PCSK9 inhibitors

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PCSK9 inhibitors
Drug class

PCSK9 inhibitors are a class of medications used to treat hypercholesterolemia.[1][2] In those on high doses of statins, they decrease risk of further problems by 1.5% over 2.5 years.[3]

A number of agents are approved in the United States to treat familial hypercholesterolemia.[4] In Canada they cost about 7,000 CAD per year as of 2018.[3]

Medical uses

PCSK9 inhibitors are promising therapeutics for the treatment of people who exhibit statin intolerance, or as a way to bypass frequent dosage of statins for higher LDL concentration reduction.[5][6]

A review published in 2015 concluded that these agents, when used in patients with high LDL-particle concentrations (thus at greatly elevated risk for cardiovascular disease) seem to be safe and effective at reducing all-cause mortality, cardiovascular mortality, and heart attacks.[7] However a 2020 review concluded that while PCSK9 inhibitor treatment provides additional benefits beyond maximally tolerated statin therapy in high-risk individuals,[8] PCSK9 inhibitor use probably produces little or no difference in mortality.[9]

Prices were very high, inhibiting adoption.[4] The drugs are approved by the FDA for treatment of hypercholesterolemia, notably the genetic condition heterozygous familial hypercholesterolemia which causes high cholesterol levels and heart attacks at a young age.[10] These drugs were later approved by the FDA for the reduction of cardiovascular events including a reduction in all-cause mortality.[11]

Side effects

An FDA warning in March 2014 about possible cognitive adverse effects of PCSK9 inhibition caused concern, as the FDA asked companies to include neurocognitive testing into their Phase III clinical trials.[12]


Under normal conditions, PCSK9 binds to the LDL-LDLR-complex and directs both to the lysosome for degradation.[13]
PCSK9-inhibitors that prevent the association between PCSK9 and the LDLR mean that when LDLR is internalised, it releases the LDL before reaching the lysosome and is instead recycled to the cell surface to be available for binding again.[14]

Monoclonal antibodies

A number of monoclonal antibodies that bind to and inhibit PCSK9 near the catalytic domain were in clinical trials as of 2014. These include evolocumab (Amgen), bococizumab (Pfizer), and alirocumab (Sanofi/Regeneron Pharmaceuticals).[15] As of July 2015, the EU approved these drugs including Evolocumab/Amgen according to Medscape news agency report. A meta-analysis of 24 clinical trials has shown that monoclonal antibodies against PCSK9 can reduce cholesterol, cardiac events and all-cause mortality.[7] The most recent guidelines for cholesterol management from the American Heart Association and American College of Cardiology now provide guidance for when PCSK9 inhibitors should be considered, particularly focusing on cases in which maximally tolerated statin and ezetimibe fail to achieve goal LDL reduction.[16]

A possible side effect of the monoclonal antibody might be irritation at the injection site. Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.[17]

Peptide mimics

Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.[18]

Gene silencing

Loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.[19] The PCSK9 antisense oligonucleotide increases expression of the LDLR and decreases circulating total cholesterol levels in mice.[20] A locked nucleic acid reduced PCSK9 mRNA levels in mice.[21][22] Initial clinical trials showed positive results of ALN-PCS, which acts by means of RNA interference.[23][24]

In 2021, scientists demonstrated that CRISPR gene editing can decrease blood levels of LDL cholesterol in vivo in Macaca fascicularis monkeys for months by 60 % via knockdown of PCSK9 in the liver.[25][26]


A vaccine that targets PCSK9 has been developed to treat high LDL-particle concentrations. The vaccine uses a VLP (virus-like particle) as an immunogenic carrier of an antigenic PCSK9 peptide. VLP's are viruses that have had their DNA removed so that they retain their external structure for antigen display but are unable to replicate; they can induce an immune response without causing infection. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high-titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides.[27]

Naturally occurring

The plant alkaloid berberine inhibits the transcription of the PCSK9 gene in immortalized human hepatocytes in vitro,[28] and lowers serum PCSK9 in mice and hamsters in vivo.[29] It has been speculated[29] that this action contributes to the ability of berberine to lower serum cholesterol.[30] Annexin A2, an endogenous protein, is a natural inhibitor of PCSK9 activity.[31]


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