Longer-term safety of alirocumab with 24,610 patient-years of placebo-controlled observation: further insights from the ODYSSEY OUTCOMES trial

Background In the ODYSSEY OUTCOMES trial (NCT01663402), alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowered low-density lipoprotein cholesterol from ∼2.3 mmol/L to ∼1.0 mmol/L at 4 months, reduced the risk of major adverse cardiovascular events (MACE: coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, unstable angina requiring hospitalization), and was associated with fewer deaths compared with placebo in 18924 patients (pts) with recent acute coronary syndrome followed for up to 5 years (yrs). Purpose In the ODYSSEY OUTCOMES trial, the overall safety of alirocumab and placebo was similar, except for an excess of local injection-site reactions with alirocumab. However, the safety among pts eligible for longer follow-up has not been fully explored. Methods The present post hoc analyses describe the efficacy and safety of alirocumab in a pre-specified subgroup (for efficacy) of pts eligible for a minimum of 3 and up to 5 yrs of follow-up. Results There were 8242 pts (43.5%) eligible for ≥3 yrs follow-up, of whom 8228 received at least one dose of study medication, comprising 24,610 pt-years of observation with a median follow-up of 3.3 yrs; 6651 pts were eligible for 3 up to 4 yrs, and 1574 patients were eligible for 4–5 yrs, follow-up. As previously reported in a pre-specified analysis of this subgroup, alirocumab significantly reduced death (4.7% vs. 5.9%; p=0.01) compared with placebo. In the present post hoc analysis, alirocumab also significantly reduced MACE vs. placebo (12.0% vs. 14.2%; Hazard Ratio 0.83 [95% CI 0.74 to 0.94]; p=0.003). In a safety analysis, 3217 (78.3%) vs. 3303 (80.2%) pts in the alirocumab vs. placebo group had at least one adverse event (AE) of whom 27.5% vs. 29.4% had a serious AE (Fig. 1). The frequency of permanent discontinuation of study drug due to AEs, incident diabetes, diabetes worsening or complications, neurocognitive events, elevations of ALT>3, AST>3, bilirubin>2, and creatine phosphokinase>10 times the upper limit of normal, were similar with alirocumab vs. placebo (Fig. 1). While pt-reported local injection-site reactions occurred more frequently with alirocumab, the Kaplan-Meier cumulative incidence for time to first local injection site reaction in the longer-term follow-up subgroup was <5% over ∼4 yrs, with most occurring within the first 6 months (Fig. 2). Conclusions In an 8228-pt subgroup of the ODYSSEY OUTCOMES trial eligible for at least 3, and up to 5 yrs follow-up, the safety of alirocumab was similar to placebo except for an excess of local injection site reactions. This subgroup also derived significant benefit from reduced MACE and death. Thus, alirocumab appears to be both a safe and effective lipid-modifying treatment when used for up to 5 yrs. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi and Regeneron