Approval Status: Approved August 2015
Specific Treatments: high cholesterol
Therapeutic Areas Cardiology/Vascular Diseases
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:
- 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).
- 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.
Repatha is supplied as an injection for subcutaneous administration. The recommended subcutaneous dosage 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 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.
The FDA approval of Repatha was based on the following trials:
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% (p < 0.0001) and -63% (p ˂ 0.0001) 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 % (p ˂0.0001).
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% (p < 0.0001).
Adverse effects associated with the use of Repatha may include, but are not limited to, the following:
- upper respiratory tract infection
- back pain
- injection site reactions
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.
For additional information regarding Repatha or elevated LDL-C, please visit https://www.repatha.com/