Pharmacodynamic relationship between PCSK9, alirocumab, and LDL-C lowering in the ODYSSEY CHOICE I trial

Abstract Background The ODYSSEY CHOICE I study (NCT01926782) evaluated alirocumab 300 mg every 4 weeks (Q4W) in patients with hypercholesterolemia receiving maximally tolerated statin or no statin. Objective To assess the relationship between alirocumab, PCSK9 and low-density lipoprotein (LDL-C) concentrations with the CHOICE I alirocumab dosing regimen. Methods This analysis included 803 patients (547 statin-treated, 256 without statin) who were randomized to alirocumab 300 mg Q4W, alirocumab 75 mg every 2 weeks (Q2W) or placebo. 300 mg Q4W and 75 mg Q2W doses were adjusted to 150 mg Q2W at week 12 if week 8 LDL-C was >70 or >100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was Results Most patients remained on 300 mg Q4W without dose adjustment as they achieved study-defined LDL-C goals at week 8 (statin-treated: 80.7%; no statin: 85.3%). LDL-C was reduced by 60.5–71.9% over weeks 20–24 in patients on 300 mg Q4W and 57.2–63.0% in patients with dose adjustment from 300 mg Q4W to 150 mg Q2W. Statin-treated patients had higher cardiovascular risk as well as higher free PCSK9 and lower alirocumab concentrations (vs no statin), suggesting increased target-mediated clearance. Regardless of statin status, the most common adverse events in alirocumab-treated patients were injection-site reaction and headache. Conclusions Data provide further insight on alirocumab’s mode of action in terms of relationship between alirocumab, PCSK9 and LDL-C, and disease severity, and support the use of alirocumab 300 mg Q4W as an efficacious dosing regimen for clinically meaningful LDL-C reductions.