Summary Basis of Decision for Vascepa

 

Clinical Pharmacology

The mechanisms of action contributing to reduction of cardiovascular events with Vascepa (Icosapent ethyl) are not completely understood but are likely multi-factorial.

The non-pivotal clinical studies included Phase I healthy volunteer studies only, which cover pharmacokinetics and drug-drug interactions in humans. The relationship of plasma triglyceride levels and clinical outcomes is unknown.

The general pharmacokinetic parameters for the proposed 1 g Vascepa capsule were based on the Phase I healthy adult volunteer studies, in which the time to maximum plasma concentration (T_max) was consistently around 5 hours across the different studies; however, the maximum plasma concentration (C_max), the area under the plasma concentration versus time curve, half-life (T_1/2), and volume of distribution (V_d) had substantial differences among clinical studies and individual patients in the trials.

Per the proposed total daily dose of 4 g/day administered as 2 g twice daily, following Vascepa administration over 28 days, peak plasma concentrations of eicosapentaenoic acid (EPA) were reached approximately 5 hours following oral doses of Vascepa. The mean volume of distribution at steady-state of EPA is approximately 88 litres. The total plasma clearance of EPA at steady state is 684 mL/hr. The plasma elimination half-life (T_1/2) of icosapentaenoic is approximately 89 hours.

The majority of EPA circulating in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, and <1% is present as the unesterified fatty acid. Greater than 99% of unesterified EPA is bound to plasma proteins.

In all the clinical trials, Vascepa was administered with or following a meal; no food effect studies were performed.

Doses higher than the proposed dose (4 g/day) have not been studied in clinical trials.

The drug-drug interactions trials were focused on cytochrome P450 metabolized medications (omeprazole, rosiglitazone, warfarin and atorvastatin) only, and did not identify clinical meaningful interactions, even though in the human tissue studies there were certain level interactions.

Vascepa was associated with an increased risk of bleeding in the REDUCE-IT trial. The incidence of bleeding was greater in patients receiving concomitant antithrombotic medications, such as aspirin, clopidogrel, or warfarin.

For further details, please refer to the Vascepa Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Vascepa for the reduction of cardiovascular risk in patients with elevated serum triglycerides despite appropriate statin therapy, and who are at high cardiovascular risk, as demonstrated by a history of myocardial infarction or stroke, or by having diabetes and at least one other cardiovascular risk factor, was based on evidence from the REDUCE-IT trial.

REDUCE-IT was an international, multicentre, randomized, double-blind, placebo-controlled study that assessed atherothrombotic cardiovascular outcomes in 8,179 patients with clinical characteristics as described above. Vascepa, or a matching mineral oil placebo, was taken twice daily with food, for a total daily dose of 4 g. The trial population consisted of patients 45 years of age or older and with a history of cardiovascular disease (70.7%), identified as the secondary prevention cohort, or of patients 50 years of age or older, with elevated cardiovascular risk and no history of documented cardiovascular disease, identified as the primary prevention cohort (29.3%). No clinically relevant imbalances of patient characteristics were noted between treatment groups at baseline.

At baseline, the median age was 64 years (range: 44 years to 92 years) with 46% being at least 65 years old, and 28.8% of patients were women. Patients enrolled in the trial included 46.7% who had prior myocardial infarction, 9.2% who had symptomatic peripheral arterial disease, 6.2% who had prior ischemic stroke, and 4.6% who had prior transient ischemic attack. Additional baseline risk factors included hypertension (86.6%), diabetes mellitus (58.5%), estimated glomerular filtration rate <60 mL/min/1.73 m² (22.2%), congestive heart failure (17.7%), and current daily cigarette smoking (15.2%). The trial population was 90.2% White, 5.5% Asian, 1.9% Black, and 4.2% Hispanic.

In addition, at baseline, most patients were taking at least one other cardiovascular medication including anti-hypertensives (95.2%), anti-platelet agents (79.4%), beta-blockers (70.7%), angiotensin-converting enzyme (ACE) inhibitors (51.9%), and angiotensin receptor blockers (ARB) (26.9%), with 77.5% taking either an ACE inhibitor or ARB. There were no significant imbalances of non-study drug use between study treatment groups.

Also at baseline, while on stable background lipid-lowering therapy, the median LDL was 1.9 mmol/L (75 mg/dL), while the median fasting serum triglyceride level was 2.4 mmol/L (216 mg/dL). Triglyceride levels ranged from 0.9 to 15.6 mmol/L (82 mg/dL to 1400 mg/dL). Per protocol, all patients had serum triglycerides of at least 1.5 mmol/L (135 mg/dL), with no between-group imbalance being evident. All patients continued receiving statin therapy throughout the trial, as well as standard therapy for prevention of atherothrombotic events, for up to 6.2 years, with a median time of follow-up of 4.9 years. Overall, 99.8% of patients were followed for vital status until the end of the trial or death.

The primary efficacy endpoint was the time-to-first-occurrence of any major adverse cardiovascular event (MACE-5), which consisted of the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina, and occurred in 17.2% of patients treated with Vascepa, compared to 22.0% treated with placebo (Hazard Ratio [HR] 0.75; 95% Confidence Interval [CI] 0.68 to 0.83, p<0.001). The key secondary endpoint, MACE-3, was a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, and occurred in 11.2% of patients treated with Vascepa, compared to 14.8% of patients treated with placebo (HR 0.74; 95% CI 0.65 to 0.83, p<0.001). The superiority of Vascepa over placebo was seen across a number of pre-specified subgroups for both composite endpoints, including patients with or without diabetes, with or without chronic kidney disease, and irrespective of baseline LDL and high sensitivity C-reactive protein levels. All components of the primary composite endpoint showed significant benefit of Vascepa over placebo.

The median difference between Vascepa and placebo in serum triglycerides from baseline to Month 4 was -20.1% (p<0.001), and from baseline to Month 12 was -19.7% (p<0.001), in favour of Vascepa. At Month 12, the median triglyceride level was 2.0 mmol/L (175 mg/dL) in the Vascepa group. Pre-specified analyses of the effect of Vascepa on cardiovascular outcomes failed to demonstrate a correlation between triglyceride response and cardiovascular effect, based on baseline triglyceride levels or on-treatment change in triglyceride levels. Therefore, the mechanisms of action contributing to reduction of cardiovascular events with Vascepa are not completely understood but are likely multi-factorial.

In analyzing the REDUCE-IT results, it was noted that a number of cardiovascular biomarkers displayed unfavorable changes over time in the mineral oil placebo treatment group. In particular, the median change in LDL levels from baseline to Year 1 was 7.0 mg/dL (10.2%) in the placebo group. The estimated median difference between placebo and Vascepa in LDL change from baseline to Year 1 was 5.0 mg/dL (6.6%). In addition, median high sensitivity C-reactive protein increased by 0.5 mg/L at Year 2 in the placebo-treated group.

A variety of analyses were considered in an attempt to assess the possible effects of the biomarker changes in the mineral oil placebo group on the overall trial outcome. Based on published meta-analyses of the effects of statin drug therapy, such as the Cholesterol Treatment Trialists' Collaboration, it was estimated by Health Canada that a 5 mg/dL increase in LDL over roughly 5 years might result in an increase in risk of major adverse cardiovascular events (MACE) of approximately 2.5%, accounting for roughly 10% of the reported 26% relative risk reduction in MACE seen in REDUCE-IT. It was also noted that analyses of changes in LDL levels at Year 1 in the placebo group failed to demonstrate a predictive relationship to clinical outcomes within this group. Similarly, changes in high sensitivity C-reactive protein levels in the placebo group at Year 2 could not be shown to be predictive of clinical outcome.

Health Canada therefore concluded that, while it could not be ruled out that a possible deleterious effect of mineral oil in the placebo group may have contributed to the apparent beneficial effect of Vascepa seen in REDUCE-IT, the evidence of cardiovascular benefit (25% relative risk reduction in 5-point MACE over 4.9 years) seen with Vascepa treatment remains convincing.

Indication

The New Drug Submission for Vascepa was filed by the sponsor with the following indication:

• Vascepa (Icosapent ethyl) is indicated to reduce the risk of ischemic cardiovascular events (death due to cardiovascular event, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, and unstable angina) in statin-treated patients with elevated triglycerides and other risk factors such as:
  • established cardiovascular disease, or
  • at high risk for cardiovascular disease.

To ensure safe and effective use of the product, Health Canada approved the following indication:

• Vascepa (Icosapent ethyl) is indicated to reduce the risk of cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization or hospitalization for unstable angina) in statin-treated patients with elevated triglycerides, who are at high risk of cardiovascular events due to:
  • established cardiovascular disease, or
  • diabetes, and at least one other cardiovascular risk factor.

The non-pivotal trials do not include data in the proposed target patient population; therefore, no efficacy and/or safety comments can be provided for the proposed indication based on these trials. Accordingly, the approved indication has been deemed by Health Canada to appropriately reflect the patient population studied in the REDUCE-IT trial.

For more information, refer to the Vascepa Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Vascepa was evaluated in 8,179 patients in the REDUCE-IT cardiovascular outcomes trial previously described in the Clinical Efficacy section. A total of 4,089 patients received Vascepa and 4,090 patients received mineral oil placebo. Patients were exposed to Vascepa or placebo for a median of 4.3 years in the safety database of the REDUCE-IT trial, with 87% of patients exposed for ≥12 months, 77% for ≥24 months, 65% for ≥36 months, 54% for ≥48 months, and 29% for ≥60 months.

With respect to safety, Vascepa was generally well tolerated. The overall adverse event rates were similar in patients treated with Vascepa (81.8%), compared to placebo (81.3%); while the incidence of serious adverse events was the same in patients treated with Vascepa (30.6%) and placebo (30.7%). The rate of adverse events leading to discontinuation of study drug was also similar in patients treated with Vascepa (7.9%) and placebo (8.2%).

The most frequent (≥5%) adverse events reported in the REDUCE-IT trial and at a rate that occurred significantly more frequently with Vascepa than placebo, were peripheral edema at 6.5% in patients treated with Vascepa, compared to 5.0% with placebo; constipation at 5.4%, and 3.6%; and atrial fibrillation at 5.3%, and 3.9%, respectively. Adverse event rates of both anemia and diarrhea were significantly higher in the placebo group than the Vascepa group.

The rate of the pre-specified adjudicated tertiary endpoint of hospitalization for atrial fibrillation or flutter was also significantly higher in the Vascepa-treated group than in the placebo group, at 3.1%, compared to 2.1% (p = 0.004).

A significantly higher incidence of total bleeding events was observed with Vascepa treatment than with placebo, at 11.8% and 9.9% of patients, respectively. Bleeding-related serious adverse events were observed in 2.7% of Vascepa-treated patients, compared to 2.1% treated with placebo. However, there were no significant differences between the Vascepa-treated group and the placebo group in the rates of adjudicated hemorrhagic stroke, at 0.3% and 0.2% (p = 0.54), or serious gastrointestinal bleeding, at 1.5% and 1.1% (p = 0.15), respectively. The incidence of bleeding was greater in patients receiving concomitant antithrombotic medications, such as aspirin, clopidogrel, or warfarin.

With respect to clinical chemistry parameters, no notable changes from baseline in the Vascepa-treated group were seen, with the exception of increases in total bilirubin, which were more frequent in the Vascepa group than the placebo group, at 7.5% and 2.7%, respectively. Increases in total bilirubin combined with increases in aspartate aminotransferase and alanine aminotransferase were not clearly increased in the Vascepa-treated patients, compared to placebo.

Less common adverse events at <5% in the Vascepa group and at least 1% greater than in the placebo group were gout and musculoskeletal pain.

The Product Monograph adequately reflects the safety and efficacy data regarding Vascepa, under the proposed conditions of use, including appropriate warnings aimed at mitigating the risks associated with Vascepa treatment.

For more information, refer to the Vascepa Product Monograph, approved by Health Canada and available through the Drug Product Database.