AMRN Amarin Corp PLC

JAMA Network Open has published “Cost-effectiveness of Icosapent Ethyl for High-risk Patients With Hypertriglyceridemia Despite Statin Treatment,”1 which evaluated the more than 8,000 patients recruited to participate in the REDUCE-IT® (Reduction of Cardiovascular Events with Icosapent-Ethyl Intervention Trial) clinical trial. REDUCE-IT was a global cardiovascular outcomes study designed to assess the cardioprotective efficacy and safety of VASCEPA® (icosapent ethyl) as an add-on to statin therapy in reducing major cardiovascular events in a high-risk patient population.2 The evaluation found that icosapent ethyl (IPE) yielded more quality-adjusted life years (QALYs) than standard care both within the trial period and over a lifetime projection.

The design of this evaluation included an in-trial cost-effectiveness analysis using patient-level study data from REDUCE-IT, as well as a lifetime analysis using a microsimulation model and data from published literature. The modeling efforts employed in the analysis utilized patient-level data, which is a more detailed and rigorous approach than typical cost-effectiveness analyses where many assumptions and data from literature are utilized. The lifetime analysis required modeling to estimate survival, event rates, adherence, and costs; there is considerable uncertainty to these values beyond the trial period, although the model performed well compared with the 4.9-year follow-up available. The analyses were performed from a U.S. healthcare sector perspective.

The evaluation looked at the 8,179 patients with hypertriglyceridemia despite stable statin therapy who were recruited between 2011 and 2018 for the REDUCE-IT clinical trial. Patients were randomized to IPE (4 grams per day) plus a statin or placebo plus a statin and followed a median of 4.9 years. The costs utilized for IPE in the model included a publicly available SSR Health net cost of $4.16 per day after rebates, and the wholesale acquisition cost of $9.28 per day. The evaluation was intended to measure incremental QALYs, total direct healthcare costs (2019 USD), and cost-effectiveness. The costs used in the study are from the U.S. healthcare system and cannot be directly applied to other countries.

“What this study shows us is that for high-risk patients – despite statin treatment – icosapent ethyl is cost-effective at commonly accepted willingness-to-pay thresholds,” said lead author William S. Weintraub, MD, of the MedStar Health Research Institute at the MedStar Washington (DC) Hospital Center. “A telling additional finding was that the outcomes data for total events – first and subsequent – significantly favor IPE compared with standard of care for cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, revascularization, and unstable angina.”

This recent JAMA Network Open paper adds to the body of knowledge citing the safety, effectiveness, and cost-effectiveness/value of VASCEPA in the US market.3 In 2019, a study reported by the Institute for Clinical and Economic Review (ICER) – an independent non-profit organization that seeks to improve healthcare value by providing comprehensive clinical and cost-effectiveness analyses of treatments, tests, and procedures – reported that IPE is cost-effective in high-risk populations.4   VASCEPA has also been added to 26 global guidelines, scientific or consensus statements to reduce atherosclerotic cardiovascular disease risk in the population studied in REDUCE-IT.5

“Given the demonstrated efficacy of IPE in high-risk statin-treated patients that originally came out of the REDUCE-IT trial, this analysis in JAMA Network Open gives further support that VASCEPA is a significant addition to our armamentarium against cardiovascular disease, and we are proud to have priced VASCEPA to be cost-effective at commonly accepted willingness-to-pay thresholds,” said Steven Ketchum, PhD, EVP, Chief Scientific Officer and President, Research & Development at Amarin.

About Amarin Amarin is an innovative pharmaceutical company leading a new paradigm in cardiovascular disease management. From our foundation in scientific research to our focus on clinical trials, and now our commercial expansion, we are evolving and growing rapidly. Amarin has offices in Bridgewater, New Jersey in the United States, Dublin in Ireland, Zug in Switzerland, and other countries in Europe as well as commercial partners and suppliers around the world. We are committed to increasing the scientific understanding of the cardiovascular risk that persists beyond traditional therapies and advancing the treatment of that risk.

About Cardiovascular Risk Cardiovascular disease is the number one cause of death in the world. In the United States alone, cardiovascular disease results in 859,000 deaths per year6 and the number of deaths in the United States attributed to cardiovascular disease continues to rise. In addition, in the United States there are 605,000 new and 200,000 recurrent heart attacks per year (approximately 1 every 40 seconds). Stroke rates are 795,000 per year (approximately 1 every 40 seconds), accounting for 1 of every 19 U.S. deaths. In aggregate, in the United States alone, there are more than 2.4 million major adverse cardiovascular events per year from cardiovascular disease or, on average, 1 every 13 seconds. Controlling bad cholesterol, also known as LDL-C, is one way to reduce a patient’s risk for cardiovascular events, such as heart attack, stroke or death. However, even with the achievement of target LDL-C levels, millions of patients still have significant and persistent risk of cardiovascular events, especially those patients with elevated triglycerides. Statin therapy has been shown to control LDL-C, thereby reducing the risk of cardiovascular events by 25-35%.7 Significant cardiovascular risk remains after statin therapy. People with elevated triglycerides have 35% more cardiovascular events compared to people with normal (in range) triglycerides taking statins.8,9,10

About REDUCE-IT® REDUCE-IT was a global cardiovascular outcomes study designed to evaluate the effect of VASCEPA in adult patients with LDL-C controlled to between 41-100 mg/dL (median baseline 75 mg/dL) by statin therapy and various cardiovascular risk factors including persistent elevated triglycerides between 135-499 mg/dL (median baseline 216 mg/dL) and either established cardiovascular disease (secondary prevention cohort) or diabetes mellitus and at least one other cardiovascular risk factor (primary prevention cohort). REDUCE-IT, conducted over seven years and completed in 2018, followed 8,179 patients at over 400 clinical sites in 11 countries with the largest number of sites located within the United States. REDUCE-IT was conducted based on a special protocol assessment agreement with FDA. The design of the REDUCE-IT study was published in March 2017 in Clinical Cardiology.11 The primary results of REDUCE-IT were published in The New England Journal of Medicine in November 2018.12 The total events results of REDUCE-IT were published in the Journal of the American College of Cardiology in March 2019.13 These and other publications can be found in the R&D section on the company’s website at www.amarincorp.com.

About VASCEPA® (icosapent ethyl) CapsulesVASCEPA (icosapent ethyl) capsules are the first-and-only prescription treatment approved by the U.S. Food and Drug Administration (FDA) comprised solely of the active ingredient, icosapent ethyl (IPE), a unique form of eicosapentaenoic acid. VASCEPA was launched in the United States in January 2020 as the first and only drug approved by the U.S. FDA for treatment of the studied high-risk patients with persistent cardiovascular risk after statin therapy. VASCEPA was initially launched in the United States in 2013 based on the drug’s initial FDA approved indication for use as an adjunct therapy to diet to reduce triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. Since launch, VASCEPA has been prescribed over ten million times. VASCEPA is covered by most major medical insurance plans. In addition to the United States, VASCEPA is approved and sold in Canada, Lebanon and the United Arab Emirates. In Europe, in March 2021 marketing authorization was granted to icosapent ethyl in the European Union for the reduction of risk of cardiovascular events in patients at high cardiovascular risk, under the brand name VAZKEPA.

Indications and Limitation of Use (in the United States)

VASCEPA is indicated:

• As an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization and unstable angina requiring hospitalization in adult patients with elevated triglyceride (TG) levels (≥ 150 mg/dL) and
  • established cardiovascular disease or
  • diabetes mellitus and two or more additional risk factors for cardiovascular disease.
• As an adjunct to diet to reduce TG levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.

The effect of VASCEPA on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.

Important Safety Information

• VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components.
• VASCEPA was associated with an increased risk (3% vs 2%) of atrial fibrillation or atrial flutter requiring hospitalization in a double-blind, placebo-controlled trial. The incidence of atrial fibrillation was greater in patients with a previous history of atrial fibrillation or atrial flutter.
• It is not known whether patients with allergies to fish and/or shellfish are at an increased risk of an allergic reaction to VASCEPA. Patients with such allergies should discontinue VASCEPA if any reactions occur.
• VASCEPA was associated with an increased risk (12% vs 10%) of bleeding in a double-blind, placebo-controlled trial. The incidence of bleeding was greater in patients receiving concomitant antithrombotic medications, such as aspirin, clopidogrel or warfarin.
• Common adverse reactions in the cardiovascular outcomes trial (incidence ≥3% and ≥1% more frequent than placebo): musculoskeletal pain (4% vs 3%), peripheral edema (7% vs 5%), constipation (5% vs 4%), gout (4% vs 3%), and atrial fibrillation (5% vs 4%).
• Common adverse reactions in the hypertriglyceridemia trials (incidence >1% more frequent than placebo): arthralgia (2% vs 1%) and oropharyngeal pain (1% vs 0.3%).
• Adverse events may be reported by calling 1-855-VASCEPA or the FDA at 1-800-FDA-1088.
• Patients receiving VASCEPA and concomitant anticoagulants and/or anti-platelet agents should be monitored for bleeding.

Key clinical effects of VASCEPA on major adverse cardiovascular events are included in the Clinical Studies section of the prescribing information for VASCEPA as set forth below:

Effect of VASCEPA on Time to First Occurrence of Cardiovascular Events in Patients with Elevated Triglyceride levels and Other Risk Factors for Cardiovascular Disease in REDUCE-IT

	VASCEPA		Placebo		VASCEPA vs Placebo
	N = 4089n (%)	Incidence Rate (per 100 patient years)	N = 4090n (%)	Incidence Rate (per 100 patient years)	Hazard Ratio (95% CI)
Primary composite endpoint
Cardiovascular death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina (5-point MACE)	705(17.2)	4.3	901(22.0)	5.7	0.75(0.68, 0.83)
Key secondary composite endpoint
Cardiovascular death, myocardial infarction, stroke (3-point MACE)	459(11.2)	2.7	606(14.8)	3.7	0.74(0.65, 0.83)
Other secondary endpoints
Fatal or non-fatal myocardial infarction	250(6.1)	1.5	355(8.7)	2.1	0.69(0.58, 0.81)
Emergent or urgent coronary revascularization	216(5.3)	1.3	321(7.8)	1.9	0.65(0.55, 0.78)
Cardiovascular death [1]	174(4.3)	1.0	213(5.2)	1.2	0.80(0.66, 0.98)
Hospitalization for unstable angina [2]	108(2.6)	0.6	157(3.8)	0.9	0.68(0.53, 0.87)
Fatal or non-fatal stroke	98(2.4)	0.6	134(3.3)	0.8	0.72(0.55, 0.93)
[1] Includes adjudicated cardiovascular deaths and deaths of undetermined causality.[2] Determined to be caused by myocardial ischemia by invasive/non-invasive testing and requiring emergent hospitalization.

FULL U.S. FDA-APPROVED VASCEPA PRESCRIBING INFORMATION CAN BE FOUND AT WWW.VASCEPA.COM.

Forward-Looking StatementsThis press release contains forward-looking statements which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including beliefs about the world-wide market potential for VASCEPA (marketed as VAZKEPA in Europe); beliefs that Amarin has the unique opportunity to lead a new paradigm in cardiovascular disease management worldwide and beliefs about the safety, effectiveness and cost effectiveness of VASCEPA. These forward-looking statements are not promises or guarantees and involve substantial risks and uncertainties. Amarin's ability to effectively commercialize VASCEPA and maintain or grow market share will depend in part on Amarin’s ability to continue to effectively finance its business, VASCEPA approval in geographies outside the U.S., efforts of third parties, Amarin’s ability to create and increase market demand for VASCEPA through education, marketing and sales activities, to achieve broad market acceptance of VASCEPA, to receive adequate levels of reimbursement from third-party payers, to develop and maintain a consistent source of commercial supply at a competitive price, to comply with legal and regulatory requirements in connection with the sale and promotion of VASCEPA and to secure, maintain and defend its patent protection for VASCEPA. Among the factors that could cause actual results to differ materially from those described or projected herein include the following: the possibility that VASCEPA may not receive regulatory approval in geographies on expected timelines or at all, the risk that additional generic versions of VASCEPA will enter the market and that generic versions of VASCEPA will achieve greater market share and more commercial supply than anticipated; the risk that the scope and duration of the COVID-19 pandemic will continue to impact access to and sales of VASCEPA; the risk that Amarin has overestimated the market potential for VASCEPA in the U.S., Europe and other geographies; risks associated with Amarin's expanded enterprise; uncertainties associated generally with research and development, clinical trials and related regulatory approvals; the risk that sales may not meet expectations and related cost may increase beyond expectations; the risk that patents may be determined to not be infringed or not be valid in patent litigation and applications may not result in issued patents sufficient to protect the VASCEPA franchise. A further list and description of these risks, uncertainties and other risks associated with an investment in Amarin can be found in Amarin's filings with the U.S. Securities and Exchange Commission, including Amarin’s quarterly report on Form 10-Q for the quarter ended September 30, 2021. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. Amarin undertakes no obligation to update or revise the information contained in its forward-looking statements, whether as a result of new information, future events or circumstances or otherwise. Amarin’s forward-looking statements do not reflect the potential impact of significant transactions the company may enter into, such as mergers, acquisitions, dispositions, joint ventures or any material agreements that Amarin may enter into, amend or terminate. Availability of Other Information About Amarin communicates with its investors and the public using the company website (www.amarincorp.com) and the investor relations website (investor.amarincorp.com), including but not limited to investor presentations and FAQs, Securities and Exchange Commission filings, press releases, public conference calls and webcasts. The information that Amarin posts on these channels and websites could be deemed to be material information. As a result, Amarin encourages investors, the media and others interested in Amarin to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Amarin’s investor relations website and may include social media channels. The contents of Amarin’s website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

Amarin Contact Information

Investor Inquiries: Investor Relations Amarin Corporation plc In U.S.: +1 (908) 719-1315 IR@amarincorp.com (investor inquiries)

Solebury Trout In U.S.: +1 (646) 378-2992 amarinir@troutgroup.com

Media Inquiries: Communications Amarin Corporation plc In U.S.: +1 (908) 892-2028 PR@amarincorp.com (media inquiries)

1 JAMA Netw Open. 2022;5(2):e2148172. doi:10.1001/jamanetworkopen.2021.48172 (accessed February 15, 2022 at https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2789004)2 Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med 2019;380:11-22.3 William S Weintraub, MedStar Washington Hosp Ctr, Washington, DC; Deepak L Bhatt, Brigham and Women's Hosp, Boston, MA; Zugui Zhang, Christiana Care Health System, Newark, DE et al., Cost-Effectiveness of Icosapent Ethyl in REDUCE-IT. Presented at American Heart Association 2019 Scientific Sessions (November 2019).4 https://icer.org/wp-content/uploads/2020/10/ICER_CVD_Final_Evidence_Report_101719_.pdf5 https://investor.amarincorp.com/static-files/cd8eef19-197e-4114-8612-e0ab7498301e (slide 10)6 American Heart Association. Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association. Circulation. 2020;141:e139-e596.7 Ganda OP, Bhatt DL, Mason RP, et al. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management. J Am Coll Cardiol. 2018;72(3):330-343.8 Budoff M. Triglycerides and triglyceride-rich lipoproteins in the causal pathway of cardiovascular disease. Am J Cardiol. 2016;118:138-145.9 Toth PP, Granowitz C, Hull M, et al. High triglycerides are associated with increased cardiovascular events, medical costs, and resource use: A real-world administrative claims analysis of statin-treated patients with high residual cardiovascular risk. J Am Heart Assoc. 2018;7(15):e008740.10 Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease - New insights from epidemiology, genetics, and biology. Circ Res. 2016;118:547-563.11 Bhatt DL, Steg PG, Brinton E, et al., on behalf of the REDUCE-IT Investigators. Rationale and Design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial. Clin Cardiol. 2017;40:138-148.12 Bhatt DL, Steg PG, Miller M, et al., on behalf of the REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380:11-22.13 Bhatt DL, Steg PG, Miller M, et al., on behalf of the REDUCE-IT Investigators. Reduction in first and total ischemic events with icosapent ethyl across baseline triglyceride tertiles. J Am Coll Cardiol. 2019;74:1159-1161.