This article is more than 5 years old. Information may no longer be current.
Novel therapy targeting ANGPTL3 protein safe, effective in early study
Click Here to Manage Email Alerts
NEW ORLEANS — A novel antisense compound that targets the ANGPTL3 protein, the loss of function of which has been linked to declines in various lipid parameters, was safe and effective in a phase 1/2a study presented at the American Heart Association Scientific Sessions.
Genetic variations of ANGPTL3 have been linked to very low levels of LDL, HDL, triglycerides and other lipids, Sotirios Tsimikas, MD, 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, La Jolla, said during a press conference.
Previous research has shown that RNA-targeted antisense drugs can block the translation of the ANGPTL3 protein, which could have the same effect on lipid levels as a loss-of-function mutation, he said.
Tsimikas presented results from a phase 1/2a study, conducted in healthy volunteers with elevated triglycerides (> 150 mg/dL), of IONIS-ANGPTL3-LRX, a ligand-conjugated formulation of the antisense agent designed to be taken up by hepatocytes to a great degree, which enables the same effect as a conventional formulation, but at a much smaller dose.
In a previous phase 1 study in healthy volunteers, the unconjugated agent reduced triglycerides by up to 63% (group means up to 49%) and total cholesterol by up to 46% (group means up to 28%), he said.
For the present study, 12 participants received a single ascending dose of the ligand-conjugated agent or placebo; and 32 participants received multiple ascending doses of placebo or 10 mg, 20 mg, 40 mg or 60 mg of the agent. Those in the single ascending dose cohort were healthy volunteers; those in the multiple ascending dose cohort were generally healthy but had triglycerides > 150 mg/dL and LDL > 70 mg/dL.
The outcomes of interest were safety, changes in various lipid levels, and pharmacokinetic parameters. The single ascending dose cohort was followed up at 30 days and 90 days; the multiple ascending dose cohort was followed up at 13 weeks.
An 80-mg dose of the agent decreased ANGPTL3 levels by 70% at 8 days, and reduced various lipid parameters but not HDL by 15 days, Tsimikas said.
In the multiple ascending dose cohort, there was a dose-response relationship with ANGPTL3 reduced by 50% with the 10-mg dose and 83% with the 60-mg dose at 50 days, he said.
All doses of the agent reduced triglycerides, total cholesterol, LDL, very LDL, non-HDL, apolipoprotein B and apolipoprotein C-III, and some had no effect on HDL, he said. Triglycerides and very LDL were reduced 60% to 70% in a dose-dependent fashion, and LDL was reduced a mean of 35%, he said.
The agent was safe, with no reported injection site reactions, flu-like symptoms, platelet count reductions, drug-related serious adverse events or study discontinuations due to adverse events, according to Tsimikas.
“We think this is going to be a promising candidate for treatment of elevated blood cholesterol, elevated triglycerides, and possibly for patients who have hepatic steatosis or [nonalcoholic steatohepatitis],” he said.
During a discussant presentation, Christie M. Ballantyne, MD, said “the most important question will be what are the effects of [the agent] on the liver long-term.” Ballantyne is professor of medicine and molecular and human genetics at Baylor College of Medicine, Houston; director of the Maria and Alando J. Ballantyne, MD, Atherosclerosis Clinical Research Laboratory at Baylor College of Medicine; co-director of the Lipid Metabolism and Atherosclerosis Clinic at The Methodist Hospital, Houston; and director of the Center for Cardiovascular Disease Prevention at Methodist DeBakey Heart Center.
Other questions of interest, he said, include how the agent will work in conjunction with high-intensity statin therapy, and whether it will confer a similar benefit as agents that increase LDL receptor expression. – by Erik Swain
Reference:
Tsimikas S, et al. LCBT.03 – Insights from New Therapeutic Trials for Lipids. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.
Disclosure: The study was funded by Ionis Pharmaceuticals. Tsimikas is an employee of Ionis Pharmaceuticals and reports receiving royalties from patents owned by the University of California – San Diego for oxidation-specific antibodies for which he was a co-inventor.
Perspective
Back to Top
Daniel J. Rader, MD
ANGPTL3 is a very interesting target. Certainly, it has major effects on lipids. I’m not that concerned about the HDL lowering. The LDL lowering was slightly surprising and rather interesting. Targeting the liver in the way that the ligand-conjugated formulation does has a lot of promise. ANGPTL3 is arguably one of the most exciting targets in the lipid field right now, and this is one way to approach it.
Click Here to Manage Email Alerts