Efficacy, Safety, and Tolerability of a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 in Combination With a Statin in Patients With Hypercholesterolaemia (LAPLACE-TIMI 57): A Randomised, Placebo-Controlled, Dose-Ranging, Phase 2 Study
How safe and effective is antibody-mediated inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with hypercholesterolemia on statin therapy?
A total of 631 subjects with low-density lipoprotein cholesterol (LDL-C) >85 mg/dl on a statin (± ezetimibe) were randomly assigned to subcutaneous injections of anti-PCSK9 (AMG 145) 70 mg, 105 mg, or 140 mg, or matching placebo every 2 weeks; or subcutaneous injections of AMG 145; 280 mg, 350 mg, or 420 mg, or matching placebo every 4 weeks. The primary endpoint was % change in LDL-C from baseline after 12 weeks.
Mean LDL-C concentrations were reduced by AMG 145 every 2 weeks (range from 41.8% to 66.1% depending on dose; p < 0.0001 for each dose vs. placebo) and AMG 145 every 4 weeks (ranging from 41.8% to 50.3%; p < 0.0001). Frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (8% vs. 11%); none of these events were severe or life-threatening.
Results suggest that PCSK9 inhibition could be a new therapy in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials.
PCSK9 is a serine protease involved in LDL receptor degradation. Reduced function mutations of PCSK9 lead to reduced LDL levels and protection from coronary artery disease. Recent studies have indicated that treatment with antibodies against PCSK9 leads to highly significant reductions in LDL-C, even in patients treated with statins. This study adds to the accumulating data that PCSK9 is a viable option for patients not tolerant of statin treatment or those who fail to reach target LDL on statins. Large clinical trials to determine cardiovascular event rates and long-term safety are now needed.
Keywords: Coronary Artery Disease, Injections, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, Serine Proteases, Hypercholesterolemia, Subtilisin, Proprotein Convertases, Mutation, Cholesterol, Biomarkers, Azetidines, Serine Endopeptidases
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