The MARINE trial

IMPORTANT SAFETY INFORMATION FOR VASCEPA

• VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components
• Use with caution in patients with known hypersensitivity to fish and/or shellfish
• In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy
• The most common reported adverse reaction (incidence >2% and greater than placebo) was arthralgia (2.3% VASCEPA, 1.0% placebo)
• Adverse events may be reported by calling 1-855-VASCEPA or the FDA at 1-800-FDA-1088
• Patients receiving treatment with VASCEPA and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically
• Patients should be advised to swallow VASCEPA capsules whole; not to break open, crush, dissolve, or chew VASCEPA

Please see full Prescribing Information for more information on VASCEPA.

IMPORTANT INFORMATION FOR HCPs ABOUT VASCEPA AS AN ADD-ON TO STATINS IN PATIENTS WITH HIGH (200-499 mg/dL) TG LEVELS

• Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease. VASCEPA should not be taken in place of a healthy diet and lifestyle or statin therapy
• The ANCHOR trial demonstrates that VASCEPA lowers TG levels in patients with high (≥200 mg/dL and <500 mg/dL) TG levels not controlled by diet and statin therapy
• In the ANCHOR trial, VASCEPA 4 g/day significantly reduced TG, non-HDL-C, Apo B, VLDL-C, TC, and HDL-C levels from baseline relative to placebo in patients with high (≥200 mg/dL and <500 mg/dL) TG levels not controlled by diet and statin therapy
• The reduction in TG observed with VASCEPA was not associated with elevations in LDL-C relative to placebo
• VASCEPA is not FDA-approved for the treatment of statin-treated patients with mixed dyslipidemia and high (≥200 mg/dL and <500 mg/dL) TG levels due to current uncertainty regarding the benefit, if any, of drug-induced changes in lipid/lipoprotein parameters beyond statin-lowered LDL-C on cardiovascular risk among statin-treated patients with residually high TG. No prospective study has been conducted to test and support what, if any, benefit exists
• Recent cardiovascular outcomes trials (ACCORD Lipid, AIM-HIGH, and HPS2-THRIVE), while not designed to test the effect of lowering TG levels in patients with high TG levels after statin therapy, each failed to demonstrate incremental cardiovascular benefit of adding a second lipid-altering drug (fenofibrate or formulations of niacin), despite raising HDL-C and reducing TG levels, among statin-treated patients with well-controlled LDL-C
• VASCEPA is not FDA-approved to reduce the risk of coronary heart disease
• The effect of VASCEPA on the risk of cardiovascular mortality and morbidity has not been determined
• A cardiovascular outcomes study of VASCEPA designed to evaluate the efficacy of VASCEPA in reducing cardiovascular mortality and morbidity in a high-risk patient population on statin therapy is currently underway (REDUCE-IT)
• VASCEPA may not be eligible for reimbursement under government healthcare programs (such as Medicare and Medicaid) to reduce the risk of coronary heart disease or for treatment of statin-treated patients with mixed dyslipidemia and high (≥200 mg/dL and <500 mg/dL) TG levels. We encourage you to check that for yourself
• The ANCHOR trial was sponsored by Amarin Pharma, Inc. and its affiliates

Results from the ANCHOR study^1,3

Co-administration therapy with statins for additional lipid management in mixed dyslipidemia

• The effects of VASCEPA as add-on therapy to treatment with statins were evaluated in a randomized, placebo-controlled, double-blind, parallel-group study of 453 adult patients (226 receiving VASCEPA and 227 receiving placebo) with persistent high triglyceride levels (≥200 mg/dL and <500 mg/dL) despite statin therapy
• All patients were receiving statin therapy (atorvastatin, rosuvastatin, or simvastatin) and were treated to LDL-C goal prior to randomization
• Patients were randomized to either VASCEPA or placebo and treated for 12 weeks with statin co-therapy
• The same statin at the same dose was continued throughout the study
• The median baseline TG and LDL-C levels in these patients were 259 mg/dL and 83 mg/dL, respectively
• The randomized population in this study was mostly Caucasian (96%) and male (61%)
• The mean age was 61 years and the mean body mass index was 33 kg/m²
• Seventy-three percent (73%) of patients had diabetes at baseline

Response to the addition of VASCEPA to ongoing statin therapy in patients with high triglyceride levels (≥200 mg/dL and <500 mg/dL)

The changes in the major lipoprotein lipid parameters for the groups receiving VASCEPA plus statin or placebo plus statin are shown in the table.

(Data reviewed and confirmed by the FDA—indication not approved by the FDA)

Important Information for Healthcare Professionals on Inflammatory Markers^3,4

• The effect of VASCEPA on inflammatory biomarkers
  • The ANCHOR and MARINE trials assessed the effect of VASCEPA 4 grams/day (g/d) on the pre-specified inflammatory markers Lp-PLA₂, hsCRP, Ox-LDL, ICAM-1, and IL-6 (see tables below)
    • With the exception of Lp-PLA₂, a secondary endpoint, all of the other inflammatory markers were exploratory endpoints
  • In the ANCHOR and MARINE trials, VASCEPA 4 g/d significantly reduced Lp-PLA₂ and hsCRP levels from baseline relative to placebo in each of the respective groups of patients with hypertriglyceridemia studied. In the ANCHOR trial, VASCEPA 4 g/d significantly reduced Ox-LDL levels from baseline relative to placebo
    • In the ANCHOR trial,
      • Lp-PLA₂ and hsCRP were measured in ≥93% of randomized patients
      • ICAM-1, Ox-LDL, and IL-6 were measured in the first 240 of 702 (34.2%) of randomized patients (or approximately 80 patients per each of the three treatment arms)
    • In the MARINE trial, inflammatory markers were measured in ≥183 of 229 (≥80%) of randomized patients (or ≥60 patients per each of the three treatment arms)
    • hsCRP is an acute-phase reactant and has high intra-individual variability
      • Therefore, a single test for hsCRP, as was performed at each timepoint of the ANCHOR and MARINE trials, may not accurately reflect an individual patient’s basal or on-treatment hsCRP levels
      • Repeat measurement may be required to firmly establish an individual’s basal hsCRP concentration, as well as to accurately understand treatment-induced changes in hsCRP

ANCHOR Inflammatory Markers: Response to the Addition of VASCEPA to Ongoing Statin Therapy in Patients with High Triglyceride Levels (≥200 mg/dL and <500 mg/dL)

MARINE Inflammatory Markers: Response to the Addition of VASCEPA in Patients with Very High Triglyceride Levels (≥500 mg/dL and ≤2000 mg/dL)

This information on inflammatory markers cannot be used in isolation. Please see additional information on the ANCHOR study above and inflammatory markers below.

• Supportive, but not conclusive, data show that reducing inflammatory biomarkers may also reduce CV events with agents other than VASCEPA, but further trials are needed [Ridker et al., NEJM 2008; Nidorf et al., JACC 2013; Martinez et al., JAHA 2015; Ridker et al., NEJM 2017; Harrington, NEJM 2017]
• Limitations of featured data
  • VASCEPA is not FDA-approved to reduce the inflammatory biomarkers discussed in this document
  • The effects of VASCEPA on inflammatory biomarkers have not been approved for inclusion in FDA-approved labeling of VASCEPA
  • Additional trials are needed to evaluate the CV benefit, if any, of reducing inflammatory biomarkers with VASCEPA
    • Despite the putative cardio-protective effects reported in earlier literature for niacin on markers including C-reactive protein (CRP), Lp-PLA₂, and other inflammatory biomarkers, a beneficial effect on major adverse cardiovascular events (MACE) was not observed for niacin in the AIM-HIGH and HPS2-THRIVE trials when studied in patients with well controlled LDL-C levels on statin therapy. Therefore, a non-statin lipid altering drug effect on such inflammatory biomarkers may not translate into a reduced risk for MACE when used in combination with statin therapy
    • Lp-PLA₂ has been evaluated in two large CV outcome trials with an investigational agent that inhibits Lp-PLA₂ activity. One study showed no impact on CV events in patients hospitalized for acute coronary syndrome [O’Donoghue et al., JAMA 2014]. The other study showed no impact on CV events in patients with chronic coronary disease (prior myocardial infarction, prior revascularization, or multivessel coronary disease) [STABILITY Investigators, NEJM 2014]. Additionally, a genetic study found that variants that reduce Lp-PLA₂ activity to a degree similar to activity associated with darapladib, an Lp-PLA₂ inhibitor, had no effect on the risk of coronary heart disease [Polfus et al., NEJM 2015]
    • hsCRP was evaluated in a CV outcomes trial that demonstrated that high-intensity statin therapy reduced CV risk in individuals with hsCRP ≥2.0 mg/L, LDL-C <130 mg/dL, and one additional CV risk factor, however, the study was not designed to evaluate whether statin therapy would still reduce atherosclerotic cardiovascular disease (ASCVD) risk in individuals with CRP <2.0 mg/L and the same 10-year cardiovascular risk [Ridker et al., NEJM 2008; Stone et al., Circulation 2014]. Additionally, this CV outcomes trial, called Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), was not designed to evaluate whether treatment guided by risk based on hsCRP levels would improve health outcomes [Stone et al., Circulation 2014]. Statins are likely to provide benefit without regard to elevated hsCRP levels [Yousuf et al., JACC 2013]
      • It is unclear to what degree hsCRP reduction contributed to the results from the JUPITER trial
      • It is unknown whether results similar to those from the JUPITER trial could be achieved with other statins or with adjuncts to statin therapy
      • JUPITER did not use any adjuncts to statin therapy to reduce lipids or inflammatory biomarkers
      • JUPITER was not a study of patients with high median triglyceride levels (≥200 mg/dL) at baseline
    • Both hsCRP and IL-6 were evaluated in the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial with the use of canakinumab, a monoclonal antibody that neutralizes IL-1β, as secondary prevention in patients (N=10,061) with a previous myocardial infarction and an elevated level of hsCRP [Ridker et al., NEJM 2017]. Over 90% of patients also received statin therapy. The effect of VASCEPA, if any, on IL-1β has not been studied
      • The CANTOS trial did show a CV relative risk reduction (15%) in patients with a prior myocardial infarction and an hsCRP level of 2 mg/L with the 150-mg dose, but not with the other doses studied
      • In CANTOS, at 48 months, there were no significant reductions from baseline in LDL-C or HDL-C and a 4%-5% median increase in TGs from baseline
    • CRP evaluation in animal data and human genetic data indicate a lack of causal relationship with coronary heart disease [Yousuf et al., JACC 2013]
    • Reductions in Ox-LDL, ICAM-1, and IL-6 have not been repeatedly studied to examine effects, if any, on cardiovascular event reduction in prospectively designed, large, randomized, placebo-controlled cardiovascular outcomes trials. Additional studies are needed

JELIS: Important Information for Healthcare Professionals Considering Co-administration Therapy with Statins for Additional Lipid Management in Mixed Dyslipidemia

The publications, the study and sub-analyses, and the study sponsor

• Yokoyama et al. 2007: The primary publication presenting the results of a long-term cardiovascular outcomes study of a highly purified eicosapentaenoic acid (EPA) product coadministered with statin therapy in 18,645 Japanese patients, the Japan EPA lipid intervention study (JELIS). JELIS was a prospective, randomized, open-label trial with blinded endpoint evaluation (PROBE design)⁵
• Saito et al. 2008: A prespecified JELIS primary prevention sub-analysis that assessed, among other things, the differences in coronary artery disease (CAD) incidences in patients with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels⁶
• Matsuzaki et al. 2009: An additional JELIS sub-analysis that assessed the incidence of secondary major cardiovascular events in patients with established CAD⁷

JELIS was supported by grants from the manufacturer of the product, Mochida Pharmaceutical Co Ltd, Tokyo, Japan.

The product studied in JELIS and VASCEPA^® (icosapent ethyl) capsules

The product studied in JELIS and VASCEPA, are highly similar based on a US Food and Drug Administration (FDA) review of both a comprehensive analytical comparison and published reports on each product’s content. Each product is highly purified EPA. The product studied in JELIS is not available in the United States.

The highly purified EPA studied in JELIS was administered at 1.8 grams/day (g/d). VASCEPA at 4 g/d is an FDA-approved product indicated for a different use than that investigated in JELIS (see VASCEPA (icosapent ethyl) Indication and Limitations of Use above). The effect of VASCEPA on cardiovascular mortality and morbidity has not been determined. VASCEPA 4 g/d is under clinical investigation to evaluate its potential in reducing cardiovascular mortality and morbidity in a combined primary and secondary prevention (high-risk) patient population receiving statin therapy (see Ongoing cardiovascular outcomes study of VASCEPA in statin-treated patients below).

Important Information for healthcare professionals about JELIS

• JELIS provides supportive but not conclusive data that EPA drug therapy may reduce major coronary events
  • JELIS reached its primary endpoint in the combined primary and secondary prevention population showing a 19% relative risk reduction in major coronary events in statin-treated patients with hypercholesterolemia in Japan
    • Major coronary events included sudden cardiac death, fatal and nonfatal myocardial infarction, and other nonfatal events, including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting
  • The main component contributing to the primary endpoint results in JELIS summarized herein was unstable angina involving hospital treatment, which is a more subjective endpoint result than, for example, objective major adverse cardiovascular event endpoints (e.g., heart attack, stroke, or cardiovascular death)
    • A subjective endpoint, such as unstable angina, may be particularly unreliable in an open-label trial, such as JELIS, where patients and healthcare professionals are making decisions regarding hospitalizations
• JELIS results cannot be generalized to other populations
  • Subjects in JELIS were limited to Japanese adults
    • The average dietary intake of fish in Japan is about 5 times higher than that in other countries
    • Baseline blood EPA levels in JELIS before pharmacotherapy with 1.8 g/d of EPA were higher than those recorded in the US population
  • Subjects in JELIS received a low dose of statin therapy based on then-current Japanese treatment guidelines that may be considered inadequate under current guidelines in the United States
• FDA determined that JELIS results could not be used as support for or against the use of TG levels as a surrogate for cardiovascular risk reduction
  • In the primary endpoint analysis, median baseline TG levels were not high (153 mg/dL [1.73 mmol/L])
    • Assessment of the TG-lowering benefits of EPA therapy in JELIS is complicated by the small number of subjects with high median TG levels (≥200 mg/dL) at baseline prior to statin treatment
      • A statin run-in or stabilization period prior to randomization to EPA would have likely further reduced the baseline median TG level
  • Patients treated with EPA and statin in JELIS achieved TG levels that were only 5% lower, on average, than those achieved among patients treated with statin alone; however, the reduction in cardiovascular risk in the primary endpoint analysis was 19% [Yokoyama]
    • Likewise, within the primary and secondary prevention sub-analyses, TG levels were lowered only 5% on average in the EPA plus statin group compared with the statin alone group; however, the relative risk reduction was
      • 53% in the primary prevention population with elevated TG and low HDL-C levels [Saito]
      • 23% in the secondary prevention population with established CAD [Matsuzaki]
  • These large differences in magnitude between TG reduction and risk reduction in JELIS suggest that the effects of EPA on TG levels alone may not be responsible for, or predict, the observed differences in cardiovascular events between treatment groups in JELIS
  • A nonstatin lipid-altering drug’s effects on biomarkers may not translate into a reduced cardiovascular risk when used in combination with statin therapy (see Important Information for HCPs about VASCEPA as an add-on to statins in patients with high [200-499 mg/dL] TG levels)
• It is possible that the putative cardioprotective effects of EPA observed in JELIS are due not to a single mode of action, such as TG lowering, but rather to multiple mechanisms working together
  • EPA may have beneficial effects on multiple atherosclerosis processes, including endothelial function, oxidative stress, foam cell formation, inflammation/cytokines, plaque formation/progression, platelet aggregation, thrombus formation, and plaque rupture⁸
  • Further study is needed to determine the clinical benefit, if any, of EPA therapy in statin-treated patients with elevated TG levels (see Ongoing cardiovascular outcomes study of VASCEPA in statin-treated patients below)
• Limitations of subpopulation analyses
  • JELIS reached its primary endpoint in the combined primary and secondary prevention population
  • JELIS was not powered to evaluate primary and secondary prevention populations individually or those explored in the Saito and Matsuzaki publications

Major coronary events: JELIS and sub-analyses

Adapted from Yokoyama et al, Figure 3: Estimated hazard ratios of clinical endpoints stratified by prevention stratum; Saito et al, Figure 3: Effects of EPA on the incidence of MCE for the high TG/low HDL-C group; Matsuzaki et al, Figure 2a: Kaplan-Meier estimates of the incidence of the primary endpoint of coronary events occurring in the group of all patients.

• Safety findings from JELIS
  • Gastrointestinal disturbances (3.8% on EPA + statin and 1.7% on statin alone; P<0.0001)
  • Skin abnormalities (1.7% on EPA + statin and 0.7% on statin alone; P<0.0001)
  • Hemorrhage (1.1% on EPA + statin and 0.6% on statin alone; P=0.0006)
    • No between-group differences in stroke, including cerebral and/or subarachnoid hemorrhage
  • Abnormal laboratory data (slight excess of aspartate aminotransferase (AST) elevations, 0.6% on EPA + statin and 0.4% on statin alone; P=0.03)
• The rate of discontinuation due to treatment-related adverse effects was 11.7% in the EPA group and 7.2% in the control group

Other cardiovascular outcomes trials in the omega-3 class have reported negligible impact on cardiovascular events

JELIS is the only cardiovascular outcomes trial that has examined the effects of EPA (1.8 g/d) plus statin vs statin alone. The 12-week end-of-treatment blood levels after 4 g/d of EPA in an American population achieved approximately the same end-of-treatment blood levels of EPA observed in the Japanese population studied in JELIS.⁹ The clinical relevance of EPA blood levels on cardiovascular outcomes has not been determined.

Following JELIS and GISSI-P (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico-Prevenzione),¹⁰ randomized placebo-controlled trials have failed to confirm definitive cardiovascular benefit with similarly low (<2 g/d) doses of omega-3 fatty acid mixtures. GISSI-P is an open-label outcomes trial (1 g omega-3 fatty acid mixture), conducted in Italy, that supported the hypothesis that omega-3 fatty acids likely exert their cardioprotective effects through nonlipid-mediated mechanisms. But, in GISSI-P, only ≈5% of patients were receiving statins at baseline compared with >40%-50% in more recent, similarly low-dose omega-3 trials that failed to confirm benefit. GISSI-P did not suggest an effect on the incidence of nonfatal cardiovascular events and the effects of omega-3 fatty acids on lipids, including serum TGs, were negligible.

The omega-3 fatty acid mixtures studied in such other outcomes trials were primarily comprised of EPA and docosahexaenoic acid (DHA) (typically, approximately 900 mg total per 1 gram capsule) and also typically included a number of other omega-3 and omega-6 acids, as well as other constituents. No head-to-head cardiovascular outcomes study of EPA vs a mixture of omega-3 acids has been conducted. No cardiovascular outcomes trial has been completed with sufficient power to prospectively evaluate the effect of EPA or omega-3 fatty acid mixtures in statin-treated patients, either with high TG levels (≥200 mg/dL) or with both high TG and low HDL-C levels.

Ongoing cardiovascular outcomes study of VASCEPA in statin-treated patients

The encouraging results of JELIS contributed to the justification to investigate the potential of VASCEPA to reduce cardiovascular risk. A cardiovascular outcomes study of VASCEPA designed to evaluate the efficacy of 4 g/d of VASCEPA in reducing cardiovascular mortality and morbidity in a high-risk patient population on statin therapy is currently underway (REDUCE-IT). The sponsor of REDUCE-IT, Amarin Pharma, Inc., and the FDA are strongly aligned in recognizing the importance of continuing to collaborate to complete REDUCE-IT so that a definitive answer may be provided to answer the question of whether VASCEPA, in combination with a statin, results in reduction of cardiovascular risk over a statin alone.

Participants in the clinical investigation of VASCEPA currently underway (REDUCE-IT) should not be advised to use VASCEPA in place of participation in that study. VASCEPA should not be taken in place of a healthy diet and lifestyle or statin therapy.

VASCEPA may not be eligible for reimbursement under government healthcare programs (such as Medicare and Medicaid) to reduce the risk of coronary heart disease or for treatment of statin-treated patients with high (≥200 mg/dL and <500 mg/dL) TG levels. We encourage you to check that for yourself.

These publications are provided to you by Amarin Pharma, Inc., the manufacturer of VASCEPA.