Abstract 14196: Evaluation of Isis Apo(a)Rx, an Antisense Inhibitor to Apolipoprotein(a), in Healthy Volunteers
ISIS APO(a)Rx is an antisense oligonucleotide designed to specifically inhibit the expression of apolipoprotein(a) [apo(a)], a distinct protein component of lipoprotein(a) [Lp(a)]. Apo(a) is produced in the liver and the assembly of apo(a) and LDL to form Lp(a) is thought to occur at the outer hepatocyte surface with the availability of apo(a) being the main determinant of Lp(a) plasma concentration. Lp(a) is implicated in both proatherogenic and prothrombogenic disease pathways. Elevated levels of Lp(a) in humans are associated with increased risk of cardiac death, myocardial infarction, stroke, and peripheral arterial disease.
In vitro pharmacological activity of ISIS APO(a)Rx was characterized following electroporation of the drug into primary hepatocytes isolated from apo(a) transgenic (Tg) mice as well as cynomolgus monkeys. In these studies, ISIS APO(a)Rx selectively reduced apo(a) mRNA in a concentration-dependent manner. Administration of ISIS APO(a)Rx, a human apo(a) antisense inhibitor, to mice containing the human apo(a) transgene, produced dose-dependent reductions in human apo(a) liver mRNA and apo(a) plasma protein after 2 weeks of ASO administration at 1.5, 5, 15 and 50 mg/kg/week. Activity of ISIS APO(a)Rx was also demonstrated in lean monkeys, where ISIS APO(a)Rx significantly reduced hepatic apo(a) mRNA by 90% relative to control.
ISIS APO(a)Rx is currently being evaluated in a blinded, placebo-controlled, Phase 1, ascending dose, healthy volunteer study. The study will evaluate dose levels of 50 to 400 mg of ISIS APO(a)Rx or placebo. Subjects in the MAD cohorts receive a loading regimen of 3 doses the first week followed by once-weekly dosing for 3 weeks. Based on results of targeting other lipoproteins with antisense inhibitors, it is anticipated that APO(a)rx will produce robust reductions in APO(a). We will also report any change in oxidized phospholipids associated with apoB-100, and lipoprotein-associated phospholipase A2. Preliminary results from the clinical study will be presented at this meeting.
- © 2013 by American Heart Association, Inc.