NEW YORK (GenomeWeb) – Researchers from two pharmaceutical companies are pursuing drugs that target the ANGPTL3 gene in a bid to treat heart disease.
The companies hope to recapitulate, to some degree, the lower triglyceride and cholesterol levels seen among people with naturally occurring loss-of-function mutations in ANGPTL3. People who are homozygous for such mutations have some 70 percent lower plasma triglycerides and LDL cholesterol levels than those without.
In two studies appearing in the New England Journal of Medicine this week, researchers from Regeneron Pharmaceuticals and from Ionis Pharmaceuticals reported that their respective approaches to targeting ANGPTL3 have had some success in mouse and early-stage human studies.
"Our team of researchers used large-scale human genetic studies and mouse models to demonstrate that inactivation of ANGPTL3 reduces key lipid levels and cardiovascular disease risk," said Frederick Dewey, the head of translational genetics at the Regeneron Genetics Center and co-author of one of the studies, in a statement.
By analyzing data collected from 58,335 participants from the DiscovEHR study, Dewey and his colleagues uncovered 13 different loss-of-function mutations within ANGPTL3, as they reported in NEJM. Some 400 people harbored these loss-of-function mutations.
The DiscovEHR study is a collaboration between the Regeneron Genetics Center and the Geisinger Health System in Pennsylvania that was launched in 2014, and aims to sequence and analyze the genomes of 100,000 Geisinger patients. The Regeneron-Geisinger team previously reported uncovering people at risk of familial hypercholesterolemia from their DiscovEHR cohort.
Within this cohort, people with a loss-of-function mutation in ANGPTL3 had 27 percent lower triglyceride levels, 9 percent lower LDL cholesterol levels, and 4 percent lower HDL cholesterol levels, as compared to non-carriers, the researchers reported. They further noted that people with an ANGPTL3 loss-of-function mutation had about 40 percent lower odds of coronary artery disease.
In a mouse model of atherosclerosis, the researchers evaluated the effect of an anti-ANGPTL3 monoclonal antibody therapeutic called evinacumab. They reported that evinacumab was associated with lower average total cholesterol and triglyceride levels than in control mice. It was also associated with a decrease in atherosclerotic lesion size in the treated mice.
Similarly, in a cohort of 83 healthy people with mildly elevated triglyceride or LDL cholesterol levels, the researchers found that evinacumab was associated with lower triglyceride and LDL cholesterol levels in a dose-dependent manner. They reported a maximum decrease of triglyceride levels of up to 76 percent and of LDL cholesterol levels of up to 23 percent.
To Dewey and his colleagues, this suggested that drugs inhibiting ANGPTL3 activity could help reduce the risk of atherosclerosis and coronary artery disease.
In a separate NEJM paper, researchers from Ionis likewise described how they targeted ANGPTL3, using an antisense oligonucleotide dubbed IONIS-ANGPTL3-LRX. In a series of mouse studies, Sotirios Tsimikas from Ionis and the University of California, San Diego, and his colleagues found that blocking ANGPTL3 led to dose-dependent reductions in hepatic ANGPTL3 mRNA, ANGPTL3 protein, triglycerides, and LDL cholesterol. They similarly noted a decreased progression of atherosclerosis as well as increased insulin sensitivity.
In a cohort of 44 healthy people randomly assigned to receive IONIS-ANGPTL3-LRX either in a single dose or multiple doses or placebo, the researchers reported the single-dose group exhibited lower levels of ANGPTL3 protein, triglycerides, VLDL cholesterol, non-HDL cholesterol, and total cholesterol than the placebo group. However, they noted that the differences were not significant, possibly due to the small cohort size.
In the multiple-dose group, though, the researchers reported significant differences in ANGPTL3, triglyceride, VLDL cholesterol, and non-HDL cholesterol levels as compared to the placebo group. In particular, they reported triglyceride level reductions of 33.2 percent to 63.1 percent.