In three separate phase II trials, a proprotein convertase subtilisin/kexin type 9 protease inhibitor achieves significant reductions in LDL levels compared with placebo or ezetimibe.
Statin therapy, which reduces both low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular risk, is unsuccessful in many patients because of poor response, intolerance, allergy, or a combination of the three. Nonstatin agents also lower LDL-C levels; to date, however, few data support their effectiveness at improving clinical outcomes. Attention is now focused on investigational, fully human, monoclonal antibodies directed against proprotein convertase subtilisin/kexin type 9 (PCSK9), which impairs the liver's ability to remove LDL-C from the blood. In three manufacturer-sponsored phase II studies of a subcutaneously administered PCSK9 inhibitor, AMG 145, investigators assessed the potential of this approach in different patient cohorts with or at risk for cardiovascular disease.
In the RUTHERFORD study, treatment with one of two doses of AMG 145 every 4 weeks resulted in significant reductions in LDL-C of up to 56% compared with placebo in 167 patients with heterozygous familial hypercholesterolemia on lipid-lowering therapy (statins with or without ezetimibe). At week 12, the proportions of patients reaching LDL levels less than 100 mg/dL were:
The proportions of patients reaching LDL levels less than 70 mg/dL were:
In the LAPLACE-TIMI 57 study, six tested dose regimens of AMG 145 all significantly decreased LDL-C compared with placebo in 629 patients with or at risk for cardiovascular disease who were taking statins (with or without ezetimibe). At week 12, AMG 145 reduced LDL-C by up to 66% compared with placebo in patients treated every 2 weeks and up to 50% compared with placebo in those treated every 4 weeks.
In MENDEL, the first study of a PCSK9 inhibitor as monotherapy, the same six regimens of AMG 145 were compared with placebo and with open-label ezetimibe (10 mg/day) only in 406 hyperlipidemic patients at low cardiovascular risk who were not taking a statin. At week 12, AMG 145, whether given every 2 or every 4 weeks, significantly reduced LDL-C compared with placebo by as much as 47% in the groups dosed biweekly and by up to 53% in the groups dosed every 4 weeks. The mean decreases in LDL-C level from baseline for the biweekly groups were:
The mean decreases in LDL-C level from baseline for the 4-week groups were:
The mean decrease in LDL-C level from baseline was also significantly greater in all AMG 145 groups than in the ezetimibe-only group.
AMG 145 was also associated with important reductions in lipoprotein(a) [Lp(a)] in the two studies that reported this endpoint. No serious adverse effects of AMG 145 were reported; the most common minor events were upper respiratory tract infection, nasopharyngitis, gastrointestinal symptoms, and injection site reactions.
Citation(s):
Koren MJ et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): A randomised, double-blind, placebo-controlled, phase 2 study. Lancet 2012 Dec 8/14; 380:1995.
Giugliano RP 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, placebo-controlled, dose-ranging, phase 2 study. Lancet 2012 Dec 8/14; 380:2007.
Tonkin AM and Watts GF. Into the future: Diversifying lipid management. Lancet 2012 Dec 8/14; 380:1971.
Raal F et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: The reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial. Circulation 2012 Nov 13; 126:2408.
