ANGPTL3 inhibitors

Evinacumab (Evkeeza)

Evinacumab is a fully human monoclonal ANGPTL3 antibody. Evinacumab is currently indicated as an adjunct to diet and other LDL-C lowering therapies for the treatment of adult and adolescent patients aged 12 years and older with homozygous familial hypercholesterolaemia (HoFH) (3).

In a pivotal trial, treatment with evinacumab (intravenous 15 mg/kg body weight) halved LDL-C levels (corrected for placebo), regardless of LDL receptor function in patients with HoFH (4). Similar findings were reported in patients with refractory hypercholesterolaemia (5). In patients with severe hypertriglyceridaemia without genetic chylomicronaemia syndrome, treatment with evinacumab led to meaningful reduction in TG (median 68.8%), as well as substantial reductions in non-HDL-C, and apoCIII and B48 (6).

Zodasiran (ARO-ANG3)

Zodasiran is a small interfering RNA (siRNA) molecule targeted to hepatocytes, via N-acetyl galactosamine (GalNAc), where it inhibits ANGPTL3 mRNA transcription, resulting in inhibition of hepatic production and secretion of ANGPTL3.

In a Phase 1 randomised, placebo-controlled, open-label study investigating single and repeat doses of zodasiran in healthy participants and those with hepatic steatosis, zodasiran was rapidly absorbed, well tolerated, and reduced levels of ANGPTL3, TG and LDL-C (7).

VERVE-201

VERVE-201 is a gene editing medicine composed of an mRNA encoding an adenine base editor and a guide RNA that targets the ANGPTL3 gene packaged in a GalNAc lipid nanoparticle. Delivered via a one-time intravenous infusion, VERVE-201 is designed to permanently inactivate ANGPTL3 in the liver via a precise A-to-G DNA base pair edit and thereby lower LDL-C and TG concentrations.

In a study of 34 non-human primates a single i.v infusion of VERVE-201cyn 3 mg/kg i.v, reduced ANGPTL3 by more that 90%, and this was maintained for 22 months (8). In primary human hepatocytes treated with VERVE-201, ANGPTL3 editing ranged from 72%-90% at a dose of 20,000 ng/mL total RNA (9).

Solbinsiran (LY3561774)

Solbinsiran (LY3561774), a GalNAc conjugated, small interfering RNA oligonucleotide designed to reduce ANGPTL3 protein expression, has been shown to significantly reduce ANGPTL3 mRNA expression in hepatocytes, and serum ANGPTL3 protein expression.

In preclinical studies, a single dose of solbinsiran 1 mg/kg s.c. reduced ANGPTL3 mRNA by 65% in mouse hepatocytes compared to hepatocytes from vehicle-treated mice (10). In cynomolgus monkeys, a single dose of solbinsiran 3 mg/kg reduced liver ANGPTL3 mRNA expression by up to 72.9% compared to placebo (p<0.0001), and serum ANGPTL3 protein expression by 68.6% (p<0.001) (10). Solbinsiran showed a long duration of activity, with >50% mRNA knockdown remaining 12 weeks after a single dose.

Vupanorsen (Pfizer-led clinical development programme discontinued in January 2022.)

Vupanorsen is a second-generation N-acetyl galactosamine (GalNAc)-modified antisense oligonucleotide that targets hepatic ANGPTL3 mRNA (4). GalNAc is a well-defined liver-targeted moiety which benefits from high affinity with the asialoglycoprotein receptor (ASGPR). This results in enhanced potency compared with the parent modalities without conjugation (11).

In patients with fasting TG > 1.7 mmol/L or > 150 mg/dL, type 2 diabetes, and hepatic steatosis, treatment with vupanorsen 80 mg every 4 weeks reduced TG by ~50%, as well as other atherogenic lipoproteins, including apoCIII by 58% and remnant cholesterol by 38% (12).