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Isis Reports Reduction of apoB-100 Levels in a Murine Model Resulting in Up to 92% Reduction of Atherosclerosis

CARLSBAD, Calif., April 18, 2008 /PRNewswire-FirstCall/ -- Isis Pharmaceuticals, Inc. presented the results of two studies designed to assess the impact of lowering apoB-100 on atherosclerosis at the 2008 Annual Atherosclerosis, Thrombosis and Vascular Biology (ATVB) Conference in Atlanta, Georgia. The data were presented in a poster entitled "Antisense Inhibition of Apolipoprotein B Ameliorated Diet-Induced Hypercholesterolemia and Reduced Atherosclerosis in LDL Receptor-Deficient Mice" by Adam E. Mullick, Ph.D. of Isis yesterday at ATVB.

Both studies were performed in a murine model in which the LDL receptor, which is responsible for the maintenance of normal serum cholesterol levels, has been genetically eliminated. These animals have very high cholesterol levels (1,000 - 2,000 mg/dL on a high fat diet) and develop severe atherosclerosis. In the first study, the impact of treatment with an antisense drug was evaluated in the context of two atherogenic high fat diets. Animals on these diets had elevated total cholesterol and LDL-cholesterol levels that increased during the two weeks of high fat diet prior to drug treatment. These cholesterol levels dramatically decreased during the 10 week treatment period. At a dose of 50 mg/kg twice weekly, the murine apoB-100 antisense drug reduced total cholesterol and LDL-cholesterol by 87% and 93%, respectively. These reductions in cholesterol directly correlated with reduction in liver and plasma apoB-100 levels. Aortic atherosclerotic lesions were reduced by 78% - 92% in the same animals.

The second study, which evaluated the effects of increasing doses of drug on lipid levels, confirms and extends the results of the previous study, and showed that the effects of the apoB-100 antisense drug were linearly dose-dependent with regard to reductions on apoB-100 and atherogenic lipid levels, triglycerides, and atherosclerotic plaques. The maximum reduction of atherosclerotic plaques was 89% in this study.

"These studies add to a growing body of data showing that reducing apoB-100 results in substantial reductions in atherosclerosis," said Rosanne Crooke, Ph.D., Executive Director of Cardiovascular Research of Isis. "We have now shown that mipomersen or species-specific analogs reduce atherosclerosis in several animal models and that the effects on atherosclerosis correlate with reductions in apoB-100 and atherogenic lipids, including LDL-cholesterol and triglycerides."

ABOUT MIPOMERSEN

Early 2008, Isis announced the licensing of mipomersen to Genzyme as the preferred partner to continue development, commercialize and market the drug.

Mipomersen is a second-generation antisense drug that reduces the production of apoB-100, a protein critical to the synthesis and transport of "bad" cholesterol. Cholesterol can be carried in the bloodstream in a variety of forms, with high-density lipoprotein, or HDL-C, being the good form, and low-density lipoproteins, or LDL-C, and very low-density lipoproteins, or VLDL-C, being bad forms directly involved in heart disease. Collectively lowering LDL-C, VLDL-C, and other bad forms of cholesterol are a key component in the prevention and management of cardiovascular disease.

Currently in Phase 3 development, mipomersen has been shown in Phase 2 trials to reduce cholesterol and other atherogenic lipids more than 40 percent beyond reductions achieved with standard lipid-lowering drugs, enabling more patients to achieve LDL-C targets. These trials have shown that treatment with mipomersen is well-tolerated, and that mipomersen has an attractive safety profile, and works equally well in the presence and absence of other lipid-lowering therapies including statins. A weekly injectable therapeutic, mipomersen is being developed primarily for patients at high cardiovascular risk who are unable to achieve target cholesterol levels with statins alone or who are intolerant of statins.

Mipomersen's initial indication will be for patients with familial hypercholesterolemia (FH). There are approximately 1.5 million people in the United States and Europe with FH, an inherited disorder that causes exceptionally high levels of LDL-cholesterol. After appropriate clinical development, the next indication pursued for mipomersen will be for other patients with high cholesterol at high risk of cardiovascular events.

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 19 drugs in development. Isis' drug development programs are focused on treating cardiovascular and metabolic diseases. Isis' partners are developing antisense drugs invented by Isis to treat a wide variety of diseases. Ibis Biosciences, Inc., Isis' majority-owned subsidiary, is developing and commercializing the Ibis T5000(TM) Biosensor System, a revolutionary system to identify infectious organisms. Isis is a joint owner of Regulus Therapeutics LLC, a joint venture focused on the discovery, development and commercialization of microRNA therapeutics. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of over 1,500 issued patents worldwide. Additional information about Isis is available at http://www.isispharm.com.

This press release includes forward-looking statements regarding the development, activity, therapeutic potential and safety of mipomersen in treating patients with high cholesterol. Any statement describing Isis' goals, expectations, financial or other projections, 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, 2007, which is on file with the SEC. Copies of this and other documents are available from the Company.

In this press release, unless the context requires otherwise, "Isis," "Company," "we," "our," and "us" refers to Isis Pharmaceuticals and its subsidiaries.

Isis Pharmaceuticals is a registered trademark of Isis Pharmaceuticals, Inc. Ibis Biosciences and Ibis T5000 are trademarks of Ibis Biosciences, Inc. Regulus Therapeutics is a trademark of Regulus Therapeutics LLC.

CONTACT: Kristina Lemonidis, Associate Director, Investor Relations,+1-760-603-2490, or Amy Blackley, Ph.D., Manager, Corporate Communications,+1-760-603-2772, both of Isis Pharmaceuticals, Inc.

Web site: http://www.isispharm.com/

Ticker Symbol: (NASDAQ-NMS:ISIS)

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Posted: April 2008

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