In the world of cholesterol management, a new player has emerged, offering hope to those with one of the most severe forms of inherited high cholesterol.
Imagine having cholesterol levels so high from birth that heart attacks can strike in childhood. This is the reality for people with homozygous familial hypercholesterolemia (HoFH), an ultra-rare genetic disorder that affects approximately 1,300 people in the United States1 .
1,300
People affected in the United States
400+ mg/dL
Typical LDL-C levels in HoFH patients
Unlike the more common high cholesterol that develops later in life, HoFH is an inherited condition characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C)—often exceeding 400 mg/dL—from birth4 8 . This accelerated atherosclerosis can lead to serious cardiovascular complications as early as the teenage years without effective treatment4 .
For decades, treatment options for HoFH have been limited. Traditional cholesterol-lowering medications like statins and PCSK9 inhibitors work by boosting the activity of LDL receptors in the liver. However, many HoFH patients have diminished or absent LDL-receptor function, rendering these treatments less effective8 . This critical gap in treatment sparked the search for a novel approach—one that would lead to the development of evinacumab.
Evinacumab (marketed as Evkeeza®) represents a breakthrough first-in-class treatment for HoFH. Approved by the U.S. Food and Drug Administration (FDA), it works through a completely different mechanism compared to traditional cholesterol medications1 8 .
Evinacumab is a fully human monoclonal antibody that binds to and blocks the function of angiopoietin-like 3 (ANGPTL3), a protein that inhibits lipoprotein lipase and endothelial lipase and regulates circulating lipids1 .
By inhibiting ANGPTL3, evinacumab enhances the clearance of VLDL remnants via remnant receptors in the liver, resulting in decreased LDL-C levels through an LDL-receptor-independent pathway8 .
The discovery of this novel therapeutic approach stemmed from an important observation: patients with a loss-of-function mutation of the ANGPTL3 protein were found to have significantly lower levels of LDL cholesterol, triglycerides, and HDL levels, along with a reduced cardiovascular risk compared to those without the mutation8 .
The approval of evinacumab was supported by compelling evidence from clinical trials demonstrating its significant cholesterol-lowering benefits in HoFH patients.
In a pivotal phase 3 trial (NCT03409744), researchers enrolled 116 patients with HoFH in a single-arm, open-label study6 . The participants had a mean age of 38.8 years, with a similar proportion of male and female patients6 .
116 patients with HoFH enrolled in the phase 3 trial
15 mg/kg every 4 weeks intravenous evinacumab alongside optimized lipid-lowering therapy
The trial results demonstrated substantial and sustained LDL-C reduction with evinacumab. At Week 96 of the study, patients experienced remarkable improvements in their cholesterol levels6 :
38.0%
Overall Reduction
57.6%
Patients <18 years
48.8%
Female patients
30.5%
Male patients
These reductions were observed regardless of age, sex, LDL receptor genotype, or background lipid-lowering therapy, highlighting the consistent efficacy of evinacumab across different patient profiles6 .
Beyond clinical trials, real-world evidence has confirmed evinacumab's effectiveness in everyday practice. A 2025 multicenter study published in Arteriosclerosis, Thrombosis, and Vascular Biology evaluated evinacumab in 24 patients with HoFH across six US academic medical centers2 .
Average LDL-C reduction in real-world study
Consistent with clinical trial results
The study found that evinacumab lowered LDL-C by approximately 53%—consistent with clinical trial results—and was generally well tolerated2 . Additionally, significantly more patients achieved the guideline-recommended LDL-C goal of <70 mg/dL after adding evinacumab to their treatment regimen2 .
Like all medications, evinacumab has potential side effects. The most common adverse reactions include1 4 :
Common cold symptoms
Fever, chills, muscle aches
Lightheadedness
Runny nose
Feeling of sickness with urge to vomit
Tiredness or weakness
In a significant recent development, the FDA approved evinacumab for children with HoFH as young as 1 year old in September 20251 . This approval extended the medication's indication to younger patients, building on earlier approvals for those aged 12 years and older (2021) and children aged 5 to 11 years (2023)3 4 .
Evinacumab approved for patients aged 12 years and older with HoFH.
Approval extended to children aged 5 to 11 years with HoFH.
FDA approval expanded to include children with HoFH as young as 1 year old.
The expanded indication was supported by data from six children with HoFH who participated in either the U.S. expanded access program or ex-U.S. compassionate use program for Evkeeza1 . Among these very young patients, no new safety concerns were identified, and they showed similarly robust reductions in LDL-C as older patients, demonstrating continued efficacy across age groups4 .
"This development underscores the importance of, and urgency needed in, identifying children with FH through pediatric screenings in accordance with guidelines," emphasized one expert4 .
Evinacumab represents more than just a new medication—it signifies a paradigm shift in how we approach cholesterol management. By targeting ANGPTL3 rather than LDL receptors, it opens up new possibilities for treating severe forms of hypercholesterolemia that were previously considered difficult to manage.
As we look to the future, this breakthrough therapy offers hope not only for those with ultra-rare HoFH but also for advancing our understanding of cholesterol metabolism more broadly.
With its unique mechanism of action and proven efficacy, evinacumab has truly earned its title as a revolutionary "cholesterol buster" in the medical community.