Release Details

Specificity and Efficiency of Isis Pharmaceuticals' Antisense Technology Platform Produce Robust Preclinical Data

CARLSBAD, Calif., June 12, 2006 /PRNewswire-FirstCall via COMTEX News Network/ -- Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) announced today results from multiple preclinical studies demonstrating potent and selective antisense inhibition of multiple gene targets involved in metabolic disorders including type 2 diabetes. Antisense drugs are very specific, making them an ideal approach for the inhibition of individual members of complex gene families and for evaluating the role of these individual genes in metabolic diseases. Due to their specificity, antisense drugs can target individual phosphatases, kinases and transcription factors, several of which are difficult to inhibit selectively with small molecules. Findings from the studies were presented by Isis and collaborators during the American Diabetes Association's (ADA) 66th Scientific Sessions in Washington, D.C.

"The efficiency of Isis' antisense drug discovery program allows us to rapidly validate novel targets in vivo for a broad range of complex diseases, including metabolic disorders," said C. Frank Bennett, Ph.D., Senior Vice President, Research at Isis Pharmaceuticals. "In our metabolics program at Isis, we have examined over 100 targets. Because of the selectivity of our drugs, we are able to observe the unique role that inhibition of one gene target plays compared to another. By comparing inhibition of these targets, we have selected the best ones to move forward, including our PTP-1B inhibitor, ISIS 113715, which is in Phase 2 clinical trials. Inhibition of several of these targets has resulted in beneficial effects that extend far beyond glucose control and include reduction of hyperlipidemia and body weight, both problems that are commonly seen in type 2 diabetes patients. As the data we presented today show, we have a robust pipeline of preclinical leads following behind this exciting drug."

Dr. Gerald Shulman, M.D., Ph.D., Professor of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, has been a close collaborator of Isis for the past 2 years investigating the role of multiple gene targets in animal models for diabetes, obesity and fatty liver disease. Dr. Shulman said, "We have evaluated over a dozen of Isis' second-generation antisense drugs and we were very encouraged to see that antisense inhibition of PKC-epsilon in animal models of diabetes prevented the development of fatty liver and fat induced insulin resistance. The pharmacological activity demonstrated with the PKC-epsilon antisense drug has great therapeutic potential for the treatment of type 2 diabetes and non alcoholic liver disease."

Key Presentations at the ADA:
Abstracts are available on Isis' website at www.isispharm.com



* Antisense Oligonucleotide Reduction of Hepatic PKC-Epsilon Expression Prevents Fat Induced Insulin Resistance



* Reduction of Hepatic Protein Tyrosine Phosphatase, Receptor, Type A (PTPRa) Expression Using an Antisense Oligonucleotide Improves Hyperglycemia, Steatosis and Plasma Triglycerides in Diabetic Mice



* Antisense Inhibition of miR-122, a Liver Specific MicroRNA, Markedly Improves Hyperlipidemia, Hepatic Steatosis and Hepatic Function in ob/ob Mice



* Reduction of Hepatic Glucagon Receptor Expression with an Optimized Antisense Oligonucleotide Increased Active GLP-1 Levels in Cynomolgus Monkeys Without Pancreatic Alpha Cell Expansion or Hyperplasia

* Decreased Adiposity and Improved Insulin Sensitivity in Diet-Induced Obese Mice with Antisense Reduction of eIF4E-BP2 Expression

* Deficiency of Adiponectin Receptor 2 Reduces Insulin Resistance, Yet Promotes Type 2 Diabetes in Mice Fed a High Fat Diet

ABOUT ISIS PHARMACEUTICALS, INC.

Isis is exploiting its expertise in RNA to discover and develop novel drugs for its product pipeline and for its partners. The Company has successfully commercialized the world's first antisense drug and has 15 drugs in development. Isis' drug development programs are aimed at treating cardiovascular, metabolic and inflammatory diseases. Isis' partners are focused in disease areas such as inflammatory, ocular, viral and neurodegenerative diseases, and cancer. In its Ibis division, Isis is developing and commercializing the IBIS biosensor system, a revolutionary system to identify infectious organisms. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of approximately 1,500 issued patents worldwide. Additional information about Isis is available at www.isispharm.com.

This press release includes forward-looking statements regarding the therapeutic and commercial potential of Isis' technologies and products in development for the treatment of metabolic diseases. Any statement describing Isis' 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' 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. Isis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward- looking statements. Although Isis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis' programs are described in additional detail in Isis' annual report on Form 10-K for the year ended December 31, 2005, and its quarterly report on Form 10-Q for the quarter ended March 31, 2006, which are on file with the SEC. Copies of these and other documents are available from the Company.

SOURCE Isis Pharmaceuticals, Inc.

Navjot Rai, Corporate Communications & Investor Relations of Isis
Pharmaceuticals, Inc., +1-760-603-2331