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Repatha (Evolocumab): Second PCSK9 Inhibitor Approved by the FDA for Patients with Familial Hypercholesterolemia

March 2016, Vol 9, Seventh Annual Payers' Guide - Drug Updates, FDA Approvals, Payers' Guide
Loretta Fala
Medical Writer

Hypercholesterolemia, a condition characterized by high levels of cholesterol in the blood, is a major controllable risk factor for coronary heart disease, myocardial infarction, and stroke.1,2 The risk for cardiovascular disease (CVD) in individuals with high cholesterol is approximately twice that for people with lower cholesterol.3 When hypercholesterolemia is combined with other risk factors, such as hypertension, diabetes, or smoking, the risk for CVD increases greatly.2

It has been estimated that 34 million people in the United States have a high level of total cholesterol (ie, >240 mg/dL).1 Moreover, approximately 71 million ­people, or one-third of the US population, have high low-density lipoprotein cholesterol (LDL-C) levels (>160 mg/dL).3,4 Excess LDL-C levels can accumulate in the inner walls of the arteries that supply blood to the heart and brain.1,2 The subsequent formation of plaque often narrows the arteries and can lead to atherosclerosis and angina. In some cases, a clot forms and blocks a narrowed artery, resulting in myocardial infarction or stroke.1,2

Hypercholesterolemia typically results from a combination of genetic and environmental factors. Diet, exercise, and tobacco smoking affect cholesterol levels.1 A person's age, sex, and comorbid conditions, such as obesity and diabetes, also play a role. In addition, cholesterol levels are influenced by heterozygous or homozygous familial hypercholesterolemia, an inherited form of the condition, which affects 1 of 500 people in most countries, according to the National Institutes of Health.1,5 However, this estimate is likely lower than the actual prevalence, because only 1% of people with familial hypercholesterolemia are diagnosed.5

Genetic forms of hypercholesterolemia are caused by mutations in the APOB, LDLR, LDLRAP1, and PCSK9 genes.1 Mutations in the APOB, LDLRAP1, and PCSK9 genes affect the function of LDL receptors (LDLRs), thereby preventing cells from generating functional receptors or altering the function of the receptors. When LDLRs are unable to remove cholesterol from the blood, hypercholesterolemia results.1

Despite the high risk for cardiovascular complications associated with elevated LDL-C levels, only 1 of 3 adults with high LDL-C levels has the condition under control.3 Less than 50% of adults with high LDL-C levels are receiving treatment.3 Dietary and lifestyle changes, along with appropriate medication, are essential to managing hypercholesterolemia effectively, reducing cardiovascular risks, and improving outcomes for affected patients. Patients who have hypercholesterolemia and high triglycerides may require treatment for both conditions.6

The pharmacologic treatment of hypercholesterolemia may include 1 or more of the following medications, depending on the patient's risk factors, age, and comorbid conditions, as well as potential drug side effects: statins; bile acid—binding resins; cholesterol absorption inhibitors; and a cholesterol absorption inhibitor combined with a statin.6 In addition, monoclonal antibodies that inhibit PCSK9, including alirocumab, have emerged as a new class of drugs to treat hypercholesterolemia.7 Recently, another novel inhibitor of the PCSK9 gene, evolocumab, became available.

Evolocumab a PCSK9 Inhibitor for Cholesterol Lowering

On August 27, 2015, evolocumab (Repatha; Amgen), a human monoclonal antibody that inhibits PCSK9, received approval from the US Food and Drug Administration (FDA) as an adjunct treatment to diet and maximally tolerated statin therapy in adults with heterozygous or homozygous familial hypercholesterolemia, or those with clinical atherosclerotic CVD, such as myocardial infarction or stroke, who require additional LDL-C lowering.8

"Repatha provides another treatment option in this new class of drugs for patients with familial hypercholesterolemia or with known cardiovascular disease who have not been able to lower their LDL cholesterol enough with statins,"8 said John Jenkins, MD, Director of the FDA's Office of New Drugs, Center for Drug Evaluation and Research.

The effect of evolocumab on cardiovascular morbidity and mortality has not been determined.9

Mechanism of Action

Evolocumab is a human monoclonal immunoglobulin G2 antibody directed against PCSK9.9 Evolocumab binds to the circulating PCSK9 protein, inhibiting it from binding to the LDLR, in turn preventing PCSK9-mediated LDLR degradation and permitting the LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.9

Dosing and Administration

Evolocumab is administered by subcutaneous injection to the abdomen, thigh, or upper arm.9 For patients with primary hyperlipidemia who have clinical atherosclerotic CVD or heterozygous familial hypercholesterolemia, the recommended subcutaneous dose of evolocumab is 140 mg every 2 weeks or 420 mg once monthly. For patients with homozygous familial hypercholesterolemia, the recommended subcutaneous dose is 420 mg once monthly.9 When administering 420 mg of evolocumab, 3 consecutive injections should be given within 30 minutes.9

If the dosing regimen is changed, the first dose of the new regimen should be administered on the next scheduled date of the previous regimen. Evolocumab is available as a 140-mg/mL solution in a single-use prefilled syringe or in a single-use prefilled SureClick autoinjector.9

Clinical Studies
Study 1: LAPLACE-2 Trial

This multicenter, double-blind, randomized, controlled trial included 296 patients with primary hyperlipidemia and clinical atherosclerotic CVD who initially received a 4-week statin regimen for lipid stabilization, followed by randomization to subcutaneous injections of evolocumab 140 mg every 2 weeks, evolocumab 420 mg once monthly, or to placebo for 12 weeks.9,10 All patients received evolocumab or placebo as add-on therapy to daily doses of atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg. The patients' mean age was 63 years. After 4 weeks of statin therapy, the mean baseline LDL-C level was 108 mg/dL.9

Results are shown in Table 1. In patients with atherosclerotic CVD who received the maximum-dose statin therapy, evolocumab 140 mg every 2 weeks resulted in a 71% reduction in mean LDL-C versus placebo, and evolocumab 420 mg once monthly resulted in a 63% reduction versus placebo (Table 1).9,10

Table

Study 2: DESCARTES Trial

This multicenter, double-blind, randomized, placebo-controlled, 52-week trial included 139 patients (mean age, 59 years) with atherosclerotic CVD who received background lipid-lowering therapy of atorvastatin 80 mg daily with or without ezetimibe 10 mg daily.9 After stabilization on background therapy, the patients were randomized to add-on placebo or to evolocumab 420 mg once monthly. After stabilization on background therapy, the mean baseline LDL-C level was 105 mg/dL.9

In patients with atherosclerotic CVD who received maximum-dose atorvastatin therapy (with or without ezetimibe), evolocumab 420 mg monthly was associated with a significant 54% reduction in LDL-C versus placebo and a significant reduction in non—high-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol.9

Study 3: RUTHERFORD-2 Trial

Study 3 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial of 329 patients (mean age, 51 years) with heterozygous familial hypercholesterolemia who received statin therapy with or without other lipid-lowering therapies.9,11 Patients were randomized to receive subcutaneous injections of evolocumab 140 mg every 2 weeks, 420 mg once monthly, or placebo.9,11 The average LDL-C level was 156 mg/dL at baseline, with 76% of patients receiving high-intensity statin therapy.9

By 12 weeks, treatment with evolocumab 140 mg every 2 weeks showed a significant reduction (61%) in mean LDL-C versus placebo.9 Evolocumab 420 mg once monthly also resulted in a significant reduction (60%) in mean LDL-C versus placebo at week 12 (Table 2).9,11 Moreover, in 68% of patients receiving evolocumab 140 mg every 2 weeks and 63% of those receiving evolocumab 420 mg once monthly, the LDL-C level declined to <70 mg/dL.11

Table

Study 4: TESLA-B Trial

This multicenter, double-blind, randomized, placebo-controlled, 12-week study included 49 patients with homozygous familial hypercholesterolemia.9,12 As an adjunct to other lipid-lowering therapies (eg, statins, ezetimibe), 33 patients received a subcutaneous injection of evolocumab 420 mg once monthly, and 16 patients received placebo. The patients' mean age was 31 years (range, 13-57 years), and 10 patients were adolescents (aged 13-17 years).9 For the 33 patients who received evolocumab, the mean reduction in LDL-C was 31% from baseline by week 12 (95% confidence interval, -44% to -18%; P<.001).9,12 The results were similar for adolescents and adults.9

Adverse Events

The safety of evolocumab was evaluated in 8 placebo-controlled trials that included 2651 patients with primary hyperlipidemia or with heterozygous familial hypercholesterolemia who received treatment for a median of 12 weeks.9

In the 52-week trial (Study 2), the adverse reactions that occurred in at least 3% of patients receiving evolocumab, and more often than in patients receiving placebo, included nasopharyngitis (10.5%), upper respiratory tract infection (9.3%), influenza (7.5%), back pain (6.2%), injection-site reaction (5.7%), cough (4.5%), urinary tract infection (4.5%), sinusitis (4.2%), headache (4.0%), myalgia (4.0%), dizziness (3.7%), musculoskeletal pain (3.3%), hypertension (3.2%), diarrhea (3.0%), and gastroenteritis (3.0%).

Adverse reactions led to treatment discontinuation in 2.2% of patients who received evolocumab and 1% of patients receiving placebo. The most common adverse reaction that led to evolocumab discontinuation was myalgia (0.3%).9

In 7 pooled 12-week studies, adverse reactions that were reported for ≥2% of the patients receiving evolocumab, and more frequently than for patients receiving placebo, included nasopharyngitis (4.0%), back pain (2.3%), and upper respiratory tract infection (2.1%).9

In the 12-week study of 49 patients with homozygous familial hypercholesterolemia (Study 4), the adverse reactions reported for at least 2 (6.1%) patients receiving evolocumab and more often than placebo included upper respiratory tract infection (9.1%), influenza (9.1%), gastroenteritis (6.1%), and nasopharyngitis (6.1%).9

As with all therapeutic proteins, there is potential for immunogenicity with evolocumab.

Contraindications

Evolocumab is contraindicated in patients who have a serious hypersensitivity to evolocumab.9

Warnings and Precautions

Hypersensitivity reactions. Hypersensitivity reactions (eg, rash, urticaria) have been reported, including some that led to discontinuation of evolocumab therapy.9 If any serious allergic reactions occur during treatment with evolocumab, patients should discontinue its use, be receiving standard of care, and be monitored until the symptoms are resolved.9

Use in Specific Populations and Conditions

Pregnancy. No data are available on the use of evolocumab in pregnant women. The benefits and risks of evolocumab, including possible risks to the fetus, should be considered before prescribing evolocumab for a pregnant woman.9

Lactation. Whether evolocumab is present in human breast milk is not known. Before prescribing evolocumab, the benefits of breast-feeding should be considered versus the mother's need for evolocumab and any potential adverse effects on the infant.9

Pediatric use. In the 12-week trial (Study 4) that included 10 adolescents (aged 13-17 years) with homozygous familial hypercholesterolemia, 7 received evolocumab. The safety of evolocumab was similar for adolescents and adults.9 The safety of evolocumab has not been established in patients with homozygous familial hypercholesterolemia aged <13 years or for pediatric patients with primary hyperlipidemia or heterozygous familial hypercholesterolemia.9

Geriatric use. In controlled clinical trials, the safety of evolocumab was similar in older (aged ≥65 years) and younger patients.9

Renal impairment. Dose adjustment is not needed for patients with mild or moderate renal impairment. The effect of evolocumab in patients with severe renal impairment is unknown.9

Hepatic impairment. Dose adjustment is not needed for patients with mild or moderate hepatic impairment (Child-Pugh A or B). There are no data for patients with severe hepatic impairment.9

Conclusion

The FDA approval of evolocumab, a novel PCSK9 inhibitor, marks the availability of a new therapeutic option to lower LDL-C in patients with heterozygous or homozygous familial hypercholesterolemia, or those with clinical atherosclerotic CVD who require additional lowering of LDL-C levels.

In phase 3 studies, adding evolocumab to lipid-lowering treatment (that included statins) resulted in significant reductions in LDL-C levels and favorable effects on other lipid parameters. Compared with placebo, evolocumab was associated with LDL-C reductions of 54% to 71% among patients with clinical atherosclerotic CVD, and 60% to 61% among patients with heterozygous familial hypercholesterolemia. For patients with homozygous familial hypercholesterolemia, evolocumab was associated with a 31% reduction in LDL-C relative to placebo.

References

1. National Institutes of Health. Genetics Home Reference. Hypercholesterolemia. October 19, 2015. http://ghr.nlm.nih.gov/condition/hypercholesterolemia. Accessed October 19, 2015.
2. American Heart Association. Why cholesterol matters. April 21, 2014. www.heart.org/HEARTORG/Conditions/Cholesterol/WhyCholesterolMatters/Why-Cholesterol-Matters_UCM_001212_Article.jsp#.Vi4sRWTBwXA. Accessed September 21, 2014.
3. Centers for Disease Control and Prevention. Cholesterol fact sheet. April 30, 2015. www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_cholesterol.htm. Accessed September 21, 2015.
4. National Heart, Lung, and Blood Institute. National Cholesterol Education Program. ATP III guidelines at-a-glance quick desk reference. May 2001. www.nhlbi.nih.gov/health-pro/guidelines/current/cholesterol-guidelines/quick-desk-reference-html. Accessed September 22, 2015.
5. Nordestgaard BG, Chapman MJ, Humphries SE, et al; for the European Atherosclerosis Society Consensus Panel. Familial hypercholesterolemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34:3478a-3490a.
6. Mayo Clinic staff. Diseases and conditions: high cholesterol. www.mayoclinic.­org/diseases-conditions/high-blood-cholesterol/basics/treatment/con-20020865. September 4, 2015. Accessed September 21, 2015.
7. Sabatine MS, Giugliano RP, Wiviott SD, et al; for the Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500-1509.
8. US Food and Drug Administration. FDA approves Repatha to treat certain patients with high cholesterol. Press release. August 27, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm. Accessed September 8, 2015.
9. Repatha (evolocumab) injection [prescribing information]. Thousand Oaks, CA: Amgen; August 2015.
10. Robinson JG, Nedergaard BS, Rogers WJ, et al; for the LAPLACE-2 Investigators. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311:1870-1882.
11. Raal FJ, Stein EA, Dufour R, et al; for the RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:331-340.
12. Raal FJ, Honarpour N, Blom DJ, et al; for the TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:341-350.

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Last modified: April 15, 2016
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