Source of information: Drugbank (External Link). Last updated on: 3rd July 18
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Active Ingredient / Synonyms
Evolocumab | Evolocumab |
Evolocumab is a monoclonal antibody designed for the treatment of hyperlipidemia by Amgen. It is a subcutaneous injection approved by the FDA for individuals on maximum statin therapy who still require additional LDL-cholesterol lowering. It is approved for both homozygous and heterozygous familial cholesterolemia as an adjunct to other first-line therapies. Evolocumab is a human IgG2 monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a protein that targets LDL receptors for degradation, therefore reducing the liver's ability to remove LDL-cholesterol (LDL-C), or "bad" cholesterol, from the blood. Evolocumab is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface, resulting in more LDL receptors on the surface of the liver to remove LDL-C from the blood. Evolocumab is the second PCSK9 inhibitor on the market, first being alirocumab.
For the treatment of heterozygous/homozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease in patients on maximum tolerated statin therapy requiring additional LDL-cholesterol lowering.
Mechanism of Action
Evolocumab is a human IgG monoclonal antibody which targets PCSK9 (proprotein convertase subtilisin/kexin type 9). PCSK9 is a serine protease produced by the liver which binds LDL receptors and creates a complex to be targeted for lysosomal degradation. LDL receptors typically bind LDL-cholesterol ("bad" cholesterol) for cellular reuptake, therefore the formation of these complexes with PCSK9 inhibits LDL receptor recycling to the cell surface, resulting in decreased cellular reuptake of LDL-C and increased levels of free LDL-C in the plasma. Individuals with familial hypercholesterolemia often may have "gain of function" mutations in the PCSK9 molecules in their body, resulting in increased LDL-C plasma levels and a consequent cardiovascular risk. Evolocumab is able to bind both the normal PCSK9 and the "gain of function" mutant, D374Y. The exact mechanism of the binding has not been published, however the precursor molecule, mAb1, is indicative of the interaction. The mAb1 molecule binds on the catalytic site of PCSK9 next to the binding site for the LDL receptor and creates hydrogen bonds and hydrophobic interactions, resulting in the steric inhibition of binding between PCSK9 and the LDL receptor. Because the formation of complexes between LDL receptor and PCSK9 are prevented, the internalized LDL receptors are less likely to be degrated by lysosomes and may recycle to the surface of the cell to serve their function of removing LDL from the blood.
Total bioavailability from subcutaneous injection was 82% in cynomolgus monkeys.
Evolocumab showed non-linear, dose-dependent clearance in healthy volunteers; clearance decreased with increasing dose.
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