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(Circulation. 2006;114:1729-1735.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Potent Reduction of Apolipoprotein B and Low-Density Lipoprotein Cholesterol by Short-Term Administration of an Antisense Inhibitor of Apolipoprotein B

John J.P. Kastelein, MD, PhD; Mark K. Wedel, MD, JD; Brenda F. Baker, PhD; John Su, PhD; JoAnn D. Bradley, PhD; Rosie Z. Yu, PhD; Emil Chuang, MD; Mark J. Graham, BS; Rosanne M. Crooke, PhD

From the Department of Vascular Medicine (J.J.P.K.), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands, and Isis Pharmaceuticals, Inc (M.K.W., B.F.B., J.S., J.D.B., R.Z.Y., E.C., M.J.G., R.M.C.), Carlsbad, Calif.

Correspondence to John J.P. Kastelein, MD, PhD, Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, PO Box 22700, Room F4-159.2, 1100 DE Amsterdam, the Netherlands. E-mail j.j.kastelein{at}amc.uva.nl

Received December 6, 2005; revision received August 4, 2006; accepted August 7, 2006.

Background— Apolipoprotein B (apoB) is an important structural component of low-density lipoprotein cholesterol (LDL-C) and plays a key role in LDL-C transport and removal. Reduction in apoB synthesis is expected to reduce circulating LDL-C, a proven risk factor of cardiovascular disease. In the present study, we describe the outcome of the first-in-humans study on the safety and efficacy of an antisense oligonucleotide inhibitor of apoB.

Methods and Results— This study was a double-blind, randomized, placebo-controlled, dose-escalation investigation conducted at a single site in 36 volunteers with mild dyslipidemia. The study utilized an initial single dose of 50 to 400 mg of ISIS 301012, a 20-mer oligonucleotide, followed by a 4-week multiple-dosing regimen with the same assigned dose. Safety was assessed by the incidence, severity, and relationship of adverse events to dose. Efficacy was determined by changes in serum apoB and LDL-C relative to baseline and placebo. The most common adverse event was erythema at the injection site (21 of 29 subjects). ApoB was reduced by a maximum of 50% (P=0.002) from baseline in the 200-mg cohort. This decrease in apoB coincided with a maximum 35% reduction of LDL-C (P=0.001). LDL-C and apoB remained significantly below baseline (P<0.05) up to 3 months after the last dose.

Conclusions— Administration of an antisense oligonucleotide to human apoB resulted in a significant, prolonged, and dose-dependent reduction in apoB and LDL-C. Although injection-site reactions were common, adherence to protocol was unaffected.

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