ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE BRIEFING DOCUMENT Vascepa® (icosapent ethyl; AMR101) REDUCE-IT® (Reduction of Cardiovascular Events with EPA – Intervention Trial) NDA Number: 202057 Applicant: Amarin Pharmaceuticals Ireland Limited Date: 14 November 2019 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Amarin Pharmaceuticals Ireland Limited Advisory Committee Briefing Document 1 EXECUTIVE SUMMARY 1.1 Introduction Amarin Pharmaceuticals Ireland Limited (hereafter referred to as Amarin or the Sponsor) submitted a supplemental New Drug Application (sNDA) on 28 March 2019, providing results from the Reduction of Cardiovascular Events with EPA – Intervention Trial (REDUCE-IT) to extend the indicated use of Vascepa® (icosapent ethyl) to include the prevention of cardiovascular (CV) events in statin-treated patients with controlled (≤100 mg/dL) low-density lipoprotein cholesterol (LDL-C), but elevated (≥135 mg/dL) triglyceride (TG) levels and other cardiovascular disease (CVD) risk factors. REDUCE-IT was conducted under a United States (US) Food and Drug Administration (FDA) Special Protocol Assessment (SPA) agreement. Development, finalization and amendment of this SPA agreement included FDA input and agreement on critical study design features; regulatory scientific dialogue with FDA included such topics as prespecified endpoints, the statistical testing hierarchy as captured in the protocol and statistical analysis plan (SAP), and the selection of placebo. This briefing document outlines the key results from REDUCE-IT and provides background information for discussion of the trial results at the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting scheduled for 14 November 2019. This briefing document was prepared by Amarin prior to release of the FDA briefing book or the question(s) within. Accordingly, this briefing book also presents anticipated topics of interest for deeper review and discussion, including efficacy findings in the secondary prevention and high-risk primary prevention cohorts, safety findings for bleeding and atrial fibrillation/flutter, the lack of impact on study conclusions with the use of light liquid paraffin (mineral oil) as the placebo, and mechanisms of action for eicosapentaenoic acid (EPA; the active metabolite of icosapent ethyl) that likely contribute to the observed CV risk reduction. 1.2 Long-Standing Unmet Medical Need and Public Health Burden CVD remains the most common cause of morbidity and mortality in the US and globally, accounting for an estimated 31.5% (17 million) of all global deaths in 2013 (Roth 2017), despite increased use of statins and other therapies that target reduction of LDL-C. Public health and healthcare costs are burdened by the clinical need for treatments that effectively lower CV risk including in statin-treated patients well managed for other modifiable risk factors such as hypertension and hemoglobin A1c (HbA1c) who still remain at high risk for CVD events, and yet investment in the multi-year, multi-hundred million dollar outcomes trials that are required to demonstrate CV risk reduction have been rare. Failures outnumber successes while significant residual CV risk persists. Reducing CV events in at-risk patients beyond available therapies is a public health priority that likely contributed toward the current application being designated for priority review by the FDA. We must endeavor toward further reducing the impact of CV disease beyond the benefits observed with statin therapy. New hypotheses and strategies must be encouraged, and one such strategy is to identify markers of CV risk that persist in statin-treated patients, and to develop clinically meaningful adjunct therapies for these patients. As discussed below, epidemiologic, clinical, and 14 November 2019 2 Amarin Pharmaceuticals Ireland Limited Advisory Committee Briefing Document genetic studies support elevated TG levels despite controlled LDL-C on statin therapy as one such marker of risk, while TG as a modifiable risk factor has yet to be established. 1.3 Icosapent Ethyl Distinct Mechanisms of Action REDUCE-IT was designed to assess the clinical efficacy and safety of icosapent ethyl in statin- treated patients with elevated TG levels. REDUCE-IT was not designed to explore the mechanisms of action of Vascepa. Determination of the mechanisms of action for a given therapy is not required for regulatory approval of a drug indication. Nonetheless, a broad array of scientific literature has explored the mechanisms of action of EPA, and many of these mechanisms differ from other therapies, including individual or mixed omega-3 fatty acid products. The active ingredient of Vascepa, icosapent ethyl, was granted new chemical entity (NCE) status by FDA, with its single active molecule considered by the agency to be a different active ingredient than the previously approved, multiple-constituent, primarily omega-3, fatty acid product Lovaza® (omega-3 ethyl esters). Omega-3 fatty acids are prone to oxidation and can be readily damaged, therefore delivery in a stable and protected form such as icosapent ethyl is critical. The totality of evidence suggests that EPA may impact multiple stages along atherosclerotic processes, resulting in reduced development, slowed progression, and increased stabilization of atherosclerotic plaque. Importantly, while based on hypothesis-generating and/or post hoc analyses, achieving substantially increased blood EPA concentrations appears necessary for an observed CV benefit in statin-treated patients as observed in REDUCE-IT and other studies. 1.4 REDUCE-IT Trial Design and Population REDUCE-IT was a multi-national, prospective, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the effect of 4 g/day icosapent ethyl (2 g twice daily [BID]) for preventing CV events in statin-treated patients with controlled LDL-C (≤100 mg/dL), moderately elevated TG levels (≥135 mg/dL), and other CVD risk factors. Patients remained on statin therapy and were treated based on the standard of care by their individual clinicians regarding cholesterol, diabetes, blood pressure and other therapies. A REDUCE-IT protocol amendment was implemented midway through patient enrollment that raised the lower TG inclusion criterion limit for the remaining patient enrollment from 135 to 200 mg/dL to ensure substantial enrollment of patients with TG >200 mg/dL and the ability to explore efficacy in a range of elevated TG levels; all enrolled patients were followed for the duration of the study. All patients enrolled before and after the protocol amendment were maintained and followed per protocol. Complete inclusion criteria can be found in Appendix A. REDUCE-IT was designed as an event-driven study. Approximately 7990 patients were to be randomized in a 1:1 fashion to icosapent ethyl or placebo and followed until approximately 1612 first occurrences of primary endpoint events. Enrollment targeted a blend of 70% secondary prevention patients with established CVD (per protocol “CV Risk Category 1”) and 30% of primary prevention patients at high-risk for developing CVD (diabetes requiring medication and additional risk factor(s), per protocol “CV Risk Category 2”). Primary endpoint attainment in this mixed patient population was agreed with FDA to support the broad assessment of the utility of icosapent ethyl in at-risk patients within one composite primary endpoint. Randomization was stratified by CV risk category, use of ezetimibe (yes/no), and geographical region (Westernized, Eastern European, and Asia Pacific). The prespecified primary, secondary, tertiary, and 14 November 2019 3 Amarin Pharmaceuticals Ireland Limited Advisory Committee Briefing Document exploratory endpoints were adjudicated by an independent blinded Clinical Endpoint Committee (CEC); see Appendix B for further details of the endpoint adjudication process. A total of 8179 patients were randomized (4089 to icosapent ethyl; 4090 to placebo) and followed for a median of 4.9 years. Consistent with the design of the study, 70.7% were enrolled in the secondary prevention cohort, and 29.3% in the high-risk primary prevention cohort. Actual versus potential total follow-up time was 93.6% in the icosapent ethyl group and 92.9% in the placebo group. A total of 89.4% (7314/8179) of patients completed the final study visit or were reported as having a fatal event; 90.1% (3684/4089) in the icosapent ethyl group and 88.8% (3630/4090) in the placebo group. Vital status was known for 99.8% (8160/8179) of patients; 99.9% (4083/4089) and 99.7% (4077/4090) in the icosapent ethyl and placebo groups, respectively. Over 35,000 patient years of data was captured. Efficacy Results The primary endpoint was the time from randomization to the first occurrence of the composite of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina determined to be caused by myocardial ischemia by invasive/non-invasive testing and requiring emergent hospitalization. A primary endpoint event occurred in 17.2% (705/4089) of patients in the icosapent ethyl group as compared to 22.0% (901/4090) of patients in the placebo group (hazard ratio [HR] of 0.752 [95% confidence interval (CI): 0.682 to 0.830; p=0.00000001]; relative risk reduction [RRR] of 24.8%). The key secondary endpoint was the time from randomization to the first occurrence of the composite of CV death, nonfatal MI, or nonfatal stroke. A key secondary endpoint event occurred