What is evolocumab (Repatha, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor)?

From the Guidelines

Evolocumab is a highly effective prescription medication for lowering LDL cholesterol in patients with high cholesterol levels, particularly those with familial hypercholesterolemia or established cardiovascular disease, as evidenced by its ability to reduce LDL cholesterol by 59% in clinical trials 1.

Key Characteristics of Evolocumab

• It belongs to a class of drugs called PCSK9 inhibitors.
• It is administered as a subcutaneous injection, typically 140 mg every two weeks or 420 mg once monthly.
• Evolocumab works by blocking the PCSK9 protein, which normally prevents the liver from removing LDL cholesterol from the blood.

Clinical Evidence Supporting Evolocumab Use

• The Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial demonstrated a 15% relative risk reduction in the composite outcome of cardiovascular death, MI, stroke, hospitalization for angina, or revascularization with evolocumab therapy 1.
• The combined endpoint of cardiovascular death, MI, or stroke was reduced by 20% with evolocumab therapy 1.

Patient Selection and Administration

• Evolocumab is approved as adjunctive therapy for patients with ASCVD or familial hypercholesterolemia who are receiving maximally tolerated statin therapy but require additional lowering of LDL cholesterol 1.
• Patients can be administered evolocumab via subcutaneous injection, with dosing typically at 140 mg every two weeks or 420 mg every month based on patient preference.

Safety and Tolerability

• Common side effects of evolocumab include injection site reactions, nasopharyngitis, and upper respiratory tract infections 1.
• Evolocumab is generally well-tolerated by most patients, making it a viable option for long-term management of high cholesterol.

From the FDA Drug Label

Evolocumab is a human monoclonal immunoglobulin G2 (IgG2) directed against human proprotein convertase subtilisin kexin type 9 (PCSK9). Evolocumab has an approximate molecular weight (MW) of 144 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells REPATHA is a sterile, preservative-free, clear to opalescent, colorless to pale yellow solution for subcutaneous use.

Evolocumab is a human monoclonal antibody that targets PCSK9, a protein that regulates low-density lipoprotein (LDL) receptors in the liver. By inhibiting PCSK9, evolocumab increases the number of LDL receptors available to clear LDL cholesterol from the blood, thereby lowering LDL-C levels 2.

• Mechanism of action: Evolocumab binds to PCSK9, preventing it from binding to LDL receptors and promoting their degradation.
• Pharmacokinetics: Evolocumab exhibits non-linear kinetics due to binding to PCSK9, with a mean systemic clearance of 12 mL/hr and an effective half-life of 11 to 17 days 2.
• Administration: Evolocumab is administered via subcutaneous injection, with available doses of 140 mg and 420 mg 2.

From the Research

What is Evolocumab

• Evolocumab is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, a class of lipid-lowering agents that significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with atherosclerotic cardiovascular disease and hyperlipidemia 3.
• It is a monoclonal antibody that inhibits PCSK9 and has been evaluated in phase II and III studies as monotherapy, in combination with statins and other lipid-lowering therapies, in patients who are statin intolerant, and in patients with heterozygous and homozygous familial hypercholesterolemia 3, 4.
• Evolocumab is administered subcutaneously at a dosage of 140 mg every 2 weeks or 420 mg once monthly 4.

Mechanism of Action

• Evolocumab reduces LDL-C levels by inhibiting PCSK9, a protein that plays a critical role in the regulation of LDL-C levels in the blood 5, 6.
• By inhibiting PCSK9, evolocumab increases the number of LDL receptors on the surface of liver cells, leading to increased removal of LDL-C from the blood and a subsequent reduction in LDL-C levels 6, 7.

Efficacy and Safety

• Evolocumab has been shown to significantly reduce LDL-C levels in patients with primary hypercholesterolemia or mixed dyslipidemia, including those with heterozygous and homozygous familial hypercholesterolemia 3, 4, 5.
• Treatment with evolocumab has also been associated with a significant reduction in major cardiovascular events, including cardiovascular death, myocardial infarction, and stroke 5, 6.
• Evolocumab has been generally well tolerated, with a safety profile similar to that of placebo or ezetimibe 3, 4, 6.