How does Repatha (evolocumab) work?

How Repatha (Evolocumab) Works

Repatha (evolocumab) works by binding to PCSK9 protein in the bloodstream, which increases the number of LDL receptors available on liver cells to clear LDL cholesterol from circulation, thereby significantly lowering blood LDL-C levels. 1, 2

Mechanism of Action in Detail

Evolocumab is a fully human monoclonal IgG2 antibody that specifically targets and binds to proprotein convertase subtilisin/kexin type 9 (PCSK9). This mechanism works in the following way:

1. PCSK9 Role in Normal Physiology:

   • PCSK9 is a circulating enzyme secreted by the liver
   • Normally, PCSK9 binds to LDL receptors (LDLR) on the surface of hepatocytes
   • This binding promotes LDLR degradation within the liver's lysosomes
   • The result is fewer LDL receptors available to remove LDL cholesterol from the bloodstream 2

2. Evolocumab's Intervention:

   • Evolocumab binds to circulating PCSK9
   • This prevents PCSK9 from binding to LDL receptors
   • LDL receptors are preserved and recycled back to the cell surface
   • More LDL receptors become available on hepatocytes
   • Enhanced clearance of LDL cholesterol from the bloodstream occurs 1, 3

Pharmacodynamic Effects

• Maximum suppression of circulating unbound PCSK9 occurs by 4 hours after administration
• Maximum LDL-C reduction occurs by:
  • 2 weeks after a single 140 mg dose
  • 3 weeks after a single 420 mg dose 2
• At steady state, peak reduction of LDL-C occurs approximately:
  • 1 week after a 140 mg dose given every 2 weeks
  • 2 weeks after a 420 mg dose given monthly 4
• LDL-C reduction magnitude:
  • 50-65% reduction from baseline when added to statins 1
  • 59% median reduction in the FOURIER cardiovascular outcomes trial 5

Clinical Significance

• Evolocumab's mechanism allows it to work effectively even when added to maximum statin therapy
• The drug can achieve LDL-C levels as low as 30 mg/dL (0.78 mmol/L) in many patients 1, 5
• Unlike statins (which work by inhibiting cholesterol synthesis), evolocumab enhances the natural clearance mechanism for LDL-C 6
• This mechanism makes it particularly valuable for:
  • Patients with heterozygous familial hypercholesterolemia
  • Patients with atherosclerotic cardiovascular disease not at LDL-C goals on statins
  • Statin-intolerant patients 1

Additional Effects

Beyond LDL-C reduction, evolocumab also:

• Reduces lipoprotein(a) [Lp(a)] by up to 25% 1, 4
• Increases HDL-C by approximately 4.5-6.8% 7
• Reduces total cholesterol and apolipoprotein B 3

Important Considerations

• The effect is dose-dependent with nonlinear kinetics due to target-mediated drug disposition
• At low concentrations, elimination occurs primarily through saturable binding to PCSK9
• At higher concentrations, elimination occurs through non-saturable proteolytic pathways
• Effective half-life is 11-17 days 2, 4

The mechanism of action of Repatha represents a significant advancement in lipid-lowering therapy by targeting a different pathway than statins, allowing for additive effects when used in combination and providing an option for patients who cannot achieve adequate LDL-C reduction with statins alone.