Abstract 17156: A Randomized Placebo-phase Clinical Trial With the Monoclonal Antibody Alirocumab Demonstrates Reductions in Low-density Lipoprotein Cholesterol in Patients With Proprotein Convertase Subtilisin/Kexin Type 9 Gain-of-Function Mutations
Background: Autosomal dominant hypercholesterolemia (ADH) is characterized by inherited high serum LDL cholesterol (LDL-C) levels and early onset cardiovascular disease. ADH causes include mutations in the LDL receptor (LDLR) and its ligand apolipoprotein B (apoB), and (in ~2% of patients) gain-of-function mutations (GOFm) in proprotein convertase subtilisin/kexin type 9 (PCSK9), a potent modulator of hepatocyte LDLR. We report initial results from the first clinical trial of a fully human PCSK9 monoclonal antibody (alirocumab) in patients with PCSK9 GOFm (NCT01604824).
Methods: Thirteen ADH-PCSK9 GOFm patients (18-70 yrs, LDL-C ≥ 70 mg/dL) were enrolled on their current lipid-lowering regimen (statin +/- ezetimibe). A double-blind, randomized placebo-phase design was used to compare alirocumab vs. placebo but later allow all patients to receive alirocumab. Patients were randomized to: group A (n=6), who received subcutaneous alirocumab 150 mg at wks 0, 2, 4, 6, and 10, or group B (n=7), who received alirocumab at wks 2, 4, 6, 8, and 12. Placebo was given on weeks in which alirocumab was not, and on wks -2, and 14. Primary endpoint was change in LDL-C from baseline to wk 2 for group A vs. group B. Secondary endpoints were treatment emergent adverse events (TEAEs), and change, from day 1 to wk 2 for group A vs. group B, of ApoB, non-HDL-C, total cholesterol (TC), and the ApoB/ApoA1 ratio, as well as lipid values throughout.
Results: Patients enrolled (mean age 44.6 yrs, mean baseline LDL-C 127.9 mg/dL) carried 4 different PCSK9 GOFm (L108R, S127R, R218S, D374Y). All patients completed the double-blind (to wk 14) and safety follow up (to wk 22) parts of the study. Alirocumab administration induced clinically meaningful improvements in lipid profiles in all patients. At wk 2, least squares (LS) mean reductions from baseline (alirocumab minus placebo) were LDL-C 53.7%, ApoB 49.6%, non-HDL-C 49.4%, TC 30.7%, and ApoB/ApoA1 LS mean difference 0.30 (all p-values ≤ 0.002). LDL-C reductions persisted throughout treatment. The most common TEAEs with alirocumab were nasopharyngitis and headache. One patient had a serious adverse event of noncardiac chest pain.
Conclusion: Alirocumab appears to be a promising therapeutic option for patients with ADH caused by PCSK9 GOFm.
- © 2013 by American Heart Association, Inc.