How does Repatha (evolocumab) work?

From the Guidelines

Repatha (evolocumab) works by inhibiting a protein called PCSK9, which normally binds to LDL receptors on liver cells and leads to their degradation, allowing more LDL receptors to remain on the liver cell surface and remove more LDL cholesterol from the bloodstream, significantly reducing levels of LDL ("bad") cholesterol in the blood, as demonstrated in the FOURIER trial, which showed a 59% reduction in LDL cholesterol from a median of 92 to 30 mg/dL in the treatment arm 1.

Mechanism of Action

Repatha is a monoclonal antibody that binds to PCSK9, preventing it from binding to LDL receptors and leading to their degradation. This mechanism enables the liver to remove more LDL cholesterol from the bloodstream, reducing the risk of cardiovascular events.

Administration and Dosage

Repatha is administered as a subcutaneous injection, typically given either as 140 mg every two weeks or 420 mg once monthly. The medication is particularly useful for patients with familial hypercholesterolemia or those with atherosclerotic cardiovascular disease who cannot achieve target LDL levels with statins alone.

Efficacy and Safety

The FOURIER trial, a large randomized controlled trial, demonstrated the efficacy and safety of Repatha in reducing LDL cholesterol levels and cardiovascular events in patients with established cardiovascular disease 1. The trial showed that Repatha reduced the risk of major cardiovascular events, including myocardial infarction, stroke, and coronary revascularization, by 15% compared to placebo.

Patient Selection and Monitoring

Patients using Repatha should continue any other prescribed cholesterol medications and maintain heart-healthy lifestyle changes. The medication begins working quickly, with measurable reductions in LDL cholesterol within 1-2 weeks, though maximum effect may take several weeks to achieve. Regular monitoring of LDL cholesterol levels and cardiovascular risk factors is recommended to assess the effectiveness of Repatha therapy.

• Key points to consider when prescribing Repatha:

• Mechanism of action: inhibition of PCSK9
• Administration and dosage: subcutaneous injection, 140 mg every two weeks or 420 mg once monthly
• Efficacy and safety: demonstrated in the FOURIER trial
• Patient selection and monitoring: continue other prescribed cholesterol medications, maintain heart-healthy lifestyle changes, and monitor LDL cholesterol levels and cardiovascular risk factors regularly.

From the FDA Drug Label

Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.

Repatha Mechanism of Action: Repatha works by inhibiting the binding of PCSK9 to LDLR, which increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.

• The drug evolocumab is a human monoclonal IgG2 that targets PCSK9.
• By blocking PCSK9, evolocumab reduces the degradation of LDLR in the liver, leading to an increase in LDL clearance from the blood 2.

From the Research

Mechanism of Action

• Repatha (evolocumab) is a fully human monoclonal antibody that targets ProProtein Convertase Subtilisin/Kexin 9 (PCSK9) 3, 4, 5, 6, 7
• PCSK9 is a circulating enzyme secreted by the liver that plays a key role in the LDL-Receptors (LDL-R) turnover 3
• Binding of PCSK9 to the extracellular part of LDL-R leads to its degradation in the lysosome, resulting in a reduction in the number of LDL-R on the cell surface and increased levels of LDL-C 3
• Inhibiting PCSK9 with evolocumab prevents its interaction with LDL-R, leading to a marked reduction in LDL-C levels 3, 4, 5, 6, 7

Efficacy

• Evolocumab has been shown to reduce LDL-C levels by 50 to 60% in most patients with and without background treatment with statins or other lipid-lowering agents 3, 4, 7
• It has also been shown to significantly reduce total cholesterol, non-HDL cholesterol, apoprotein B, and lipoprotein(a) levels 3, 4, 6
• Evolocumab has been effective in reducing LDL-C levels in patients with heterozygous and homozygous familial hypercholesterolemia, as well as in patients with primary hypercholesterolemia or mixed dyslipidemia 3, 4, 5, 6, 7

Administration and Safety

• Evolocumab is administered subcutaneously at a dose of 140 mg every 2 weeks or 420 mg once per month 3, 4, 7
• The safety profile of evolocumab appears satisfactory, with no increase in adverse events observed when used in combination with statins 6, 7
• Concerns regarding the risk of neurocognitive events have largely been dispelled 7