Efficacy and Safety of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia Associated With Proprotein Convertase Subtilisin/Kexin Type 9 Gain-of-Function or Apolipoprotein B Loss-of-Function Mutations.

Autosomal dominant hypercholesterolemia results from mutations affecting the low-density lipoprotein receptor pathway, including proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GoFm) and apolipoprotein B (APOB) loss-of-function mutations (LoFm). This study examined the long-term efficacy and safety of alirocumab in patients with PCSK9 GoFm and APOB LoFm who participated in the open-label extension to a Phase 2 double-blind study (NCT01604824). Of the 23 patients who completed the 14-week double-blind period and 8-week follow-up, 21 opted to continue in the open-label extension (PCSK9 GoFm, n = 15; APOB LoFm, n = 6). Patients received alirocumab 150 mg every 2 weeks from week 32 up to 3 years for PCSK9 GoFm and 2 years for APOB LoFm. Mean duration of alirocumab exposure was 129 weeks (median: 144 weeks). After initiation of alirocumab treatment, low-density lipoprotein cholesterol (LDL-C) decreased in both groups. At week 80, mean percent reduction in LDL-C from baseline was 58.0% and 47.1% for PCSK9 GoFm and APOB LoFm groups, respectively. Treatment-emergent adverse events were reported in 19 patients (90.5%); no patients discontinued treatment due to treatment-emergent adverse events. In patients with autosomal dominant hypercholesterolemia and elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapies, alirocumab 150 mg every 2 weeks resulted in clinically meaningful reductions in LDL-C, sustained through to 3 years and 2 years for patients with PCSK9 GoFm and APOB LoFm, respectively. Alirocumab was generally well tolerated with no unexpected safety concerns.