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AMR101 / Derivatives

AMAR101 / DERIVATIVES FOR CARDIOVASCULAR DISEASE

INTRODUCTION

Amarin’s cardiovascular strategy was initiated in November 2007 to capitalize on the known therapeutic benefits of unsaturated fatty acids in cardiovascular disease. While neurology remains Amarin’s core focus, Amarin can utilize its extensive know-how and experience in lipid science, including AMR101 (ultra-pure ethyl-EPA), to develop a series of products targeting the vascular system, endothelial dysfunction and vascular re-modeling. Amarin plans to demonstrate proof of concept with its cardiovascular programs and thereafter will seek a partner to fund further development and to commercialize.

AMR101 is believed to impact on a number of biological factors in the body such as anti-inflammatory mechanisms, cell membrane composition and plasticity, triglyceride levels and regulation of glucose metabolism.

Endothelial dysfunction is a physiological dysfunction of normal biochemical processes carried out by the endothelium, the cells that line the inner surface of all blood vessels including arteries and veins (as well as the innermost lining of the heart). Diseases associated with endothelial dysfunction are amenable to vascular remodeling by unsaturated fatty acids, like AMR101. Endothelial dysfunction is associated with significant morbidity resulting from diseases such as atherosclerosis, peripheral vascular disease, metabolic syndrome (a component of which is dyslipidemia), ischaemic heart disease and stroke.

The expansion of Amarin’s therapeutic reach into diseases with a significantly greater prevalence than neurological disease enhances our development portfolio mix and creates added value from our lipid technology platform. It is estimated that total U.S. pharmaceutical sales in the cardiovascular segment in 2006 were approximately $43.7 billion. The dyslipidemia market, excluding statins, was estimated at approximately $2.2 billion in 2006, representing a compound annual growth rate of 31% since 2002. The major driver of this growth is believed to be an overall broadening of dyslipidemia treatment beyond reduction in low density lipoprotein (LDL) cholesterol.

DEVELOPMENT STRATEGY/INDICATIONS

Amarin believes that proof of concept with AMR101 in cardiovascular disease can be established relatively quickly and inexpensively, as efficacy is measured by well defined biochemical endpoints. This should enable rapid progress of effective compounds into the final stages of development.

Amarin has already commenced its cardiovascular clinical program and is evaluating AMR101 in the attenuation of niacin-induced flushing. Flushing is a common side effect of niacin treatment (for dyslipidemia) which significantly limits patient compliance.

Another potential indication for AMR101 is in triglyceride lowering, where its efficacy is already established1-5. In excess of two million patients in Japan have been prescribed Epadel (ultra-pure ethyl-EPA) for the treatment of high triglyceride levels since its approval over 17 years ago. In the US, an EPA-based prescription compound called Lovaza (46% pure EPA/38% DHA), was launched in late 2005 for the treatment of very high triglycerides and is already generating approximately $300 million in annual net sales and growing rapidly. In Amarin’s most recent trials with AMR101 in Huntington’s disease, AMR101, as expected, was shown to lower triglycerides in patients with elevated baseline levels. The safety profile of ultra-pure ethyl-EPA is excellent, especially in comparison to other triglyceride lowering agents such as fibrates, statins and niacin. Amarin is currently preparing a submission for the FDA to obtain guidance regarding the development program required for approval of AMR101 in triglyceride lowering, which would be developed in conjunction with a potential partner.

In addition, Amarin intends to explore the application of new second generation compounds from its existing development portfolio for cardiovascular diseases.

REFERENCES 

1. Matsumoto et al - Abstract from ISSFAL meeting in Cairns Australia, 2006 (available upon request form Amarin) – “Oral Administration of Eicosapentaenoic Acid Reduces and Stabilizes Atherosclerotic Lesions Through Lipid Lowering Independent Mechanism in APO E-Deficient Mice”
2. Cawood et al - Abstract from ISSFAL meeting in Cairns Australia, 2006 (available upon request form Amarin) – “N-3 Fatty Acids From Omacor Enter Advanced Atherosclerotic Plaques and are Associated with Decreased Inflammation and Decreased Inflammatory Gene Expression”
3. Mori et al – Am J Clin Nutr 2000;71:1085-1094 – “Purified Eicosapentaenoic and Docosahexaenoic Acids Have Different Effects on Serum lipids and Lipoproteins, LDL Particle Size, Glucose and Insulin in Mildly Hyperlipidemic Men”
4. Yokoyama et al – Lancet 2007;369;1090-1098 - “Effects of Eicospentaenoic Acid on Major Coronary Events in Hypercholesterolaemic patients (Jelis): A Randomised Open-Label, Blinded Endpoint Analysis”
5. The Lancet 1999;354: 447-455 – “Dietary Supplementation with n-3 polyunsaturated Fatty Acids and Vitamin E After Myocardial Infarction: Results of the GISSI-Prevenzione Trial”
   

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