Isis Pharmaceuticals, Inc. Initiates Phase 2 Program Of ISIS 301012 In Patients With Familial Hypercholesterolemia

CARLSBAD, Calif., Feb. 6 /PRNewswire-FirstCall/ -- Isis Pharmaceuticals, Inc. announced today it has initiated the development program of ISIS 301012 in patients with familial hypercholesterolemia (FH), a genetic disorder that causes extremely high cholesterol levels and results in the early onset of heart disease. The Phase 2 studies in patients with FH are part of a broad Phase 2 development program of ISIS 301012. ISIS 301012, a second-generation antisense drug, reduces levels of apoB-100, a protein critical to the synthesis and transport of the "bad" cholesterol involved in heart disease -- low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein (VLDL). Lowering cholesterol levels is a key component in the prevention and management of cardiovascular disease.

The Phase 2 studies will evaluate the safety and efficacy of ISIS 301012 in patients with FH who are not achieving their cholesterol target levels on lipid-lowering therapy. In the studies, patients will be dosed with 50 mg, 100 mg or 200 mg of ISIS 301012 for 6 weeks treatment period and then followed for 5 months.

"Patients with FH have extremely high levels of cholesterol and, as a consequence, die very early of cardiovascular disease, often as early as age 10," said John J.P. Kastelein, M.D. Ph.D., Professor of Internal Medicine, Academic Medical Center Department of Vascular Medicine at the University of Amsterdam in The Netherlands. "Currently available lipid-lowering medications such as statins, do not adequately control their lipid levels, and aphaeresis treatments are time consuming, costly and very disruptive to a patient's life. Because ISIS 301012 directly inhibits the production of apoB-100 and reduces LDL-C and VLDL, it has the potential to have a significant effect on the lipid levels in FH patients. In addition, ISIS 301012 works through an entirely different mechanism than statins and has the potential to add to the activity of statins in a very significant way."

"Demonstrating efficacy of ISIS 301012 in patients with FH may lead to an advance in therapy for these desperately ill patients and establish ISIS 301012 as a powerful new cholesterol-lowering drug. The results, if positive, could also provide a faster route to commercialization of the drug because of the unmet medical need in this patient population," said Mark Wedel, MD, JD, Senior Vice President of Development and Chief Medical Officer at Isis Pharmaceuticals.

"We have shown that ISIS 301012 produces rapid and prolonged reductions of its target, apoB-100, with concomitant reductions in LDL-C, VLDL and total cholesterol levels in preclinical and Phase 1 studies. Based on these data, we believe that ISIS 301012 has the potential to lower cholesterol as an add-on therapy in patients who can not reach their therapeutic target or as an alternative for patients who can not tolerate currently available therapies," Dr. Wedel added. "In less than one month following dosing, normal volunteers with mildly elevated cholesterol, who were treated with an average of 350 mg/week of ISIS 301012 for one month, achieved a median reduction of 54% in LDL-C. Reduction of cholesterol in both animals and man were prolonged, suggesting that ISIS 301012 can be dosed infrequently. In addition, preliminary data suggest that the higher the baseline levels of apoB-100 and LDL-C, the greater the percentage reduction achieved with ISIS 301012 treatment, which could mean that in sicker patients the drug will work even better, an attribute that could be of particular benefit to patients with FH. We continue to be excited about the potential effects of ISIS 301012 in patients who are suffering from high cholesterol and combating cardiovascular disease, the number one killer worldwide."

In September 2005, Isis initiated the Phase 2 development program of ISIS 301012. Phase 2 trials of ISIS 301012 are being conducted in patients with high cholesterol. Isis is conducting a Phase 2 single-agent trial designed to optimize dose and frequency of dosing, and to further evaluate the safety and efficacy of ISIS 301012 in patients with high cholesterol. Isis is also conducting a Phase 2 trial of ISIS 301012 in combination with statin therapy in patients with high cholesterol.

ABOUT FAMILIAL HYPERCHOLESTEROLEMIA

Familial hypercholesterolemia is a dominantly inherited genetic condition that results in markedly elevated LDL (low-density lipoprotein) cholesterol levels beginning at birth, and resulting in heart attacks at an early age. Affected people have consistently high levels of low-density lipoprotein, which leads to premature atherosclerosis of the coronary arteries. Typically in affected men, heart attacks occur in their 40s to 50s, and 85% of men with this disorder have experienced a heart attack by age 60, according to Medline. The incidence of heart attacks in women with this disorder is also increased, but delayed 10 years later than in men. It is possible for a person to inherit two genes for this disorder (homozygous familial hypercholesterolemia). This magnifies the severity of the condition. Cholesterol values may exceed 600 mg/dL. Affected individuals develop waxy plaques (xanthomas) beneath the skin over their elbows, knees, buttocks. These are deposits of cholesterol in the skin. In addition, they develop deposits in tendons and around the cornea of the eye. Atherosclerosis begins before puberty and heart attacks and death may occur before age 20.

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, 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 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, ocular 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 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 development, therapeutic potential and safety of ISIS 301012 to lower high cholesterol. 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 September 30, 2005, which are on file with the SEC. Copies of these and other documents are available from the Company.

Isis Pharmaceuticals, Inc.

CONTACT: Navjot Rai, Corporate Communications & Investor Relations of IsisPharmaceuticals, Inc., +1-760-603-2331

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