Now that cardiologists and other doctors are comfortable talking about PCSK9 inhibitors they can start preparing to add a new mouthful of a therapeutic target to their vocabulary: angiopoietin-like-3 (ANGPTL3). Two papers published in the New England Journal of Medicine by industry researchers provide a snapshot of promising but still early research on two new drugs that target the protein.
The new research follows recent studies, including large outcome studies with ezetimibe and the PCSK9 inhibitor evolocumab, suggesting that new lipid lowering approaches targeting the LDL receptor are likely to yield diminishing returns, at least in the setting of statins.
The new research on ANGPTL3 stems from earlier genetic studies that identified beneficial genetic variations which the new drugs are designed to emulate. In these studies ANGPTL3 loss-of-function variants were associated with beneficial lipid and metabolic effects, including LDL and triglyceride levels 70% lower than in people without the variants. One mechanism by which ANGPTL3 appears to exerts its effect is through the inhibition of lipoprotein lipase, an important and untapped target to date.
One report involves evinacumab, a new monoclonal antibody against ANGPTL3 under development by Regeneron. They reported observational data showing that people who had loss-of-function variants in ANGPTL3 had lower levels of triglycerides, HDL cholesterol and LDL cholesterol, and that people with coronary artery disease were significantly less likely to have a loss-of-function variant.
In dyslipidemic mice, evinacumab reduced the size of atherosclerotic lesions and necrotic content. In healthy human volunteers evinacumab resulted in a 76% reduction in triglyceride levels and a 23% reduction in LDL.
The second paper, by Mark Graham and colleagues, reports on a different approach to ANGPTL3 inhibition, an antisense oligonucleotide targeting Angptl3 messenger RNA under development by Ionis Pharmaceuticals. The authors reported dose-dependent reductions in triglycerides and LDL in mice who received the compound, in addition to a slowing of atherosclerosis progression and an increase in insulin sensitivity. Human participants who received weekly injections of the oligonucleotide had triglyceride reductions ranging from 33% to 63%, LDL reductions ranging from 1% to 33%, VLDL reductions of 28%-60%, and non-HDL level reductions of 10% to 36.6%.
“We found that inhibition of ANGPTL3 mRNA results in favorable cardiometabolic effects in several different mouse models and in healthy human volunteers,” the authors concluded.
“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 cardiovascular disease in persons who are already taking recommended medical and preventative therapies.”
The authors cited a potential advantage of an antisense approach over a monoclonal antibody. Because the antisense drugs inhibit ANGPTL3 synthesis within the hepatocyte in addition to lowering plasma ANGPTL3 levels, they may lower hepatic triglyceride levels and possibly help people with hepatic steatosis, they said.
Sekar Kathiresan (Massachusetts General Hospital) performed genetic studies that pointed to the significance of ANGPTL3 and its potential as a therapeutic target.
The literature now “validates ANGPTL3 as a therapeutic target for dyslipidemia and coronary disease” and “provide an approach complementary to LDL lowering,” which can “lower plasma triglycerides and possibly coronary disease risk.” Kathiresan pointed out that “fish oils are another way to lower plasma triglyceride-rich lipoproteins but unlike ANGPTL3 we do not know the molecular target for fish oils and thus, have less confidence that the medicine will reduce disease risk.”
James Stein (University of Wisconsin) expressed enthusiasm for the papers. “This is really exciting and promising research.” But, he cautioned, “because genetic variants often don’t precisely match the effects of pharmacological interventions, we need to develop precise interventions, such as the targeted oligonucleotides used in the [Graham] paper.
“Together these two papers take us two steps towards a product that some day could be used in humans,” Stein added. “Sometimes the drug effects nicely match the gene variant effects on the surrogates and on ASCVD events (like PCSK9 inhibitors and ezetimibe) – other times, not so much (CETP inhibitors). I am eager to demonstrate safety, lack of off target effects, and of course, efficacy in humans. These are great scientists.”
This article has been re-published from Larry’s blog CardioBrief as part of a licensing agreement between Everyday Health and the limbic.