Background Analysis: US FDA Advisory Committee to Review Proposed Expansion of the Indication of Amarin’s Vascepa – NOV 14, 2019 (EMDAC)

Announcement

The US FDA has scheduled an Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting for Thursday, November 14, 2019 to discuss a supplemental new drug application (sNDA) for Vascepa (icosapent ethyl) capsules for oral administration, sponsored by Amarin Pharma Inc. (Amarin), for the following proposed indication: To reduce the risk of cardiovascular events, as an adjunct to statin therapy in adult patients with elevated triglycerides levels (135 mg/dL or greater) and other risk factors for cardiovascular disease.

Product Background

Vascepa is a purified ethyl ester of eicosapentaenoic acid (EPA) derived from fish oil.

In July 2012, Vascepa was FDA-approved for use as an adjunct to diet to reduce triglyceride (TG) levels in adults with severe hypertriglyceridemia (defined as TG ≥ 500 mg/dL), at a dose of 4 grams per day.

On February 21, 2013, Amarin submitted an sNDA seeking to expand Vascepa’s indication to the treatment of patients with mixed dyslipidemia and coronary heart disease (CHD) or CHD risk equivalent, in co-administration with statin therapy. The results of a pivotal efficacy trial, named ANCHOR, were submitted to support the proposed use. The ANCHOR trial randomized 702 patients with TG levels ≥200 mg/dL and <500 mg/dL, LDL-C  ≥40 mg/dL and ≤115 mg/dL on statin therapy, and CHD or CHD risk equivalent, to receive either placebo or treatment with Vascepa. The median treatment difference in TG levels from baseline to Week 12 between Vascepa 4g/day and placebo was -21.5% (p<0.0001) and between Vascepa 2g/day and placebo was -10.1% (p=0.0005).

On October 16, 2013, the FDA convened the EMDAC to obtain the committee’s input on the sNDA. A majority of the EMDAC voted (2-yes versus 9-no) that the effects of Vascepa demonstrated in ANCHOR were not sufficient to support the proposed expansion. The consensus view was that ANCHOR showed that Vascepa is effective in lowering TG, but there was uncertainty about whether this would translate to cardiovascular (CV) disease benefit, the end purpose of the drug. There also was some concern about the placebo used in the trial due to a possible lack of inertness of the mineral oil component, which could lead to an overstatement of effects. Although this was a concern, there was not a conclusion that the mineral oil placebo was an inappropriate comparator. The committee commended Amarin for their research to date, but they concluded that results of the CV outcomes trial (CVOT) for Vascepa, which was ongoing at the time, were needed prior to approval.

In April 2015, Amarin reported that the FDA had issued a Complete Response Letter in response to the sNDA.

On March 28, 2019, after completion of the CVOT, named REDUCE-IT, Amarin announced that they submitted a second sNDA submission seeking to expand Vascepa’s indication, based on the trial results.

Clinical Trials of Proposed Indication

A summary of the design and top-line results of REDUCE-IT is provided below based on information provided in a press release made by Amarin on March 28, 2019. A comprehensive summary of the full data package submitted to the FDA, and detailed analyses by both Amarin and the FDA, will be made available two days prior to the EMDAC meeting, in meeting materials posted by the FDA. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary. At the time of publishing this report, trial results were not yet posted at the ClinicalTrials.Gov database (ClinicalTrials.Gov ID: NCT01492361).

Amarin reported that REDUCE-IT was a CVOT in patients with high CV risk who, despite stable statin therapy, had elevated TG levels (at least 135 mg/dL). The trial enrolled 8,179 patients. The company says a 25% relative risk reduction for Vascepa treatment compared to mineral oil placebo in the first occurrence of Major Adverse CV Event (MACE), a composite of CV death, nonfatal myocardial infarction (MI or heart attack), nonfatal stroke, coronary revascularization (procedures such as stents and by-pass) and unstable angina requiring hospitalization, was demonstrated in the intent-to-treat population. Adverse events (AEs) occurring with Vascepa use at greater than 5% and greater than placebo were as follows: peripheral edema (6.5% Vascepa versus 5.0%), although the company pointed out that there was no increase in the rate of heart failure in Vascepa patients; constipation (5.3% Vascepa versus 3.6%), although the company pointed out that mineral oil, as used as placebo, is known to lower constipation; and atrial fibrillation (5.3% Vascepa versus 3.9%), although the company pointed out that there were reductions in rates of cardiac arrest, sudden death and MIs observed in Vascepa patients.

Regulatory Background

US Regulatory Background

December 28, 2019 – Current PDUFA goal date. This date was confirmed in a press release made by Amarin on September 16, 2019.

September 28, 2019 – Initial PDUFA goal date

August 8, 2019 – Amarin announced that they were notified by the FDA that an advisory committee meeting was tentatively scheduled for November 14, 2019. The company also said they anticipated the PDUFA date to be extended to December 2019.

March 28, 2019 – Amarin announced the sNDA submission (NDA 202057/S-035).

Ex-US Regulatory Background

Canada

April 29, 2019 - Amarin announced that its licensee in Canada, HLS Therapeutics Inc. has filed a New Drug Submission (NDS) with Health Canada for Vascepa seeking an indication to reduce the risk of MACE in statin-treated patients with elevated triglycerides and other risk factors. This NDS was granted priority review.

Europe

September 3, ,2019 – Amarin announced that they plan to submit an application seeking approval for Vascepa in Europe for reducing CV events before the end of 2019.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Amarin Pharma Inc. Drug Name: icosapent ethyl Drug Class: omega-3 fatty acid Indication: cardiovascular disease

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.