What is Evolocumab (Repatha)?

What is Evolocumab (Repatha)?

Evolocumab is a fully human monoclonal antibody (IgG2) that binds to and inhibits PCSK9 (proprotein convertase subtilisin/kexin type 9), thereby preventing PCSK9 from degrading LDL receptors on hepatocytes, which dramatically increases the number of LDL receptors available to clear LDL cholesterol from the blood. 1

Mechanism of Action

• PCSK9 normally binds to LDL receptors on the surface of liver cells and promotes their degradation in lysosomes rather than recycling them back to the cell surface 2, 3
• By inhibiting PCSK9, evolocumab increases the number of functional LDL receptors available to remove LDL cholesterol from circulation 1, 4
• This mechanism does not require functional LDL receptors to be present initially, making it effective even in severe genetic conditions 2

LDL Cholesterol Lowering Efficacy

• Evolocumab reduces LDL cholesterol by approximately 50-65% when added to statin therapy 2, 5
• When added to maximally tolerated statin therapy, evolocumab 140 mg every 2 weeks reduces LDL-C by an additional 64%, and 420 mg monthly reduces it by 58% 5
• Median LDL cholesterol levels can reach as low as 30 mg/dL (0.78 mmol/L) with evolocumab treatment 6, 7
• Maximum LDL-C reduction occurs by 2 weeks after a 140 mg dose and by 3 weeks after a 420 mg dose 1

FDA-Approved Indications

Evolocumab is approved for three main clinical scenarios 2, 7:

1. Primary Hyperlipidemia and Mixed Dyslipidemia:

• As adjunct to diet and maximally tolerated statin therapy in adults requiring additional LDL-C lowering 2, 7

2. Atherosclerotic Cardiovascular Disease (ASCVD):

• To reduce risk of myocardial infarction, stroke, and coronary revascularization in adults with established ASCVD 2, 7
• The FOURIER trial demonstrated a 15% reduction in the composite endpoint of CV death, MI, stroke, revascularization, or hospitalization for unstable angina 6, 7

3. Familial Hypercholesterolemia:

• For adults and pediatric patients ≥10 years with heterozygous familial hypercholesterolemia (HeFH) as adjunct to diet and other LDL-lowering therapies 2, 7
• For adults and pediatric patients ≥10 years with homozygous familial hypercholesterolemia (HoFH), where it reduces LDL-C by approximately 30% 2

Dosing and Administration

• Standard dosing: 140 mg subcutaneously every 2 weeks OR 420 mg subcutaneously once monthly 2, 7
• Administration sites: Thigh, abdomen, or upper arm 2, 1
• For HoFH: Start with 420 mg monthly; may increase to 420 mg every 2 weeks if more LDL-C reduction is needed after 12 weeks 2, 7
• Available as prefilled autoinjector, prefilled syringe, or on-body infusor system 1

Pharmacokinetics

• Bioavailability: 72% after subcutaneous administration 1
• Peak concentrations: Achieved in 3-4 days after subcutaneous injection 1, 4
• Effective half-life: 11-17 days 1, 4
• Steady state: Reached by 12 weeks of dosing with 2-3 fold accumulation in trough concentrations 1
• Exhibits nonlinear kinetics due to saturable binding to PCSK9 at lower concentrations and nonsaturable proteolytic degradation at higher concentrations 1, 4

Safety Profile

• Well tolerated in trials up to 78 weeks in duration 2, 5
• Common adverse effects: Nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions 5, 1
• Injection site reactions: More common with evolocumab (2.1%) versus placebo (1.6%) but generally mild 6
• No clinically significant drug-drug interactions have been identified 7, 4
• Neurocognitive and ophthalmologic events: Small, nonsignificant increases reported but no excess adverse events in patients achieving very low LDL-C levels (<25 mg/dL or <15 mg/dL) 2
• Muscle-related adverse events: Comparable to ezetimibe in statin-intolerant patients 2

Contraindications and Special Populations

• Only contraindication: History of hypersensitivity to evolocumab 7, 1
• No dose adjustment needed for renal impairment (including renal failure) or mild-to-moderate hepatic impairment 1, 4
• No data available for severe hepatic impairment 1
• Pediatric use: Established safety and efficacy in patients ≥10 years with HeFH or HoFH 1
• Geriatric use: No dose adjustment needed; no differences in safety or efficacy observed in patients ≥65 years 1

Additional Lipid Effects

Beyond LDL-C reduction, evolocumab also improves other lipid parameters 2, 8:

• Reduces lipoprotein(a) by up to 25% 2, 4
• Reduces apolipoprotein B 8
• Reduces non-HDL cholesterol 8
• Reduces triglycerides 8

Clinical Benefit in Cardiovascular Outcomes

• The FOURIER trial showed that evolocumab reduced the risk of the primary composite endpoint (CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) with a hazard ratio of 0.85 (95% CI 0.79-0.92, P<0.001) 6
• The key secondary endpoint (CV death, MI, or stroke) was reduced with a hazard ratio of 0.80 (95% CI 0.73-0.88, P<0.001) 6
• Benefits were consistent across subgroups, including patients with baseline LDL-C as low as 74 mg/dL 6