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Targeting ANGPTL3 may reduce atherogenic lipoproteins
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Antisense oligonucleotides that targeted ANGPTL3 successfully lowered atherogenic lipoproteins in humans, according to a study published in The New England Journal of Medicine.
Sotirios Tsimikas, MD, FACC, FAHA, FSCAI, vice president of clinical development at Ionis Pharmaceuticals and professor of medicine and director of vascular medicine at the University of California, San Diego School of Medicine, and colleagues analyzed data from 44 patients who were assigned a single dose of an antisense oligonucleotide (IONIS-ANGPTL3-LRX, Ionis/Akcea) targeting ANGPTL3 messenger RNA (20 mg, 40 mg or 80 mg), multiple doses once a week for 6 weeks (10 mg, 20 mg, 40 mg or 60 mg) or placebo.
All patients had a fasting LDL greater than 70 mg/dL. Patients assigned a single dose of 40 mg or 80 mg had a fasting triglyceride level between 90 mg/dL and 150 mg/dL, whereas the fasting triglyceride level in patients assigned a 20-mg single dose or multiple doses was at least 150 mg/dL.
At 43 days, patients assigned multiple doses had mean reductions of ANGPTL3 levels of 46.6% in the 10-mg group (P = .001 vs. placebo), 72.5% in the 20-mg group (P = .003), 81.3% in the 40-mg group (P = .001) and 84.5% in the 60-mg group (P = .001). Other maximum reductions from baseline in the multiple-treatment group included apolipoprotein C-III (58.8%; P = .001), triglyceride levels (63.1%; P = .01), apolipoprotein B (25.7%; P = .001) and non-HDL (36.6%; P = .001).
No serious adverse events occurred in all treatment groups. Two patients assigned multiple doses of the antisense oligonucleotide and one patient assigned placebo reported headache. Dizziness was reported by two patients assigned placebo and one patient treated with multiple doses of the antisense oligonucleotide.
Researchers also evaluated oligonucleotides targeting Angptl3 mRNA in mice and its effect on triglyceride clearance, plasma lipid levels, insulin sensitivity, liver triglyceride content and atherosclerosis. Mice treated with the therapies targeting Angptl3 had dose-dependent decreases in Angptl3 protein (by 50% to 90%), Angptl3 mRNA (by 61% to 91%), LDL (by 7% to 64%), triglycerides (by 35% to 85%), atherosclerosis progression (52%) and liver triglyceride content and an increase in insulin sensitivity.
“These studies provide a rationale for pursuing the development of an ANGPTL3 therapeutic agent as treatment for elevated levels of triglyceride-rich lipoproteins in order to further reduce the risk of [CVD] in persons who are already taking recommended medical and preventive therapies,” Tsimikas and colleagues wrote. – by Darlene Dobkowski
Disclosures: The study was funded by Ionis Pharmaceuticals. Tsimikas reports receiving personal fees from Ionis Pharmaceuticals and University of California San Diego Medical Center. Please see the study for all other authors’ relevant financial disclosures.
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