Regeneron Pharmaceuticals, Inc. announced the U.S. Food and Drug Administration (FDA) has accepted for Priority Review the supplemental Biologics License Application (sBLA) for Evkeeza(R) (evinacumab-dgnb) as an adjunct to other lipid-lowering therapies to treat children aged 5 to 11 years with homozygous familial hypercholesterolemia (HoFH). The FDA target action date is March 30, 2023. HoFH is an ultra-rare inherited condition that affects approximately 1,300 patients in the U.S. and is the most severe form of familial hypercholesterolemia (FH).

The disease occurs when two copies of the FH-causing genes are inherited, one from each parent, resulting in dangerously high levels (usually >400 mg/dL) of low-density lipoprotein-cholesterol (LDL-C or bad cholesterol). Those living with HoFH are at risk for premature atherosclerotic disease and cardiac events even in their teenage years. The sBLA is supported by data from a three-part trial evaluating Evkeeza in children aged 5 to 11 years with HoFH.

Efficacy was assessed in 14 children enrolled in the Part B portion of the trial. Despite treatment with other lipid- lowering therapies, these children entered the trial with an average LDL-C level of 264 mg/dL, more than twice the target (<110 mg/dL) for pediatric patients with HoFH. The trial met its primary endpoint, showing children who added Evkeeza to other lipid-lowering therapies reduced their LDL-C by 48% at week 24 on average.

Furthermore, 79% (n=11) saw their LDL-C reduced by at least half at 24 weeks following Evkeeza treatment, with an average absolute reduction in LDL- C from baseline of 132 mg/dL. Among 20 children evaluated for long-term safety across Parts A, B and C of the trial (mean exposure: 52 weeks, range: 42-64 weeks), the most common adverse events (AEs) occurring in >=15% of patients included COVID-19 (n=15), pyrexia (n= 5), headache (n=4), throat pain (oropharyngeal pain, n=4) as well as upper abdominal pain, diarrhea, vomiting, fatigue, nasopharyngitis, rhinitis and cough (all n=3). Most reported AEs were mild or moderate, and none led to study discontinuation.

The safety profile of Evkeeza observed in these patients was generally consistent to those seen in adults and pediatric patients aged 12 years and older. Evkeeza is the first angiopoietin-like 3 (ANGPTL3) targeted therapy approved by the FDA, European Commission and the United Kingdom's Medicines and Healthcare products Regulatory Agency as an adjunct therapy for patients aged 12 years and older with HoFH. The potential use of Evkeeza in HoFH patients aged 5 to 11 years has not been fully evaluated by any regulatory authority.

About the Trial The three-part, single-arm, open-label trial evaluated Evkeeza in pediatric patients with HoFH aged 5 to 11 years. Part A (n=6) was a Phase 1b trial designed to assess the pharmacokinetics (PK), safety and tolerability of Evkeeza. Efficacy was evaluated in the 24-week treatment period in the Phase 3 Part B portion, which enrolled 14 patients with an average age of 9 years.

Among them, 86% were on statins, 93% were on ezetimibe, 50% were on LDL apheresis and 14% were on lomitapide. Patients received Evkeeza 15 mg/kg every four weeks delivered intravenously alongside their lipid- lowering treatment regimen. The primary endpoint was change in LDL-C at week 24.

Secondary endpoints included the effect of Evkeeza on other lipid parameters (i.e., apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein[a] and total cholesterol), efficacy by mutation status, safety and tolerability, immunogenicity and PK. Patients who completed Part A or B were allowed to continue treatment in Part C (n=20), an ongoing Phase 3 extension trial. Parts A, B and C were not designed to evaluate the effect of Evkeeza on cardiovascular events.

About Evkeeza(R) (evinacumab) Evkeeza was invented using Regeneron's VelocImmune(R) technology and is a fully human monoclonal antibody that binds to and blocks the function of ANGPTL3, a protein that inhibits lipoprotein lipase (LPL) and endothelial lipase (EL) and regulates circulating lipids, including LDL-C. Regeneron scientists discovered the angiopoietin gene family more than two decades ago. Human genetics research published in New England Journal of Medicine in 2017 by scientists from the Regeneron Genetics Center(R) found that patients whose ANGPTL3 gene did not function properly (called a "loss-of function mutation") have significantly lower levels of key blood lipids, including LDL-C, and that this is associated with a significantly lower risk of coronary artery disease. The generic name for Evkeeza in its approved U.S. indications is evinacumab-dgnb, with dgnb the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the FDA.

The safety and effectiveness of Evkeeza have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH). The effect of Evkeeza on cardiovascular morbidity and mortality has not been determined.