What is the mechanism of action (MOA) of Repatha (evolocumab)?

Mechanism of Action of Repatha (Evolocumab)

Repatha (evolocumab) is a human monoclonal IgG2 antibody that binds to circulating PCSK9 protein, preventing it from binding to LDL receptors, 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

Detailed Mechanism

Evolocumab works through the following steps:

1. PCSK9 Binding: Evolocumab specifically binds to proprotein convertase subtilisin kexin type 9 (PCSK9) in the bloodstream 1

2. Prevention of LDLR Degradation: Normally, PCSK9 binds to low-density lipoprotein receptors (LDLR) on hepatocytes, promoting LDLR degradation within the liver 1

3. LDLR Preservation: By inhibiting the binding of PCSK9 to LDLR, evolocumab:

   • Prevents LDLR degradation in lysosomes
   • Preserves and enables recycling of LDLRs back to the cell surface
   • Increases the number of LDLRs available on hepatocytes 3, 2

4. Enhanced LDL-C Clearance: The increased number of LDLRs leads to enhanced clearance of LDL cholesterol from the bloodstream, resulting in lower circulating LDL-C levels 1

Pharmacodynamic Effects

• Rapid PCSK9 Suppression: Maximum suppression of circulating unbound PCSK9 occurs within 4 hours after administration 1, 4

• LDL-C Reduction Timeline:

  • Maximum LDL-C reduction occurs by 2 weeks after a single 140 mg dose
  • Maximum LDL-C reduction occurs by 3 weeks after a single 420 mg dose 1

• Magnitude of LDL-C Reduction:

  • Reduces LDL-C by approximately 50-65% from baseline when added to statins 2
  • Can achieve LDL-C levels as low as 30 mg/dL in many patients 2, 5

Additional Lipid Effects

Beyond LDL-C reduction, evolocumab also affects other lipid parameters:

• Reduces lipoprotein(a) [Lp(a)] by up to 25% 2, 4
• Increases HDL-C by approximately 4.5-6.8% 2
• Reduces total cholesterol and apolipoprotein B 2, 4

Clinical Significance of MOA

The mechanism of action of evolocumab translates to significant clinical benefits:

• The FOURIER trial demonstrated that evolocumab significantly reduces the incidence of major cardiovascular adverse events by 15% in patients with atherosclerotic cardiovascular disease 6

• There is a direct relationship between the reduction in clinical events and the diminution of LDL-C levels, even at very low LDL-C concentrations 6

• The safety profile remains excellent even in patients achieving very low LDL-C levels 6

Key Differences from Other Lipid-Lowering Therapies

Unlike statins that inhibit cholesterol synthesis in the liver by blocking HMG-CoA reductase, evolocumab works by enhancing LDL receptor recycling and availability, offering a complementary mechanism for LDL-C reduction 5. This makes it particularly valuable for:

• Patients with heterozygous or homozygous familial hypercholesterolemia
• Patients with atherosclerotic cardiovascular disease not at LDL-C goals on statins
• Statin-intolerant patients 2

The unique mechanism of evolocumab provides a potent approach to LDL-C lowering that can be used alone or in combination with other lipid-lowering therapies for enhanced cardiovascular risk reduction.