PCSK9 Inhibitors Topic Review

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that binds to the LDL receptor on hepatocytes, promoting its internalization and degradation within the cell. [Repatha package insert;9a]

When PCSK9 is inactivated or inhibited, the LDL receptor/LDL cholesterol (LDL-C) particle complex is still internalized by endocytosis; however, once in the cell, the LDL-C particle is degraded and the LDL receptor returns to the cell membrane, and can bind more LDL-C particles and remove them from the blood. [Repatha package insert;9a; Robinson JG. Clinical Lipid Management;453a]

Because the PCSK9 protein does not possess suitable clefts into which a small molecule could bind and inactivate it, the most successful PCSK9 inhibitors have been biologics — to date, two monoclonal antibodies (mAbs; alirocumab and evolocumab) and a small interfering RNA (siRNA; inclisiran). [Robinson JG. Clinical Lipid Management;455a ]

Monoclonal antibodies are large and complex proteins which are specific to their target; anti-PCSK9 mAbs are able to bind to the catalytic domain of the PCSK9 protein, impairing its function. [Robinson JG. Clinical Lipid Management;455a] Alirocumab (Praluent, Regeneron) and evolocumab (Repatha, Amgen) are the two mAbs currently approved by the FDA; both received approval in 2015. [Repatha package insert; 1a; 23a; Praluent package insert;1a;6b]

The activity of PCSK9 can also be inhibited by siRNAs. These short, double-stranded RNA molecules silence specific target genes by binding via sequence complementarity to the target gene’s mRNA and recruiting the RNA-induced silencing complex (RISC), which degrades the target mRNA. [Hu B, et al. Signal Transduct Target Ther. 2020;1a;2a;8b] Inclisiran (Leqvio, Novartis) is an siRNA that specifically targets the human PCSK9 mRNA. Inclisiran first received FDA approval in 2021. [Leqvio package insert;1a;6a]

Indications

Alirocumab is currently FDA-approved for the following indications:

• Adult patients with established CVD: Alirocumab is indicated to reduce the risk of myocardial infarction (MI), stroke and unstable angina requiring hospitalization [Praluent package insert;1a]
• Adult patients with mixed primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH): Alirocumab is indicated as an adjunct to diet, alone or in combination with other LDL-C-lowering therapies, to reduce LDL-C [Praluent package insert;1a]
• Adult patients with homozygous familial hypercholesterolemia (HoFH): Alirocumab is indicated as an adjunct to other LDL-C-lowering therapies to reduce LDL-C [Praluent package insert;1a]

Evolocumab is currently FDA-approved for the following indications:

• Adults with established CVD: Evolocumab is indicated to reduce the risk of MI, stroke and coronary revascularization [Repatha package insert;2a]
• Adult patients with primary hyperlipidemia, including HeFH: Evolocumab, alone or in combination with other LDL-C-lowering therapies, is indicated as an adjunct to reduce LDL-C [Repatha package insert;2a]
• Pediatric patients aged 10 years and older with HeFH: Evolocumab is indicated as an adjunct to diet and other LDL-C-lowering therapies to reduce LDL-C [Repatha package insert;2a]
• Adult and pediatric adults aged 10 years and older with HoFH: Evolocumab is indicated as an adjunct to other LDL-C-lowering therapies to reduce LDL-C [Repatha package insert;2a]

Inclisiran is currently FDA-approved and indicated as an adjunct to diet for the treatment of adult patients with HeFH or clinical atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C. [Leqvio package insert;2a]

Dosage and Administration

The recommended dosage of alirocumab depends on the patient population:

• In adult patients with established CVD or with primary hyperlipidemia (including HeFH): Either 75 mg once every 2 weeks or 300 mg once every 4 weeks, administered subcutaneously. If the LDL-C response is inadequate, the dosage may be adjusted to 150 mg once every 2 weeks [Praluent package insert;1d]
• In adult patients with HeFH undergoing LDL apheresis or in adult patients with HoFH: 150 mg once every 2 weeks, administered subcutaneously [Praluent package insert;1e]

The recommended dosage of evolocumab likewise depends on the patient population:

• In adult patients with established CVD or with primary hyperlipidemia, and in pediatric patients with HeFH aged 10 years of older: Either 140 mg once every 2 weeks or 420 mg once monthly, administered subcutaneously [Repatha package insert;2e]
• In adult and pediatric patients with HoFH aged 10 years or older: a subcutaneous 420 mg once-monthly dose is recommended initially; if a clinically meaningful response is not achieved within 12 weeks, the dose can be increased to 420 mg subcutaneously every 2 weeks [Repatha package insert;2g]

The recommended dosage schedule of inclisiran consists of an initial subcutaneous injection of 284 mg, followed by another at 3 months, and at every 6 months thereafter. [Leqvio package insert;2b]

Guideline Recommendations

The current (2018) multisociety (including the American College of Cardiology [ACC] and American Heart Association [AHA]) guideline on blood cholesterol management contains recommendations on nonstatin LDL-C lowering drugs, including ezetimibe, bile acid sequestrants and PCSK9 inhibitors. In general, the guidelines recommend the use of these agents only in circumstances when maximally tolerated statin therapy has failed to effect a desired LDL-C reduction. [Grundy SM, et al. Circulation;10b,d-e] Specific recommendations on the use of PCSK9 inhibitors are shown below, organized by patient population. Note that at the time of publication of the guideline (2018), the only available PCSK9 inhibitors were monoclonal antibodies; the siRNA inclisiran was approved later (2021).

For secondary prevention in patients with clinical ASCVD, the guideline makes the following recommendations:

• Following a clinician-patient discussion about the net benefit, addition of a PCSK9 inhibitor to a maximally tolerated LDL-C-lowering therapy is reasonable (class of recommendation [COR] IIa) for patients with very high-risk ASCVD whose LDL-C levels are ≥ 70 mg/dL (≥ 1.8 mmol/L) or whose non-HDL-C levels are ≥ 100 mg/dL (≥ 2.6 mmol/L) [Grundy SM, et al. Circulation;10e]
• Before addition of a PCSK9 inhibitor for patients with very high-risk ASCVD is considered, their maximally tolerated LDL-C-lowering therapy should (COR I) include ezetimibe and a statin [Grundy SM, et al. Circulation;10c]

For primary prevention in patients with primary severe hypercholesterolemia, the guideline states:

• Addition of a PCSK9 inhibitor may be considered (COR IIb) in patients 30 to 75 years of age with familial hypercholesterolemia (FH) and an LDL-C level of ≥ 100 mg/dL (≥ 2.6 mmol/L) while on maximally tolerated statin and ezetimibe combination therapy [Grundy SM, et al. Circulation;14b]
• Addition of a PCSK9 inhibitor may be considered (COR IIb) in patients 40 to 75 years of age with a baseline LDL-C level of ≥ 220 mg/dL (≥ 5.7 mmol/L) whose LDL-C levels on a maximallytolerated statin and ezetimibe regimen are ≥ 130 mg/dL (≥ 3.4 mmol/L) [Grundy SM, et al. Circulation;14c]

The guideline also contains a value statement on PCSK9 inhibitors, declaring them low cost-value drugs in patients with ASCVD (at 2018 prices, the cost was > $150,000 per quality-adjusted life year [QALY]; a good cost-value is < $50,000 per QALY); [Grundy SM, et al. Circulation;11b] the guideline considers the cost-value of PCSK9 inhibitors in patients with familial hypercholesterolemia but no clinical ASCVD uncertain. [Grundy SM, et al. Circulation;14d]

Efficacy and Safety

The LDL-C-lowering efficacy of PCSK9 inhibitor mAbsvaries depending on the dosing regimen. Clinical trials have demonstrated that, when added to a statin therapy, alirocumab and evolocumab lower LDL-C levels by 43% to 58% and 47% to 71%, respectively. [Robinson JG. Clinical Lipid Management;255a-b,256a-b] In the ORION-10 and ORION-11 trials, which enrolled patients with clinical ASCVD or an ASCVD risk equivalent who were on maximally tolerated LDL-C-lowering therapy, inclisiran lowered LDL-C by approximately 50%. [Ray KK, et al. N Engl J Med;2a,5a] In ORION-9, which enrolled patients with HeFH on maximally tolerated statin therapy with or without ezetimibe, inclisiran reduced LDL-C by 39.7% compared to the baseline, with a 47.9% difference from the placebo group, in which LDL-C levels increased by 8.2%. [Raal FJ, et al. N Engl J Med;2a,4a]

The cardiovascular (CV) outcome efficacy of PCSK9 inhibitor mAbs was tested in two pivotal trials, ODYSSEY OUTCOMES (alirocumab) and FOURIER (evolocumab).

The ODYSSEY OUTCOMES trial enrolled 18,924 patients aged 40 and older with a recent history of hospitalization for an acute coronary syndrome (ACS) and LDL-C levels ≥ 70 mg/dL, and randomly assigned them to alirocumab 75 mg every 2 weeks (9,462 patients) or a placebo (9,462 patients). [Schwartz GG, et al. N Engl J Med;2a,3a,4a] Most patients were receiving (and continued receiving) other LDL-C-lowering medication, primarily statins. [Schwartz GG, et al. N Engl J Med;4b] The primary endpoint was a composite outcome, including death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. [Schwartz GG, et al. N Engl J Med;3b] At 4 years, alirocumab treatment significantly lowered the incidence of the composite endpoint, with a Kaplan-Meier probability estimate of 12.5% and 14.5% in the alirocumab and placebo groups, respectively (P < .001). [Schwartz GG, et al. N Engl J Med;6a]

The FOURIER trial enrolled a total of 27,564 patients aged 40 to 85 years with a history of MI, nonhemorrhagic stroke or symptomatic peripheral artery disease, whose LDL-C levels were ≥ 70 mg/dL (or non-HDL-C levels ≥ 100 mg/dL) on optimized lipid-lowering therapy (a statin with or without ezetimibe). [Sabatine MS, et al. N Engl J Med;2a,2b] Patients were randomized to receive either evolocumab (140 mg every 2 weeks or 420 mg every month; 13,784 patients) or placebo (13,780 patients). [Sabatine MS, et al. N Engl J Med;2c,3a] The primary endpoint was a composite of CV death, MI, stroke, hospitalization for unstable angina or coronary revascularization. [Sabatine MS, et al. N Engl J Med;2d] Treatment with evolocumab resulted in a significant reduction of the incidence of the composite endpoint, which occurred in 1,344 (9.8%) patients treated with evolocumab and 1,563 (11.3%) of patients who received placebo (P < .001). [Sabatine MS, et al. N Engl J Med;5a]

Although initial data from ORION-10 and ORION-11 suggested that inclisiran may provide a CV outcomes benefit, these trials were not powered to address this question; a CV outcomes trial of inclisiran, ORION-4, is currently underway. [Ray KK, et al. N Engl J Med;11a]

PCSK9 inhibitors have a good safety profile. In the ODYSSEY OUTCOMES and FOURIER trials, adverse event rates were not different between the alirocumab or evolocumab groups and the placebo group, except for injection-site reactions, which were more common with the PCSK9 inhibitor than with placebo in both trials. [Schwartz GG, et al. N Engl J Med;6a; Sabatine MS, et al. N Engl J Med;6a,7a] In ORION-10 and ORION-11, adverse reactions and serious adverse reactions occurred at comparable rates in the inclisiran and placebo groups. [Ray KK, et al. N Engl J Med;6a,7b] As with mAb PCSK9 inhibitors, injection-site reactions were more common with inclisiran than with placebo, but were mostly mild. [Ray KK, et al. N Engl J Med;7a]

References:

• Grundy SM, et al. Circulation. 2019;doi:10.1161/CIR.0000000000000625.
• Hu B, et al. Signal Transduct Target Ther. 2020;doi:10.1038/s41392-020-0207-x..
• Leqvio. Prescribing information. Novartis Pharmaceuticals Corp. www.novartis.com/us-en/sites/novartis_us/files/leqvio.pdf. Revised December 2021. Accessed Nov. 28, 2022.
• Praluent. Prescribing information. Regeneron Inc. www.regeneron.com/downloads/praluent_pi.pdf. Revised April 2021. Accessed Nov. 28, 2022.
• Raal FJ, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1913805.
• Ray KK, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1912387.
• Repatha. Prescribing information. Amgen Inc. www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/repatha/repatha_pi_hcp_english.pdf. Revised September 2021. Accessed Nov. 28, 2022.
• Robinson JG. Clinical Lipid Management. First ed. Montvale NJ: Professional Communications; 2016.    
• Sabatine MS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615664.
• Schwartz GG, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1801174.