FDA Expands Repatha Indication to Include Adults at High Risk for Cardiovascular Events Without Prior Disease Diagnosis
Key Insights
The FDA has expanded Repatha's (evolocumab) indication to include adults at increased risk for major adverse cardiovascular events due to uncontrolled LDL cholesterol, removing the requirement for prior cardiovascular disease diagnosis.
Real-world data from over 1.3 million patients showed a 1.4% incidence of major adverse cardiovascular events within one year, rising to 6.9% at four years among at-risk patients.
Repatha, a PCSK9 inhibitor, has demonstrated 54% to 77% LDL cholesterol reduction compared to placebo in clinical trials spanning 15 years of research across 50 studies involving more than 57,000 patients.
The FDA has updated the label for Amgen's Repatha (evolocumab) to include adults at increased risk for major adverse cardiovascular events (MACE) linked to uncontrolled low-density lipoprotein cholesterol (LDL-C). The expanded indication removes the prior restriction that patients must already have diagnosed cardiovascular disease (CVD), broadening access to individuals considered to have an elevated risk.
"Far too many adults at risk of cardiovascular disease are not achieving their LDL-C goals, despite it being one of the most modifiable risk factors for a heart attack or stroke," said Murdo Gordon, executive vice president of global commercial operations at Amgen.
Mechanism and Clinical Evidence
Repatha is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). By binding to PCSK9, evolocumab prevents it from breaking down LDL receptors on the surface of liver cells. This action increases the number of available LDL receptors, which helps clear more LDL cholesterol from the blood, causing the LDL-C levels to lower.
The safety and effectiveness of evolocumab have been supported by 15 years of research across 50 clinical trials that included more than 57,000 patients. Various phase 3 trials that added evolocumab to background lipid-lowering therapy that included statins resulted in significant reductions in LDL-C levels. Patients with atherosclerotic cardiovascular disease and heterozygous familial hypercholesterolemia demonstrated a reduced LDL-C by about 54% to 77% compared with placebo.
Real-World Risk Data Supports Expanded Access
The decision to expand Repatha's label reflects the persistent risk of cardiovascular events among at-risk patients. According to a 2020 study published in the National Center for Biotechnology Information, patients with established atherosclerotic CVD or multiple risk factors remain at notable risk for MACE.
Drawing on real-world data from more than 1.3 million patients aged 45 years and older, the study reported a 1.4% incidence of MACE within one year, rising to 6.9% at four years. The analysis also showed that risk climbed sharply with the number of vascular beds affected, with patients facing more than triple the risk if disease was present in the coronary, cerebrovascular, and peripheral arteries simultaneously.
Safety Profile and Adverse Events
In a cardiovascular outcomes trial, the most common adverse effects seen in more than 5% of patients taking evolocumab were diabetes, nasopharyngitis, and upper respiratory tract infections. These adverse events were more frequently observed in the treatment group than in those receiving placebo. Among individuals who did not have diabetes at the start of the study, new cases of the condition occurred in 8.1% of the group treated with evolocumab compared with 7.7% in the placebo group.
Historical Label Expansions
Repatha was first approved in August 2015 to treat adults with homozygous familial hypercholesterolemia or established CVD whose LDL cholesterol could not be adequately controlled with statins alone. Since then, the drug has gained multiple expanded indications:
In December 2017, Repatha became the first PCSK9 inhibitor indicated to prevent heart attacks, strokes, and coronary revascularizations in adults with established CVD. Approval was based on the Phase III FOURIER trial, which showed Repatha significantly reduced MACE when added to statin therapy.
In September 2021, Repatha was approved for pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia. The approval was supported by the Phase IIIb HAUSER-RCT trial, which demonstrated a mean 38% LDL-C reduction compared to placebo, along with improvements in non-HDL cholesterol, total cholesterol, and ApoB.
The expansion of evolocumab is indicated to reduce the risk of MACE events, including cardiovascular death, myocardial infarction, stroke, unstable angina requiring hospitalization, or coronary revascularization among adults that are at an increased risk of these events.
"This label update highlights the real-world need for additional treatment options for at-risk patients. Repatha is an effective therapy for reducing LDL-C, particularly in patients whose disease remains uncontrolled with statins or who cannot tolerate them," Gordon said.