By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a recombinant, fully human monoclonal antibody that binds angiopoietin-like protein 3 (ANGPT3) for the treatment of homozygous familial hypercholesterolemia (HoFH), an ultra-rare, severe form of familial hypercholesterolemia. ANGPT3 is involved in the regulation of lipid metabolism in the liver.1 Evinacumab was designated as a breakthrough therapy, an orphan product, and received a priority review. It is distributed as Evkeeza.
Evinacumab should be prescribed as an adjunct to other low-density lipoprotein cholesterol (LDL-C)-lowering therapy to treat patients age 12 years and older with HoFH.1
The recommended dose for evinacumab is 15 mg/kg, given by intravenous infusion (over 60 minutes) once every four weeks.1 It is available as 345 mg/2.3 mL and 1,200 mg/8 mL single-dose vials.
Evinacumab reduces LDL-C levels independent of the activity of LDL receptors that normally act to remove LDL-C from the circulation.1,2 It provides significant LDL-C reduction in HoFH patients on maximum doses of currently available lipid-lowering therapy.1,3
Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported (1%), and the drug may cause embryo-fetal toxicity.1 Evinacumab reduces HDL cholesterol by about 30%.3 Dose administration requires monthly intravenous infusions. The effect of evinacumab on cardiovascular morbidity or mortality has not been determined.1
HoFH is caused by mutations in genes regulating plasma levels of LDL-C, including LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes.4 The most common is the impairment or loss-of-function variants in the LDLR, resulting in the inability to clear LDL-C from the circulation. Inhibition of ANGPT3 results in less production of LDL-C by the liver and is independent of LDLR function.4
The efficacy and safety of evinacumab were evaluated in a double-blind, randomized, placebo-controlled, 24-week trial that included 65 subjects with HoFH.1,3 Subjects were randomized to evinacumab (n = 43) or placebo (n = 22). The primary endpoint was the percent change in the calculated LDL-C from baseline to week 24. At baseline, the mean age was 41.7 years ± 15.5 years, 54% of subjects were female, 74% were white, the mean LDL-C was 255.1 mg/dL ± 165.2 mg/dL, 32% showed a complete absence of LDLR expression, 94% were on a statin, 77% were on a PCSK9 inhibitor, and 34% were on extracorporeal LDL-C filtration (apheresis).
At week 24, there was a mean difference from placebo of -49%. Non-LDL-C, triglycerides, APOB, and total cholesterol were similarly reduced. Lipid-lowering with evinacumab in pediatric subjects (n = 13) generally was similar to those seen in adults.1
HoPH affects about one in 160,000 people worldwide.4 These individuals often live with defective or loss of function of the LDLR gene.5 The clinical spectrum of the disease is dependent on the severity of the LDLR mutation. It is characterized by high LDL-C (> 387 mg/dL), resulting in premature atherosclerotic cardiovascular disease and early mortality. Current therapies include high-intensity statins and PCSK9 inhibitors for those with LDLR gene-defective mutations (but residual function) and apheresis in those with loss-of-function mutations.5 Evinacumab provides an alternative therapy for patients with severe HoFH and no LDLR function. The cost of a single dose for a 70 kg patient is $37,500 or $487,500 per year (every four weeks for one year).
- Regeneron Pharmaceuticals, Inc. Evkeeza prescribing information. February 2021.
- Adam RC, Mintah IJ, Alexa-Braun CA, et al. Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance. J Lipid Res 2020;61:1271-1286.
- Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med 2020;383:711-720.
- FH Foundation. Homozygous familial hypercholesterolemia.
- Bélanger AM, Akioyamen L, Alothman L, Genest J. Evidence for improved survival with treatment of homozygous familial hypercholesterolemia. Curr Opin Lipidol 2020;31:176-181.