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Isis Pharmaceuticals and Partners Present Preclinical Results From Broad Antisense Drug Discovery Programs Targeting Lung Diseases at American Thoracic Society Meeting

CARLSBAD, Calif., May 25 /PRNewswire-FirstCall/ -- In multiple preclinical studies, second-generation antisense drugs selectively inhibited activity of proteins that promote inflammation and improved a variety of symptoms in mouse models of asthma and chronic lung inflammation, according to data presented this week at the 100th Annual Meeting of the American Thoracic Society (ATS). Scientists from Isis Pharmaceuticals, Inc. (Nasdaq: ISIS), and its partners presented data that demonstrate the efficacy of aerosolized second-generation antisense drugs in vivo and the potential of antisense inhibitors as inhaled therapeutics for inflammatory diseases of the lung. This body of data complements the recent advancement of Isis' first drug to be delivered by aerosol administration into development, ISIS 369645, a second-generation antisense inhibitor of IL4-receptor-alpha to treat chronic asthma.

"With one aerosol drug in development, and a number of aerosol drugs in late-stage preclinical research, Isis has now demonstrated the feasibility of this new route of administration for antisense drugs and created an exciting drug pipeline," said C. Frank Bennett, Ph.D., Isis' Vice President of Antisense Research. "Our presentations at the ATS meeting demonstrate the extraordinary value of antisense technology for identifying highly specific and effective novel drug therapies for the treatment of pulmonary diseases, allowing us to create an exciting aerosol drug pipeline," added Dr. Bennett.

The data presented at ATS showcase second-generation antisense drugs targeted to p38-alpha MAPK, TNF-alpha, and VLA-4 as potential treatment modalities for inflammatory diseases of the lung. Isis scientists evaluated a large number of second-generation antisense inhibitors to these targets and advanced the best lead candidates further into preclinical development. Lead antisense candidates reduced numerous measures of inflammation and improved airflow in acute and chronic models of lung disease. In more detail:

* Antisense Oligonucleotides Targeting p38-alpha-MAPK Reduce Ovalbumin-induced Pulmonary Inflammation and Airway Hyper responsiveness in Mice



Mitogen-activated protein kinases (MAPK) are important cellular mediators of inflammatory responses. In this presentation, Isis scientists demonstrated that an aerosolized selective inhibitor of p38-alpha (one member of the MAPK family) potently and safely improved numerous measures of inflammation and airflow in several animal models of asthma while inhibiting p38-alpha protein levels in several key inflammatory cell types in the lung. The p38-alpha antisense oligonucleotide did not inhibit expression of the highly related p38-beta isoform in mice, demonstrating the specificity and versatility of antisense.



In the acute model of asthma in mice, local antisense inhibition of p38-alpha improved airway hyper-responsiveness to methacholine in antigen-challenged mice at doses as low as 3.3 microgram oligonucleotide/kg. Treatment also reduced antigen-induced airway eosinophilia and mucus production, two hallmark causative factors in asthma. Local treatment with the p38-alpha antisense inhibitor was also effective in reducing airway hyper-responsiveness, Th2 cytokines and lung inflammatory cell infiltrates in antigen re-challenged animals.



* Inhaled TNF-alpha Antisense Oligonucleotide Inhibits Lung Inflammation and Airway Hyper-responsiveness in a Mouse Model of Chronic Asthma



TNF-alpha has been implicated as a causative factor in persistent asthma, chronic obstructive pulmonary disease (COPD), and emphysema. Local administration of a second-generation inhibitor of TNF-alpha improved airflow, lung inflammation, and mucus production in chronically challenged mice. However, in contrast to the results with inhibitors of IL4R-alpha, p38-alpha, or VLA-4, the TNF-alpha inhibitor had limited effects in acutely challenged mice.



These data are consistent with the view that TNF-alpha is more likely to be involved in severe, persistent asthma and other chronic pulmonary inflammatory diseases.



* Aerosol Delivery of VLA-4 Specific Antisense Oligonucleotides Inhibit Airway Inflammation and Hyperresponsiveness in Mice



Isis scientists and collaborators at Antisense Therapeutics Limited evaluated the effects of a second-generation inhibitor of VLA-4. VLA-4 is a cell surface receptor that is known to be involved in inflammatory diseases such as multiple sclerosis and Crohn's disease. Systemically administered anti-VLA-4 antibodies have demonstrated pharmacological efficacy in animal models of asthma. Local administration of an antisense inhibitor to VLA-4 for asthma may provide a safer and more effective approach for treating asthma.



Treatment with an inhaled VLA-4 antisense inhibitor improved lung function and reduced airway eosinophilia in acutely challenged mice.

ABOUT ISIS PHARMACEUTICALS, INC.

Isis Pharmaceuticals, Inc. is exploiting its expertise in RNA to discover and develop novel human therapeutic drugs for its pipeline and for its partners. The Company has successfully commercialized the world's first antisense drug and has 11 antisense products in development to treat metabolic, cardiovascular and inflammatory diseases, and cancer. Through its Ibis division, Isis is developing a system to identify infectious organisms. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of more than 1,500 issued patents worldwide. Additional information about Isis is available at http://www.isispharm.com.

This press release includes forward-looking statements regarding antisense technology, the development and therapeutic potential of antisense drugs to specific inflammation targets, and the success of Isis and its partners' inflammatory drug discovery programs. Any statement describing our goals, expectations, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement, including those statements that are described as Isis' clinical goals. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics and in the endeavor of building a business around such products. Our forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause our results to differ materially from those expressed or implied by such forward-looking statements. Although our forward-looking statements reflect the good faith judgment of our management, these statements are based only on facts and factors currently known by us. As a result, you are cautioned not to rely on these forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to, those discussed in Isis' Annual Report on Form 10-K for the year ended December 31, 2004, and quarterly report on Form 10-Q for the quarter ended March 31, 2005, which are on file with the U.S. Securities and Exchange Commission (SEC), and available from the Company.

Bibliography and Abstracts Presented at ATS



Antisense Oligonucleotides targeting p38-alpha-MAPK Reduce Ovalbumin-induced Pulmonary Inflammation and Airway Hyper-responsiveness in Mice. WA Gaarde, KJ McKay, JR Crosby, DA Miller, D Kowalski, D Tung, C Arberg, D Lin, T Osgood, M Guha, BP Monia, JG Karras, SA Gregory. Isis Pharmaceuticals, Inc., Carlsbad, CA 92008.



Inhaled TNF-alpha Antisense Oligonucleotide Inhibits Lung Inflammation and Airway Hyper-responsiveness in a Mouse Model of Chronic Asthma. JR Crosby, D Tung, M Guha, D Luther, D Kowalski, T Osgood, BGaarde, B Monia, J Karras, and SA Gregory Isis Pharmaceuticals, Inc., Carlsbad, CA 92008.



Aerosol Delivery of VLA-4 Specific Antisense oligonucleotides Inhibit Airway Inflammation and Hyper-responsiveness in Mice. Jeffery R Crosby, David Tung, Mausumee Guha, Doreen Miller, Dominic Kowalski, Chad Arberg, Tao Osgood, Kelly McKay, William Gaarde, Shari Lofthouse,* Christopher Wraight,* George Tachas,* Brett P. Monia, James G. Karras, and Susan A. Gregory. *Antisense Therapeutics, Victoria 3142, Australia and Department of Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, California 92008.

SOURCE Isis Pharmaceuticals, Inc.
05/25/2005

CONTACT: Claudine Prowse, Ph.D., of Isis Pharmaceuticals, Inc., +1-760-603-2331

Web site: http://www.isispharm.com
(ISIS)
05/25/2005 07:55 EDT http://www.prnewswire.com