Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtitisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations

BACKGROUND: Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm). OBJECTIVE: The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm. METHODS: Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C >= 70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22. RESULTS: At Week 8, mean +/- standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 +/- 1.81 vs 16.74 +/- 2.53 mg/L). APOB LOFm carriers had higher mean +/- SE total PCSK9 (6.56 +/- 0.73 mg/L) and lower mean +/- SE free PCSK9 (0.025 +/- 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 +/- 0.35 and 0.11 +/- 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean +/- SE percent LDL-C reduction was lower in APOB LOFm (55.3 +/- 1.0%) compared with PCSK9 GOFm carriers (73.1 +/- 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group. CONCLUSIONS: Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm. (C) 2019 National Lipid Association. Published by Elsevier Inc.