Efficacy and Safety of Alirocumab in Japanese Subjects (Phase 1 and 2 Studies)

Abstract

We assessed the safety and tolerability of ascending single doses of alirocumab in healthy Japanese subjects and evaluated the effect of alirocumab at 3 doses (50, 75, 150mg) on low-density lipoprotein cholesterol (LDL-C) reduction in patients with primary hypercholesterolemia on atorvastatin. A randomized, single ascending-dose study of alirocumab (100, 150, 250, or 300mg) or placebo (3:1 ratio), administered subcutaneously, was conducted in 32 healthy Japanese men. The phase 2, randomized, double-blind, placebo-controlled, parallel-group study was performed in patients with primary hypercholesterolemia (defined as calculated LDL-C ≥100mg/dl [2.6mmol/l]) who were on a stable dose of atorvastatin (5to 20mg). Patients were randomized to alirocumab (50, 75, or 150mg) or placebo (in single 1.0-ml injection volumes) administered every 2weeks (Q2W) for 12weeks; the primary outcome was the mean percent change in calculated LDL-C from baseline to week 12. Single subcutaneous administration of alirocumab in healthy subjects was well tolerated over 15weeks and resulted in highest mean percent reductions in LDL-C from baseline of approximately 40% to 60%. In the multiple-dose study, least-square mean (SE) changes in calculated LDL-C concentrations from baseline to week 12 were-54.8% (3.1%) for alirocumab 50mg,-62.3% (3.1%) for alirocumab 75mg, and-71.7% (3.1%) for alirocumab 150mg, with a least-square mean (SE) difference versus placebo of-52.2% (4.3%),-59.6% (4.3%), and-69.1% (4.3%), respectively (all p <0.0001). In conclusion, alirocumab was well tolerated and significantly reduced LDL-C concentrations in Japanese patients with primary hypercholesterolemia on atorvastatin.