Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol

Abstract

In three phase 1 trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01026597, NCT01074372, and NCT01161082.).

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“…For the groups that received drug s.c., the least-squares mean difference in the change from baseline in LDL cholesterol ranged from -32.5 ± 8.5 to -45.7 ± 7.2 percentage points compared with the placebo group (P < 0.001 for all 4 groups). 11 The degree and duration of LDL cholesterol lowering were dose-dependent in these two studies. In the multiple-dose Phase 1 study, patients received s.c. administered placebo or alirocumab at doses of 50, 100 or 150 mg on study days 1, 29 and 43.…”

“…was evaluated in two singledose Phase 1 studies of healthy volunteers, and the s.c. administered drug was also evaluated in one multiple-dose study of patients with either familial or non-familial hypercholesterolemia. 11 In the single-dose study of i.v. administration, a total of 40 participants received placebo (n = 10) or alirocumab at a dose of 0.3, 1.0, 3.0, 6.0, or 12.0 mg/kg (n = 6 per dose).…”

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“…Reduced LDLR levels result in decreased metabolism of LDL-C, which could lead to hypercholesterolemia. It is also possible that PCSK9, one of the serine proteases, increases LDL cholesterol because it binds to LDL receptors, leading to their accelerated degradation resulting in to increased LDL cholesterol levels [3] . Thus PCSK9 inhibitors act by preventing degradation of LDL receptors resulting in to increased LDL receptor activity on hepatocytes close to physiological function.…”

“…These agents are called Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which have been tried in multicenter studies to demonstrate their efficacy and safety and effect on blood lipoproteins [1][2][3][4] . Recently evolocumab and alirocumab have been demonstrated to have beneficial effects on cardiovascular events which appears to be a new achievement in the treatment of coronary artery disease (CAD) [1,2] .…”

“…Recently evolocumab and alirocumab have been demonstrated to have beneficial effects on cardiovascular events which appears to be a new achievement in the treatment of coronary artery disease (CAD) [1,2] . Randomized, controlled intervention trials with both the agents have demonstrated the efficacy and safety of these agents in reducing blood lipids without a decrease in HDL cholesterol [1][2][3][4] . It is possible that treatment with PCSK9 inhibitors can cause further decline in acute coronary syndromes (ACS) among high risk patients receiving statins.…”