The following are 10 points to remember about proprotein convertase subtilism/kexin 9 (PCSK9) inhibitors in the cardiovascular field:

1. Clearance of circulating low-density lipoprotein cholesterol (LDL-C) results primarily from binding to hepatocyte LDL-receptors (LDL-Rs) that undergo endocytosis with the LDL-R recirculated back to the cell surface about 150 times. The binding of circulating PCSK9 to LDL-R is responsible for stopping recirculation of LDL-R to the membrane by enhancing the degradation in the lysosome.
2. Gain-of-function mutations in PCSK9 reduce the LDL-Rs and are one of the genetic causes of familial hypercholesterolemia. The finding that loss-of-function in PCSK9 results in a modest lowering of LDL-C over a lifetime and reduces coronary heart disease triggered the development of the PCSK9 inhibitors.
3. Among the many PCSK9 inhibitors developed to lower LDL-C, parenteral monoclonal antibodies (MoAbs) have been the most successful. The most advanced in late-stage clinical trials are alirocumab (Regeneron Pharmaceutical Inc.) and evolocumab (Amgen Inc.).
4. A dose-dependent reduction in LDL-C (up to 70%) occurred at between 4 and 14 days with a 2 to 8+ week delay in return to baseline with each of the MoAbs.
5. Alirocomab dosing is 150 mg subcutaneous (SC) every 2 weeks and evolocumab 140 mg SC every 2 weeks or 420 mg every 4 weeks. In phase 2, 12-week placebo-controlled studies, each reduced LDL-C in the majority of patients 60-70% (75-85 mg/dl) at trough and >90% (>100 mg/dl) at peak. Over 70% of patients with hyperlipidemia on statins were able to achieve an LDL-C <70 mg/dl. Two other MoAbs in phase 2 trials were less effective.
6. LDL-C was lowered by both highly effective MoAbs to the same degree regardless of whether subjects were also on lipid-lowering agents (statins or ezetamibe) or had heterozygous familial hypercholesterolemia. There was no difference of response by age, sex, diabetes, or cardiovascular risk. The reduction at 1 year of treatment was similar to that in the 12-week studies.
7. Evolocumab reduced LDL-C in homozygous familial hypercholesterolemia patients who had between 2% and 25% of LDL-R activity, but not in those with nonfunctioning LDL-Rs. Both MoAbs significantly reduced apolipoprotein (apo) B, total cholesterol, triglycerides, non–high-density lipoprotein (HDL), and lipoprotein (a), but not HDL, apo A, or C-reactive protein.
8. Placebo-controlled trials in statin-intolerant patients showed no excess in myalgias or other adverse events such has viral infections, insulin resistance, or glucose intolerance.
9. In phase 3 placebo-controlled trials in patients on maximally tolerated statin, both MoAbs reduced the LDL-C about 2x that of ezetamibe. In patients on high-intensity statins and an LDL-C >150 mg/dl, evolocumab reduced mean LDL-C by 63-75%, and results were similar on moderate statin dosing.
10. Given the finding of a 22% reduction in major cardiovascular events for each 1 mmol/L (37.8 mg/dl) reduction of LDL-C in cholesterol-lowering trials that was constant across a broad range of LDL-C values, the LDL-C reduction from MoAbs is expected to result in about a 40% reduction in major cardiovascular events. Ongoing phase 3 trials in persons at high risk are powered to examine the effect of MoAbs on cardiovascular events. Completion is projected for late 2017.

Keywords: Antibodies, Monoclonal, Apolipoproteins A, Apolipoproteins B, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Dyslipidemias, Endocytosis, Hepatocytes, Hyperlipidemias, Hyperlipoproteinemia Type II, Lipoprotein(a), Lipoproteins, HDL, Lipoproteins, LDL, Mutation, Myalgia, Primary Prevention, Proprotein Convertases, Receptors, LDL, Risk Factors, Saccharomyces cerevisiae Proteins, Triglycerides

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