Design and Rationale of Lp(a)HORIZON Trial: Assessing the Effect of Lipoprotein(a) Lowering With Pelacarsen on Major Cardiovascular Events in Patients With CVD and Elevated Lp(a)

BACKGROUND: Lipoprotein(a), abbreviated Lp(a), consists of apolipoprotein B-100 covalently bound to apolipoprotein(a), and represents an independent, genetically-determined, causal risk factor for atherosclerotic cardiovascular disease (CVD) and calcific aortic stenosis. More than 20% of the world CVD population has elevated Lp(a). Currently there are no approved pharmacologic treatments to lower Lp(a) levels, and no randomized trials have demonstrated that lowering Lp(a) reduces CVD risk. STUDY DESIGN: Lp(a) HORIZON is a phase 3, randomized, placebo-controlled, double-blind, parallel-group, multinational trial in 8,323 patients with established CVD and elevated Lp(a) levels of ≥70 mg/dL (approximately 149 nmol/L), testing the effect of pelacarsen, an antisense oligonucleotide (ASO) on the incidence of major adverse cardiovascular events (MACE). Established CVD is defined as history of myocardial infarction (MI), ischemic stroke or symptomatic peripheral artery disease. The minimum follow-up is required to be 2.5 years. The study will end when 993 CEC confirmed primary CV events have accumulated. Based on the current event accrual trend, the overal study duration is anticipated to be approximately 6 years. Patients were randomized in a 1:1 ratio to receive either monthly subcutaneous (SQ) injections of pelacarsen 80 mg or matching placebo on a background of optimized standard of care therapy for CVD. The primary endpoint is a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or urgent coronary revascularization requiring hospitalization. This endpoint will be evaluated in the overall population and in a subpopulation of Lp(a) ≥90 mg/dL (approximately 192 nmol/L) at screening, with multiplicity control designed to test the primary endpoint in both the overall population and the subpopulation. CONCLUSION: Lp(a) HORIZON will determine the effect of pelacarsen on cardiovascular morbidity and mortality in patients with elevated Lp(a) and established CVD. TRIAL REGISTRATION: NCT04023552.