Lipid Metabolism Disorders

– Olezarsen met the primary endpoint with statistically significant reduction of fasting triglycerides and showed substantial, clinically meaningful reduction in acute pancreatitis events – – Results demonstrate olezarsen may represent a novel treatment option for this rare, life-threatening disease, for which there are no approved treatments in the U.S. – – Data presented today at ACC 2024 and published in The New England Journal of Medicine – – Ionis to host webcast on Monday, April 8 at 10:00 am ET – CARLSBAD, Calif., April 7, 2024 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) today announced full results from the Phase 3 Balance study of Ionis' lead independent investigational medicine, olezarsen, for the treatment of adults with familial chylomicronemia syndrome (FCS). The olezarsen 80 mg monthly dose met the primary endpoint of significantly reducing triglycerides (TGs) in patients with genetically validated FCS at six months. In addition, olezarsen demonstrated robust and sustained reductions in TGs and serum apolipoprotein C-III (apoC-III) levels. Importantly, olezarsen reduced the incidence of acute pancreatitis (AP) events over the 12-month treatment period compared to placebo. Olezarsen also demonstrated a favorable safety and tolerability profile. These results were presented in an oral presentation at the 2024 American College of Cardiology (ACC) Annual Meeting in Atlanta, Georgia and published simultaneously in The New England Journal of Medicine (NEJM). Based on these data, Ionis is pursuing regulatory approval of olezarsen as a potential breakthrough treatment for adults with FCS. "As a physician who has seen first-hand the struggles of people living with FCS and its serious complications, there is significant need for an effective therapy to lower triglycerides and reduce acute pancreatitis events," said Erik Stroes, M.D., professor of medicine, Amsterdam University Medical Centers, and a principal investigator of the Balance study. "Olezarsen represents a potentially life-changing new medicine for these patients who experience debilitating chronic symptoms, including abdominal pain and cognitive symptoms, as well as hospitalizations associated with potentially fatal acute pancreatitis events." Balance Study Results In the study, patients were treated with olezarsen 80 mg (n=22), 50 mg (n=21) or placebo (n=23) once every four weeks. In the 80 mg group, olezarsen met the primary endpoint, with a statistically significant placebo-adjusted reduction in TG levels from baseline to six months (44%, p<0.001). Reductions from six to 12 months were sustained, with olezarsen 80 mg achieving a placebo-adjusted 59% reduction in TGs. ApoC-III placebo-adjusted reductions were robust and sustained at six and 12 months (74% and 81% reductions, respectively). In the 50 mg group, olezarsen reduced TG levels, however this difference was not statistically significant at six months compared to placebo (22%, p=0.078). Reductions from six to 12 months were improved, with olezarsen 50 mg achieving a placebo-adjusted 44% reduction in TGs. Olezarsen-treated patients had markedly fewer AP events during the 12-month period, compared to placebo. Eleven episodes of AP occurred in the placebo group versus one episode in the 80 mg olezarsen group and one episode in the 50 mg group. Furthermore, there was a substantially greater time to the first event with olezarsen compared to placebo (one year (80 mg) and 102 days (50 mg), vs. nine days for placebo). Olezarsen-treated patients experienced a placebo-adjusted 84% reduction in all-cause hospitalizations between baseline and 12 months. A favorable safety and tolerability profile was observed, with a higher number of treatment-emergent adverse events (TEAEs) in the placebo group. There were no serious TEAEs related to olezarsen. The most common AEs were COVID-19, abdominal pain and diarrhea, none of which were more frequent in patients treated with either dose of olezarsen versus placebo. Serious AEs occurred in 14% of patients treated with olezarsen 80 mg, 19% treated with olezarsen 50 mg, and 39% treated with placebo. "Balance is the first clinical study to validate the association of reduced triglyceride levels with reduced incidence of acute pancreatitis events in patients with severely elevated triglycerides. This important finding supports the potential for olezarsen to be the standard of care for patients with FCS, if approved. These data further strengthen our confidence for a successful outcome in the ongoing Phase 3 CORE studies evaluating olezarsen in the much more prevalent severe hypertriglyceridemia patient population," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "Our team looks forward to working closely with the FDA to advance the first potential treatment for FCS in the U.S., and to successfully delivering Ionis' first independent commercial launch later this year, assuming priority review. We offer our sincerest gratitude to the patients and investigators who participated in this pivotal study." The ACC Balance presentation can be found on Ionis' website after today's presentation at 10:08 am ET. In addition to the Balance data, a late-breaking abstract entitled, "Efficacy and Safety of Olezarsen in Patients with Hypertriglyceridemia and High Cardiovascular Risk: Primary Results of the Bridge-TIMI 73a Trial" was also presented at ACC and published in NEJM. Webcast Ionis will host a webcast to discuss the detailed results from the Balance study on Monday, April 8 at 10:00 am ET. Interested parties may access the webcast here. A webcast replay will be available for a limited time. About the Balance Study The global, multicenter, randomized, double-blind, placebo-controlled Phase 3 Balance study (NCT04568434) enrolled 66 patients aged 18 and older with confirmed FCS. Patients in the study received background therapies including statins, fibrates and omega-3 fatty acids. Patients were randomized in a 1:1:1 ratio to receive olezarsen 80 mg or 50 mg or placebo via subcutaneous injection once every four weeks for 53 weeks. The primary endpoint was the percent change from baseline in fasting triglyceride levels at six months compared to placebo. Secondary endpoints included percent changes in triglyceride levels at 12 months, percent changes in other lipid parameters, and adjudicated acute pancreatitis event rates over the treatment period. About Olezarsen Olezarsen is an RNA-targeted investigational LIgand Conjugated Antisense (LICA) medicine being evaluated for people at risk of disease due to elevated triglyceride levels, including those with familial chylomicronemia syndrome (FCS). Olezarsen is designed to inhibit the body's production of apoC-III, a protein produced in the liver that regulates triglyceride metabolism in the blood.1,2 The U.S. FDA granted olezarsen Fast Track designation for the treatment of FCS in January 2023, as well as Orphan Drug designation and Breakthrough Therapy designation in February 2024. In addition to FCS, Ionis is evaluating olezarsen for the treatment of severe hypertriglyceridemia (sHTG) in Phase 3 clinical trials. Olezarsen is an investigational medicine that has not been reviewed or approved for the treatment of any disease by any regulatory authority. About FCS FCS is a rare, genetic disease characterized by extremely elevated triglyceride levels. It is caused by impaired function of the enzyme lipoprotein lipase (LPL).3 Because of limited LPL production or function, people with FCS cannot effectively break down chylomicrons, lipoprotein particles that are 90% triglycerides.3,4 FCS is estimated to impact one to 13 people per million in the U.S.5,6,7 People living with FCS are at high risk of acute pancreatitis (AP) in addition to other chronic health issues such as fatigue and severe, recurrent abdominal pain.3,8,9 People living with FCS are sometimes unable to work, adding to the burden of disease.9 Currently, there are no U.S. FDA-approved therapies for the treatment of FCS and standard triglyceride lowering therapies are generally ineffective in patients with FCS.10,11 People living with this condition currently rely solely on nutrition management through extremely restrictive and difficult to manage diets to navigate the health risks associated with FCS.11,12 About Ionis Pharmaceuticals, Inc. For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has five marketed medicines and a leading pipeline in neurology, cardiology, and other areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit Ionispharma.com and follow us on X (Twitter) and LinkedIn. Forward-looking Statements This press release includes forward-looking statements regarding olezarsen, Ionis' business, and the therapeutic and commercial potential of Ionis' commercial medicines, additional medicines in development and technologies. Any statement describing Ionis' goals, expectations, financial or other projections, intentions, or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, including but not limited to those related to our commercial products and the medicines in our pipeline, and particularly those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended Dec. 31, 2023, and most recent Form 10-Q, which are on file with the SEC. Copies of these and other documents are available at . Ionis Pharmaceuticals® is a registered trademark of Ionis Pharmaceuticals, Inc. Ionis Pharmaceuticals Investor Contact: D. Wade Walke, Ph.D. - [email protected] - 760-603-2331; Ionis Pharmaceuticals Media Contact: Hayley Soffer - [email protected] - 760-603-4679 1Alexander VJ, et al. Eur Heart J 2019;40(33):2785-2796. 2Tardif JC, et al. Eur Heart J 2022;43(14):1401-1412. 3Gaudet D, et al. N Engl J Med. 2014;371:2200-2206. 4Ginsberg HN, et al. Eur Heart J. 2021;42:4791-4806. 5Pallazola VA, et al. Eur J Prev Cardiol 2020;27(19):2276-8. 6Warden BA, et al. J Clin Lipidol 2020;14(2):201-6. 7Tripathi M, et al. Endocr Pract 2021;27(1):71-6. 8Bashir B, et al. Metabolites. 2023;(5):621. 9Davidson M, et al. J Clin Lipidol. 2018;12(4):898-907.e2. 10Gouni-Berthold I. J Endocr Soc. 2019;4(2):bvz035. 11Paquette M, et al. Atherosclerosis. 2019;283:137-142. 12Williams L, et al. J Clin Lipidol. 2018;4:908-919. SOURCE Ionis Pharmaceuticals, Inc.

V-INITIATE trial demonstrates that early initiation with Leqvio, prior to guideline-recommended ezetimibe, for ASCVD patients unable to achieve LDL-C goal on statin therapy alone led to significant LDL-C reduction vs. clinician-determined usual care (60% vs. 7% respectively)1 A significantly greater proportion of the ASCVD patients receiving Leqvio achieved guideline-recommended LDL-C goal vs. the usual care arm while maintaining adherence to statin treatment1 Results from usual care arm reinforce the urgent need for more aggressive LDL-C lowering in ASCVD patients, 92% of whom did not reach their LDL-C goal with statins alone1 The Leqvio safety profile was consistent with the Phase III clinical studies and long-term open-label extension trials for up to 6 years of treatment1-4 EAST HANOVER, N.J., April 6, 2024 /PRNewswire/ -- Novartis today announced new data demonstrating the early addition of twice-yearly* Leqvio® (inclisiran) to maximally tolerated statin therapy, prior to guideline-recommended ezetimibe, in a real-world setting significantly reduced low-density lipoprotein cholesterol (LDL-C) in patients with atherosclerotic cardiovascular disease (ASCVD), including those with a history of an ASCVD-related event, who could not reach their goal on statin therapy alone1. The late-breaking data were presented at the 2024 American College of Cardiology's Annual Scientific Session & Expo and simultaneously published in the Journal of the American College of Cardiology. "V-INITIATE evaluated a solution to the important challenge seen in clinical practice of too many patients with ASCVD not achieving guideline-recommended LDL-C goal on statins alone and effective non-statin therapies being markedly underutilized," said Michael Koren, M.D., Medical Director and CEO of Jacksonville Center for Clinical Research, and the primary investigator of the study. "Given the urgent need to more aggressively manage LDL-C, the results from V-INITIATE show that when added earlier in the treatment continuum, the structured use of effective non-statin therapies like Leqvio can significantly reduce LDL-C for ASCVD patients who are struggling to reach or maintain their LDL-C goal." In the V-INITIATE study, patients receiving Leqvio experienced significant reductions in LDL-C compared to those receiving usual care (60% vs. 7%, respectively; p<0.001), which consisted mostly of statin therapy alone (73%)1. Four in five patients receiving Leqvio achieved the guideline-recommended LDL-C goal of <70 mg/dL compared to just one in five patients receiving usual care (81.8% vs. 22.2%, respectively; p<0.001)1. Notably, patients receiving health care provider (HCP)-administered Leqvio maintained adherence to existing lipid-lowering therapy, and the discontinuation rate of background statin therapy did not differ between the Leqvio and usual care arms (5.8% vs. 16.7%, respectively)1. The safety results from V-INITIATE were consistent with findings from the pivotal Phase III clinical trial program and long-term open-label extension trials, ORION-3 and ORION-8, which demonstrated sustained safety for up to six years of treatment1-4. "The data from V-INITIATE illustrate that earlier initiation of innovative non-statin therapies, like Leqvio, presents a real opportunity to do better for ASCVD patients and improve the way we approach LDL-C lowering," said David Soergel, M.D., Global Head of Cardiovascular, Renal and Metabolic Drug Development at Novartis. "This study adds data from a real-world setting to the growing body of evidence for Leqvio being generated through our robust VictORION program, and further reinforces the clinical value of this twice-yearly HCP-administered therapy." V-INITIATE is a 12-month Phase IIIb open-label study evaluating the effectiveness of adding Leqvio earlier, following a patient's failure to reach LDL-C goal on maximally tolerated statin therapy, compared to usual care, in a setting that reflects U.S. clinical practice. It was designed to more accurately represent the diversity of the U.S. general population across age, sex, race, ethnicity, insurance status, income level, education, prior medical history and statin intolerance1. Unlike placebo arms in typical double-blind trials, the usual care arm reflected U.S. clinical practice by allowing treating physicians to make changes to lipid-lowering treatment based on LDL-C measurements. Usual care was defined as clinician determined based on the 2018 American College of Cardiology/American Heart Association guideline recommendations1. *After an initial dose and another at three months. Indication LEQVIO (inclisiran) is an injectable prescription medicine used along with diet and other cholesterol-lowering medicines in adults with high blood cholesterol levels called primary hyperlipidemia (including a type of high cholesterol called heterozygous familial hypercholesterolemia [HeFH]) to reduce low-density lipoprotein (LDL-C) or "bad" cholesterol. Important Safety Information: The most common side effects of Leqvio were: injection site reaction (including pain, redness, and rash), arthralgia (joint pain), bronchitis (chest cold). These are not all the possible side effects of Leqvio. Ask your health care provider for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit , or call 1-800-FDA-1088. Please click here for Leqvio full Prescribing Information. About Leqvio Leqvio is a subcutaneous injection given by a health care provider (HCP) with an initial dose, another at three months, and then every six months2,5. As a twice-yearly, HCP-administered treatment, Leqvio may help to circumvent the challenges of treatment adherence, a common issue in cholesterol management. Leqvio is the first and only small interfering RNA (siRNA) therapy to lower LDL-C. It is approved in over 90 countries, including the U.S., EU, Japan and China1,5,6. Novartis has obtained global rights to develop, manufacture and commercialize Leqvio under a license and collaboration agreement with Alnylam Pharmaceuticals, a leader in RNAi therapeutics. About V-INITIATE V-INITIATE is a 12-month, randomized, multicenter, open-label Phase IIIb study in 450 atherosclerotic cardiovascular disease (ASCVD) patients in the U.S. with elevated LDL cholesterol (LDL-C) ≥70 mg/dL. The study evaluated the effectiveness of adding HCP-administered Leqvio earlier, following a patient's failure to reach LDL-C goal on maximally tolerated statin therapy, compared to usual care1. Usual care was determined by the clinicians and based on the 2018 American College of Cardiology/American Heart Association guideline recommendations; most patients (73%) in the usual care arm remained on statins only1. The co-primary endpoints were the percentage change in LDL-C from baseline to Day 330 and the discontinuation of statin therapy, defined as no statin use ≥30 days before the end of study visit1. This is the first Novartis trial where all patients have been tokenized with the intention of following their outcomes for two additional years post-trial completion, providing additional insights on the real-world effectiveness of Leqvio7. About VictORION The V-INITIATE trial is part of VictORION, an innovative and robust clinical program for Leqvio, comprising more than 30 trials and enrolling over 60,000 patients in more than 50 countries worldwide7. The program is designed to expand on the foundational evidence of LDL-C reduction with Leqvio in diverse patient populations to include randomized clinical trials, implementation research, real-world evidence, and trials that aim to establish its potential benefits on cardiovascular outcomes in primary and secondary prevention. A growing number of studies are planned to generate a vast array of data with major trials such as ORION-4 (secondary prevention), V(VictORION)-2-PREVENT (secondary prevention), V-1-PREVENT (high-risk primary prevention), V-INCEPTION and V-MONO. About Atherosclerotic Cardiovascular Disease (ASCVD) ASCVD refers to a variety of diseases caused by the development and growth of plaques in the inner lining of the arteries8. The atherosclerotic plaque is mainly composed of low-density lipoprotein cholesterol (LDL-C) which accumulates over time8. Cumulative exposure to LDL-C is proportionally related to arterial plaque growth and progression leads to subsequent risk of cardiovascular events such as a heart attack or stroke8,9. Accounting for 85% of all cardiovascular disease deaths, ASCVD is the primary cause of mortality in the European Union and its burden in the United States is greater than that of any other chronic diseases10-13. ASCVD risk-equivalent corresponds to conditions that confer a similar risk for an ASCVD event (e.g., diabetes and heterozygous familial hypercholesterolemia)4,13. About Novartis in Cardiovascular Cardiovascular disease (CVD) affects hundreds of millions of people and claims more lives globally than cancer, chronic lung disease and diabetes combined14. It is time to change that. Around 80% of premature cardiovascular deaths can be prevented by addressing factors that cause or worsen CVD15. We have a responsibility to make that a reality for more people. Novartis has been advancing the scientific understanding and treatment of CVD for more than four decades. Through early intervention, pioneering science and technological innovation, we are addressing factors that increase the risk of heart attacks and strokes, improving the function of damaged hearts and easing the burden of care for patients. We also collaborate with healthcare professionals, patient communities and diverse organizations to improve preventive CV care worldwide. Together, we will help more people with CVD get the right treatments at the right time and live longer and healthier lives. Disclaimer This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "may," "could," "would," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. About Novartis Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people's lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide. Reimagine medicine with us: Visit us at and and connect with us on LinkedIn, LinkedIn US, Facebook, X/Twitter, X/Twitter US and Instagram. Novartis previously filed its 2023 annual report with the Swiss SIX exchange in Switzerland, as well as its 2023 Annual Report on Form 20-F with the US Securities and Exchange Commission, and posted these documents on . Novartis shareholders may receive a hard copy of either of these documents, each of which contains our complete audited financial statements, free of charge, upon request. References Koren MJ, Rodriguez F, East CA, et al. Comparison of an "inclisiran first" strategy with usual care in patients with atherosclerotic cardiovascular disease: results from the VICTORION-INITIATE randomized trial. Data presented at: American College of Cardiology Congress; April 6, 2024; Atlanta, GA. Leqvio. Prescribing information. Novartis Pharmaceuticals Corp. Wright RS, Raal FJ, Koenig W, et al. ORION-8: Long-term efficacy and safety of twice-yearly inclisiran in high cardiovascular risk patients. Data presented at: European Society of Cardiology Congress; August 28, 2023; Amsterdam, the Netherlands. Ray KK, Troquay RPT, Visseren FLJ, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol. 2023;11(2):109-119. European Medicines Agency. Leqvio (inclisiran): An overview of Leqvio and why it is authorized in the EU. Last updated June 2021. Accessed March 12, 2024. National Medical Products Administration. Drug approval document delivery information. Published August 24, 2023. Accessed March 12, 2024. Data on file. NCT04929249. Novartis Pharmaceuticals Corp; 2024. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell. 2015;161(1):161-172. Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of lipids on cardiovascular health: JACC Health Promotion Series. J Am Coll Cardiol. 2018;72(10):1141-1156. World Health Organization. Cardiovascular diseases (CVDs). Published June 11, 2021. Accessed March 12, 2024. (cvds) Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2-e220. Kim H, Kim S, Han S, et al. Prevalence and incidence of atherosclerotic cardiovascular disease and its risk factors in Korea: a nationwide population-based study. BMC Public Health. 2019;19(1):1112. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082–e1143. American Heart Association. More than half of U.S. adults don't know heart disease is leading cause of death, despite 100-year reign. Published January 24, 2024. Accessed March 12, 2024. World Heart Federation. World Heart Report. Published May 20, 2023. Accessed March 12, 2024. # # # SOURCE Novartis Pharmaceuticals Corporation

-- Findings Presented on VASCEPA/VAZKEPA Utility in REDUCE-IT Patient Subgroups by Baseline High/Low Lp(a), LDL-C Levels -- -- Lp(a) Results Published Simultaneously in the Journal of the American College of Cardiology (JACC) – DUBLIN, Ireland and BRIDGEWATER, N.J., April 06, 2024 (GLOBE NEWSWIRE) -- Amarin Corporation plc (NASDAQ:AMRN) today highlighted two data presentations at ACC.24 describing the effects of VASCEPA®/VAZKEPA® (icosapent ethyl) on reducing MACE (Major Adverse Cardiovascular Events) in patients with baseline high or low Lipoprotein(a) [Lp(a)] levels, as well as reducing the risk of cardiovascular (CV) events in patients irrespective of baseline LDL-C level. The REDUCE-IT analysis results relating Lp(a) concentrations with CV risk were also published online today in the Journal of the American College of Cardiology (JACC). “These new findings provide additional important evidence about the clinical utility of VASCEPA/VAZKEPA and further demonstrate its value in reducing cardiovascular events in at-risk patients in key subgroups,” said Nabil Abadir, MB. CH.B., Chief Medical Officer and Head of Global Medical Affairs, Amarin. “At Amarin, we’re focused on the continuous generation of science to further advance the medical community’s understanding of the role and value of VASCEPA/VAZKEPA in reducing cardiovascular events in at-risk patients globally, and we are proud to add to the body of research that further demonstrates our commitment to value creation.” The subgroup analyses and their key findings are outlined below: Icosapent Ethyl Reduces MACE in Patients with Elevated Triglycerides and High or Low Lipoprotein(a) Concentrations: A REDUCE-IT Subanalysis High Lp(a) concentrations are associated with increased CV event risk, even when LDL-C levels are well-managed. There are no treatments currently approved to reduce residual CV risk on top of contemporary medical therapy in patients with high Lp(a) levels. In this post hoc analysis of REDUCE-IT, the relationship between continuous baseline Lp(a) concentration and risk of MACE was analyzed in models that also accounted for baseline LDL-C, baseline triglycerides (TG), and double-blind treatment. REDUCE-IT participants were randomized to receive either 2g twice daily of icosapent ethyl (IPE) or matching placebo and followed for a median 4.9 years. In this subanalysis, there were 7,026 REDUCE-IT patients with baseline Lp(a) data and a median Lp(a) value of 11.6 (Q1-Q3: 5.0-37.4) mg/dL. Results showed that baseline Lp(a) had a strong and significant relationship with MACE irrespective of baseline LDL-C, baseline TGs, and treatment assignment, and that the benefit of IPE was consistent across Lp(a) concentrations. Importantly, the treatment benefit of IPE was evident across subgroups with both high (≥50 mg/dL) and low (<50 mg/dL) Lp(a) concentrations. Specifically, for first MACE, the relative IPE treatment effects for Lp(a) ≥50 mg/dL and <50 mg/dL were HR 0.79 (95% CI 0.64-0.97; P=0.0248) and HR 0.75 (95% CI 0.66-0.84; P<0.0001), respectively. Absolute risk reductions at 5 years with IPE were 6.5% and 5.7% for Lp(a) ≥50 mg/dL and <50 mg/dL, respectively.1 Limitations include that participants in REDUCE-IT were not selected on the basis of their baseline Lp(a) concentration and that not all REDUCE-IT patients had available baseline Lp(a) data. “In this analysis, IPE showed a clear clinical benefit for patients with both high and low Lp(a) levels. IPE provided a relative risk reduction of 21% among patients with an Lp(a) level of ≥50 mg/dL and 25% for those patients with an Lp(a) level of <50 mg/dL,” said Dr. Michael Szarek, professor, Division of Cardiology, University of Colorado School of Medicine and a faculty member at CPC Clinical Research. “These findings are important, as high baseline Lp(a) concentrations are a predictor for MACE, and this analysis reinforces IPE’s clinical benefit in these at-risk patient sub-populations.” The analysis and its findings were published simultaneously online in JACC. Efficacy of Icosapent Ethyl for Reducing Cardiovascular Outcomes by Baseline Low Density Lipoprotein Cholesterol Level Elevated low-density lipoprotein cholesterol (LDL-C) is a well-established major CV risk factor supported by clinical evidence showing decreased atherosclerotic disease events when LDL-C is therapeutically lowered. Recent international guidelines recommend lowering LDL-C to <55 mg/dL in those patients who are at very high risk for a future CV event. In this post hoc analysis, investigators explored REDUCE-IT data to determine if IPE reduces CV outcomes among high-risk CV patients irrespective of baseline LDL-C. Patients were stratified by LDL-C <55 vs ≥55 mg/dL. The primary outcome was a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. Among statin-treated REDUCE-IT patients with baseline LDL-C data, 1,058 (12.9%) had LDL-C <55 mg/dL and 7,117 (87.1 %) had LDL-C ≥55 mg/dL. The primary outcome rate among patients with LDL-C <55 mg/dL was 16.2% in the IPE group and 22.8% in the placebo group, HR 0.66 (95% CI 0.50-0.87; P=0.003). Findings were consistent in the LDL-C ≥55 mg/dL subgroup, with rates of 17.4% in the IPE group and 21.9% in the placebo group, HR 0.76 (95% CI 0.69-0.85; P<0.0001). No significant interaction by baseline LDL-C was observed. Limitations are that randomization was not stratified by baseline LDL-C, however, baseline characteristics were similar among the two baseline LDL-C subgroups. REDUCE-IT patients were on statin therapy, but with low rates or unavailability of other lipid therapies such as ezetimibe, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, or small interfering RNA (siRNA) therapies. “As we know, LDL-C is a well-established major CV risk factor. These data are important and show that among adults with increased CV risk and elevated TGs, icosapent ethyl clearly reduced the rate of CV outcomes irrespective of baseline LDL-C, including in those with very well controlled LDL-C <55 mg/dL,” said Deepak L. Bhatt, MD, MPH, MBA, Director of Mount Sinai Fuster Heart Hospital. All analyses highlighted above were funded by Amarin. Dr. Deepak L. Bhatt served as the principal investigator for REDUCE-IT and his institution received research funding from Amarin. About AmarinAmarin is an innovative pharmaceutical company leading a new paradigm in cardiovascular disease management. We are committed to increasing the scientific understanding of the cardiovascular risk that persists beyond traditional therapies and advancing the treatment of that risk for patients worldwide. 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. 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.2 The primary results of REDUCE-IT were published in The New England Journal of Medicine in November 2018.3 The total events results of REDUCE-IT were published in the Journal of the American College of Cardiology in March 2019.4 These and other publications can be found in the R&D section on the company’s website at www.amarincorp.com. 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 year.5 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%.6 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.7,8,9 About VASCEPA®/VAZKEPA® (icosapent ethyl) CapsulesVASCEPA (icosapent ethyl) capsules are the first 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 drug approved by the U.S. FDA for treatment of the studied high-risk patients with persistent cardiovascular risk despite being on 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 more than twenty million times. VASCEPA is covered by most major medical insurance plans. In addition to the United States, VASCEPA is approved and sold in Canada, China, 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. In April 2021 marketing authorization for VAZKEPA (icosapent ethyl) was granted in Great Britain (applying to England, Scotland and Wales). VAZKEPA (icosapent ethyl) is currently approved and sold in Europe in Sweden, Denmark, Finland, Austria, the UK, Spain and the Netherlands. United StatesIndications and Limitation of UseVASCEPA 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 ordiabetes 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. FULL U.S. FDA-APPROVED VASCEPA PRESCRIBING INFORMATION CAN BE FOUND AT WWW.VASCEPA.COM. Europe For further information about the Summary of Product Characteristics (SmPC) for VAZKEPA® in Europe, please click here. Globally, prescribing information varies; refer to the individual country product label for complete information. Forward-Looking Statements This 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 potential for VASCEPA (marketed as VAZKEPA in Europe); beliefs about icosapent ethyl (IPE)’s role concerning appropriate patients suffering from cardiovascular disease (CVD) and potential population health impact, as well as general beliefs about the safety and effectiveness of VASCEPA. These forward-looking statements are not promises or guarantees and involve substantial risks and uncertainties. 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 annual report on Form 10-K for the full year ended 2023. 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 (amarincorp.com/investor-relations), 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 InformationInvestor & Media Inquiries:Mark MarmurAmarin Corporation plcPR@amarincorp.comInvestor.relations@amarincorp.com 1 Szarek M, Bhatt DL, Miller M, et al. Lipoprotein(a) blood levels and cardiovascular risk reduction with icosapent ethyl. J Am Coll Cardiol. 2024; epub ahead of print.2 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;40:138-148.3 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;380:11-22.4 Bhatt DL, Steg PG, Miller M, et al., on behalf of the REDUCE-IT Investigators. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J Am Coll Cardiol. 2019;73:2791-2802.5 American Heart Association. Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association. Circulation. 2020;141:e139-e596.6 Ganda OP, Bhatt DL, Mason RP, et al. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management. J Am Coll Cardiol. 2018;72(3):330-343.7 Budoff M. Triglycerides and triglyceride-rich lipoproteins in the causal pathway of cardiovascular disease. Am J Cardiol. 2016;118:138-145.8 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):e008740.9 Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease - New insights from epidemiology, genetics, and biology. Circ Res. 2016;118:547-563