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| Primary information |
|---|
| ID | 10771 |
| Therapeutic ID | Th1179 |
| Protein Name | Evolocumab |
| Sequence | NA
|
| Molecular Weight | 141800 |
| Chemical Formula | C6242H9648N1668O1996S58 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | NA |
| Description | 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. |
| Indication/Disease | 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. |
| Pharmacodynamics | Following single subcutaneous administration of 140 mg or 420 mg of evolocumab, maximum suppression of circulating unbound PCSK9 occurred by 4 hours. Unbound PCSK9 concentrations returned toward baseline when evolocumab concentrations decreased below the limit of quantitation. |
| 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. |
| Toxicity | NA |
| Metabolism | NA |
| Absorption | Total bioavailability from subcutaneous injection was 82% in cynomolgus monkeys. |
| NA |
| Clearance | Evolocumab showed non-linear, dose-dependent clearance in healthy volunteers; clearance decreased with increasing dose. |
| Categories | Amino Acids, Peptides, and Proteins,Antibodies,Antibodies, Monoclonal,Anticholesteremic Agents,Antimetabolites,Blood Proteins,Globulins,Hypolipidemic Agents,Hypolipidemic Agents Indicated for Hyperlipidemia,Immunoglobulins,Immunoproteins,Lipid Modifying Agents,Lipid Modifying Agents, Plain,Lipid Regulating Agents,Non-statin Hypolipidemic Agents Indicated for Hyperlipidemia,Noxae,PCSK9 Inhibitor,Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Inhibitors,Proteins,Serum Globulins,Toxic Actions |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | The risk or severity of adverse effects can be increased when Evolocumab is combined with Belimumab. |
| Target | Proprotein convertase subtilisin/kexin type 9 |
| Brand Name | Repatha |
| Company | Amgen Canada Inc |
| Brand Description | Amgen Canada Inc |
| Prescribed For | REPATHAâ„¢ is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C); Also indicated as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. |
| Chemical Name | NA |
| Formulation | 140 mg |
| Physical Appearance | solution |
| Route of Administration | Subcutaneous |
| Recommended Dosage | The recommended subcutaneous dosage of REPATHA in patients with HeFH or patients with primary hyperlipidemia with established clinical atherosclerotic CVD is either 140 mg every 2 weeks OR 420 mg once monthly. When switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen. The recommended subcutaneous dosage of REPATHA in patients with HoFH is 420 mg once monthly. In patients with HoFH, measure LDL-C levels 4 to 8 weeks after starting REPATHA, since response to therapy will depend on the degree of LDL-receptor function. |
| Contraindication | REPATHA is contraindicated in patients with a history of a serious hypersensitivity reaction to REPATHA |
| Side Effects | Allergic reactions |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |