Conference Coverage

VIDEO: New antisense inhibitor nets impressive reductions in lipids

Publish date: January 6, 2017
By
Susan London

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Lipid reduction impressive, but safety assessments still needed

The trial shows a very clear proof of concept in regards to the effects on lipids.

In contrast to agents that increase LDL receptor levels (statins, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, bile acid–binding resins, and ezetimibe), IONIS-ANGPTL3-LRx produces greater reductions in non-HDL cholesterol than in LDL cholesterol, suggesting different mechanisms are at work.

Dr. Christie M. Ballantyne

Dr. Christie M. Ballantyne

This raises the question of whether the benefits of this therapy will be the same as we have seen with statins and other drugs. Another question is going to be, on top of statins, what will be the effects on lipoproteins? We have seen, for example, with fibrates, they look quite impressive sometimes in monotherapy, but when you add them to statins, particularly with fenofibric acid, you do not get further reduction of ApoB or non-HDL cholesterol.

But the key issue at this point is to ascertain the longer-term safety of IONIS-ANGPTL3-LRx in the liver and other organs.

One of the most impressive aspects of the combination of biotechnology and genetics is how rapidly you can come to a proof of concept in humans, and this is unprecedented, compared with what we have seen over the last 20 or 30 years. Unfortunately, the determination of safety is not quite as rapid, and it takes large numbers and long duration of follow-up. Obviously, we need that in terms of understanding benefits and risks.

Christie M. Ballantyne, MD, director of the Center for Cardiovascular Disease Prevention at the Methodist DeBakey Heart Center, Baylor College of Medicine in Houston, made these comments as the invited discussant. He has been a consultant to and received research support from trial sponsor Ionis Pharmaceuticals.


 

AT THE AHA SCIENTIFIC SESSIONS

NEW ORLEANS – A new antisense inhibitor to angiopoietinlike protein 3 (ANGPTL3) reduces lipids in healthy adults with elevated triglyceride levels, according to results of a phase I/IIa ascending-dose trial reported at the American Heart Association scientific sessions.

ANGPTL3 regulates lipid and possibly general metabolism through actions in the liver, gut, muscle, and adipose tissue, explained presenting author Sotirios Tsimikas, MD, an investigator with Ionis Pharmaceuticals, Carlsbad, Calif., and a professor of medicine and director of vascular medicine at the University of California, San Diego. Individuals having loss-of-function mutations in the gene encoding this protein have very low plasma levels of cholesterol and triglycerides.

In the trial, sponsored by Ionis Pharmaceuticals, 32 healthy volunteers with elevated triglyceride levels were treated with various doses of the antisense inhibitor, called IONIS-ANGPTL3-LRx, or a placebo, given by weekly subcutaneous injections for 6 weeks.

Results showed that participants treated at the higher-dose levels had a reduction from baseline of 66% in triglycerides, 68% in apoliprotein C-III (ApoC-III), 35% in LDL cholesterol, 36% in total cholesterol, and 40% in non-HDL cholesterol, as well as 25% in HDL cholesterol, Dr. Tsimikas reported. They also had reductions in apolipoprotein B (ApoB).

“All these lipid parameters are really going in the right direction in terms of postulating potential clinical benefit,” he commented.

Safety and tolerability results showed that only a single participant experienced a local injection site adverse event related to the inhibitor (erythema and pruritus). None experienced flulike symptoms, platelet reductions, or serious adverse events, and none left the study because of adverse events.

“Among all known therapies that lower triglycerides, this [IONIS-ANGPTL3-LRx] is also associated with a reduction not only in LDL cholesterol levels, but also in ApoB as well, which portends well for future outcomes trials,” noted Dr. Tsimikas.

“We think this is going to be a promising candidate for patients who have uncontrolled LDL cholesterol, elevated triglycerides, and possibly patients who have hepatic steatosis and NASH [nonalcoholic steatohepatitis],” he concluded.

Dr. Tsimikas, who is an employee of and shareholder in the trial’s sponsor, Ionis Pharmaceuticals, discussed his findings in a video interview.

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