What is Repatha (Evolocumab)?
Repatha (evolocumab) is a fully human monoclonal antibody that blocks PCSK9 protein, preventing degradation of LDL receptors and thereby dramatically lowering LDL cholesterol by 50-65% when added to statin therapy. 1
Mechanism of Action
Evolocumab works by targeting a specific protein pathway that regulates cholesterol:
PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) is a circulating enzyme secreted by the liver that binds to LDL receptors on liver cells and marks them for destruction in lysosomes rather than allowing them to recycle back to the cell surface 2
By blocking PCSK9, evolocumab prevents this degradation process, allowing more LDL receptors to remain on the liver cell surface, which increases LDL cholesterol uptake from the blood and lowers circulating LDL-C levels 2
This mechanism is completely independent of statins, making it highly effective when combined with statin therapy or used alone in statin-intolerant patients 3, 4
FDA-Approved Indications
Repatha is approved for four specific clinical situations 1:
To reduce major adverse cardiovascular events (CV death, MI, stroke, unstable angina requiring hospitalization, or coronary revascularization) in adults with established cardiovascular disease 1
As adjunct to diet, alone or with other LDL-lowering therapies, in adults with primary hyperlipidemia including heterozygous familial hypercholesterolemia (HeFH) to reduce LDL-C 1
As adjunct to diet and other LDL-lowering therapies in pediatric patients ≥10 years with HeFH to reduce LDL-C 1
As adjunct to other LDL-lowering therapies in adults and pediatric patients ≥10 years with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C 1
Dosing and Administration
The standard dose is 140 mg subcutaneously every 2 weeks OR 420 mg subcutaneously once monthly—both regimens provide comparable LDL-C reduction (64% and 58% respectively when added to maximally tolerated statin therapy) 5
Specific Dosing by Condition:
For adults with ASCVD, primary hypercholesterolemia, or HeFH: 140 mg every 2 weeks or 420 mg monthly 5, 1
For pediatric patients ≥10 years with HeFH: Same dosing as adults (140 mg every 2 weeks or 420 mg monthly) 5
For HoFH: Start with 420 mg monthly; if inadequate LDL-C reduction after 12 weeks, increase to 420 mg every 2 weeks 5, 1
Administration sites include thigh, abdomen, or upper arm, with rotation of injection sites recommended 5
Clinical Efficacy
In the landmark FOURIER trial, evolocumab reduced the primary composite endpoint of CV death, MI, stroke, revascularization, or hospitalization for unstable angina by 15% (HR 0.85; 95% CI 0.79-0.92; P<0.001) in patients with prior ASCVD 5, 6
LDL-C Reduction:
Evolocumab achieves 58-64% additional LDL-C reduction when added to maximally tolerated statin therapy, with median LDL-C levels reaching as low as 30 mg/dL 7, 6
In heterozygous familial hypercholesterolemia patients, evolocumab produced approximately 60% LDL-C reduction at both dosing schedules (every 2 weeks and monthly) 8
The LDL-lowering effect can be measured as early as 4 weeks after initiation 1
Guideline-Based Use
For very high-risk patients with ASCVD on high-intensity (and maximally tolerated) statin therapy with LDL-C ≥70 mg/dL, addition of nonstatin LDL-lowering therapy like evolocumab can be considered 7
For patients with heterozygous familial hypercholesterolemia aged 30-75 years taking maximal tolerated statin and ezetimibe with LDL-C ≥100 mg/dL, adding evolocumab or alirocumab may be reasonable 7
Treatment Algorithm:
First-line: Maximize statin therapy (high-intensity statin aiming for ≥50% LDL-C reduction) 7
Second-line: Add ezetimibe if LDL-C remains ≥100 mg/dL despite maximal tolerated statin 7
Third-line: Consider PCSK9 inhibitor (evolocumab) if LDL-C remains elevated despite statin plus ezetimibe 7
Safety Profile
Evolocumab is well-tolerated with an excellent safety profile demonstrated in trials up to 78 weeks and cardiovascular outcomes trials extending several years 9
Common Adverse Effects:
Nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions are the most common (>5% of patients) 1
Injection site reactions are relatively infrequent and mild 9
No excess adverse events in patients achieving very low LDL cholesterol levels over 78 weeks 9
No evidence of increased cognitive adverse effects in FOURIER or EBBINGHAUS trials 5, 9
Monitoring and Contraindications:
No specific laboratory monitoring for hepatic or muscle toxicity is required, unlike with statins 9
The only absolute contraindication is history of serious hypersensitivity reaction to evolocumab or any excipients 9, 1
Latex-sensitive patients should be aware that some presentations contain dry natural rubber (latex derivative) in the needle cover; latex-free presentations are available 5, 1
Important Clinical Considerations
No clinically significant drug-drug interactions have been identified for evolocumab 6
Evolocumab is well-accepted by statin-intolerant patients, with muscle-related adverse events comparable to those seen with ezetimibe 9
The decision to add evolocumab should follow a clinician-patient discussion about net benefit, safety, and cost of combination therapy, as the lower cost of ezetimibe may be preferred by many patients 7