What is evolocumab targeted against?

Evolocumab Targets PCSK9 to Lower LDL Cholesterol

Evolocumab is a human monoclonal antibody (IgG2) that specifically targets and inhibits proprotein convertase subtilisin kexin type 9 (PCSK9). By binding to PCSK9, evolocumab prevents PCSK9 from binding to low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, thereby increasing the number of LDLRs available to clear LDL from the bloodstream and lowering LDL cholesterol levels 1.

Mechanism of Action

• PCSK9 is a circulating enzyme secreted by the liver that plays a key role in LDL receptor turnover 2
• When PCSK9 binds to the extracellular part of the LDL receptor, it directs the receptor toward lysosomal degradation instead of allowing it to recycle to the cell surface 2
• Evolocumab binds to PCSK9 in the bloodstream, preventing it from interacting with LDL receptors 1
• This inhibition increases the number of LDL receptors on hepatocyte cell surfaces, enhancing LDL clearance from circulation 1
• The result is a significant reduction in circulating LDL cholesterol levels, typically by 50-65% 3

Pharmacological Properties

• Evolocumab is a fully human monoclonal IgG2 antibody with an approximate molecular weight of 144 kDa 1
• It is produced in genetically engineered mammalian (Chinese hamster ovary) cells 1
• Following subcutaneous administration, maximum suppression of circulating unbound PCSK9 occurs by 4 hours 1
• Maximum LDL-C reduction occurs by 2 weeks after a single 140 mg dose and by 3 weeks after a single 420 mg dose 1
• The drug exhibits non-linear kinetics due to its binding to PCSK9 1
• Evolocumab has an effective half-life of 11 to 17 days 1

Clinical Efficacy

• When added to maximally tolerated statin therapy, evolocumab 140 mg every 2 weeks and 420 mg every 4 weeks reduces LDL-C by an additional 64% and 58%, respectively 3
• On maximal statin therapy, mean LDL cholesterol levels of approximately 0.9 mmol/L (35 mg/dL) are achievable with PCSK9 monoclonal antibodies 3
• Many patients achieve LDL cholesterol levels below 0.64 mmol/L (25 mg/dL) 3
• In the FOURIER trial, evolocumab significantly reduced the risk of cardiovascular events (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization) compared to placebo 4
• Evolocumab also reduces other lipid parameters, including Lp(a) by up to 25% 3

Clinical Applications

• Evolocumab is FDA-approved for:

  • Lowering LDL-C in adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) as an adjunct to diet, alone or in combination with other lipid-lowering therapies 3
  • Reducing the risk of MI, stroke, and coronary revascularization in adults with established atherosclerotic cardiovascular disease 3
  • Lowering LDL-C in adults and pediatric patients (aged ≥10 years) with homozygous familial hypercholesterolemia 3

• Particularly beneficial for:

  • Patients with familial hypercholesterolemia (FH) 3
  • High-risk patients unable to tolerate high-intensity statin therapy 3
  • Patients unable to achieve >50% LDL cholesterol reduction on statin therapy 3
  • Individuals with recurrent cardiovascular events despite maximally tolerated doses of oral therapies 3

Safety Profile

• Evolocumab appears well-tolerated in trials up to 78 weeks in duration 3
• Common adverse effects include nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions 3
• No excess of adverse events has emerged in patients with very low LDL cholesterol levels (<0.65 mmol/L or <25 mg/dL) 3
• The EBBINGHAUS trial showed no detriment in cognitive function, even in patients attaining very low LDL-C levels 3
• No clinically significant drug-drug interactions have been identified for evolocumab 3

Dosing and Administration

• Administered subcutaneously in the thigh, abdomen, or upper arm 3
• For adults with established ASCVD or primary hypercholesterolemia: 140 mg every 2 weeks or 420 mg once monthly 3
• For homozygous FH: 420 mg once monthly; may increase to 420 mg every 2 weeks if needed after 12 weeks 3
• The 420 mg dose is administered either using the prefilled single-dose on-body infusor or by giving 3 consecutive 140 mg injections within 30 minutes 3

In summary, evolocumab specifically targets PCSK9, preventing it from binding to LDL receptors and thereby increasing the availability of these receptors to clear LDL cholesterol from the bloodstream. This mechanism results in substantial reductions in LDL-C levels and has been shown to reduce cardiovascular events in high-risk patients.