Repatha: A Lipid-lowering Monoclonal Antibody

Evolocumab (Repatha), a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, is used for prevention of cardiovascular disease and to reduce low-density lipoprotein (LDL) cholesterol. Amgen used genome studies in individuals with a PCSK9 mutation in order to find the unique mechanism of this drug.¹ Evolocumab was approved by FDA in August 2016.²

This treatment shows promise for individuals struggling to control their cholesterol with statins, diet, or a combination of both.² LDL cholesterol, commonly termed “bad cholesterol,” can be harmful in excess amounts. LDL cholesterol circulates in the blood and may increase a patient’s risk for developing cardiovascular disease due to a build-up in arteries, known as atherosclerosis.³

Cardiovascular disease is an overarching term used to describe a group of heart and blood vessel disorders. A few common disorders are coronary heart disease, peripheral arterial disease, and cerebrovascular disease, which increase the risk of myocardial infarction or stroke. Hyperlipidemia is one of the main risk factors for developing cardiovascular disease. Therefore, it is crucial for these patients to maintain proper LDL cholesterol levels.⁴

Indications

Evolocumab, when used with diet, can be used as monotherapy or in combination with other lipid-lowering agents for the prevention of cardiovascular events and to reduce LDL cholesterol in patients with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH). Repatha has also been approved as an adjunct to diet and other LDL-lowering therapies for the treatment of homozygous familial hypercholesterolemia (HoFH).²

Mechanism of Action

Evolocumab is a humanized monoclonal antibody that inhibits PCSK9. The normal function of PCSK9 is to bind to LDL receptors on the surface of hepatocytes to promote LDL receptor degradation within the liver. LDL receptors are involved in the clearance of circulating LDL. By inhibiting PCSK9, there are more receptors available to degrade circulating LDL cholesterol, thereby lowering LDL cholesterol levels.²

Dosing and Administration

Evolocumab is administered via subcutaneous injection into the abdomen, thigh, or upper arm. Dosing varies depending on the indication in which evolocumab is being used. For patients with established cardiovascular disease or in patients with primary hyperlipidemia, including HeFH, the recommended doses are 140 mg every 2 weeks or 420 mg once monthly. Dosing is dependent on patient preference for these 2 indications as frequency and volume of drug administered vary. In patients with HoFH, the recommended dose is 420 mg once monthly.

Patients using the 420 mg dose must administer it over 9 minutes if using the single-use on-body infusor with prefilled cartridge. Patients using the 140 mg/mL solution single-use prefilled syringe or single-use prefilled SureClick autoinjector must administer 3 injections consecutively within 30 minutes to achieve a 420 mg dose.²

Clinical Studies

Prevention of Cardiovascular Disease: There was 1 large double-blind, randomized, placebo-controlled, event-driven study completed in this patient population. FOURIER evaluated the time to first occurrence of cardiovascular death, myocardial infraction, stroke, hospitalization for unstable angina, or coronary revascularization. This study included patients with established cardiovascular disease with LDL-C >70 mg/dL and/or non-HDL-C >100 mg/dL despite high or moderate intensity statin use. This trial found that evolocumab significantly reduced the risk for additional cardiovascular events.²

Primary Hyperlipidemia (including HeFH): There were 4 trials completed in this patient population. Evolocumab was studied alone, as adjunct to other lipid-lowering agents (ezetimibe, statins), and in combination with diet alterations. All of the studies were multicenter, double-blind, randomized controlled trials evaluating the mean percent change from baseline on lipid levels. Each of the studies showed a statistically significant mean percent decrease in LDL-C levels from baseline.²

HoFH: There was 1 multicenter, double-blind, placebo-controlled trial completed in adults and adolescents with HoFH. This study compared the difference in percent change in LDL-C levels of evolocumab to placebo at 12 weeks. The trial found that patients had a -31% decrease in LDL-C from baseline to 12 weeks, which was considered statistically significant.²

Contraindications/Warnings and Precautions

Evolocumab is contraindicated in patients who have experienced a serious hypersensitivity reaction, such as rash or urticaria, to evolocumab.²

Drug Interaction Studies

There were no clinically significant meaningful interactions that affect dosing of evolocumab or concurrent medications.²

Use in Special Populations

Pregnancy: There are no data available on the use of evolocumab in pregnant women to inform a drug-associated risk. When evolocumab was used in animal studies, there were no effects on pregnancy or the neonatal/infant development. It is known that evolocumab, like other IgG antibodies, crosses the placental barrier. This is more likely to occur in the third trimester. There is a pregnancy exposure registry to monitor outcomes of women exposed to evolocumab during pregnancy.²

Lactation: There are no data available on the presence of evolocumab in human milk effects on the breastfed infant, or effects on milk production. It is known that human IgG is present in breastmilk, but that breastmilk antibodies do not enter the neonatal and infant circulation in substantial amounts.²

Pediatric Use: Evolocumab has been studied in patients 13 years of age or older with HoFH administered at a dose of 420 mg subcutaneously once monthly. The safety and efficacy of evolocumab were similar to those adults with HoFH. Evolocumab has not been studied regarding safety or efficacy in patients younger than 13 years of age, or in pediatric patients with primary hyperlipidemia or HeFH.²

Geriatric Use: There is no difference in safety or efficacy in geriatric patients compared to younger patients.²

Hepatic and Renal Impairment: There are no dose adjustments for patients with renal impairment or mild-moderate hepatic impairment. There are no data available in patients with severe hepatic impairment.²

Adverse Events (AEs)

Nasopharyngitis, upper respiratory tract infection, and influenza were the most common adverse effects. These AEs occurred in >3% of patients being treated with evolocumab, and more frequently than those patients in the placebo group. The most common AE leading to discontinuation of was myalgia, which occurred more frequently in the evolocumab group versus placebo.²

Storage and Handling

Evolocumab can be stored in the refrigerator or at room temperature in the original carton. If kept at room temperature, evolocumab must be used within 30 days. It is recommended that evolocumab not be warmed in any other way.²

References

• Servick K. Pricey new cholesterol drug scrapes by in heart risk study. SCIENCE. 2017. doi:10.1126/science.aal0927.
• Repatha® [package insert]. Thousand Oaks, CA: Amgen Inc; 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125522s014lbl.pdf
• Pirahanchi Y, Huecker MR. Biochemistry, LDL Cholesterol. StatPearls [Online]. January 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519561/. Accessed April 1, 2020.
• World Health Organization. Cardiovascular Diseases (CVD). https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds). Published May 2017. Accessed April 1, 2020.

About the Author

Madelyn Stabinski will graduate from the Duquesne University School of Pharmacy in May 2020.

Jonathan Ogurchak is the Founder & CEO of STACK, a pharmacy information ecosystem, and serves as preceptor for a virtual Advanced Pharmacy Practice Experiential rotation for specialty pharmacy, during which this article was composed.