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

Abstract

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% (Pϭ0.002) from baseline in the 200-mg cohort. This decrease in apoB coincided with a maximum 35% reduction of LDL-C (Pϭ0.001). LDL-C and apoB remained significantly below baseline (PϽ0.05) 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.

Antisense oligonucleotide reduction of apoB-ameliorated atherosclerosis in LDL receptor-deficient mice

“…We have demonstrated, both in animal models and with the human apoB ASO mipomersen in the clinic, that ASO suppression of hepatic apoB mRNA produces substantial reductions in all atherogenic apoB-containing lipoproteins (12)(13)(14)(15). Furthermore, the effi cacy of mipomersen in reducing plasma apoB is maintained in hoFH patients, as well as when co-administered with HMG-CoA reductase inhibitors (statins) ( 16,17 ).…”

Management of Familial Hypercholesterolemia: A Review of the Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia

“…88 Recently, mipomersen, a second-generation antisense oligonucleotide, was approved by the FDA as an adjunct to lipidlowering medications and diet to reduce LDL-C, apo B, total cholesterol, and non-HDL-C in patients with HoFH. 89 Apo B is important for the structure and receptor binding of lipoproteins, including LDL-C. 90,91 In a phase 3 trial of patients with HoFH randomly assigned to receive either mipomersen or placebo, patients receiving mipomersen had a mean reduction in LDL-C levels of 24.7% compared with 3.3% in patients receiving placebo (P = 0.0003). 91 The most common adverse effect in patients receiving mipomersen was injection-site reactions.…”

Novel Targeted Therapy for Precursor B-Cell Acute Lymphoblastic Leukemia: Anti-CD22 Antibody-MXD3 Antisense Oligonucleotide Conjugate

“…The use of oligonucleotides, such as ASO and small interfering RNA (siRNA), has been studied as an emerging method to target specific RNA sequences (27,57,58). However, clinical translation of these techniques has had limited therapeutic success in oncology (31)(32)(33). The primary challenge is target specific and efficient intracellular delivery of oligonucleotides (26,27,(36)(37)(38).…”

“…Antisense oligonucleotides (ASOs) have enormous potential as gene-targeted agents that have high specificity (26)(27)(28)(29)(30). Over the past decade, clinical trials using ASO therapies have demonstrated modest efficacy for cancers, including chronic lymphocytic leukemia (31), prostate and lung cancers (32)(33)(34)(35). Major challenges with ASO-based cancer therapies remain, however, and include non-specific delivery and inefficient intracellular uptake (36)(37)(38).…”