PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects

Abstract

In 2003, clinical observations led to the discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism. Functional studies demonstrated that PCSK9 binds to the low-density lipoprotein (LDL) receptor directing it to its lysosomal degradation. Therefore, carriers of gain-of-function mutations in PCSK9 exhibit decreased expression of LDL receptors on the hepatocyte surface and have higher LDL cholesterol (LDL-C) levels. On the contrary, loss-of-function mutations in PCSK9 are associated with low LDL-C concentrations and significantly reduced lifetime risk of cardiovascular disease. These insights motivated the search for strategies to pharmacologically inhibit PCSK9. In an exemplary rapid development, fully human monoclonal antibodies against PCSK9 were developed and found to effectively reduce LDL-C. Administered subcutaneously every 2–4 weeks, the PCSK9 antibodies evolocumab and alirocumab reduce LDL-C by up to 60% in a broad range of populations either as monotherapy or in addition to statins. Two large cardiovascular outcome trials involving a total of ∼46,000 cardiovascular high-risk patients on guideline-recommended lipid-lowering therapy showed that treatment with evolocumab and alirocumab led to a relative reduction of cardiovascular risk by 15% after 2.2 and 2.8 years of treatment, respectively. These findings expanded the armamentarium of pharmacological approaches to address residual cardiovascular risk associated with LDL-C. Furthermore, the unprecedented low LDL-C concentrations achieved (e.g., 30 mg/dL in the FOURIER study) suggest that the relationship between LDL-C and cardiovascular risk is without a lower threshold, and without associated adverse events during the timeframe of the studies. The side effect profile of PCSK9 antibodies is favorable with few patients exhibiting injection-site reactions. Currently, the access to PCSK9 antibodies is limited by high treatment costs. The development of novel approaches to inhibit PCSK9 such as the use of small interfering RNA to inhibit PCSK9 synthesis seems promising and may soon become available.

Rapid Decline of Serum Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) in Non-Cirrhotic Patients with Chronic Hepatitis C Infection Receiving Direct-Acting Antiviral Therapy

“…Hepatic LDL-receptor protein is degraded upon PCSK9 binding, and serum LDL is increased. Blockage of PCSK9 lowers serum LDL and may protect from cardiovascular diseases [ 15 , 16 , 17 ].…”

High-Throughput Screening Identifies MicroRNAs Regulating Human PCSK9 and Hepatic Low-Density Lipoprotein Receptor Expression

“…The discovery that loss-of-function mutations in PCSK9 are associated with lifelong low cholesterol levels and protection from ASCVD sparked intense efforts to develop inhibitors of this circulating protein ( 7 ). The first approved PCSK9 inhibitors, human monoclonal antibodies that bind extracellular PCSK9, show remarkable efficacy in reducing LDL-C either as monotherapy (50% reduction) or in combination with a statin (70% reduction) ( 24 ). Although highly effective, these monoclonal antibodies require injections every 2–4 weeks, and additional approaches for PCSK9 inhibition are being actively pursued ( 25 ).…”

“…Synthetic RNAs can also be conjugated to triantennary N -acetylgalactosamine carbohydrates to enhance hepatic uptake via asialoglycoprotein receptors and show an extended duration of action. Indeed, in Phase II clinical trials, two doses of inclisiran resulted in profound suppression of PCSK9 and LDL-C for at least 6 months ( 24 ). The success of this siRNA-based therapy reflects the remarkable improvements in the safety and efficacy of RNA-targeted treatment approaches over the last decade and suggests that miRNA-based therapies might not be far behind.…”

Acanthaster planci Inhibits PCSK9 and Lowers Cholesterol Levels in Rats

“…To date, two drugs (Alirocumab and Evolocumab) have been approved by the Food and Drug Administration (FDA) and commercially available for the treatment for hypercholesterolemia since 2015 [ 32 , 33 ]. In addition, another drug (inclisiran) that uses a gene silencing approach that specifically destroys PCSK9 mRNA and inhibits the synthesis of PCSK9 protein has been given an approval by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) to be used in European Union in December 2020 [ 34 , 35 , 36 ]. However, these drugs are biotechnology-based and the cost of prescribing these drugs to patients are extremely high [ 15 , 37 ], therefore, not economical to prescribe to all patients suffering from hypercholesterolemia as compared to statin, a natural product-based, which is more economical [ 16 ].…”