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The information contained in this FAQ section of Amarin's website is accurate only as of the date this page was last updated. Amarin disavows any obligation to update the information contained in this FAQ section after such date. This information is intended for communication with investors and should not be construed as marketing the use of any Amarin products or product candidates.


 

The article and program center on safety concerns, unsubstantiated or overstated claims, poor manufacturing quality and insufficient government testing and oversight associated with dietary supplement products.  These products are not designed or intended to treat disease. The program did not question the efficacy, safety and potential utility of FDA-approved drug products, such as Vascepa® (icosapent ethyl) capsules.

Prescription medicines (and the regulatory system governing their approval and marketing) address every concern raised about dietary supplement products in the reports: prescription drugs are subject to strict requirements imposed by federal regulators based on recognized scientific principles to support claims made, tight regulation of manufacturing processes, and ongoing monitoring to ensure product safety and to ensure that product contents precisely match the labels.

Unlike regulated prescription and over-the-counter (OTC) drugs, 1-3 in the United States dietary supplements are not required to meet strict FDA drug standards for safety, efficacy, and manufacturing.2-5 Of the three categories, there are no OTC omega-3 products available in the United States, only regulated prescription forms or dietary supplements.

Many dietary supplement fish oils are low in omega-3 content, may vary in content from lot to lot, may contain contaminants that may raise safety concerns, and are prone to oxidation (spoilage indicated by fishy smell) that may mitigate antioxidant effects.2,6-9 For example, as highlighted in the Frontline piece, various investigators found that approximately 20 – 83% of dietary supplements had oxidation levels higher than the industry standard maximum, and the cited New Zealand study also reported that 91% of supplements tested contained less omega-3 content than reported on their labels28.  In addition, many omega-3 dietary supplements contain DHA, which has been associated with increases in bad cholesterol in patients with high and very high blood levels of triglycerides.  Finally, oxidized low-density lipoprotein (LDL) levels are associated with cardiovascular disease29.  The pharmaceutical medicine Vascepa has been shown in clinical studies to reduce oxidized LDL in certain patients30, although the full clinical impact of this reduction has not been established.  In contrast, pre-clinical in vitro (i.e. in the test tube) studies suggest that oxidized omega-3 fatty acids may lose their ability to act as an antioxidant for lipoproteins29.  Current federal regulations do not require dietary supplements to establish clinical efficacy in general, and the potential clinical impact of higher oxidation levels in some omega-3 supplements has not been established.

Due to the differences in regulation and lack of required efficacy and safety data, dietary supplements are not recommended by FDA at any dose to treat or mitigate disease, and supplements with the omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are not recommended by the FDA at doses of more than 2 grams per day (total of 3 grams including consumption from food sources).10

The following chart provides an at-a-glance comparison of prescription (Rx) and dietary supplement regulatory categories.

Misperceptions about prescription 
and dietary supplement product differences can place patients at risk.

For patients with diagnosed medical conditions, such as very high triglycerides (VHTG),
it’s critical to consult with a doctor about lifestyle changes, diet and,
if appropriate, FDA-approved drug therapy.

 

 

Rx Products

Dietary Supplements

EFFICACY

Rigorous clinical trial results required to prove efficacy prior to marketing1-3

Yes

 

All health claims supported by FDA-accepted trials and evaluated by the FDA3

Yes

 

May have high oxidation levels, which may offset positive effects8,9

No

Yes

May have high saturated fat content, which in excess is unhealthy11

No

Yes

 

SAFETY

Pre-clinical laboratory studies completed to prove that the product should be safe for humans1,2

Yes

 

Rigorous clinical trial results required to prove safety prior to marketing1-3

Yes

 

Safety is reviewed prior to marketing2-4 and adequate reporting systems for monitoring safety2,5

Yes

 

 

REGULATORY REVIEW

Product is approved by the FDA for the treatment of disease12-17

Yes

 

All evidence from pre-clinical and clinical trials must be submitted to the Center for Drug Evaluation and Research where physicians, statisticians, chemists, pharma-cologists and other scientists review the scientific evidence for safety and efficacy1

Yes

 

Possible side effects must be listed on the label12-17

Yes

 

Manufacturing process results in highly purified product6

Yes

 

All aspects of production and distribution regulated and subject to inspections by the FDA Drug Compliance Programs18-20

Yes

 

Standardized formulations provide consistent quality, omega-3 content, and purity10

Yes

 

Variable content, ingredients, and possible contamination2,6-9

No

Yes

This program raises important considerations.  Most importantly, dietary supplements should not be used to treat disease.  Careful analysis of relevant studies and the latest scientific knowledge are essential for patients and physicians to make informed decisions on how best to care for their health and treat serious medical conditions. The program focuses on study data associated with low-dose omega-3 dietary supplementation. It does not question the efficacy of FDA-approved drug products in the omega-3 class or the latest clinical trials in the field, like Amarin’s ongoing REDUCE-IT cardiovascular outcomes study of Vascepa® (icosapent ethyl) capsules.

Amarin remains a leader in the research and development of the omega-3 acid, EPA, through clinical study of its highly pure pharmaceutical grade lead product, Vascepa.  Amarin received FDA approval of 4 gram daily use of Vascepa in July 2012 as an adjunct to diet to lower triglycerides in patients with very high (≥ 500 mg/dL) triglycerides (VHTG). The effect of VASCEPA on cardiovascular mortality and morbidity or on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined. FDA approved use of Vascepa is consistent with numerous national and international treatment guidelines and position statements.20-27

Amarin is dedicated to improved patient care. As part of its ongoing commitment to patient care and improved health outcomes, Amarin is further evaluating the effectiveness of Vascepa in reducing the prevalence of major cardiovascular events in a high-risk patient population by conducting a first-of-its-kind cardiovascular outcomes study in patients with high triglyceride levels who either have established or are at high risk for atherosclerotic cardiovascular disease despite statin therapy, the REDUCE-IT study. Amarin initiated the REDUCE-IT study in 2011 and enrollment is nearly complete.

About the REDUCE-IT study

REDUCE-IT (Reduction of Cardiovascular Events with EPA - Intervention Trial), is a multinational, prospective, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the effectiveness of 4 grams daily of Vascepa, the active ingredient in which is EPA, in reducing the prevalence of first major cardiovascular events in a high-risk patient population. The control arm of the study is comprised of patients on stable statin therapy plus placebo. The active arm of the study is comprised of patients on stable statin therapy plus Vascepa.

Patients enrolled in the REDUCE-IT study have high triglyceride levels despite statin therapy and either established atherosclerotic cardiovascular disease or are at high risk for atherosclerotic cardiovascular disease.

The REDUCE-IT study is designed with an expanded composite MACE (Major Adverse Cardiovascular Event) endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina caused by myocardial ischemia. The study also includes secondary and tertiary endpoints and subgroup analyses agreed-upon with FDA.

The REDUCE-IT trial continues on schedule towards anticipated completion in 2017 and publication of results in 2018. Completion of the REDUCE-IT study is based on attainment of 1,612 cumulative patients with documented primary cardiovascular events. The results of this important trial could lead to improved medical care for tens of millions of patients.

Amarin is blinded to the ongoing study results. An independent data monitoring committee (DMC) conducts ongoing unblinded safety reviews of REDUCE-IT, and an interim review by the DMC of the trial's efficacy and safety results is expected to occur during 2016 upon reaching 60% of the target aggregate number of cardiovascular events. Based on comprehensive review of clinical, epidemiological, and genetic data, Amarin continues to believe that REDUCE-IT is positioned for success at completion. Given the high thresholds of overwhelming efficacy and safety typically required to be achieved prior to an independent DMC recommending an early stop to a cardiovascular outcomes trial like REDUCE-IT, Amarin continues to believe that it is most likely that the REDUCE-IT study will run to its completion.

Enrollment reached approximately 7,900 patients as of December 31, 2015, representing 99% of total targeted patient enrollment in this event-driven study.

About VASCEPA® (icosapent ethyl) capsules

VASCEPA® (icosapent ethyl) capsules, known in scientific literature as AMR101, is a highly pure-EPA omega-3 prescription product in a 1 gram capsule.

Indications and Usage

  • VASCEPA (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.
  • The effect of VASCEPA on cardiovascular mortality and morbidity or on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.

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

FULL VASCEPA PRESCRIBING INFORMATION CAN BE FOUND AT WWW.VASCEPA.COM.

Vascepa has been approved for use by the FDA as an adjunct to diet to reduce triglyceride levels in adult patients with severe (>500 mg/dL) hypertriglyceridemia. Vascepa is under various stages of development for potential use in other indications that have not been approved by the FDA. Nothing in this document should be construed as promoting the use of Vascepa in any indication that has not been approved by the FDA.

Further study such as the REDUCE-IT trial is needed to determine if the effects of Vascepa can reduce residual risk in coronary heart disease patients already on statin therapy.

Dated January 20, 2016.

ENDNOTES:

1. Food and Drug Administration. Development & Approval Process (Drugs) Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/default.htm. Accessed September 29, 2015.

2. ASHP statement on the use of dietary supplements. Am J Health Syst Pharm. 2004;15:1707-1711.

3. National Center for Complementary and Alternative Medicine (NCCAM). Using dietary supplements wisely. Available at: http://nccam.nih.gov/health/supplements/wiseuse.htm.  Accessed September 29, 2015.

4. U.S. Food and Drug Administration. Dietary Supplements. Available at:  http://www.fda.gov/Food/DietarySupplements/. Accessed September 29, 2015. 

5. Cohen PA. Hazards of hindsight – monitoring the safety of nutritional supplements. N Engl J Med. 2014;370:1277-1280/

6. Weintraub H. Update on marine omega-3 fatty acids: management of dyslipidemia and current omega-3 treatment options. Atherosclerosis. 2013;230(2):381-389. 

7. Kleiner AC, Cladis DP, Santerre CR. A comparison of actual versus stated label amounts of EPA and DHA in commercial omega-3 dietary supplements in the United States. J Sci Food Agric. 2015;95:1260-1267.

8. Ritter JCS, Budge SM, Jovica F. Quality analysis of commercial fish oil preparations.  J Sci Food Agric.2013;93:1935-1939.

9. Albert BB, et al. Fish oil supplements n New Zealand are highly oxidised  and do not meet label content of n-3 PUFA. Sci Rep. 2015;5:7928.

10. Letter Regarding Dietary Supplement Health Claim for Omega-3 Fatty Acids and Coronary Heart Disease. Docket No. 91N-0103. Available athttp://www.fda.gov/ohrms/dockets/dockets/95s0316/95s-0316-Rpt0272-38-Appendix-D-Reference-F-FDA-vol205.pdf. Accessed November 13, 2015.

11. National Lipid Association. Insights into vascular and antioxidant effects of EPA relevant to atherogenesis . Available at: https://www.lipid.org/education/online_activities/2015027. Accessed September 29, 2015. 

12. Lovaza [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.

13. Omtryg [package insert]. Arlington, VA: Trygg Pharma, Inc.; 2014.

14. Epanova [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2014.

15. Vascepa [package insert]. Bedminster, NJ: Amarin Pharma Inc.; 2015.

16. Omega-3-acid ethyl esters [package insert]. Sellersville, PA: Teva Pharmaceuticals; 2014.

17. Omega-3-acid ethyl esters [package insert].Spring Valley, NY: Par Pharmaceuticals Companies, Inc.; 2014.7. U.S.

18. US Food and Drug Administration. Compliance Program Guidance Manual. Program 7356.002.  Available at: http://www.fda.gov/downloads/ICECI/ComplianceManuals/ComplianceProgramManual/UCM125404. Accessed September 29, 2015.

19. U.S. Food and Drug Administration. Drug Compliance Programs. Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm252671.htm. Accessed September 29, 2015. 

20. U.S. Food and Drug Administration. Dietary Supplements-Import and Domestic. Available at:  http://www.fda.gov/Food/ComplianceEnforcement/FoodCompliancePrograms/ucm071547.htm. Accessed September 29, 2015. 

20. Jacobson TA,  et al. National Lipid Association recommendations for patient-centered management of dyslipidemia. J. Clin. Lipidol. 2014; 8:473.488.

21. Jellinger PS, et al. American Association of Clinical Endocrinologists' guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract. 2012;18(Suppl 1):1-78.

22. Hegele RA, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2:655-666. 

23. Expert Dyslipidemia Panel of the International Atherosclerosis Society, An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia – full report. J Clin Lipidol. 2014;8:29-60.

24. L. Berglund et al., Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline.  J. Clin. Endocrinol. Metab. 2012;97:2969-2989.

25. Chapman MJ, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur. Heart J. 2011;32:1345-1361.

26. Reiner Z, et al. ESC/EAS Guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS), Eur. Heart J. 2011;32:1769-1818.

27. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment on High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NECP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421. 

28. Benjamin B. Albert, Jose´ G. B. Derraik, David Cameron-Smith, Paul L. Hofman, Sergey Tumanov, Silas G. Villas-Boas, Manohar L. Garg, Wayne S. Cutfield. Fish oil supplements in New Zealand are highly oxidised and do not meet label content of n-3 PUFA.  Sci Rep. 2015 Jan 21;5:7928.

29. Kenneth M. Borow, John R. Nelson, R. Preston Mason. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis 242 (2015) 357-366.

30. Harold E. Bays, Christie M. Ballantyne, Rene A. Braeckman, William G. Stirtan, Paresh N. Soni. Icosapent Ethyl, a Pure Ethyl Ester of Eicosapentaenoic Acid: Effects on Circulating Markers of Inflammation from the MARINE and ANCHOR Studies. Am J Cardiovasc Drugs (2013) 13:37–46.

 

The program centers on safety concerns, unsubstantiated or overstated claims, poor manufacturing quality and insufficient government testing and oversight associated with dietary supplement products.  These products are not designed or intended to treat disease. The program did not question the efficacy, safety and potential utility of FDA-approved drug products, such as Vascepa® (icosapent ethyl) capsules.

Prescription products (and the regulatory system governing their approval and marketing) address every concern raised about dietary supplement products in the CBC report: prescription drugs are subject to strict requirements imposed by federal regulators based on recognized scientific principles to support claims made, tight regulation of manufacturing processes, and ongoing monitoring to ensure product safety and to ensure that product contents match the labels precisely.

Unlike regulated prescription and over-the-counter (OTC) drugs,1-3 in the United States (like in Canada) dietary supplements are not required to meet strict FDA drug standards for safety, efficacy, and manufacturing.2-5 Of the three categories, there are no OTC omega-3 products available in the United States, only regulated prescription forms or dietary supplements.

Many dietary supplement fish oils are low in omega-3 content, may vary in content from lot to lot, may contain contaminants that may raise safety concerns, and are prone to oxidation (spoilage indicated by fishy smell) that may mitigate antioxidant effects.2,6-9 For example, as highlighted in the CBC piece, various investigators found that approximately 20 – 83% of dietary supplements had oxidation levels higher than the industry standard maximum, and the cited New Zealand study also reported that 91% of supplements tested contained less omega-3 content than reported on their labels28.  In addition, many omega-3 dietary supplements contain DHA, which has been associated with increases in bad cholesterol in patients with high and very high blood levels of triglycerides.  Finally, oxidized low-density lipoprotein (LDL) levels are associated with cardiovascular disease29.  The pharmaceutical product Vascepa has been shown in clinical studies to reduce oxidized LDL in certain patients30, although the full clinical impact of this reduction has not been established.  In contrast, pre-clinical in vitro (i.e. in the test tube) studies suggest that oxidized omega-3 fatty acids may lose their ability to act as an antioxidant for lipoproteins29.  Current federal regulations do not require dietary supplements to establish clinical efficacy in general, and the potential clinical impact of higher oxidation levels in some omega-3 supplements has not been established.

Due to the differences in regulation and lack of required efficacy and safety data, dietary supplements are not recommended by FDA at any dose to treat or mitigate disease, and supplements with the omega-3 fatty acids EPA and DHA are not recommended by the FDA at doses of more than 2 grams per day (total of 3 grams including consumption from food sources).10

The following chart provides an at-a-glance comparison of prescription (Rx) and dietary supplement regulatory categories.

Misperceptions about prescription
and dietary supplement product differences can place patients at risk.

For patients with diagnosed medical conditions, such as very high triglycerides (VHTG),
it’s critical to consult with a doctor about lifestyle changes and diet and,
if appropriate, FDA-approved drug therapy.

 

Rx Products

Dietary Supplements

EFFICACY

Rigorous clinical trial results required to prove efficacy prior to marketing1-3

Yes

 

All health claims supported by FDA-accepted trials and evaluated by the FDA3

Yes

 

May have high oxidation levels, which may offset positive effects8,9

No

Yes

May have high saturated fat content, which in excess is unhealthy11

No

Yes

SAFETY

Pre-clinical laboratory studies completed to prove that the product should be safe for humans1,2

Yes

 

Rigorous clinical trial results required to prove safety prior to marketing1-3

Yes

 

Safety is not reviewed prior to marketing2-4  and current reporting systems for supplements are inadequate for monitoring safety2,5

No

Yes

REGULATORY REVIEW

Product is approved by the FDA for the treatment of disease12-17

Yes

 

All evidence from pre-clinical and clinical trials must be submitted to the Center for Drug Evaluation and Research where physicians, statisticians, chemists, pharma-cologists and other scientists review the scientific evidence for safety and efficacy1

Yes

 

Possible side effects must be listed on the label12-17

Yes

 

Manufacturing process results in highly purified product6

Yes

 

All aspects of production and distribution regulated and subject to inspections by the FDA Drug Compliance Programs18-20

Yes

 

Standardized formulations provide consistent quality, omega-3 content, and purity10

Yes

 

Variable content, ingredients, and possible contamination2,6-9

No

Yes

This program raises important considerations.  Most important that dietary supplements should not be used to treat disease.  Careful analysis of relevant studies and the latest scientific knowledge are essential for patients and physicians to make informed decisions on how best to care for their health and treat serious medical conditions. The program focuses on study data associated with low-dose omega-3 dietary supplementation. It does not question the efficacy of FDA-approved drug products in the omega-3 class or the latest clinical trials in the field, like Amarin’s ongoing REDUCE-IT cardiovascular outcomes study of Vascepa® (icosapent ethyl) capsules.

Amarin remains a leader in the research and development of the omega-3 acid, EPA, through clinical study of its highly pure pharmaceutical grade lead product, Vascepa.  Amarin received FDA approval of 4 gram daily use of Vascepa in July 2012 as an adjunct to diet to lower triglycerides in patients with very high (≥ 500 mg/dL) triglycerides (VHTG). The effect of VASCEPA on cardiovascular mortality and morbidity or on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined. FDA approved use of Vascepa is consistent with numerous national and international treatment guidelines and position statements.20-27

Amarin is dedicated to improved patient care. As part of its ongoing commitment to patient care and improved health outcomes, Amarin is further evaluating the effectiveness of Vascepa in reducing the prevalence of major cardiovascular events in a high-risk patient population by conducting a first-of-its-kind cardiovascular outcomes study in patients with high triglyceride levels who either have established or are at high risk for atherosclerotic cardiovascular disease despite statin therapy, the REDUCE-IT study. Amarin initiated the REDUCE-IT study in 2011 and enrollment is nearly complete.

About the REDUCE-IT study

REDUCE-IT (Reduction of Cardiovascular Events with EPA - Intervention Trial), is a multinational, prospective, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the effectiveness of 4 grams daily of Vascepa, the active ingredient in which is EPA, in reducing the prevalence of first major cardiovascular events in a high-risk patient population. The control arm of the study is comprised of patients on stable statin therapy plus placebo. The active arm of the study is comprised of patients on stable statin therapy plus Vascepa.

Patients enrolled in the REDUCE-IT study have high triglyceride levels despite statin therapy and either established atherosclerotic cardiovascular disease or are at high risk for atherosclerotic cardiovascular disease.

The REDUCE-IT study is designed with an expanded composite MACE (Major Adverse Cardiovascular Event) endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina caused by myocardial ischemia. The study also includes secondary and tertiary endpoints and subgroup analyses agreed-upon with FDA.

The REDUCE-IT trial continues on schedule towards anticipated completion in 2017 and publication of results in 2018. Completion of the REDUCE-IT study is based on attainment of 1,612 cumulative patients with documented primary cardiovascular events. The results of this important trial could lead to improved medical care for tens of millions of patients.

Amarin is blinded to the ongoing study results. An independent data monitoring committee (DMC) conducts ongoing unblinded safety reviews of REDUCE-IT, and an interim review by the DMC of the trial's efficacy and safety results is expected to occur during 2016 upon reaching 60% of the target aggregate number of cardiovascular events. Based on comprehensive review of clinical, epidemiological, and genetic data, Amarin continues to believe that REDUCE-IT is positioned for success at completion. Given the high thresholds of overwhelming efficacy and safety typically required to be achieved prior to an independent DMC recommending an early stop to a cardiovascular outcomes trial like REDUCE-IT, Amarin continues to believe that it is most likely that the REDUCE-IT study will run to its completion.

More than 7,700 patients have been enrolled in the REDUCE-IT cardiovascular outcomes study representing more than 97% of total targeted patient enrollment in this event-driven study.

About VASCEPA® (icosapent ethyl) capsules

VASCEPA® (icosapent ethyl) capsules, known in scientific literature as AMR101, is a highly pure-EPA omega-3 prescription product in a 1 gram capsule.

Indications and Usage

  • VASCEPA (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe ( ≥ 500 mg/dL) hypertriglyceridemia.
  • The effect of VASCEPA on cardiovascular mortality and morbidity or on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.

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

FULL VASCEPA PRESCRIBING INFORMATION CAN BE FOUND AT WWW.VASCEPA.COM.

Vascepa has been approved for use by the FDA as an adjunct to diet to reduce triglyceride levels in adult patients with severe (>500 mg/dL) hypertriglyceridemia. Vascepa is under various stages of development for potential use in other indications that have not been approved by the FDA. Nothing in this document should be construed as promoting the use of Vascepa in any indication that has not been approved by the FDA.

Further study such as the REDUCE-IT trial is needed to determine if the effects of Vascepa can reduce residual risk in coronary heart disease patients already on statin therapy.

Dated November 24, 2015.

ENDNOTES:

1. Food and Drug Administration. Development & Approval Process (Drugs) Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/default.htm. Accessed September 29, 2015.

2. ASHP statement on the use of dietary supplements. Am J Health Syst Pharm. 2004;15:1707-1711.

3. National Center for Complementary and Alternative Medicine (NCCAM). Using dietary supplements wisely. Available at: http://nccam.nih.gov/health/supplements/wiseuse.htm.  Accessed September 29, 2015.

4. U.S. Food and Drug Administration. Dietary Supplements. Available at:  http://www.fda.gov/Food/DietarySupplements/. Accessed September 29, 2015. 

5. Cohen PA. Hazards of hindsight – monitoring the safety of nutritional supplements. N Engl J Med. 2014;370:1277-1280/

6. Weintraub H. Update on marine omega-3 fatty acids: management of dyslipidemia and current omega-3 treatment options. Atherosclerosis. 2013;230(2):381-389. 

7. Kleiner AC, Cladis DP, Santerre CR. A comparison of actual versus stated label amounts of EPA and DHA in commercial omega-3 dietary supplements in the United States. J Sci Food Agric. 2015;95:1260-1267.

8. Ritter JCS, Budge SM, Jovica F. Quality analysis of commercial fish oil preparations.  J Sci Food Agric.2013;93:1935-1939.

9. Albert BB, et al. Fish oil supplements n New Zealand are highly oxidised  and do not meet label content of n-3 PUFA. Sci Rep. 2015;5:7928.

10. Letter Regarding Dietary Supplement Health Claim for Omega-3 Fatty Acids and Coronary Heart Disease. Docket No. 91N-0103. Available at http://www.fda.gov/ohrms/dockets/dockets/95s0316/95s-0316-Rpt0272-38-Appendix-D-Reference-F-FDA-vol205.pdf. Accessed November 13, 2015.

11. National Lipid Association. Insights into vascular and antioxidant effects of EPA relevant to atherogenesis . Available at: https://www.lipid.org/education/online_activities/2015027. Accessed September 29, 2015. 

12. Lovaza [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.

13. Omtryg [package insert]. Arlington, VA: Trygg Pharma, Inc.; 2014.

14. Epanova [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2014.

15. Vascepa [package insert]. Bedminster, NJ: Amarin Pharma Inc.; 2015.

16. Omega-3-acid ethyl esters [package insert]. Sellersville, PA: Teva Pharmaceuticals; 2014.

17. Omega-3-acid ethyl esters [package insert].Spring Valley, NY: Par Pharmaceuticals Companies, Inc.; 2014.7. U.S.

18. US Food and Drug Administration. Compliance Program Guidance Manual. Program 7356.002.  Available at: http://www.fda.gov/downloads/ICECI/ComplianceManuals/ComplianceProgramManual/UCM125404. Accessed September 29, 2015.

19. U.S. Food and Drug Administration. Drug Compliance Programs. Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm252671.htm. Accessed September 29, 2015. 

20. U.S. Food and Drug Administration. Dietary Supplements-Import and Domestic. Available at:  http://www.fda.gov/Food/ComplianceEnforcement/FoodCompliancePrograms/ucm071547.htm. Accessed September 29, 2015. 

20. Jacobson TA,  et al. National Lipid Association recommendations for patient-centered management of dyslipidemia. J. Clin. Lipidol. 2014; 8:473.488.

21. Jellinger PS, et al. American Association of Clinical Endocrinologists' guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract. 2012;18(Suppl 1):1-78.

22. Hegele RA, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2:655-666. 

23. Expert Dyslipidemia Panel of the International Atherosclerosis Society, An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia – full report. J Clin Lipidol. 2014;8:29-60.

24. L. Berglund et al., Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline.  J. Clin. Endocrinol. Metab. 2012;97:2969-2989.

25. Chapman MJ, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur. Heart J. 2011;32:1345-1361.

26. Reiner Z, et al. ESC/EAS Guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS), Eur. Heart J. 2011;32:1769-1818.

27. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment on High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NECP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421. 

28. Benjamin B. Albert, Jose´ G. B. Derraik, David Cameron-Smith, Paul L. Hofman, Sergey Tumanov, Silas G. Villas-Boas, Manohar L. Garg, Wayne S. Cutfield. Fish oil supplements in New Zealand are highly oxidised and do not meet label content of n-3 PUFA.  Sci Rep. 2015 Jan 21;5:7928.

29. Kenneth M. Borow, John R. Nelson, R. Preston Mason. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis 242 (2015) 357-366.

30. Harold E. Bays, Christie M. Ballantyne, Rene A. Braeckman, William G. Stirtan, Paresh N. Soni. Icosapent Ethyl, a Pure Ethyl Ester of Eicosapentaenoic Acid: Effects on Circulating Markers of Inflammation from the MARINE and ANCHOR Studies. Am J Cardiovasc Drugs (2013) 13:37–46.

The addition of 1.8 g/day EPA (eicosapentaenoic acid) therapy (as opposed to the 4.0 g/day EPA dose being evaluated in Amarin’s REDUCE-IT study) to statin therapy significantly reduced coronary plaque and lipid volume from baseline in CHERRY, and according to the CHERRY investigators may reduce residual risk in coronary heart disease (CHD) patients who are already on lipid-lowering statin therapy [1]. CHERRY is the first known study to use integrated backscatter-intravascular ultrasound (IB-IVUS) to investigate the effects of combination therapy with statin and EPA on plaque regression. The study’s primary endpoint was the change in coronary tissue characteristics as evaluated by IB-IVUS. Secondary end points included changes in the volume of target coronary plaques and major adverse cardiovascular events (MACE) [1-3]. 

In the CHERRY study, approximately 200 Japanese hypercholesterolemic patients [total cholesterol (TC) ≥ 220 mg/dL or low-density lipoprotein cholesterol (LDL-C) ≥ 140 mg/dL, or when cholesterol-lowering treatment was in the investigator’s judgment deemed necessary when LDL-C ≥ 100 mg/dL or TC ≥ 180 mg/dL] 20 years of age or older with either stable angina or acute coronary syndrome (ACS) who had received successful percutaneous coronary intervention (PCI) with IB-IVUS guidance and had coronary plaques (≥500 m in thickness or ≥20% plaque coverage) ≥5 mm from the previously treated area in the same coronary artery branch.  All of the patients were treated with statin (pitavastatin 4 mg/day). The patients were randomized within one week of successful PCI to either statin alone (N=96) or statin plus EPA 1.8 g/day (N=97). Baseline LDL-C levels for the statin alone and statin/EPA groups were 99 and 107 mg/dL, respectively, and TC levels were 166 and 175 mg/dL, respectively.  Triglyceride levels were in the normal range at baseline in both arms.

After 6-8 months of study there was a statistically significant reduction in coronary plaque volume (from 74.5 to 61.4 mm3; p<0.001), lipid volume (from 39.2 to 34.8 mm3; p<0.05), and fibrous volume (from 28.9 to 22.8 mm3; p<0.05) of the non-stented lesions in the statin plus EPA group, but in each case no statistically significant difference was observed in the statin-only group. Clinically significant plaque regression was defined as a percent change in plaque volume greater than -15%.

The prevalence of clinically significant plaque regression was significantly greater in the statin plus EPA group than in the statin group alone (48% vs. 25%; p<0.001). Through multivariate logistic analysis and after adjusting confounding variables, it was determined that EPA was independently associated with plaque regression.

The EPA/arachidonic acid (AA) ratio was significantly increased in the statin plus EPA group compared to the statin only group, with a significant inverse correlation between change in EPA/AA ratio and changes in plaque volume (r= -0.332; p<0.001). 

Patient safety was evaluated by regular medical examinations and laboratory tests at 1, 3, and 6–8 months after enrollment. An assessment committee evaluated MACE and any other adverse events. MACE was defined as cardiac death, myocardial infarction, PCI and coronary artery bypass graft. In this short term trial with <100 patients per arm, there were no statistically significant differences between groups in major adverse cardiac events or adverse events.  Although MACE was evaluated in CHERRY, the study was not a large or long-term cardiovascular outcomes trial like REDUCE-IT.  CHERRY was not designed or adequately sized or powered to detect clinically significant differences in MACE or adverse events, nor did CHERRY examine a daily dose of EPA as large as that under investigation in the REDUCE-IT trial (1.8 g/day in CHERRY versus 4.0 g/day in REDUCE-IT). 

Coronary atherosclerosis progression/regression evaluation by IVUS is reported to be a feasible means to predict future cardiovascular events [4-6], and IB-IVUS analysis of specific tissue components (calcification, dense fibrosis, fibrosis, lipid pool) of coronary plaques in vivo [4,5] has been considered a useful tool for assessing risk of experiencing a coronary event in patients with coronary atherosclerosis [6-8]. IB-IVUS has been reported to have high sensitivity and specificity (90-95%) for the characterization of plaque tissue components using histology as a gold standard and the reliability and the usefulness of IB-IVUS have been established in previous reports [4-13].

Previous animal and human studies have shown that the role of EPA in the reduction of atherosclerotic plaque size and increase in plaque stability may be related to its anti-inflammatory effects [14-16].  Previous clinical studies have shown that EPA has a positive effect on markers of plaque stability [16-20] and measures of plaque volume.[21-25]

The results of CHERRY show the potentially beneficial effect of EPA on coronary artery plaque stabilization and its potential role in the reduction of residual risk in patients treated with high-dose statin for secondary prevention. Positive changes in coronary plaque tissue characteristics observed in this post-PCI study highlight the potential ability of EPA to slow or inhibit atherosclerotic plaque progression. It is possible that because EPA is incorporated into membrane phospholipids and atherosclerotic plaques, its effects may be exerted on the entire pathophysiologic cascade from plaque formation through thrombus rupture [26].

The CHERRY investigators concluded from their study that additional administration of EPA to high dose PTV treatment significantly reduced coronary plaque volume and suggested from their study results that EPA therapy may reduce the residual risk that remains in secondary prevention patients being treated with statin therapy [27,28].

The CHERRY study was not sponsored by or affiliated with Amarin. The study was presented by Dr. Kaoru Ando (Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan) and his colleagues at the American Heart Association Scientific Sessions in Orlando, Florida on November 8 and has been published in Circulation. 2015; 132: A12007. Information on the CHERRY study is based on publicly presented data. Amarin disclaims responsibility for inaccuracies of publicly presented data. Amarin looks forward to a full publication of the CHERRY study to more fully assess the strengths and limitations of the study and the resulting data.

Amarin is encouraged by the results of the CHERRY study as the active ingredient of Vascepa is EPA. The study adds to a body of evidence that suggests that the Amarin-sponsored cardiovascular outcomes trial, REDUCE -IT (Reduction of Cardiovascular Events with EPA - Intervention Trial), may be positioned for success.

About the REDUCE-IT study

REDUCE-IT (Reduction of Cardiovascular Events with EPA - Intervention Trial), is a multinational, prospective, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the effectiveness of 4 grams daily of Vascepa in reducing the prevalence of first major cardiovascular events in a high-risk patient population. The control arm of the study is comprised of patients on stable statin therapy plus placebo. The active arm of the study is comprised of patients on stable statin therapy plus Vascepa.

Patients enrolled in the REDUCE-IT study have elevated or high triglyceride levels despite statin therapy and either coronary heart disease or risk factors for coronary heart disease. 

The REDUCE-IT study is designed with a composite MACE (Major Adverse Cardiovascular Event) endpoint of cardiovascular death, nonfatal myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina caused by myocardial ischemia. The study also includes secondary and tertiary endpoints and subgroup analyses agreed-upon with FDA.

The REDUCE-IT trial commenced patient enrollment and randomization in 2011 and continues on schedule towards anticipated completion in 2017 and publication of results in 2018. Completion of the REDUCE-IT study is based on attainment of 1,612 cumulative patients with documented primary cardiovascular events. The results of this important trial could lead to improved medical care for tens of millions of patients.

Amarin is blinded to the ongoing study results. An interim review by the independent data monitoring committee (DMC) of the trial's efficacy and safety results is expected to occur during 2016 upon reaching 60% of the target aggregate number of cardiovascular events. Based on comprehensive review of clinical, epidemiological, and genetic data, Amarin continues to believe that REDUCE-IT is positioned for success at completion. Given the high thresholds of overwhelming efficacy and safety typically required to be achieved prior to an independent DMC recommending an early stop to a cardiovascular outcomes trial like REDUCE-IT, Amarin continues to believe that it is most likely that the REDUCE-IT study will run to its completion.

About VASCEPA® (icosapent ethyl) capsules

VASCEPA® (icosapent ethyl) capsules, known in scientific literature as AMR101, is a highly pure-EPA omega-3 prescription product in a 1 gram capsule.

Indications and Usage

  • VASCEPA (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe ( ≥ 500 mg/dL) hypertriglyceridemia.
  • The effect of VASCEPA on the risk for pancreatitis and cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

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.
  • The most common reported adverse reaction (incidence > 2% and greater than placebo) was arthralgia (2.3% for Vascepa, 1.0% for placebo). There was no reported adverse reaction > 3% and greater than placebo.
  • Patients receiving treatment with VASCEPA and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.
  • In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy.
  • Patients should be advised to swallow VASCEPA capsules whole; not to break open, crush, dissolve, or chew VASCEPA.
  • Adverse events and product complaints may be reported by calling 1-855-VASCEPA or the FDA at 1-800-FDA-1088.

FULL VASCEPA PRESCRIBING INFORMATION CAN BE FOUND AT WWW.VASCEPA.COM.

Vascepa has been approved for use by the FDA as an adjunct to diet to reduce triglyceride levels in adult patients with severe (>500 mg/dL) hypertriglyceridemia. Vascepa is under various stages of development for potential use in other indications that have not been approved by the FDA. Nothing in this press release should be construed as promoting the use of Vascepa in any indication that has not been approved by the FDA.

Further study such as the REDUCE-IT trial is needed to determine if the effects of Vascepa can reduce residual risk in coronary heart disease patients already on statin therapy.

Forward-looking statements

This FAQ contains forward-looking statements, including statements about the potential efficacy, safety and therapeutic benefits of EPA and Amarin's product candidates, Amarin's statements regarding clinical trial results, including statements about the clinical importance of certain biomarkers and the impact and potential impact of EPA drug therapy and Vascepa on such biomarkers, cardiovascular risk reduction after statin therapy and the endpoints defined in the REDUCE-IT study. These forward-looking statements are not promises or guarantees and involve substantial risks and uncertainties. Among the factors that could cause actual results to differ materially from those described or projected herein include uncertainties associated generally with research and development, clinical trials and related regulatory reviews and approvals, including the risk that historical and comparable clinical trial results may not be predictive of future REDUCE-IT study results, that regulatory reviews may impact the current design of the REDUCE-IT study and cause a change in strategic direction with respect to continuation of the study, and that changes in studied lipid biomarkers may not have clinically meaningful effect or support regulatory approvals. 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 its most recent Quarterly Report on Form 10-Q. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Amarin undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise.

Dated November 9, 2015

  1. Ando K, Wantanabe T, Daidoji H, et al. Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography: A Randomized Controlled Trial. Circulation. 2015;132:A12007.
  2. Ando K. Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography: A Randomized Controlled Trial. Presented at the 2015 AHA Scientific Sessions. Orlando, Florida.
  3. Watanabe T, Miyamoto T, Miyasita T, et al. Combination therapy of eicosapentanoic acid and pitavastatin for coronary plaque regression evaluated by integrated backscatter intravascular ultrasonography (CHERRY study)–rationale and design. J Cardiol. 2014;64(3):236-9.
  4. Dohi T, Miyauchi K, Okazaki S, Yokoyama T, Yanagisawa N, Tamura H, Kojima T, Yokoyama K, Kurata T, Daida H. Plaque regression determined by intravascular ultrasound predicts long-term outcomes of patients with acute coronary syndrome. J Atheroscler Thromb. 2011;18:231–9.
  5. Nicholls SJ, Hsu A, Wolski K, Hu B, Bayturan O, Lavoie A, Uno K, Tuzcu EM, Nissen SE. Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol. 2010;55(21):2399-407.
  6. Miyauchi K, Daida H, Morimoto T, Hiro T, Kimura T, Nakagawa Y, Yamagishi M,Ozaki Y, Kadota K, Kimura K, Hirayama A, Hasegawa Y, Uchiyama S, MatsuzakiM. Reverse vessel remodeling but not coronary plaque regression could predict future cardiovascular events in ACS patients with intensive statin therapy—the extended JAPAN-ACS study. Circ J. 2012;76:825–32.
  7. Amano T, Matsubara T, Uetani T, Nanki M, Marui N, Kato M, Arai K, Yokoi K,Ando H, Ishii H, Izawa H, Murohara T. Impact of metabolic syndrome on tissue characteristics of angiographically mild to moderate coronary lesions integrated backscatter intravascular ultrasound study. J Am Coll Cardiol. 2007;49:1149–56.
  8. Kawasaki M, Takatsu H, Noda T, Sano K, Ito Y, Hayakawa K, Tsuchiya K, AraiM, Nishigaki K, Takemura G, Minatoguchi S, Fujiwara T, Fujiwara H. In vivo quantitative tissue characterization of human coronary arterial plaques by use of integrated backscatter intravascular ultrasound and comparison with angioscopic findings. Circulation 2002;105:2487–92.
  9. Kawasaki M, Sano K, Okubo M, Yokoyama H, Ito Y, Murata I, Tsuchiya K, Minatoguchi S, Zhou X, Fujita H, Fujiwara H: Volumetric quantitative analysis of tissue characteristics of coronary plaques after statin therapy using three dimensional integrated backscatter intravascular ultrasound. J Am Coll Cardiol. 2005;45:1946-1953.
  10. Tsujita K, Sugiyama S, Sumida H, et al. Impact of Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary Plaque Regression in Patients With Percutaneous Coronary Intervention: The Multicenter Randomized Controlled PRECISE-IVUS Trial. J Am Coll Cardiol. 2015;66:495-507.
  11. Okubo M, Kawasaki M, Ishihara Y, Takeyama U, Yasuda S, Kubota T, TanakaYamaki T, Ojio S, Nishigaki K, Takemura G, Saio M, Takami T, Fujiwara H,Minatoguchi S. Tissue characterization of coronary plaques: comparison of integrated backscatter intravascular ultrasound with virtual histology intravascular ultrasound. Circ J. 2008;72:1631–9.
  12. Amano T, Matsubara T, Uetani T, Kato M, Kato B, Yoshida T, Harada K, Kumagai S, Kunimura A, Shinbo Y, Ishii H, Murohara T. Lipid-rich plaques predict nontarget-lesion ischemic events in patients undergoing percutaneous coronary intervention. Circ J. 2011;75:157–66.
  13. Sano K, Kawasaki M, Ishihara Y, Okubo M, Tsuchiya K, Nishigaki K, Zhou X, Minatoguchi S, Fujita H, Fujiwara H. Assessment of vulnerable plaques causing acute coronary syndrome using integrated backscatter intravascular ultrasound. J Am Coll Cardiol. 2006;47:734-741.
  14. Cawood AL, Ding R, Napper FL, et al. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis. 2010;212(1):252-259.
  15. Thies F, Garry JM, Yaqoob P, et al. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet. 2003;361(9356):477-485.
  16. Nishio R, Shinke T, Otake H, et al. Stabilizing effect of combined eicosapentaenoic acid and statin therapy on coronary thin-cap fibroatheroma. Atherosclerosis. 2014;234(1):114-119.
  17. Nishio R, Shinke T, Otake H, et al. Stabilizing effect of combined eicosapentaenoic acid and statin therapy on coronary thin-cap fibroatheroma. Atherosclerosis. 2014;234(1):114-119
  18. Uehara H, Miyagi N, Shimajiri M, Nago C. The additional effect of eicosapentaenoic acid on coronary plaque stability in stable angina patients with statin use by optical coherence tomography analysis [abstract P5495]. Eur Heart J. 2013;34 (suppl 1):1011.
  19. Yamano T, Kubo T, Shiono Y, et al. Impact of eicosapentaenoic acid treatment on the fibrous cap thickness in patients with coronary atherosclerotic plaque: an optical coherence tomography study. J Atheroscler Thormb. 2015;22(1):52-61.
  20. Niki T, Wakatsuki T, Bando M, et al. Effects of additional eicosapentaenoic acid to statin therapy on inflammatory cytokines and the tissue characterization of coronary plaque assessed by integrated backscatter intravascular ultrasound systems [abstract]. Circulation. 2012;126(21 suppl):A14434.
  21. Katoh A, Ikeda H. Daily intake of eicosapentaenoic acid inhibits the progression of carotid intimal-media thickness in patients with dyslipidemia [in Japanese]. Ther Res. 2011;32(6):863-868.*
  22. Mita T, Watada H, Ogihara T, et al. Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes. Atherosclerosis. 2007;191(1):162-167.
  23. Maeda K. Effect of highly purified eicosapentaenoic acid (EPA) for patients with multiple artery atherosclerotic risk factors and clinical usefulness of the ratio of serum EPA to arachidonic acid (AA) as the indicator of therapy effect of atherosclerosis [in Japanese]. Ther Res. 2014;35(2):177-182.*
  24. Wakita Y, Wakida Y, Itou T, Mizuno R. High-purity-eicosapentaenoic-acid in addition to a strong statin makes regression of coronary plaque in patients with angina-pectoris and impaired glucose tolerance [abstract]. Circ J. 2013;77(suppl I):I-2678.
  25. Shintani Y, Kawasaki T. The impact of a pure-EPA omega-3 fatty acid on coronary plaque stabilization; a plaque component analysis with 64-slice multi-detector row computed tomography [abstract]. J Am Coll Cardiol. 2012;59(13 suppl):E1731.
  26. Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis. 2015;242:357-66.
  27. Bayturan O, Kapadia S, Nicholls SJ, et al. Clinical predictors of plaque progression despite very low levels of low-density lipoprotein cholesterol. J Am Coll Cardiol. 2010;55:2736-2742.
  28. Matsuzaki M, Yokoyama M, Saito Y, Origasa H, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, et al. Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease. Circ J. 2009;73:1283–90.

*English translation available from upon request

In this publication (http://www.atherosclerosis-journal.com/article/S0021-9150(15)30055-1/pdf) Drs. Borow, Nelson and Mason provide an in-depth analysis of the evidence supporting the biological effects of EPA within the atherothrombotic process, in addition to the lipid lowering effects, and its potential clinical benefit in atherosclerotic cardiovascular disease.

Dr. Borow and colleagues assessed the literature-reported effects of EPA across the cellular and molecular mechanisms responsible for endothelial dysfunction, vasodilation, oxidation, inflammation, atherosclerotic plaque development and rupture, and thrombus formation.

The article points out that the antioxidant effects of EPA as reported in in vitro and in vivo studies may be attributed to the intercalation of EPA into the cell membranes where it may interfere with the propagation of oxidation and preserve membrane lipid structural organization and fluidity. The authors link these mechanisms to the published evidence supporting the beneficial effects of EPA on endothelial function.

The authors also discuss the biological mechanisms by which EPA may exert anti-inflammatory effects and review the clinical evidence for reductions in markers of inflammation from the ANCHOR, MARINE, and other studies.

Importantly, the observed effects of EPA in atherosclerotic plaques are reviewed. The authors note that EPA has been shown to increase fibrous cap thickening, reduce plaque volume and arterial stiffness, and exert favorable changes on plaque extracellular matrix, all of which may increase plaque stability and decrease the vulnerability of plaque to rupture. Additionally, the authors suggest that EPA’s potential effects on platelet aggregation may help limit thrombus size in the event of a plaque rupture. These reported pleotropic effects of EPA inform the authors’ discussion around the biologic plausibility of EPA therapy to reduce atherosclerotic cardiovascular events.

The authors indicate that REDUCE-IT (NCT01492361), an ongoing, randomized, controlled clinical trial is designed to evaluate the efficacy of Vascepa® (icosapent ethyl), a highly purified prescription EPA-only product, administered at 4/g day in combination with a statin as compared to statin alone in reducing CV events in high-risk patients with persistently high triglycerides despite statin treatment. Based on the literature reporting  favorable effects of EPA on lipid parameters and on the pleiotropic effects of EPA within the atherothrombotic process, the authors anticipate that the results of REDUCE-IT will clarify the potential role of Vascepa in reducing CV events in statin-treated patients.

Amarin provided support and funding for writing assistance as acknowledged in the publication.

About VASCEPA® (icosapent ethyl) capsules

VASCEPA® (icosapent ethyl) capsules, known in scientific literature as AMR101, is a highly pure-EPA omega-3 prescription product in a 1 gram capsule.

FDA-approved Indications and Usage

  • VASCEPA (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.
  • The effect of VASCEPA on the risk for pancreatitis and cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

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.
  • The most common reported adverse reaction (incidence >2% and greater than placebo) was arthralgia (2.3% for Vascepa, 1.0% for placebo). There was no reported adverse reaction >3% and greater than placebo.
  • Patients receiving treatment with VASCEPA and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.
  • In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy.
  • Patients should be advised to swallow VASCEPA capsules whole; not to break open, crush, dissolve, or chew VASCEPA.
  • Adverse events and product complaints may be reported by calling
    1-855-VASCEPA or the FDA at 1-800-FDA-1088.

FULL VASCEPA PRESCRIBING INFORMATION CAN BE FOUND AT WWW.VASCEPA.COM.

Vascepa has been approved for use by the FDA as an adjunct to diet to reduce triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. Vascepa is under various stages of development for potential use in other indications that have not been approved by the FDA. Nothing in this FAQ response should be construed as promoting the use of Vascepa in any indication that has not been approved by the FDA.

This update was posted on August 6, 2015 and speaks only as of that date. Amarin undertakes no obligation to update or revise the information contained in this update, whether as a result of new information, future events or circumstances or otherwise.

VASCEPA® is a registered trademark of the Amarin group of companies.

Amarin is pleased to announce the publication of “Rationale and Design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial” in the March issue of Clinical Cardiology.

The article can be accessed here. Also, an Amarin press release has been issued related to this publication.

The following are key points regarding the study design for REDUCE-IT:

REDUCE-IT: Study Design

  • REDUCE-IT is a landmark global study involving approximately 8,000 patients
  • It is a randomized, multicenter, double-blind, placebo-controlled study designed to determine if treatment with VASCEPA® 4 g/day versus placebo reduces major adverse cardiovascular events (MACE) in statin-treated patients with persistent hypertriglyceridemia and high cardiovascular risk
  • The primary endpoint of the study is the time to the first occurrence of the composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina
  • Secondary endpoints include time to event analyses of components of the primary endpoint
  • The study is being conducted under a special protocol assessment agreement with the FDA

Please see the attached document for a detailed response. This information is intended for communication with investors and should not be construed as marketing the use of any Amarin products or product candidates. Click Here.

In this publication (http://online.liebertpub.com/doi/pdfplus/10.1089/met.2014.0137) Drs. Bays, Ballantyne, and colleagues, provide an analysis of the effects of VASCEPA® (icosapent ethyl) on high-sensitivity C-reactive protein (hsCRP) and lipid parameters in patients from the MARINE and ANCHOR studies (two phase 3 studies) with metabolic syndrome, with and without stable statin therapy.

A constellation of metabolic and physical attributes including increased waist circumference, high blood pressure, hyperglycemia and elevated triglyceride (TG) levels comprise metabolic syndrome.1-5 The incidence of metabolic syndrome is increasing with the prevalence of excess body weight, obesity, and sedentary lifestyles, and patients with metabolic syndrome are at increased risk for developing cardiovascular disease (CVD) and type 2 diabetes.2,6 Increased hsCRP is a marker for CVD and can reflect a proinflammatory response from excess body fat and/or from proinflammatory and proatherogenic vasculature.7,8

In this post-hoc analysis, Dr. Bays and colleagues assessed changes in inflammatory markers and lipid parameters in the subgroup of patients in the MARINE trial (TG levels ≥ 500 and ≤ 2000 mg/dL with or without statin therapy) and in the ANCHOR trial (TG ≥ 200 and < 500 mg/dL, despite low-density lipoprotein cholesterol [LDL-C] control with stable statin therapy) who had metabolic syndrome at baseline. Through analysis of baseline characteristics, it was determined that 89.1% of patients in MARINE had metabolic syndrome and that 91.9% of patients in ANCHOR had metabolic syndrome at baseline.

In patients with metabolic syndrome in MARINE (n=204) and ANCHOR (n=645), Vascepa 4 g/day significantly lowered hsCRP levels by 40.0% and 23.0%, respectively, compared with placebo. In the subgroup of patients with metabolic syndrome on statin therapy in the MARINE trial, Vascepa 4 g/day significantly reduced hsCRP levels by 78.0% (n=16).

In MARINE and ANCHOR, respectively, Vascepa 4g/day also significantly reduced: TGs (35.0%, 21.7%); non-high-density lipoprotein cholesterol (non-HDL-C; 19.9%, 13.5%); and apolipoprotein B (Apo B; 9.1%, 8.8%), all compared with placebo. In MARINE this was accomplished without raising LDL-C levels compared with placebo, and in ANCHOR a significant reduction in LDL-C of 5.2% was achieved compared with placebo.

This report is of interest to clinicians as the patient population with the metabolic syndrome continues to increase along with the prevalence of excess body weight and obesity. Importantly, in hypertriglyceridemic patients with metabolic syndrome and with or without statin therapy, Vascepa 4 g/day significantly lowered hsCRP levels and improved other lipid parameters without raising LDL-C.

Amarin sponsored the MARINE and ANCHOR studies and provided funding for writing assistance as acknowledged in the publication.

About Vascepa® (icosapent ethyl) capsules

Vascepa® (icosapent ethyl) capsules, known in scientific literature as AMR101, is a highly-pure EPA omega-3 prescription product in a 1 gram capsule.

Indications and Usage

  • Vascepa (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.
  • The effect of Vascepa on the risk for pancreatitis and cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

Important Safety Information for Vascepa

  • Vascepa is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to Vascepa or any of its components and should be used with caution in patients with known hypersensitivity to fish and/or shellfish.
  • The most common reported adverse reaction (incidence > 2% and greater than placebo) was arthralgia (2.3% for Vascepa, 1.0% for placebo). There was no reported adverse reaction > 3% and greater than placebo.

FULL VASCEPA PRESCRIBING INFORMATION CAN BE FOUND AT WWW.VASCEPA.COM.

Vascepa has been approved for use by the FDA as an adjunct to diet to reduce triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia. Vascepa is under various stages of development for potential use in other indications that have not been approved by the FDA. Nothing in this update should be construed as marketing the use of Vascepa in any indication that has not been approved by the FDA.

VASCEPA® is a registered trademark of the Amarin group of companies

____

1. Grundy SM, Brewer HB, Jr., Cleeman JI, et al. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433-438.

2. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640-1645.

3. Bays HE, Toth PP, Kris-Etherton PM, et al. Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association. J Clin Lipidol. 2013;7:304-383.

4. Yang J, Kang J, Guan Y. The mechanisms linking adiposopathy to type 2 diabetes. Front Med. 2013;7:433-444.

5. Bays HE. Adiposopathy, diabetes mellitus, and primary prevention of atherosclerotic coronary artery disease: treating "sick fat" through improving fat function with antidiabetes therapies. Am J Cardiol. 2012;110:4B-12B.

6. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008;28:629-636.

7. Ridker PM, Kastelein JJ, Genest J, et al. C-reactive protein and cholesterol are equally strong predictors of cardiovascular risk and both are important for quality clinical care. Eur Heart J. 2013;34:1258-1261.

8. Kaptoge S, Di AE, Pennells L, et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med. 2012;367:1310-1320.

In this publication [http://dx.doi.org/10.1016/j.jacl.2014.11.009], Dr. Ballantyne and coauthors report that Vascepa® 4g/day, as an add-on to statin therapy, reduced key atherogenic lipoprotein particle concentrations, compared to placebo, in hypertriglyceridemic patients who are at high cardiovascular (CV) risk and at low-density-lipoprotein cholesterol (LDL-C) goal.

The authors point out that lipoprotein particle concentration plays an important role in atherogenicity and that decreases in key atherogenic lipoprotein particle concentrations in these patients may be of clinical benefit.

Vascepa is a high-purity prescription form of eicosapentaenoic acid ethyl ester approved at a dose of 4 g/day as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (TG≥500 mg/dL).

From Amarin's perspective, the results of this study show that Vascepa had additional favorable effects on atherogenic lipoproteins in hypertriglyceridemic patients who are on statin therapy which we believe to be consistent with the broad positive effect Vascepa has demonstrated on other lipid markers thought to be associated with heart disease and atherosclerosis.

The authors suggest that the observed reductions in LDL particle number with Vascepa treatment compared with placebo are due, at least in part, to reductions in TG production and increases in TG clearance, coupled with efficient LDL particle clearance. They propose that the reductions in LDL particle number with Vascepa could be related to the finding that Vascepa did not raise LDL-C relative to placebo in either the MARINE or ANCHOR phase 3 clinical studies.

In this article, Dr. Ballantyne and his coauthors detail the results from this prespecified exploratory analysis of the effects of Vascepa on lipoprotein particle concentration and size from the ANCHOR study of patients at high cardiovascular risk with TG ≥200 and <500 mg/dL despite statin control of LDL-C.

The authors report that treatment with Vascepa 4 g/day, compared with placebo, achieved statistically significant reductions in the concentration of: total, large, and medium very-low-density lipoprotein (VLDL) particles; total and small LDL particles; and total and large high-density lipoprotein (HDL) particles. Compared with placebo, Vascepa 4 g/day also statistically significantly reduced VLDL and HDL particle size with a modest but significant increase in LDL particle size.

These reductions in total VLDL particle concentration and size with Vascepa are consistent with its TG-lowering effects.

Amarin sponsored the ANCHOR study and provided funding for writing assistance as acknowledged in the publication.

About Vascepa® (icosapent ethyl) capsules

Vascepa® (icosapent ethyl) capsules, known in scientific literature as AMR101, is a highly-pure EPA omega-3 prescription product in a 1 gram capsule.

Indications and Usage

  • Vascepa (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.
  • The effect of Vascepa on the risk for pancreatitis and cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

Important Safety Information for Vascepa

  • Vascepa is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to Vascepa or any of its components and should be used with caution in patients with known hypersensitivity to fish and/or shellfish.
  • The most common reported adverse reaction (incidence > 2% and greater than placebo) was arthralgia (2.3% for Vascepa, 1.0% for placebo). There was no reported adverse reaction > 3% and greater than placebo.

FULL VASCEPA PRESCRIBING INFORMATION CAN BE FOUND AT WWW.VASCEPA.COM.

Vascepa has been approved for use by the FDA as an adjunct to diet to reduce triglyceride levels in adult patients with severe ( >500 mg/dL) hypertriglyceridemia. Vascepa is under various stages of development for potential use in other indications that have not been approved by the FDA. Nothing in this update should be construed as marketing the use of Vascepa in any indication that has not been approved by the FDA.

VASCEPA® is a registered trademark of the Amarin group of companies

This article centers on low-dose dietary supplement products that are not designed or intended to treat cardiovascular disease. The FDA permits a dietary health claim for use with food products and applicable to dietary supplements stating that “supportive but not conclusive research shows that consumption of EPA and DHA may reduce the risk of coronary heart disease.”  This claim and other unapproved claims by dietary supplement manufacturers has led to increased use of dietary supplements in place of appropriate medical treatment for serious disease conditions.

Importantly, dietary supplements with EPA and DHA are not recommended by the FDA at doses of more than 2 grams per day and are not recommended by FDA at any dose to treat or mitigate disease. Dietary supplements are not required to meet strict FDA drug standards for safety, efficacy, and manufacturing. Many dietary supplement fish oils are low in omega-3 content, may vary in content from lot to lot, can contain harmful contaminants, are prone to oxidation that mitigates antioxidant effects, and contain DHA, which is associated with increases in bad cholesterol in patients at high risk characterized by high and very high blood levels of triglycerides. 

Amarin remains a leader in the research and development of the omega-3 acid, EPA, through clinical study of its highly pure pharmaceutical grade lead product, Vascepa® (icosapent ethyl) capsules.  Amarin received FDA approval of 4 gram daily use of Vascepa in July 2012 as an adjunct to diet to lower triglycerides in patients with very high (500 mg/dL) triglycerides (VHTG), and is pursuing FDA approval in the treatment of patients with persistent high (200-499 mg/dL) triglycerides despite statin therapy.  The effect of Vascepa on the risk for cardiovascular mortality and morbidity in patients has not been determined.  FDA approved use of Vascepa is consistent with numerous national and international treatment guidelines and position statements.

Amarin is also investing more than $100 million in a first-of-its-kind cardiovascular outcomes study called the REDUCE-IT study.  REDUCE-IT is being conducted to evaluate the efficacy of Vascepa in reducing cardiovascular risk in a high risk, elevated triglyceride-level patient population on statin therapy.  The REDUCE-IT study is expected to be completed in 2017 with results published in 2018.  The REDUCE-IT study follows the only other outcomes study of a highly pure EPA product, the JELIS study. JELIS, an open label study, showed that EPA in conjunction with statins in Japanese patients (N=18,645) reduced cardiovascular events by 19% compared to statins alone. Importantly, this result was obtained in a population in which triglycerides were in the normal range in approximately half of the patients. The JELIS study showed a 53% reduction in cardiovascular events in the EPA with statin group compared to the statin-only group within the subset of patients (N=957) who had both elevated levels of triglycerides (>150 mg/dL) and low levels of HDL-C (<40 mg/dL).  This result in patients with high triglyceride levels and low HDL-C is directionally consistent with subgroup analyses of patients treated with other triglyceride lowering agents in the ACCORD-Lipid and AIM-HIGH studies.

The REDUCE-IT study is the subject of a special protocol assessment with the FDA and was designed by Amarin to take into account many of the perceived weaknesses of some studies of omega-3s that did not show clinical benefit, including the use of low-doses of omega-3s, the study of patient populations at normal triglyceride levels and the use of omega-3 compositions that are not pharmaceutical grade and include the omega-3 acid, DHA.  Amarin clinical trials have demonstrated that Vascepa is effective in studied patients at lowering triglycerides without increasing bad cholesterol.  

The New York Times article raises important considerations.  Most important, careful analysis of the relevant studies and the latest scientific knowledge are essential for patients and physicians to make informed decisions on how best to care for their health and treat serious medical conditions. Amarin is dedicated to improved patient care and is spending more than $100 million to generate additional outcomes study and other data relevant to the potential of appropriate doses of pharmaceutical grade EPA to reduce cardiovascular risk in high risk patients.

Vascepa has been approved for use by the United States Food and Drug Administration (FDA) as an adjunct to diet to reduce triglyceride levels in adult patients with severe (>500 mg/dL) hypertriglyceridemia. Vascepa is under various stages of development for potential use in other indications that have not been approved by the FDA. Nothing in this information should be construed as marketing the use of Vascepa in any indication that has not been approved by the FDA.

About Vascepa® (icosapent ethyl) capsules

Vascepa® (icosapent ethyl) capsules, known in scientific literature as AMR101, is a highly pure-EPA omega-3 prescription product in a 1 gram capsule.

Indications and Usage

  • Vascepa (icosapent ethyl) is indicated in the United States as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.
  • The effect of Vascepa on the risk for pancreatitis and cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

Important Safety Information for Vascepa

  • Vascepa is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to Vascepa or any of its components and should be used with caution in patients with known hypersensitivity to fish and/or shellfish.
  • The most common reported adverse reaction (incidence > 2% and greater than placebo) was arthralgia (2.3% for Vascepa, 1.0% for placebo).There was no reported adverse reaction > 3% and greater than placebo.

FULL VASCEPA PRESCRIBING INFORMATION CAN BE FOUND AT WWW.VASCEPA.COM.

In this case series report [DOI:10.1007/s40119-014-0032-9], Dr. Hassan and coauthors share the results of a retrospective analysis of records from a private endocrinology practice of patients with prediabetes or diabetes who received Lovaza® (4 g/day) and were subsequently switched to Vascepa® (4 g/day).  Dr. Hassan and colleagues note that their patients were switched to Vascepa, which contains only icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA), due to the potential for Lovaza, which contains docosahexaenoic acid (DHA) as well as EPA, to raise low-density lipoprotein cholesterol (LDL-C) and/or cause gastrointestinal upset in some patients.1   Vascepa was well tolerated by all patients who switched from Lovaza to Vascepa, and LDL-C and other lipid parameters improved in most patients.

Patients with diabetes and prediabetes are at increased risk for dyslipidemia and cardiovascular disease (CVD). To reduce this risk, statins and additional therapies may be considered. The authors note that even when LDL-C and glycemic treatment goals are reached, some patients may have residual risk of cardiovascular (CV) events due to elevated triglycerides (TGs).  Prescription omega-3 fatty acids offer an option to reduce TGs and potentially improve other lipid parameters, although, in some patients, products that contain DHA may increase LDL-C levels.

The authors included the records of the 10 patients in this practice that met the criteria for this analysis, but were outside of Vascepa FDA-approved product labeling. Patient records were analyzed for LDL-C, TG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and non-HDL-C measured before and after the switch to Vascepa. They found that, in most cases, patients experienced decreases in LDL-C, TG, non-HDL-C, and TC and increases in HDL-C following the switch to Vascepa.

Nine of the 10 patients were on concomitant statin therapy throughout the study period.  Reductions in LDL-C, TC, and non-HDL-C were observed in 8 patients, reductions or no changes in TG were observed in 8 patients, and increases or no changes in HDL-C were observed in 8 patients. No gastrointestinal adverse events were observed.  Two patients experienced increases in LDL-C, TG, non-HDL-C, and TC after switching to Vascepa.

The authors’ findings are similar to those of other recent reports of patients switched from EPA + DHA formulations to Vascepa.2,3  The authors note that their analysis was exploratory and may be of interest to the clinical community for potential future prospective studies.

Dr. Hassan acknowledged that the role for omega-3 fatty acids in the prevention of CV events bears further investigation, and points to the ongoing cardiovascular outcomes study REDUCE-IT as highly anticipated. REDUCE-IT is Amarin’s ongoing, large, phase III trial to assess the efficacy of Vascepa 4 g/day in preventing a first major cardiovascular event in patients with persistent hypertriglyceridemia despite statin treatment who also have established CVD or are at high risk for CVD.

Amarin provided support and funding for writing assistance as acknowledged in the publication.

______

Note:

 

  • LOVAZA® is a registered trademark of the GlaxoSmithKline group of companies
  • VASCEPA® is a registered trademark of the Amarin group of companies

 

  1. LOVAZA (omega-3-acid ethyl esters) capsules [package insert]. Research Triangle Park, NC: GlaxoSmithKline; May 2014.
  2. Hilleman DE, Malesker MA. Potential benefits of icosapent ethyl on the lipid profile: case studies. Clin Med Insights Cardiol. 2014;8:13-15.
  3. Castaldo RS. A retrospective case series of the lipid effects of switching from omega-3 fatty acid ethyl esters to icosapent ethyl in hyperlipidemic patients. Postgrad Med. 2014;126:268-273.

In this article (doi: 10.1016/j.bbamem.2014.10.016), Dr. R. Preston Mason (Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School) and his colleague Robert F. Jacob report the results of a study that tested the comparative effects of EPA and other triglyceride-lowering agents (fenofibrate, niacin, and gemfibrozil) on lipid oxidation (i.e. oxidative stress) in human low-density lipoprotein (LDL) as well as on polyunsaturated fatty acids-enriched membrane lipid vesicles.The antioxidant effects were also tested for EPA in combination with the active metabolite arising from atorvastatin (i.e. the o-hydroxy (active) metabolite (ATM)). Additionally, this study compared the effects of EPA and the other triglyceride-lowering agents on the formation of cholesterol crystalline domains that can form in membranes under oxidative stress conditions.Oxidative stress and the resultant damage leads to endothelial dysfunction, inflammation, and foam cell formation during atherogenesis.

In this study, EPA was found to inhibit LDL oxidation in a dose-dependent manner and was distinguished from the other triglyceride-lowering agents, which had no significant effect.Similar effects were observed in membrane lipid vesicles, an effect that was significantly enhanced in combination with ATM.Additionally, in this study, only EPA inhibited glucose-induced cholesterol domain formation.

These data demonstrate that EPA inhibits hyperglycemia-induced changes in membrane lipid structural organization through a potent antioxidant mechanism associated with its distinct physicochemical interactions with the membrane bilayer.

Amarin provided financial support for this study.

In this publication (https://postgradmed.org/doi/10.3810/pgm.2014.11.2828), Dr. Howard S. Weintraub, Clinical Professor of Medicine, New York University School of Medicine, Clinical Director, NYU Center for the Prevention of Cardiovascular Disease, offers a comprehensive summary of efficacy, safety, and key considerations of currently approved prescription omega-3 fatty acids (OM3FA) products in patients with elevated triglycerides, with or without concomitant elevations in other atherogenic parameters, who may be at a higher risk for cardiovascular disease.

Excluding generic formulations of Lovaza, there are four prescription OM3FA formulations approved in the United States:  omega-3-acid ethyl esters (Lovaza® and Omtryg™), omega-3-carboxylic acids (Epanova®), each of which contains both EPA and DHA, and icosapent ethyl (Vascepa®), which is an EPA-only formulation.

The discussion includes review of both older clinical study results of Lovaza as well as more recent clinical results for Lovaza as studied as a separate arm of the phase 3 trial of Omtryg.  All prescription OM3FA products effectively lower triglycerides.  Products that contain DHA can raise levels of low-density lipoprotein cholesterol (LDL-C), which is of particular concern in patients with atherosclerosis.  The only approved prescription OM3FA that does not contain DHA is Vascepa.

The review also emphasizes that omega-3 dietary supplements should not be substituted for prescription OM3FA’s as the efficacy of such products have not been clinically demonstrated or FDA approved and the safety and tolerability of supplements are not well known, particularly at prescription OM3FA dose levels.

Amarin provided support and funding for writing assistance as acknowledged in the publication.

_____________

Note:

  • LOVAZA® is a registered trademark of the GlaxoSmithKline group of companies
  • OMTRYG is a trademark of Trygg Pharma, Inc.
  • EPANOVA® is a registered trademark of the AstraZeneca group of companies
  • VASCEPA® is a registered trademark of the Amarin group of companies

In September 2014, the National Lipid Association (NLA) launched a nationwide triglyceride campaign during National Cholesterol Education Month. The NLA's announced goal is to encourage patient education and drive discussions about lipid management and the consequences of high cholesterol and triglyceride levels.

According to the NLA, the mission of the campaign is to encourage physicians to inform patients about the importance of proper treatment and prevention as it relates to their entire lipid profile - not just cholesterol, but elevated triglyceride levels, too.

"We want to raise awareness around elevated triglycerides with patients and health care providers alike, as they may unsuspectingly affect patients' health, even if they look and feel healthy," said NLA President Terry A. Jacobson, MD. "Fortunately, health care providers are committed to offering their patients their best care, and we're committed to ensuring they have the tools to do so."

In a recent survey of health care providers, the NLA discovered a need for standard protocols surrounding the measure of patients' total lipid profiles, including triglycerides. To jumpstart these educational and preventive efforts, the NLA urges health care providers to compare patients' triglyceride levels to the following categories:

With this campaign, NLA hopes to provide the necessary resources for clinical practice and education, as well as generate awareness about lipid management.

Amarin is not responsible for the content of NLA's campaign.

Amarin has reviewed with enthusiasm the publication on June 18th in The New England Journal of Medicine of two independent studies by leading research groups funded by the National Institutes of Health and the European Union related to reduced triglyceride (TG) levels and reduced cardiovascular (CV) risk.  One study was led by Dr. Sekar Katherisan of the Cardiovascular Research Center and Center for Human Genetic Research at Massachusetts General Hospital in Boston (DOI: 10.1056/NEJMoa1307095) and the other by Dr. Anne Tybjærg-Hansen from the Department of Clinical Biochemistry and Molecular Genetics at the Copenhagen University Hospital in Denmark( DOI: 10.1056/NEJMoa1308027).  Amarin did not provide funding or support for either study.  As the medical community eagerly searches for ways to further reduce CV risk beyond LDL-C-lowering, Amarin believes these two independent studies provide encouraging new data connecting reduced TG levels to reduced CV risk.  We encourage investors to review the publications and related press reports on the new studies for more information and consider this new information alongside our public disclosures filed with the Securities and Exchange Commission and other public comments we have made on the results of our ANCHOR study and our related pending REDUCE-IT cardiovascular outcomes study.   Of relevance to the new data, we refer investors to our May 2, 2014 press release titled, Amarin Announces Presentation of New MARINE and ANCHOR Post-Hoc Analyses at National Lipid Association Annual Scientific Sessions Showing Vascepa® Significantly Reduced Apolipoprotein C-III Levels.

The Lancet, August 16th review article, Triglycerides and cardiovascular disease, by Drs. Nordestgaard and Varbo, University of Copenhagen (doi:10.1016/S0140-6736(14)61177-6), discusses how the medical community has sought to further reduce cardiovascular risk beyond low-density lipoprotein cholesterol (LDL-C)-lowering and how the therapeutic raising of high-density lipoprotein cholesterol (HDL-C) has not demonstrated a cardiovascular benefit.  The article then offers an overview of the compelling epidemiological, clinical and genetic data connecting the treatment of elevated triglyceride levels to reduced cardiovascular risk. 

The authors summarize that “[t]he magnitude of the effect caused by triglyceride-lowering compares favourably with the reduction of… major vascular events and… all-cause mortality… [with] reduction in LDL cholesterol in statin trials, while acknowledging that the totality of evidence supporting the therapeutic lowering of LDL-C is more extensive than that for the therapeutic lowering of triglycerides.   Investors can review this publication to consider how this information may influence continued healthcare professional interest in triglyceride lowering therapies.  

The authors note that “[n]o large-scale randomized trial has examined the effect of reducing triglycerides on cardiovascular disease risk in people with raised triglycerides”, and cite REDUCE-IT as a study that is providing an “urgently needed” randomized intervention trial in patients with elevated triglycerides despite statin therapy. 

Please note, in referring to the REDUCE-IT study, the review article presents 2016 as the projected date for study completion.  As described in Amarin’s public disclosures, 2016 is the current estimated timing for an interim look at the study results.

Amarin has no connection to The Lancet article. Investors should consider this information together with Amarin public disclosures filed with the Securities and Exchange Commission, public comments on MARINE and ANCHOR studies and updates on the pending REDUCE-IT cardiovascular outcomes study.

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Updated: March 8, 2016 at 4:00 PM Eastern Time