Release Details

CARLSBAD, Calif., Sept 20, 2005 /PRNewswire-FirstCall via COMTEX News Network/ -- Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) announced today it has initiated Phase 2 development of ISIS 301012 for the lowering of high cholesterol. ISIS 301012 is a second-generation antisense drug that targets apoB-100, the protein component of low density lipoprotein cholesterol (LDL-C) or the "bad" cholesterol involved in heart disease. Lowering cholesterol levels is a key component in the management of cardiovascular disease.

The initial study in the Phase 2 development program is designed to optimize dose and frequency of dosing of ISIS 301012 in patients with high cholesterol. The study will also allow Isis to further evaluate the safety and efficacy of ISIS 301012 in patients with high cholesterol. In the double-blinded placebo-controlled study, patients will be dosed from 50mg to 200mg per week for three months and will be followed for an additional six months.

"The rapid, significant reduction of apoB-100, total cholesterol, and LDL-C, the bad cholesterol, we saw in our initial study of ISIS 301012 in subjects with mildly elevated cholesterol was impressive, and we are excited to continue to study the drug in patients with high cholesterol. This study will help us to further optimize the dose and treatment regimen of ISIS 301012 and to evaluate longer term dosing," said Mark Wedel, MD, JD, Vice President of Clinical Research and Chief Medical Officer of Isis Pharmaceuticals. "Many patients afflicted with high cholesterol, who are being treated with existing therapies, are still not reaching their targeted cholesterol levels as set by the U.S. National Cholesterol Education Program. ISIS 301012 has the potential to be used as an add-on therapy to lower cholesterol in patients who cannot reach their therapeutic target or as an alternative for patients who are not tolerating currently available therapies."

Isis has previously reported data from two Phase 1 clinical studies of ISIS 301012. In these studies, ISIS 301012 concomitantly reduced apoB-100, total cholesterol and LDL-C in normal subjects with elevated cholesterol. In the first study, ISIS 301012 produced average reductions in apoB-100 from 30% (50mg) to 52% (400mg), average reductions in LDL-C from 17% (50mg) to 48% (400mg), and average reductions in total cholesterol from 16% (50mg) to 40% (400mg). At 200mg per week, ISIS 301012 produced an average reduction of apoB-100 of 50% and an average reduction of LDL-C of 35%. In the second study, an average of 350mg per week of ISIS 301012 produced a median reduction of apoB-100 of 60% and a median reduction of LDL-C of 54%. In both studies, the drug was well-tolerated with no treatment-related severe adverse events.

Isis plans to commence additional Phase 2 trials of ISIS 301012 shortly. A Phase 2 study is planned to evaluate the safety and efficacy of ISIS 301012 in combination with a statin in patients with high cholesterol. Additional Phase 2 trials are planned to study the effects of ISIS 301012 in patients with familial hypercholesterolemia (FH). FH is a genetic disorder characterized by extremely high lipid levels.

ABOUT CHOLESTEROL AND CARDIOVASCULAR DISEASE

According to the American Heart Association, an estimated 106.9 million American adults have total blood cholesterol values of 200 mg/dL and higher, and of these about 37.7 million American adults have levels of 240 or above. In adults, total cholesterol levels of 240 mg/dL or higher are considered high risk. Levels from 200 to 239 mg/dL are considered borderline-high risk. Low-density lipoprotein, or LDL, is known as the "bad" cholesterol can clog arteries, increasing the risk of heart attack and stroke.

According to the World Health Organization (WHO), heart disease and stroke kill 17 million people a year, which is almost one-third of all deaths globally. By 2020, the WHO projects that heart disease and stroke will become the leading cause of both death and disability worldwide, with the number of fatalities projected to increase to over 20 million a year and by 2030 to over 24 million a year.

ABOUT ISIS PHARMACEUTICALS, INC.

Isis Pharmaceuticals, Inc. 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 12 antisense drugs in development to treat metabolic, cardiovascular and inflammatory diseases, and cancer. In its Ibis division, Isis is developing and commercializing the TIGER 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 more than 1,500 issued patents worldwide. Additional information about Isis is available at www.isispharm.com.

This press release includes forward-looking statements regarding the development, therapeutic potential and safety of ISIS 301012 in treating high cholesterol and cardiovascular disease. 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, 2004, and its quarterly report on Form 10-Q for the quarter ended June 30, 2005, 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

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