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

Abstract

Background: LDL cholesterol (LDL-C) is a well established risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDL receptors, targeting them for degradation. We therefore assessed the efficacy, safety, and tolerability of AMG 145, a human monoclonal IgG2 antibody against PCSK9, in stable patients with hypercholesterolemia on a statin.

Methods: In a phase 2, dose-ranging study done in 78 centres in the USA, Canada, Denmark, Hungary, and Czech Republic, patients (aged 18-80 years) with LDL-C greater than 2·2 mmol/L on a stable dose of statin (with or without ezetimibe), were randomly assigned equally, through an interactive voice response system, to subcutaneous injections of 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. Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules. The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01380730.

Findings: 631 patients with hypercholesterolaemia were randomly assigned to AMG 145 70 mg (n=79), 105 mg (n=79), or 140 mg (n=78), or matching placebo (n=78) every 2 weeks; or AMG 145 280 mg (n=79), 350 mg (n=79), and 420 mg (n=80), and matching placebo (n=79) every 4 weeks. At the end of the dosing interval at week 12, the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks (ranging from 41·8% to 66·1%; p<0·0001 for each dose vs placebo) and AMG 145 every 4 weeks (ranging from 41·8% to 50·3%; p<0·0001). No treatment-related serious adverse events occurred. The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or life-threatening.

Interpretation: The results suggest that PCSK9 inhibition could be a new model in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials.

Funding: Amgen.

Figure 1. Trial profile

LDL-C=LDL cholesterol.

Figure 2. Percentage change in ultracentrifugation LDL-C concentration in the main subgroups given AMG 145 140 mg every 2 weeks (A) and AMG 145 420 mg every 4 weeks (B)

Treatment differences (95% CI) compared with placebo were calculated by use of least squares mean and treatment group and stratification factors as covariates. LDL-C=LDL-cholesterol.

Figure 3. Percentage change in calculated LDL-C concentration in 2 week intervals from baseline to week 12 in groups assigned to treatment every 2 weeks (A) and every 4 weeks (B)

Data are mean (SE), with no imputation for missing data. Error bars indicate SE. The numbers of patients for whom data were available at each visit are shown. LDL-C=LDL-cholesterol.

Figure 4. Frequency of attainment of lipoprotein targets at week 12

The percentage of patients who achieved concentrations of LDL-C of less than 1.8 mmol/L by ultracentrifuge, non-HDL-C of less than 2.6 mmol/L, ApoB of less than 0.8 g/L, and all three of these lipoprotein targets are shown for each of the eight groups after 12 weeks of treatment. Trend p<0.0001 for every 2 weeks and every 4 weeks groups for each of the four measures. LDL-C=LDL cholesterol. Non-HDL-C=non-HDL cholesterol. ApoB=apolipoprotein B.