Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo in patients with heterozygous familial hypercholesterolemia

Abstract

Patients with heterozygous familial hypercholesterolemia (HeFH) are characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels. Long-term effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have not been thoroughly investigated in these patients. We evaluated efficacy and safety of alirocumab, a PCSK9 inhibitor, vs placebo in patients with HeFH. In total, 1257 patients with HeFH on maximally tolerated statin±other lipid-lowering therapies from four 78-week ODYSSEY trials were analyzed. In FH I and II, patients with baseline LDL-C levels ≥70/100mg/dL (n=735), depending on documented cardiovascular disease history, received placebo or alirocumab 75mg every 2weeks (Q2W; with dose increase to 150mg Q2W at week 12 if week 8 LDL-C was ≥70mg/dL). Separately, data were pooled from HIGH FH (baseline LDL-C ≥160mg/dL) and patients with HeFH from LONG TERM (baseline LDL-C ≥70mg/dL), where patients received placebo or alirocumab 150mg Q2W (n=522). At week 24, alirocumab reduced LDL-C levels by -48.8% (75/150mg Q2W; placebo:+7.1%) and -55.0% (alirocumab 150mg Q2W; placebo:+1.3%) (both P<.0001 vs placebo; intention-to-treat analysis). Least-squares mean LDL-C levels of 69.1 to 75.6mg/dL (alirocumab 75/150mg/dL Q2W; baseline: 141.3mg/dL) and 72.2 to 82.3mg/dL (alirocumab 150mg Q2W; baseline: 168.4mg/dL) were achieved at weeks 24 to 78 (on-treatment analysis). Additional beneficial effects were observed in other lipids. Treatment-emergent adverse event rates were similar in the alirocumab (80.5%) and placebo groups (83.0%). In this large cohort of patients with HeFH, alirocumab significantly reduced LDL-C levels. Alirocumab was generally well tolerated.