PCSK9 Inhibition With Monoclonal Antibodies: Modern Management of Hypercholesterolemia

Abstract

Current guidelines for hypercholesterolemia treatment emphasize lifestyle modification and lipid‐modifying therapy to reduce the risk for cardiovascular disease. Statins are the primary class of agents used for the treatment of hypercholesterolemia. Although statins are effective for many patients, they fail to achieve optimal reduction in lipids for some patients, including those who have or are at high risk for cardiovascular disease. The PCSK9 gene was identified in the past decade as a potential therapeutic target for the management of patients with hypercholesterolemia. Pharmacologic interventions to decrease PCSK9 levels are in development, with the most promising approach using monoclonal antibodies that bind to PCSK9 in the plasma. Two monoclonal antibodies, alirocumab and evolocumab, have recently been approved for the treatment of hypercholesterolemia, and a third one, bococizumab, is in phase 3 clinical development. All 3 agents achieve significant reductions in levels of low‐density lipoprotein cholesterol, as well as reductions in non‐high‐density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). Long‐term outcome trials are under way to determine the sustained efficacy, safety, and tolerability of PCSK9 inhibitors and whether this novel class of agents decreases the risk for major cardiovascular events in patients on lipid‐modifying therapy. Available data suggest that PCSK9 inhibitors provide a robust reduction in atherogenic cholesterol levels with a good safety profile, especially for patients who fail to obtain an optimal clinical response to statin therapy, those who are statin intolerant or have contraindications to statin therapy, and those with familial hypercholesterolemia.

Proprotein convertase inhibition: Paralyzing the cell’s master switches

“…These inhibitors have been the focus of successful clinical trials. At this stage, the first two PCSK9 inhibitors, alirocumab and evolocumab, have been in clinical use for lowering LDL-particle concentrations for cases in which classical statins and other drugs were not effective or badly tolerated [35, 36]. Recently, several excellent reviews have been published regarding the spectacular effects of PCSK9 inhibition in cardiovascular therapeutics.…”

Expression of LDLRs (Low-Density Lipoprotein Receptors), Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibition in Homozygous Familial Hypercholesterolemia

“…10,11 In the long-term open-label extension of TAUSSIG (Trial Assessing LongTerm Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders), evolocumab reduced LDL-C in HoFH patients on average by a lesser extent, ≈20%, but with wide variability as indicated by an SD of response of 24%. This means that some HoFH patients treated with evolocumab had >50% LDL-C reduction, whereas others did not respond to treatment at all.…”

The Proprotein Convertases in Hypercholesterolemia and Cardiovascular Diseases: Emphasis on Proprotein Convertase Subtilisin/Kexin 9

“…Three human mAbs are now in multiple phase 3 clinical trials. Two of them, Evolocumab (Repatha; Amgen; Thousand Oaks, CA) and Alirocumab (Praluent; Sanofi; Bridgewater, NJ), are already prescribed to FH patients worldwide, whereas the Bococizumab (Pfizer; Groton, CT) is not yet available commercially (Ito and Santos, 2016). However, very recently Pfizer discontinued the global development of Bococizumab, as the efficacy of this noncompletely humanized mAb decreased with time (http://www.pfizer.com/news/pressrelease/press-release-detail/pfizer_discontinues_global_ development_of_bococizumab_its_investigational_pcsk9_ inhibitor).…”