Repatha (evolocumab) - 3 indications

Scroll down for more information on each indication:

• for the use in adults with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease; approved August of 2015
• to prevent heart attacks, strokes and coronary revascularizations in adults with established cardiovascular disease; approved December of 2017
• for pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C; approved September of 2021

General Information

Repatha (evolocumab) is a fully human monoclonal antibody to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), a negative regulator of low density lipoprotein receptor (LDLR). 

Repatha is specifically indicated for the following:

• for adults with established cardiovascular disease to reduce the risk of myocardial infarction, stroke, and coronary revascularization
• as an adjunct to diet, alone or in combination with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce LDL-C
• as an adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged 10 years and older with HeFH and HoFH, to reduce LDL-C

Repatha is supplied as an injection for subcutaneous administration. Scroll down for the recommended dosing/administration for each indication.

Mechanism of Action

Repatha (evolocumab) is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting 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.

Side Effects

Adverse effects associated with the use of Repatha for primary hyperlipidemia may include, but are not limited to, the following:

• nasopharyngitis
• upper respiratory tract infection
• influenza
• back pain
• injection site reactions

Adverse effects associated with the use of Repatha for established CVD may include, but are not limited to, the following:

• diabetes mellitus
• nasopharyngitis
• upper respiratory tract infection

Indication 1 - adults with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease

approved August of 2015

Dosing/Administration

HeFH:

• The recommended dosage of is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously. If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.

HoFH:

• The initial recommended dosage of Repatha is 420 mg once monthly administered subcutaneously. The dosage can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks. Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule. Administer Repatha after the apheresis session is complete

Hyperlipidemia:

• The recommended dosage of Repatha is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously. If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.

Clinical Trial Results

Primary Hyperlipidemia in Patients with Clinical Atherosclerotic Cardiovascular Disease:

Study 1 was a multicenter, double-blind, randomized controlled trial in which patients were initially randomized to an open-label specific statin regimen for a 4-week lipid stabilization period followed by random assignment to subcutaneous injections of Repatha 140 mg every 2 weeks, Repatha 420 mg once monthly, or placebo for 12 weeks. The trial included 296 patients with atherosclerotic CVD who received Repatha or placebo as add-on therapy to daily doses of atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg. After 4 weeks of statin therapy, the mean baseline LDL-C was 108 mg/dL. In these patients with atherosclerotic CVD who were on maximum-dose statin therapy, the difference between Repatha and placebo in mean percent change in LDL-C from baseline to Week 12 was -71% and -63% for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively.

Study 2 was a multicenter, double-blind, randomized, placebo-controlled, 52-week trial that included 139 patients with atherosclerotic CVD who received protocol-determined background lipid-lowering therapy of atorvastatin 80 mg daily with or without ezetimibe 10 mg daily. After stabilization on background therapy, patients were randomly assigned to the addition of placebo or Repatha 420 mg administered subcutaneously once monthly. After stabilization on the assigned background therapy, the mean baseline LDL-C was 105 mg/dL. In these patients with atherosclerotic CVD on maximum-dose atorvastatin therapy with or without ezetimibe, the difference between Repatha 420 mg once monthly and placebo in mean percent change in LDL-C from baseline to Week 52 was -54 %.

Heterozygous Familial Hypercholesterolemia (HeFH):

Study 3 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 329 patients with heterozygous familial hypercholesterolemia (HeFH) on statins with or without other lipid-lowering therapies. Patients were randomized to receive subcutaneous injections of Repatha 140 mg every two weeks, 420 mg once monthly, or placebo. HeFH was diagnosed by the Simon Broome criteria (1991). In Study 3, 38% of patients had clinical atherosclerotic cardiovascular disease. The average LDL-C at baseline was 156 mg/dL with 76% of the patients on high- intensity statin therapy. In these patients with HeFH on statins with or without other lipid lowering therapies, the differences between Repatha and placebo in mean percent change in LDL-C from baseline to Week 12 was -61% (p < 0.0001) and -60% (p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively.

Homozygous Familial Hypercholesterolemia:

Study 4 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipid-apheresis therapy) with homozygous familial hypercholesterolemia (HoFH). In this trial, 33 patients received subcutaneous injections of 420 mg of Repatha once monthly and 16 patients received placebo as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe). The trial included 10 adolescents (ages 13 to 17 years), 7 of whom received Repatha. The mean LDL-C at baseline was 349 mg/dL with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration > 500 mg/dL together with either xanthoma before 10 years of age or evidence of HeFH in both parents. In these patients with HoFH, the difference between Repatha and placebo in mean percent change in LDL-C from baseline to Week 12 was -31%.

Indication 2 - to prevent heart attacks, strokes and coronary revascularizations in adults with established cardiovascular disease

approved December of 2017

Dosing/Administration

The recommended dosage of Repatha is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously. If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.

Clinical Trial Results

The 27,564-patient Repatha cardiovascular outcomes study (FOURIER) demonstrated that adding Repatha to optimized statin therapy resulted in a statistically significant 20 percent reduction in major adverse cardiovascular events (MACE) represented in the key secondary composite endpoint of time to first heart attack, stroke or cardiovascular death. The study found a statistically significant 15 percent reduction in the risk of the primary composite endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death. The magnitude of risk reduction in both the primary and key secondary composite endpoints grew over time, with the robust benefit starting as early as six months and accruing through the median 2.2 years of the study. Patients on Repatha experienced a reduction in the risk of heart attack (27 percent), stroke (21 percent) and coronary revascularization (22 percent). There was no observed effect on cardiovascular mortality. Similarly, there was no observed effect on hospitalization for unstable angina.

Indication 3 - pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C

approved September of 2021

Dosing/Administration

HeFH:

• The recommended dosage of is either 140 mg every 2 weeks OR 420 mg once monthly administered subcutaneously. If switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.

HoFH:

• The initial recommended dosage of Repatha is 420 mg once monthly administered subcutaneously. The dosage can be increased to 420 mg every 2 weeks if a clinically meaningful response is not achieved in 12 weeks. Patients on lipid apheresis may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule. Administer Repatha after the apheresis session is complete

Clinical Trial Results

HoFH: 

Approval was based on a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipid-apheresis therapy) with homozygous familial hypercholesterolemia (HoFH). In this trial, 33 patients received subcutaneous injections of 420 mg of Repatha once monthly and 16 patients received placebo as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe). The trial included 10 adolescents (ages 13 to 17 years), 7 of whom received Repatha. The mean LDL-C at baseline was 349 mg/dL with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe. The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration > 500 mg/dL together with either xanthoma before 10 years of age or evidence of HeFH in both parents. In these patients with HoFH, the difference between Repatha and placebo in mean percent change in LDL-C from baseline to Week 12 was -31%.

HeFH:

The approval was based on the HAUSER-RCT Phase 3b study evaluating the safety and efficacy of Repatha in pediatric patients, 10 - 17 years of age, with HeFH. Monthly treatment with Repatha reduced LDL-C by mean 38% from baseline compared to placebo, meeting its primary endpoint. Reductions in LDL-C were observed by the first post-baseline assessment at the Week 12 time point and were maintained throughout the trial. Patients treated with Repatha had improved secondary lipid parameters from baseline in comparison to placebo, including a 35% reduction in non-high-density lipoprotein cholesterol (non-HDL-C) at week 24, a 27% reduction in total cholesterol at week 24 and a 32% reduction in apolipoprotein B (ApoB) at week 24.