Regulatory Decision Summary for Vascepa

Atherothrombotic cardiovascular (CV) disease is a leading cause of morbidity and mortality, and in Canada it is the second most common cause of death after cancer, despite major advances in treatment and prevention of CV disease over the last several decades.

Evidence for the efficacy and safety of Vascepa was derived from a single, multicentre, randomized, double-blind, placebo-controlled clinical trial, REDUCE-IT. In the study, 8,179 patients were randomized 1:1 to receive Vascepa twice daily, at a total daily dose of 4 grams, or matching mineral oil placebo. Patients were either: 1) 45 years of age or older and had a history of coronary artery disease or stroke (70.7%; secondary prevention cohort); or 2) 50 years of age or older and had an elevated CV risk, defined as having diabetes and at least one other major CV risk factor, but no history of cardiovascular disease (29.3%); primary prevention cohort). All patients were taking a statin.

At baseline, characteristics of the patients in the treatment groups were balanced. Median age was 64 years and 29% of patients were women; 95% were taking anti-hypertensives and 79% anti-platelet agents, and median low-density lipoprotein cholesterol (LDL-C) level was 1.9 mmol/L. As per protocol, all patients were to have serum triglycerides ≥1.5 mmol/L, and the median fasting serum triglyceride level was 2.4 mmol/L.

The primary efficacy analysis was the time to first occurrence of a composite endpoint of major adverse cardiovascular events (MACE), including CV death, non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization, or hospitalization for unstable angina (MACE 5). The key secondary endpoint was conventional MACE, a composite of CV death, non-fatal MI, or non-fatal stroke.

Following a median exposure to study drug for 4.9 years, the primary efficacy endpoint (MACE-5) 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) occurred in 11.2% of Vascepa patients, compared to 14.8% of placebo patients (HR 0.74; 95% CI 0.65 to 0.83, p<0.001). Results were consistent for the individual components of the composite endpoints, as well as across a variety of prespecified subgroups, including patients with or without diabetes, chronic kidney disease (CKD), and regardless of baseline LDL-C and high sensitivity C-reactive protein (hsCRP) levels. Efficacy was demonstrated in both the primary and secondary prevention cohorts.

The median decrease in serum triglycerides in the Vascepa group compared to placebo at Month 4 was -20.1% (p<0.001), and -19.7% at Month 12 ((p<0.001), with a median triglyceride level of 2.0 mmol/L in the Vascepa group at Month 12. Of note, however, prespecified analyses failed to demonstrate a correlation between triglyceride response and reduction in cardiovascular events, based on either baseline triglyceride levels or change in triglyceride levels during treatment.

In analyzing the REDUCE-IT results, it was noted that a number of CV biomarkers displayed unfavorable changes over time in the mineral oil placebo treatment group. In particular, median LDL-C levels in the placebo group increased by 0.18 mmol/L (10.2%) from baseline at Year 1, an increase of 0.13 mmol/L (6.6%) over that observed with Vascepa at Year 1. In addition, median hsCRP increased by 0.6 mg/L by 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 study outcome. Based on published meta-analyses of the effects of statin drug therapy, such as the Cholesterol Treatment Trialists (CTT) Collaboration, it was estimated that a 5 mg/dL increase in LDL-C, over roughly 5 years, might result in an increase in risk of 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-C levels at Year 1 in the placebo group failed to demonstrate a predictive relationship to clinical outcomes within this group. Similarly, changes in hsCRP levels in the placebo group at Year 2 also could not be shown to be predictive of clinical outcome. Also considered was an analysis of the relationship between Eicosapentaenoic Acid (EPA) concentration in Vascepa-treated and placebo-treated patients and cardiovascular outcome, which suggested a consistent dose-response effect, with greater CV benefit seen with increasing EPA concentration tertiles, including the placebo group, which had the lowest, endogenous EPA concentrations.

Health Canada 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 CV benefit of Vascepa nevertheless remains.

With respect to safety, Vascepa was generally well tolerated, with rates of adverse events (AE), serious adverse events (SAE) and study discontinuations due to AEs comparable between the treatment groups. The most common AEs reported more frequently by patients in the Vascepa group were peripheral edema (6.5% of patients treated with Vascepa compared to 5.0% with placebo) and constipation (5.4% and 3.6%, respectively). Of note, there were significant increases in the rate of atrial fibrillation and bleeding events in the Vascepa group, compared to placebo. Thus, AEs of atrial fibrillation were seen in 5.8% of patients in the Vascepa group, compared to 4.5% of patients in the placebo group (p = 0.008). Bleeding events were reported in 11.8% of patients with Vascepa, compared to 9.9% with placebo (p = 0.006). Rates of adjudicated hemorrhagic stroke were 0.3% and 0.2%, for the Vascepa and placebo groups, respectively, and serious gastrointestinal bleeding was reported 1.5% and 1.1%, of the Vascepa-treated and placebo-treated patients, respectively. The Vascepa Product Monograph (PM) includes appropriate warnings describing the increased risk of both atrial fibrillation and bleeding seen with Vascepa.

Overall, despite an apparent increased risk of bleeding and atrial fibrillation, in light of the evidence of substantial benefit on serious CV endpoints demonstrated in REDUCE-IT, Health Canada considers the overall benefit-risk of Vascepa is favorable for reduction of cardiovascular risk in high risk patients with elevated serum triglycerides despite treatment with a statin.

A Risk Management Plan (RMP) for Vascepa was submitted and reviewed by the Marketed Health Products Directorate, and was considered acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Educational materials will be made available to health care providers to reduce the risk of off-label use.