Related Experiment Video
Updated: Apr 9, 2026
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field?
Robert P Giugliano1, Marc S Sabatine1
1Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Abstract:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor, escorting it to its destruction in the lysosome and thereby preventing the recirculation of the low-density lipoprotein receptor to the hepatocyte cell surface. Both gain-of-function mutations in PCSK9 (causing marked increases in low-density lipoprotein cholesterol [LDL-C] concentration and premature atherosclerosis) and loss-of-function mutations (causing modest LDL-C reduction with low rates of coronary heart disease) have been described. Several monoclonal antibodies to PCSK9 have achieved LDL-C reductions of 50% to 70% across various patient populations and background lipid therapies. Phase 2/3 trials have demonstrated good tolerability without clear drug-related toxicity, although the number and duration of patients treated to date is modest. Currently, 4 phase 3 trials involving >70,000 patients are testing whether these drugs reduce cardiovascular events. The U.S. Food and Drug Administration is currently reviewing the existing data to determine whether these agents could be made available prior to the completion of these cardiovascular endpoint trials expected in 2018.
Insights
Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) effectively reduce low-density lipoprotein cholesterol (LDL-C). Ongoing trials will determine if these PCSK9 inhibitors reduce cardiovascular events.
Area of Science:
- Cardiovascular Medicine
- Biochemistry
- Pharmacology
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein receptor (LDLR) levels.
- Gain-of-function PCSK9 mutations increase LDL-C and atherosclerosis; loss-of-function mutations decrease LDL-C and coronary heart disease.
- PCSK9 inhibition is a novel therapeutic strategy for hypercholesterolemia.
Purpose of the Study:
- To review the role of PCSK9 in lipoprotein metabolism.
- To summarize the efficacy and safety of PCSK9-targeted monoclonal antibodies.
- To discuss ongoing cardiovascular outcome trials of PCSK9 inhibitors.
Main Methods:
- Review of preclinical and clinical studies on PCSK9.
- Analysis of data from Phase 2/3 trials of PCSK9 monoclonal antibodies.
- Overview of ongoing large-scale cardiovascular event trials.
Main Results:
- PCSK9 monoclonal antibodies achieve significant LDL-C reductions (50-70%).
- These agents demonstrate good tolerability in clinical trials to date.
- Large Phase 3 trials are evaluating cardiovascular event reduction.
Conclusions:
- PCSK9 antibodies represent a promising therapeutic class for lowering LDL-C.
- Further data from cardiovascular outcome trials are needed to confirm clinical benefit.
- Regulatory review is underway for potential early availability.
Related Concept Videos
01:29Pharmacogenomics: Identification of New Drug Targets
01:18Cardiovascular Drugs: Classification based on Therapeutic Indications
01:28Treatment for Pulmonary Arterial Hypertension: Phosphodiesterase Inhibitors
Among the PDE5 inhibitors, sildenafil (Revatio) stands out as a competitive and selective inhibitor. It operates by elevating cellular levels of cGMP and augmenting signaling through the cGMP-PKG pathway, promoting vasodilation. Upon oral...
01:23Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...
01:20Lipid-Lowering Drugs: Statins and Miscellaneous Agents
01:26Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...