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40337911000001103

New Medicines

Vazkepa (EU), Vascepa (US)Reduction of cardiovascular risk in high-risk patients with elevated triglycerides

Information

Vazkepa (EU), Vascepa (US)
New formulation
Amarin
Amarin

Development and Regulatory status

Launched
Approved (Licensed)
Launched
January 2022
Jan 22Vazkepa capsules available in the UK. Price for 120 capsules = £173.00 [45].
Apr 21Approved in UK [43]
Apr 21Approved in the EU. Amarin plan to launch in Germany initially before the end of Q3 2021 and will then seek market access in another 10 European countries in the following months. Launch plans for the UK are not specified but the company reports that they anticipate regulatory authorities in the UK will rely on the CHMP opinion for review and approval of Vazkepa reflecting that the EMA centralised review was nearly complete at the time Brexit became effective. Approval in the UK is thus expected soon after EU approval [42].
Jan 21Recommended for EU approval by CHMP - the full indication is "to reduce the risk of cardiovascular events in adult statin-treated patients at high cardiovascular risk with elevated triglycerides (≥150 mg/dL) and: established cardiovascular disease, or; diabetes, and at least one other cardiovascular risk factor. For study details including cardiovascular risk factors and results with respect to effects on cardiovascular events see section 5.1" [41].
May 20Marketing plans for Vascepa in the US have hit a hurdle, after Amarin suffered a surprise patent loss followed by FDA approval of a generic (icosapent ethyl capsules 1g) from Hikma Pharmaceuticals. Amarin plan to appeal and are weighing options for the path forward for Vascepa [40].
Dec 19US FDA approves Vascepa as adjunctive therapy to reduce risk of cardiovascular events among adults with elevated triglyceride levels [36].
Dec 19Amarin are seeking approval in the EU for use as a treatment to reduce the risk of cardiovascular events in high-risk patients who have their cholesterol levels controlled with statin treatment, but have elevated triglycerides,135 mg/dL or above, and other cardiovascular risk factors. The submission for Vascepa is sufficiently complete for the EMA to begin its review procedure, which is currently expected to be completed before the end of 2020 [35].
Nov 19EMA accepts for review MAA for icosapent ethyl (Vascepa) for reduction of cardiovascular risk in high-risk patients [34].
Aug 19In the US, the FDA has delayed the advisory committee meeting until November 19. Amarin anticipates that the PDUFA date will be extended to a date in late December 19 [33].
May 19In the US, a supplemental new drug application has been accepted by the FDA and granted priority review designation for reduction of residual cardiovascular risk in patients with statin-managed LDL-C cholesterol, but persistent elevated triglycerides, as studied in the REDUCE-IT cardiovascular outcomes study. The PDUFA date assigned is September 28, 2019 [32].
Nov 18Amarin announced plan to submit an sNDA to the FDA in early 2019 to expand the label based on its cardioprotective effect as demonstrated in the REDUCE-IT study.[28]
May 15Still in phase III trials in EU for Hypertriglyceridaemia [25].
Sep 14FDA rejects Amarin´s appeal to reconsider its clinical data for a label extension [24].
Jan 14Amarin has been notified by the FDA´s Division of Metabolism and Endocrinology Products (DMEP) that a determination on Amarin´s request for reconsideration of DMEP´s Oct 13 decision to rescind the ANCHOR clinical trial SPA agreement will be delayed. The FDA had orginially planned to convey its decision to Amarin no later than Jan 15, 2014; no definitive date has been set but Amarin does not expect the delay to be significant [23].
Oct 13An FDA panel voted 9 to 2 against approving the expanded use of Vascepa in patients with high triglyceride levels [21]
Oct 13The FDA has formally withdrawn its Special Protocol Assessment agreement for a study supporting the supplemental new drug application. The agency will no longer accept that a change in serum triglyceride levels reduces the risk of cardiovascular events among statin-treated patients with mixed dyslipidemia and residually high serum triglyceride levels. The agency hasn´t formally rejected the application for expanded approval, but is widely expected to do so [22]
Apr 13The FDA has accepted its Supplemental New Drug Application (sNDA) seeking approval for the marketing and sale of Vascepa for use as an adjunct to diet in the treatment of adult pts with high triglycerides (TG =200 mg/dL and <500 mg/dL) with mixed dyslipidemia [20].
Feb 13A licence application has yet to be filed in the EU [18].
Feb 13The company has filed a Supplemental New Drug Application in the US seeking approval for use as an adjunct to diet in the treatment of adult patients with high triglycerides (TG ≥200 mg/dL and <500 mg/dL) with mixed dyslipidaemia [16].
Jan 13Launched for hypertriglyceridaemia in the US [17].
Jul 12Approved in the US as an adjunct to diet to reduce triglyceride levels in adult patients with severe (TG greater than or equal to hypertriglyceridaemia (≥ 500mg/dL) [15].
Nov 11FDA decision on approval expected by 26 Jul 12 [12]
Nov 11Filing accepted by US FDA [11].
Sep 11Filed in US [10].
Apr 11US filing expected 3Q/2011 [8].
Nov 10Based on the timing and nature of the ANCHOR study results, Amarin intends to file in the US in 2011 (6).
Jan 10Two PIII studies, MARINE and ANCHOR, started in Dec 09: Estimated completion dates: Dec 11, MARINE, Jul 11, ANCHOR [4].
May 09 PIII study planned for mid-2009, at sites in America, EU, India and S. Africa (2)

Category

Phospholipase A2 inhibitor, a prescription grade omega-3 fatty acid
Hypertriglyceridemia may be caused by genetic defects (primary causes) or, more commonly, secondary causes such as obesity, alcohol consumption, diabetes mellitus, hypothyroidism or drug-induced. Mild hypertriglyceridemia is often asymptomatic. Severe primary hypertriglyceridemia (triglyceride level > 10.0 mmol/L) can be associated with abdominal pain, pancreatitis, difficulties with short-term memory & flushing with alcohol [19].
Reduction of cardiovascular risk in high-risk patients with elevated triglycerides
Oral

Further information

Yes

Trial or other data

Nov 21Analysis of PIII REDUCE-IT study (NCT01492361; n=8179) of statin-treated patients with elevated triglycerides who had CVD or diabetes and one additional risk factor found icosapent ethyl reduced the primary and secondary composite endpoints across a range of eGFR categories [44].
Nov 20Amarin note that if marketing authorisation is granted by the EMA, icosapent ethyl could become the first and only EMA-approved, non-LDL lowering agent with a cardiovascular disease risk reduction indication as an adjunct to statin therapy in dyslipidemic patients in Europe. A recent survey showed that about 25% of a representative sample survey of more than 7,800 patients from 27 European countries with coronary heart disease and controlled LDL-cholesterol levels had elevated triglycerides levels (>150 mg/dL), illustrating the potential pervasiveness of high-risk cardiovascular disease in Europe beyond currently available therapies [35].
Nov 19Interim results from the Phase IV EVAPORATE (NCT02926027) trial which aims to assess the efficacy of icosapent ethyl in reducing plaque burden among patients with known angiographic coronary artery disease on statins were presented at the American Heart Association Annual Scientific Sessions. Eligible patients were recruited in 2 centres in the US and randomised in a 1:1 fashion to either icosapent ethyl 4 g/day (n = 40) or placebo (n = 40). The primary outcome, % change in low attenuation plaque volume, for icosapent ethyl vs placebo, was: 94% vs. 74% (p = 0.47). Secondary outcomes for icosapent ethyl vs. placebo were: change in fibrofatty plaque volume 25% vs. 87% (p = 0.65), and change in total plaque volume 26% vs. 15% (p = 0.0004). Results suggest that icosapent ethyl 4 g/day does not reduce low attenuation plaque volume compared with placebo, but does reduce total plaque volume, and may help explain the cardiovascular benefit noted with icosapent ethyl in the REDUCE-IT trial [37-39].
Mar 19Based on REDUCE-IT trial results, updated American Diabetes Association guidelines now include a recommendation that ethyleicosapentaenoic acid be considered for patients with diabetes and atherosclerotic cardiovascular disease (ASCVD) or other cardiac risk factors on a statin with controlled LDL-C, but with elevated triglycerides to reduce cardiovascular risk [31].
Mar 19Further data from REDUCE-IT presented at the American College of Cardiology annual meeting. Vascepa reduced the risk of total CV events by 30% vs placebo in statin-treated patients at a median follow-up of 4.9 years. Specifically, in the study on patients (n=8,179) with well-managed LDL-cholesterol but raised triglycerides, the second events were reduced by 32% (140 cases), third events by 31% and fourth or more by 48% [30].
Nov 18Company released data from REDUCE-IT study involving 8179 pts with elevated CV risk who were on statins. Around 59% and 71% of pts had diabetes and established CV disease. The primary endpoint was acheive with a hazard ratio (HR) of 0.75; 95% CI, 0.68-0.83; p<0.001) in first occurrence of major adverse CV events (MACE) in the ITT population which were; composite of CV death, nonfatal MI or stroke, coronary revascularization and unstable angina requiring hospitalization. The NNT was 21 for the first occurrence of MACE. Overall adverse event rates in REDUCE-IT were similar across the statin plus Vascepa and the statin plus placebo treatment groups. Adverse events which were more frequent with Vascepa were peripheral oedema, constipation and AF.[28]
Nov 18Full study results from REDUCE-IT published in the NEJM. Analysts have noted a problem with the study´s design, with a mineral oil pill used as placebo and some unusual results in CV biomarkers. Subjects in the placebo arm experienced a 10% rise in LDL-cholesterol vs 3% in the Vascepa arm, and levels of hs-CRP (a marker of inflammation) also rose by 30% with placebo [29].
Sep 18Topline results from the REDUCE-IT trial announced by Amarin. Efficacy: Approximately 25% relative risk reduction (p<0.001) in the primary endpoint composite of the first occurrence of major adverse CV events (MACE), supported by demonstrations of efficacy across multiple secondary endpoints. Safety: well tolerated with a safety profile consistent with clinical experience associated with omega-3 fatty acids. The proportions of patients experiencing adverse events and serious adverse events were similar between the active and placebo treatment groups. Median follow-up time in REDUCE-IT was 4.9 years [27].
Aug 16Top-line data from the REDUCE-IT trial are due in 2018 [26].
May 12Amarin is developing ethyl eicosapentaenoic acid (AMR 101), an approximately 97% pure, semi-synthetic ethyl ester of eicosapentaenoic acid, as a therapy for hypertriglyceridaemia. This indication encompasses pts with very high triglyceride levels (≥500 mg/dL) & those with high triglyceride levels (≥200 mg/dL but <500 mg/dL) who are also receiving statins for elevated LDL-cholesterol levels. The drug is a potentially first-in-class therapy in pts with high triglyceride levels [14].
Dec 11NCT01492361- REDUCE-IT (Reduction of Cardiovascular Events With EPA - Intervention Trial) - a PIII evaluation of AMR101 on cardiovascular health and mortality in 8000 hypertriglyceridemic patients with cardiovascular disease or at high risk for cardiovascular disease. The primary outcome is incidence of cardiovascular events, such as coronary revascularization over 4-6 years. The study started in Nov 11 and is due to complete Nov 16 [13].
Apr 11Results from ANCHOR trial (n=702). Purpose of the ANCHOR trial was to demonstrate that AMR101 is effective in reducing triglyceride levels in patients with high triglycerides without increasing LDL-C levels in patients on background statin therapy. 73% of patients were diabetic. Primary endpoint was the percentage change in triglyceride levels from baseline compared to placebo after twelve weeks of treatment - this was achieved with both 4g and 2g per day. Median placebo-adjusted reductions in TG levels were 21.5% and 10.1% respectively (p<0.0001 and p=0.0005). [9]
Apr 11Data from the MARINE trial, a pivotal Phase 3 study investigating AMR101 as a treatment for very high triglycerides (500 mg/dL), will be presented at the National Lipid Association (NLA) 2011 Annual Scientific Sessions on May 19-22, 2011 [7]
Nov 10The MARINE study, investigating use of AMR101 for very high triglycerides (≥500 mg/dL), met its primary efficacy endpoint, the percent change in triglyceride (TG) levels from baseline to week 12, for both the 4g (median TG decrease of 33%, P<0.0001) and 2g (median TG decrease of 20%, P=0.0051) doses vs. placebo. 25% of patients were on background statin therapy. AMR101 did not result in an increase in median LDL-C vs. placebo. The ongoing ANCHOR study is a PIII study designed to investigate AMR101 in patients with high triglycerides (≥200 and <500mg/dL) with mixed dyslipidemia treated with statins (6).
Aug 10Update on MARINE and ANCHOR PIII trials. MARINE trial patient randomisation completed with top-line data expected in early 2011; ANCHOR tria, more than half of 650 pts targeted have been randomised, top line data expected in 2011. [5]
Jul 09The FDA has agreed the design of a PIII trial in patients with mixed dyslipidaemia. Company plans to start this trial (and the MARINE study) in 3Q 2009, pending funding. Around 650 patients with triglyceride levels of ≥200 mg/dL and <500 mg/dL who are on statin therapy will enroll in the US multi-centre, randomised, double-blind, 12-week study comparing 2 and 4gm AMR 101 vs placebo. The primary endpoint is the % change in triglyceride level from baseline to week 12 [3].
May 09Amarin has reached agreement with the FDA for its planned PIII registration trial. The multi-centre, placebo-controlled 12-week study will evaluate two doses of AMR 101, in around 240 patients with fasting triglyceride levels of ≥500 mg/dL (the AMR101 MARINE Study). The primary endpoint is the % change in triglyceride level from baseline. Patients will be eligible to enter a 40-week, open-label, extension period. A PIII trial in patients with high triglyceride levels (≥200 mg/dL and ≤500 mg/dL) who are on statin therapy is also planned (2).

Evidence based evaluations