December 16, 2019 — The U.S. Food and Drug Administration (FDA), on Dec. 13, approved the use of Vascepa (icosapent ethyl) capsules as an adjunctive therapy to reduce the risk of cardiovascular events in adults with elevated triglyceride levels.

The new FDA indication states this concentrated, refined fish oil drug can be used in patients with triglyceride levels of 150 milligrams per deciliter (mg/dL) or higher. Patients must also have either established cardiovascular disease or diabetes and two or more additional risk factors for cardiovascular disease. Patients are also supposed to be advised to continue physical activity and maintain a healthy diet.

After more than a decade of development and testing, Vascepa is now the first drug cleared by the FDA “as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride (TG) levels (≥150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease.”

The new indication was driven by data from the landmark REDUCE-IT study,[1] presented at the American Heart Association (AHA) 2018 meeting. The trial served as the basis for the supplemental New Drug Application to the FDA for Vascepa.

“The FDA approval of icosapent ethyl as an addition to statin therapy to reduce the risk of cardiovascular events is a major milestone in cardiovascular prevention,” said Deepak L. Bhatt, M.D., M.P.H., executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School, and lead investigator of the REDUCE-IT study. “Nothing this significant has happened in the world of cardiovascular prevention since the introduction of statins nearly three decades ago. Many patients stand to benefit from this historic advance in care.”

It is estimated that millions of high-risk patients in the United States could benefit from this new secondary drug therapy.[2]

Watch a VIDEO interview with Deepak Bhatt on the REDUCE-IT trial.

FDA Granted Priority Review to Expand the Indication for Vascepa

Amarin Pharma Inc. initially gained FDA approval for Vascepa in 2012 for adults with severe triglyceride levels. This new supplement application received FDA Priority Review status. The FDA grants priority review to applications for drugs that, if approved, would improve the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions.

“The FDA recognizes there is a need for additional medical treatments for cardiovascular disease,” said John Sharretts, M.D., acting deputy director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval will give patients with elevated triglycerides and other important risk factors, including heart disease, stroke and diabetes, an adjunctive treatment option that can help decrease their risk of cardiovascular events.”

High levels of triglycerides can play a role in the hardening of arteries or thickening of the artery wall, which can increase the risk of a heart attack or stroke. However, the mechanisms of action that contribute to reduced cardiovascular events among patients taking Vascepa are not completely understood, the FDA said in a statement about the new indication.

The agency also said Vascepa’s efficacy and safety were established in a study with 8,179 patients who were either 45 years and older with a documented history of coronary artery, cerebrovascular, carotid artery and peripheral artery disease, or 50 years and older with diabetes and additional risk factors for cardiovascular disease. Patients who received Vascepa were significantly less likely to experience a cardiovascular event, such as a stroke or heart attack. Vascepa’s active ingredient is the omega-3 fatty acid, eicosapentaenoic acid, derived from fish oil. Vascepa is taken orally.

In clinical trials, Vascepa was associated with an increased risk of atrial fibrillation or atrial flutter (irregular heart rhythms) requiring hospitalization. The incidence of atrial fibrillation was greater among patients with a history of atrial fibrillation or atrial flutter. Vascepa was also associated with an increased risk of bleeding events. The incidence of bleeding was higher among patients who were also taking other medications that increase the risk of bleeding, such as aspirin, clopidogrel or warfarin at the same time.

Landmark REDUCE-IT Clinical Trial Showed Big Improvements in Outcomes

In the global REDUCE-IT cardiovascular outcomes study, about 28 percent of patients in the control arm treated with statins and other contemporary therapy, but not treated with Vascepa, experienced a major adverse cardiovascular event (MACE). This was defined as the first occurrence of either myocardial infarction (heart attack), stroke, coronary revascularization, unstable angina requiring hospitalization or cardiovascular death.[1]

As evidenced by this MACE occurrence, there is a group of patients who, despite controlling their cholesterol on statin therapy, continue to have a high need for additional preventive cardiovascular care. For those adult patients in this group who have elevated triglycerides (TG) ≥150 mg/dL and established cardiovascular disease or diabetes and two or more additional risk factors for cardiovascular disease, Vascepa is the first drug approved to help reduce this persistent cardiovascular risk.

In a published exploratory analysis of the REDUCE-IT study, examining total (first and subsequent) cardiovascular events over a period of approximately five years, patients taking Vascepa on average experienced one fewer MACE per six patients studied, representing a 30 percent risk reduction in total MACE compared to placebo.[3]

The overall rates of adverse events and serious adverse events in the 5-year REDUCE-IT study were similar between Vascepa-treated patients and placebo-treated patients. As reflected in Vascepa’s expanded label and described below, Vascepa has been associated with increased risks of bleeding and atrial fibrillation/flutter, the latter being more prevalent in patients with a previous history of atrial fibrillation or flutter. It is recommended that patients taking Vascepa and concomitant anticoagulants and/or anti-platelet agents for bleeding be monitored. Also noted in the REDUCE-IT study is that patients for whom bleeding and/or atrial fibrillation/flutter were reported appeared to obtain a similar reduction in MACE as patients not reporting such adverse events. Such findings are consistent with published results of the study, which noted that the increased rates of such adverse events were low, notably lower than the reduction in MACE.[3]

Recurrent event analyses were conducted of the total primary endpoint events and total key secondary endpoints in REDUCE-IT using a series of statistical models and published in the Journal of the American College of Cardiology. These analyses are not in FDA labeling, were tertiary or exploratory endpoints. Most of the models used were pre-specified and one was post hoc. Each recurrent event statistical model has inherent strengths and weaknesses, with no single model considered definitive or outperforming the other models, and this is an evolving field of science. Nonetheless, results from these analyses are consistent across the various models; they also are consistent with the original primary and secondary endpoint results.

Together, the REDUCE-IT recurrent event analyses and the original primary and key secondary endpoint analyses support the robustness of the clinical benefit of Vascepa therapy in reducing cardiovascular risk.

Recently, a health economics study conducted by an expert group presented at the American Heart Association (AHA) 2019 Scientific Sessions showed the use of Vascepa offers potential cost savings for the overall healthcare system. This included the cost of Vascepa being offset by cost savings from reducing the occurrence of high-cost major adverse cardiovascular events.[4]

This rare finding follows conclusions from a separate independent drug pricing watchdog group, the Institute for Clinical and Economic Review (ICER). ICER found Vascepa was cost effective for cardiovascular risk reduction, a result seldom achieved in this organization’s analyses.[5]

Based on the great results of the REDUCE-IT outcomes study, multiple professional societies have updated guidelines or issued advisories to incorporate icosapent ethyl. These include the American Diabetes Association,[6] the European Society of Cardiology, The European Atherosclerosis Association,[7] and the National Lipid Association.[8]

Side Effects of Vascepa

Patients with allergies to fish or shellfish should be advised about the potential for allergic reactions. They should discontinue treatment and seek medical attention if any allergic reactions occur. The most common side effects reported in the clinical trials for Vascepa were musculoskeletal pain, peripheral edema (swelling of legs and hands), atrial fibrillation and arthralgia (joint pain).

New Vascepa Indication Expected to See Rapidly Expanded Use in 2020

Amarin reaffirmed its intention to promptly launch Vascepa in the United States for this new preventive care indication. Amarin said it was doubling the size of its sales force near the beginning of 2019 and said it is on track to double the size of its sales force again to a total of 800 sales representatives by the beginning of 2020.

Related Vascepa Content:

Vascepa Markedly Reduces First, Repeat and Total Cardiovascular Events

VIDEO: REDUCE-IT Trial Shows New Therapy Option for Patients With Uncontrolled Triglycerides — Interview with Deepak Bhatt, M.D.

Vascepa and Statins Significantly Reduce Cardiovascular Events

FDA Grants Priority Review for Vascepa sNDA



References:

1. Deepak L. Bhatt, P. Gabriel Steg, Michael Miller, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. January 3, 2019

N Engl J Med 2019; 380:11-22. DOI: 10.1056/NEJMoa1812792. https://www.nejm.org/doi/full/10.1056/NEJMoa1812792

2. Fan W, Philip S, Toth PP, et al. Prevalence of United States adults with triglycerides ≥ 135 mg/dL: NHANES 2007–2014. Cardiol J. 2019;26(5). DOI:

10.5603/CJ.2019.0000.

3. Bhatt DL, Steg PG, Miller M, et al. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J Am Coll Cardiol. Volume 73, Issue 22, June 2019; 73:2791-2802.

http://www.onlinejacc.org/content/73/22/2791

4. Cost-Effectiveness of Icosapent Ethyl in REDUCE-IT. Session FS.AOS.01 - Featured Science Population Science. AHA 2019. https://www.abstractsonline.com/pp8/#!/7891/presentation/35097.

5. ICER Issues Final Report and Policy Recommendations Regarding Additive Treatments for Cardiovascular Disease. Institute for Clinical and Economic Review. Publicjed online Oct. 17, 2019. https://icer-review.org/announcements/cvd_final_report/

6. American Diabetes Association. [web annotation]. Diabetes Care 2019;42(Suppl.1):S103–S123.

7. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019; ehz455. doi: 10.1093/eurheartj/ehz455.

8. Orringer CE, Jacobson TA, Maki KC. National Lipid Association scientific statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high- or very-high ASCVD risk. J Clin Lipidol. 2019. doi: 10.1016/j.jacl.2019.10.014.