Evolocumab
[CAS# 1256937-27-5]

Identification

• Classification: API >> Other chemicals
• Name: Evolocumab
• Synonyms: AMG 145
• Molecular Weight: ~141800
• CAS Registry Number: 1256937-27-5

Properties

• Boiling point: 1364.0±75.0 ºC 760 mmHg (Calc.)^*
• Flash point: 778.7±37.1 ºC (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319
• Precautionary Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovory and Applicatios

Evolocumab is a fully human monoclonal antibody developed to target proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that plays a critical role in cholesterol metabolism. PCSK9 binds to low-density lipoprotein receptors (LDLR) on hepatocyte surfaces and promotes their degradation, reducing the liver’s ability to clear low-density lipoprotein cholesterol (LDL-C) from the bloodstream. Evolocumab works by inhibiting PCSK9, thereby increasing the number of LDL receptors available on liver cells to remove LDL-C, ultimately leading to a significant reduction in plasma LDL-C levels.

The discovery of PCSK9 as a regulator of LDL-C began with genetic studies in the early 2000s, which identified gain-of-function mutations in the PCSK9 gene as a cause of autosomal dominant hypercholesterolemia. Conversely, individuals with loss-of-function mutations in PCSK9 were found to have low LDL-C levels and a reduced risk of coronary heart disease. These observations provided a strong rationale for targeting PCSK9 to lower LDL-C and prevent cardiovascular disease.

Evolocumab was developed using recombinant DNA technology to generate a monoclonal antibody capable of specifically binding and neutralizing circulating PCSK9. It was one of the first therapies of its kind to be approved for clinical use. The drug underwent extensive clinical evaluation in large-scale trials that demonstrated its efficacy in lowering LDL-C by up to 60% when used alone or in combination with statins and other lipid-lowering therapies. These trials also evaluated its impact on cardiovascular outcomes, including myocardial infarction and stroke.

Evolocumab received regulatory approval from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2015. It is indicated for use in patients with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, and clinical atherosclerotic cardiovascular disease who require additional LDL-C lowering despite maximally tolerated statin therapy. The drug is administered by subcutaneous injection, typically every two to four weeks.

In clinical practice, evolocumab has become a key option for patients who are unable to achieve LDL-C targets with conventional therapies or who are statin-intolerant. It is particularly beneficial for individuals with genetic lipid disorders and those at high or very high risk of cardiovascular events. Its mechanism of action is independent of that of statins, allowing for additive effects when used together. This has contributed to its role in comprehensive lipid-lowering strategies.

In addition to its effects on LDL-C, evolocumab has shown modest effects on other lipid parameters, such as lipoprotein(a), triglycerides, and high-density lipoprotein cholesterol. These additional lipid changes, while secondary, may also contribute to cardiovascular benefit. The safety profile of evolocumab has been generally favorable, with the most common adverse events including injection site reactions, nasopharyngitis, and upper respiratory tract infections.

Evolocumab represents a significant advancement in the management of hyperlipidemia and cardiovascular risk. Its development underscores the success of precision medicine approaches based on genetic insights and molecular targets. The drug has expanded the therapeutic arsenal available to clinicians managing complex lipid disorders and has established a new class of lipid-lowering agents known as PCSK9 inhibitors.

The long-term utility of evolocumab continues to be evaluated in post-marketing surveillance and ongoing research. Its use has also sparked interest in alternative methods of PCSK9 inhibition, including small interfering RNA therapies and vaccines, which may offer new options for lipid management in the future.

References

2012. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA, 308(23).
DOI: 10.1001/jama.2012.25790

2015. Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. The New England Journal of Medicine, 372(16).
DOI: 10.1056/nejmoa1500858