AMG 145, A Monoclonal Antibody Against PCSK9, Facilitates Achievement of NCEP-ATP III LDL-C Goals Among High Risk Patients: An Analysis From the LAPLACE-TIMI 57 Trial.

Desai NR, Giugliano RP, Zhou J, et al.
J Am Coll Cardiol. 2013 Oct 11. doi: 10.1016/j.jacc.2013.09.048. [Epub ahead of print]

Background

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) recommended LDL-c levels below 100 mg/dL in patients with established cardiovascular disease (CVD) or CVD equivalents. The 2004 updated guidelines with an optional target of <70 mg/dL [1] are not often achieved by patients at high risk for CV events, despite high potency statin treatment [2,3].
AMG 145 is a fully human, monoclonal, IgG2 antibody against proprotein convertase subtilisin
kexin type 9 (PCSK9), that yielded significant, dose-dependent reductions in LDL-c of up to 66% in the double blind, placebo-controlled LAPLACE-TIMI 57 trial [4]. This analysis evaluated the ability of AMG 145 to enable subjects at high risk for adverse CV events in LAPLACE-TIMI 57 to achieve NCEP-ATP III LDL-c and other lipid goals.

Main results

• AMG 145 reduced LDL-C at 12 weeks as compared to baseline and as compared to placebo, by up to 64% for AMG 145 treatment every two weeks and up to 45% for treatment every 4 weeks.
• As compared to placebo, each dose of AMG 145 significantly increased the proportion of patients who achieved the NCEP-ATP III LDL-c target of <70 mg/dL at week 12, to 90% and 70% of subjects who received the top dose every 2 and 4 weeks respectively.
• LDL-c was sampled every 2 weeks, also in patients receiving AMG 145 once every 4 weeks. Up to 97% of these patients met the NCEP-ATP III LDL-c target at week 10. Up to 90% of patients receiving biweekly AMG 145 attained the NCEP-ATP III recommended LDL-c levels.
• All AMG 145 dose regimens were more likely than placebo to achieve non-HDL-c < 100 mg/dL or ApoB < 80 mg/dL or to achieve all three lipid targets.
• There were no significant differences in the rate of adverse events, including serious adverse events and elevations of creatine kinase and liver enzymes.

Conclusion

This analysis of the LAPLACE-TIMI 57 trial of subjects with established CVD shows that the addition of AMG 145 to background lipid-lowering therapy increases the potential of high risk individuals to achieve NCEP-ATP III LDL-c and other lipid parameter targets. Treatment with the highest tested dose once every two or once every four weeks allows almost all high-risk individuals to reach lipid targets. AMG 145 was well tolerated over 12 weeks.

References

1. Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Journal of the American College of Cardiology 2004;44:720-32.
2. Kuklina EV, Yoon PW, Keenan NL. Trends in high levels of low-density lipoprotein cholesterol in the United States, 1999-2006. JAMA 2009;302:2104-10.
3. Karalis DG, Subramanya RD, Hessen SE, et al. Achieving optimal lipid goals in patients with coronary artery disease. Am J Cardiol 2011;107:886-90.
4. Giugliano RP, Desai NR, Kohli P et al. 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, placebocontrolled, dose-ranging, phase 2 study. Lancet 2012;380:2007-17.

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