PRODUCTS

AMR101 for Reducing Cardiovascular Risk

AMR101 for Hypertriglyceridemia and Dyslipidemia (multiple lipid disorders)

INTRODUCTION

AMR101 is a prescription-grade omega-3 fatty acid, comprising not less than 96% ultra pure EPA (icosapent ethyl), that Amarin is developing as a potentially best-in-class prescription medicine for the treatment of patients with very high triglyceride levels (≥500 mg/dL) and as a potentially first-in-class therapy for patients with high triglyceride levels (≥200 and <500mg/dL) who are also on statin therapy for elevated LDL-cholesterol levels (which we refer to as mixed dyslipidemia). Triglycerides are fats in the blood. Significant scientific and clinical evidence support the efficacy and safety of ethyl-EPA in reducing triglyceride levels and other important lipid and inflammation biomarkers, including Apo-B, non-HDL-C, Total-Cholesterol, VLDL-C, Lp-PLA2, and hs-CRP without increasing LDL-C. AMR101 demonstrated a safety profile comparable to placebo in two complete Phase 3 clinical trials.

Amarin's cardiovascular strategy leverages our extensive knowledge and experience in lipid science and the potential therapeutic benefits of polyunsaturated fatty acids in cardiovascular disease. 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.

AMR101 has completed Phase 3 clinical development for the treatment of hypertriglyceridemia in patients with very high triglycerides (≥500mg/dl) and for patients with high triglycerides (≥200 and <500mg/dl) who also have mixed dyslipidemia. Hypertriglyceridemia refers to a condition in which patients have high blood levels of triglycerides and is recognized as an independent risk factor for cardiovascular disease. Mixed dyslipidemia refers to a condition in which patients have a combination of two or more lipid abnormalities including elevated triglycerides, low high-density lipoprotein cholesterol (HDL-C), and elevated low-density lipoprotein cholesterol (LDL-C). It is estimated that 75 million people in U.S. alone have triglyceride levels greater than 150mg/dL, including 4 million people with very high triglyceride levels (the triglyceride range studied in the MARINE trial) and 36 million people with high triglyceride levels (the triglyceride range studied in the ANCHOR trial). Elevated triglycerides are clinically stratified into three groups: very high triglycerides (>500 mg/dL), high triglycerides (>200 and <500 mg/dL) and borderline high triglycerides (>150 and <200 mg/dL). Clinical treatment guidelines include recommendations for triglyceride reductions in each of these groups and each group represents a multi-billion dollar market opportunity. In the top seven world markets it is estimated that the number of people with elevated triglyceride levels is at least two times that of the U.S. alone.

Currently there are no omega-3 fatty acid based drugs approved in the U.S. for patients with high triglycerides (≥200 and <500 mg/dl) who also have mixed dyslipidemia and only one U.S. prescription grade omega-3 fatty acid based drug (LovazaTM) approved for treatment of patients with very high triglycerides (≥500 mg/dl). LovazaTM is marketed by GlaxoSmithKline in the United States (the same product is marketed in Europe as OmacorTM). As illustrated below, it is estimated that there are approximately ten times as many patients with high triglycerides than very high triglycerides.

The growth of prescription grade Omega-3 fatty acids, which are known to be highly effective in lowering triglycerides, is underpinned by the growing acceptance of high triglycerides as an independent risk factor in cardiovascular disease. In addition to their efficacy, their safety and tolerability profile also make them very suitable for combination treatments, an important treatment approach in the effective management of dyslipidemia. A distinguishing feature of AMR101 is its single active moiety of ethyl-EPA.

DEVELOPMENT STATUS – PHASE 3 COMPLETE

Amarin has completed two pivotal Phase 3 clinical trials with AMR101 under Special Protocol Agreement (SPA) with the FDA. The first is a Phase 3 trial for the treatment of very high triglycerides (The MARINE Study). The second is a Phase 3 trial to treat high triglycerides in patients with mixed dyslipidemia who are on statins for elevated LDL-C levels (the ANCHOR Study). These two studies are designed to support the broadest label in this drug class.

The MARINE study is a multi-center, placebo-controlled, randomized, double-blind, 12-week study to evaluate the efficacy and safety of two doses of AMR101 in patients with fasting triglyceride levels of ≥500 mg/dL. The primary endpoint in the trial is the percentage change in triglyceride level from baseline to week 12. Following completion of the 12-week double-blind treatment period, patients will be eligible to enter a 40-week, open-label, extension period. The data from the extension period is not required to submit the NDA. On November 29th, 2010 the company reported that the MARINE study met the primary efficacy endpoint as defined in the clinical trial protocol and demonstrated a positive safety profile. Amarin submitted a New Drug Application (NDA) to the FDA in September 2011 requesting approval to market and sell AMR101 for the indication being studied in the MARINE trial in the United States. The submission is based on the entire data set from the Company's AMR101 development program, including safety and efficacy data from the Phase 3 MARINE and ANCHOR studies. Further description of the MARINE study can be found listed on the clinical trials website (http://clinicaltrials.gov/ct2/show/NCT01047683?term=amarin&rank=3.)

The ANCHOR study is a multi-center, placebo-controlled, randomized, double-blind, 12-week study to evaluate the efficacy and safety of 2 grams and 4 grams of AMR101 in patients with high triglyceride levels of ≥200 mg/dL and <500 mg/dL who are on statin therapy. The primary endpoint in the trial is the percentage change in triglyceride level from baseline compared to placebo after 12 weeks of treatment. The secondary endpoint was LDL-C non-inferiority. On April 18, 2011, the Company reported positive, statistically significant top-line results for the trial's primary endpoint and announced that it also achieved the LDL-C non-inferiority criterion. No prescription omega-3 based drug is currently approved in the United States for treating high triglyceride levels in statin-treated patients who have mixed dyslipidemia. The Company plans to use the results of this Phase 3 trial as the basis for seeking a broader label than similar prescription products for triglyceride lowering. Further description of the ANCHOR study can be found listed on the clinical trials website (http://clinicaltrials.gov/ct2/show/NCT01047501?term=amarin&rank=2).

Amarin has previously investigated AMR101 in central nervous system disorders in several double-blind, placebo controlled studies, including Phase 3 trials in Huntington's disease. Over 900 patients have received AMR101 in these studies, with over 100 receiving continuous treatment for a year or more. In all studies performed to date, AMR101 has shown a very good safety and tolerability profile.

Numerous independent studies have demonstrated the safety and efficacy of ethyl-EPA in lowering plasma triglycerides in patients with high triglyceride levels of varying degrees of severity. In Japan, an ethyl-EPA prescription product has been approved for the treatment of hyperlipidemia and has been on the market for more than ten years.

*A SPA is a written agreement between the Company, as the trial's sponsor, and the FDA regarding the design, endpoints, and planned statistical analysis of the Phase 3 trial to be used in support of an (NDA).

INTELLECTUAL PROPERTY & EXCLUSIVITY

Amarin seeks to protect the global exclusivity of AMR101 through a multi-tiered strategy of patents, regulatory exclusivity, manufacturing barriers and trade secrets. With respect to patents, Amarin is developing a patent estate around its EPA and related fatty acid platform in conjunction with its studies of AMR101. Amarin has been granted one disease non-specific ethyl-EPA related patent in the US and the Company has numerous other pending U.S. applications, encompassing hundreds of claims, that are positioned to seek additional protection for composition and uses of AMR101, including numerous claims based upon positive and unexpected findings from the Company’s successfully completed Phase 3 clinical trials. Amarin is also pursuing an extensive foreign filing patent strategy in countries around the world.

REFERENCES

  • Yokoyama et al – Lancet 2007;369;1090-1098 - "Effects of Eicosapentaenoic Acid on Major Coronary Events in Hypercholesterolaemic patients (Jelis): A Randomised Open-Label, Blinded Endpoint Analysis"
  • Matsumoto et al - Abstract from ISSFAL meeting in Cairns Australia, 2006 – "Oral Administration of Eicosapentaenoic Acid Reduces and Stabilizes Atherosclerotic Lesions Through Lipid Lowering Independent Mechanism in APO E-Deficient Mice"
  • 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"
  • Datamonitor Market Dynamics: Anti-dyslipidemics, Nov 2002
  • Archives of Internal Medicine, 2009;169(6):572-578