and Autoimmune Disorders

SOUTH SAN FRANCISCO, Calif., June 15 /PRNewswire/ -- Proteolix, Inc. announced that in an article published today in Nature Medicine, Proteolix's selective immunoproteasome inhibitor PR-957 was shown to block disease progression in mouse models of rheumatoid arthritis in a dose-dependent manner and to completely eliminate visible signs of disease at the highest dose. The anti-inflammatory effect induced by PR-957 was rapid and long-lasting, lowering expression of multiple inflammatory mediators, including TNF-a and IL-6. Disease regression was evident 24 hours after dosing and a complete amelioration of disease was achieved with a single dose. When compared to anti-TNF-a therapy (etanercept), PR-957 mediated a more rapid resolution of clinical symptoms, including joint inflammation, and was more effective than etanercept in a model of aggressive arthritis.

These data were published in the June 14, 2009 online edition of Nature Medicine and will be published in the upcoming July 2009 print edition in an article titled: A Selective Inhibitor of the Immunoproteasome Subunit LMP7 Blocks Cytokine Production and Attenuates Progression of Experimental Arthritis. The authors of the article included members of the laboratory of Dr. Marcus Groettrup at the University of Constance (Konstanz, Germany) and researchers, led by Dr. Christopher Kirk, at Proteolix, Inc. (South San Francisco, CA), where the drug candidate was discovered and developed.

PR-957 is the first highly selective, small molecule inhibitor of the immunoproteasome. The proteasome is an intracellular complex present in most cells that mediates the degradation of intracellular proteins, including key components of pathways that contribute to cancer cell growth and immune signaling. It is a proven and validated target for therapeutic intervention in oncology, but the side effect profiles of existing inhibitors have restricted the potential of this target for therapeutic intervention in autoimmune diseases. However, a specific form of the proteasome, known as the immunoproteasome, is found in many cells of the immune system. PR-957 selectively targets a subunit of the immunoproteasome, known as LMP7. Inhibition of this subunit results in a decrease of the immune cell signaling cascade and a halt of the production of cytokines associated with autoimmune inflammation, without affecting proteasome function in non-immune cells. As a consequence, PR-957 induces an anti-inflammatory response at doses less than one tenth the Maximum Tolerated Dose (MTD). In contrast, nonselective inhibitors, such as bortezomib and carfilzomib, induce anti-inflammatory responses only at or near their MTD. These findings also underline the key role played by the immunoproteasome in development of the inflammatory process.

"Targeting protein degradation pathways via the proteasome represents a completely novel approach to regulating the immune response. Using a specially designed proprietary assay, our team of researchers was able to discover and optimize a small molecule capable of demonstrating exquisite selectivity for the LMP7 immunoproteasome subunit," said Susan Molineaux, Ph.D., Chief Scientific Officer at Proteolix. "This selective inhibition of the immunoproteasome results in an increased therapeutic margin compared to that achieved with non-selective proteasome inhibitors, and can have dramatic impact on the inflammatory response without risking broad suppression of immune system function."

Proteolix plans to file an Investigational New Drug Application for PR-957 in mid-2010.

"The research published today in Nature Medicine provides a strong rationale for clinical development of PR-957 in rheumatoid arthritis and other inflammatory and autoimmune diseases," said John A. Scarlett, M.D., President and Chief Executive Officer of Proteolix. "Proteolix has now discovered and developed carfilzomib, a proteasome inhibitor in late Phase 2 clinical trials for the treatment of multiple myeloma, PR-047 as an oral proteasome inhibitor also targeted in oncology, and now PR-957 as a strong drug candidate for the treatment of autoimmune disorders. This demonstrates the Company's unique discovery and development capabilities, as well as its leadership in the field of proteasome inhibition."

About Proteolix

Founded in December 2003, Proteolix, Inc. is a privately-held biotechnology company, headquartered in South San Francisco, dedicated to discovering, developing and commercializing novel therapeutics that target protein degradation pathways for cancer and autoimmune diseases. Proteolix's lead product, carfilzomib, is the first in a new class of selective, irreversible proteasome inhibitors. Proteolix is also developing a pipeline of novel proteasome inhibitors, including a selective, oral proteasome inhibitor and a selective immunoproteasome inhibitor. For additional information on Proteolix, please visit

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