Homozygous familial hypercholesterolemia (HoFH) is a rare, severe, genetic disorder of lipid metabolism caused by variation(s) in the LDLR gene, which leads to low or absent hepatic clearance of low-density lipoprotein (LDL) cholesterol (LDL-C) from the circulation, resulting in LDL-C levels usually above 400 mg/dL. HoFH affects approximately 1 in 300,000 individuals. Individuals with HoFH are at an increased risk of premature atherosclerotic cardiovascular disease; heart attacks and/or mortality before age 30 may occur if they are not aggressively treated. Another characteristic of HoFH is xanthomas, firm nodules occurring in the skin or tendons, caused by cholesterol build-up. Treatment
consists of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitors (statins,
e.g., atorvastatin, rosuvastatin, simvastatin), ezetimibe (Zetia), and proprotein
convertase subtilisin/kexin type 9 (PCSK9) inhibitors (e.g., alirocumab
[Praluent], evolocumab [Repatha]), with or
without apheresis. Apheresis and some statins are at this time
the only US Food and Drug Administration (FDA)–approved treatment options
for children 5 to 10 years of age. The FDA has approved the other therapies for
older children or adults, due to safety and efficacy established in studies. If these
treatments do not lead to the individual reaching their LDL-C goals, or are
unavailable to the individual, then a liver transplantation may be attempted.
Evinacumab-dgnb (Evkeeza) is a recombinant human monoclonal antibody that binds to and inhibits angiopoietin-like protein3 (ANGPTL3). ANGPTL3 slows the function of certain enzymes that break down fats in the body. Evinacumab-dgnb (Evkeeza) blocks ANGPTL3, allowing faster breakdown of fats that leads to a reduction in LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), total cholesterol (TC), and apolipoprotein B and TG. Note: The effects of evinacumab-dgnb (Evkeeza) on cardiovascular morbidity and mortality have not been determined. The recommended dose of evinacumab-dgnb (Evkeeza) is 15 mg/kg administered by intravenous (IV) infusion over 60 minutes once monthly (every 4 weeks).
PEER-REVIEWED LITERATURE
SUMMARY
Adults
The safety and effectiveness of evinacumab-dgnb (Evkeeza) was evaluated in a multicenter, double-blind, randomized, placebo-controlled trial in 65 individuals with HoFH (NCT03399786; Raal et al.,
2020). The diagnosis of HoFH was determined by genetic testing (documented variant in two LDLR alleles OR the presence of homozygous or compound heterozygous variants in apolipoprotein B [APOB] or PCSK9) OR demonstrated in
The safety and effectiveness of evinacumab-dgnb (Evkeeza) was evaluated in a multicenter, double-blind, randomized, placebo-controlled trial in 65 individuals with HoFH (NCT03399786; Raal et al., 2020). The diagnosis of HoFH was determined by genetic testing (documented variant in two LDLR alleles OR the presence of homozygous or compound heterozygous variants in apolipoprotein B [APOB] or PCSK9) OR demonstrated in individuals with untreated TC greater than 500 mg/dL, LDL-C 70 mg/dL or greater, and triglycerides less than 300 mg/dL and either a presence of cutaneous or tendinous xanthomas before 10 years of age or documentation of TC greater than 250 mg/dL in both parents. Patients who had compound heterozygosity or homozygosity for variants in the gene encoding LDL receptor adaptor protein-1 (LDLRAP1) were also eligible. Participants were receiving other lipid-lowering therapies at baseline: 94% were on a statin (77% high-intensity statin), 75% on ezetimibe, 77% on a PCSK9 inhibitor, 25% on lomitapide, 34% undergoing apheresis. Participants were on the following combination therapies at baseline: 44% were receiving a three-drug regimen (ezetimibe, PCSK9 inhibitor, and statin), 11% on a four-drug regimen (ezetimibe, lomitapide, PCSK9 inhibitor, and statin), and 63% were on at least three lipid-lowering therapies.
Participants received either evinacumab-dgnb (Evkeeza), 15 mg/kg IV every 4 weeks (N=43) or placebo (N=22) for 24 weeks. After the double-blind treatment period, 64 of 65 participants entered a 24-week open-label extension period in which all participants received evinacumab-dgnb (Evkeeza) 15 mg/kg IV every 4 weeks. The primary efficacy endpoint was percent change in LDL-C from baseline to Week 24. At Week 24, those who received evinacumab-dgnb (Evkeeza) experienced LDL-C reduction from baseline of 47.1% compared with an increase of 1.9% in those on placebo (P<0.0001). Adverse events occurred in 66% of individuals receiving evinacumab-dgnb (Evkeeza) versus 81% for placebo; adverse events did not lead to discontinuation in either group. Serious adverse events occurred in two individuals (5%) in the evinacumab-dgnb (Evkeeza) group (urosepsis and suicide attempt); both patients recovered.
Pediatric Individuals Aged 12 to 17 Years
At Week 24, evinacumab-dgnb (Evkeeza) reduced LDL-C by 73% in one pediatric individual, compared with a 60% reduction in the individual on placebo.
In an open-label extension study, 13 pediatric individuals with HoFH (12 to 17 years of age) received 15 mg/kg IV of evinacumab-dgnb (Evkeeza) every 4 weeks as an adjunct to other lipid-lowering therapies for a median of 33 weeks. Evinacumab-dgnb (Evkeeza) reduced LDL-C by 52% in the nine individuals who completed treatment and had a lipid assessment at Week 24. The researchers stated that overall, the effect of evinacumab-dgnb (Evkeeza) on lipid parameters in pediatric individuals with HoFH was generally similar to that seen in adults with HoFH.
Pediatric Individuals Aged 5 to 11 Years
The safety and effectiveness of evinacumab-dgnb (Evkeeza) in pediatric individuals aged 5 to 11 years was evaluated in a multicenter, three-part, single-arm, open-label trial performed in 14 individuals with HoFH (NCT04233918; Wiegman et al., 2024). At baseline, individuals had LDL-C greater than 130 mg/dL despite aggressive lipid-lowering therapies. Part A was a phase 1b, single-dose, open-label, 16-week study that assessed the safety, pharmacokinetics, and pharmacodynamics of evinacumab in six individuals. Part B evaluated the efficacy of evinacumab-dgnb (Evkeeza) 15 mg/kg given intravenously every 4 weeks as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe, lomitapide, and lipoprotein apheresis). At Week 24, evinacumab-dgnb (Evkeeza) reduced LDL-C by 48%. Part C is an ongoing, phase 3, 48-week open-label extension study with a 24-week follow-up period, designed to assess the long-term safety and efficacy of evinacumab, which includes all 20 individuals from both parts A and B.
Pediatric
Individuals Aged 1 to Less Than 5 Years
The FDA
approval for this indication was obtained from the providers of six children
enrolled in an expanded access program. The providers were required to provide
evidence that the children met the criteria of the program as well as safety
and efficacy data. Prior to enrollment 83% of the participants were being
treated with statins and ezetimibe. At baseline, the mean LDL-C level was 499
mg/dL (range 238-873 mg/dL). Participants received evinacumab-dgnb (Evkeeza) in
accordance with the FDA label. At week 40, LDL-C levels were reduced by a mean
of -60%.
OFF-LABEL INDICATION
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
