Journal Article

Randomized, Placebo-Controlled Trial of Mipomersen in Patients with Severe Hypercholesterolemia Receiving Maximally Tolerated Lipid-Lowering Therapy

Ceska, Richard, Soran, Handrean, Tardif, Jean-Claude, Burgess, Lesley J., McGowan, Mary P., Gouni-Berthold, Ioanna, Chasan-Taber, Scott, Wagener, Gilbert

2012

Overview

Mipomersen, an antisense oligonucleotide targeting apolipoprotein B synthesis, significantly reduces LDL-C and other atherogenic lipoproteins in familial hypercholesterolemia when added to ongoing maximally tolerated lipid-lowering therapy. Safety and efficacy of mipomersen in patients with severe hypercholesterolemia was evaluated. Randomized, double-blind, placebo-controlled, multicenter trial. Patients (n  = 58) were ≥18 years with LDL-C ≥7.8 mmol/L or LDL-C ≥5.1 mmol/L plus CHD disease, on maximally tolerated lipid-lowering therapy that excluded apheresis. Weekly subcutaneous injections of mipomersen 200 mg (n  = 39) or placebo (n  = 19) were added to lipid-lowering therapy for 26 weeks. percent reduction in LDL-C from baseline to 2 weeks after the last dose of treatment. Mipomersen (n = 27) reduced LDL-C by 36%, from a baseline of 7.2 mmol/L, for a mean absolute reduction of 2.6 mmol/L. Conversely, mean LDL-C increased 13% in placebo (n = 18) from a baseline of 6.5 mmol/L (mipomersen vs placebo p<0.001). Mipomersen produced statistically significant (p<0.001) reductions in apolipoprotein B and lipoprotein(a), with no change in high-density lipoprotein cholesterol. Mild-to-moderate injection site reactions were the most frequently reported adverse events with mipomersen. Mild-to-moderate flu-like symptoms were reported more often with mipomersen. Alanine transaminase increase, aspartate transaminase increase, and hepatic steatosis occurred in 21%, 13% and 13% of mipomersen treated patients, respectively. Adverse events by category for the placebo and mipomersen groups respectively were: total adverse events, 16(84.2%), 39(100%); serious adverse events, 0(0%), 6(15.4%); discontinuations due to adverse events, 1(5.3%), 8(20.5%) and cardiac adverse events, 1(5.3%), 5(12.8%). Mipomersen significantly reduced LDL-C, apolipoprotein B, total cholesterol and non-HDL-cholesterol, and lipoprotein(a). Mounting evidence suggests it may be a potential pharmacologic option for lowering LDL-C in patients with severe hypercholesterolemia not adequately controlled using existing therapies. Future studies will explore alternative dosing schedules aimed at minimizing side effects. ClinicalTrials.gov NCT00794664.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alanine / Alanine transaminase / Anticholesteremic agents / Anticholesteremic Agents - administration & dosage / Anticholesteremic Agents - adverse effects / Anticholesteremic Agents - therapeutic use / Antisense oligonucleotides / Apheresis / Apolipoprotein B / Apolipoproteins / Aspartate / Aspartate transaminase / Atherosclerosis / Biology / Blood lipids / Cardiology / Cardiovascular agents / Care and treatment / Cholesterol / Cholesterol, LDL - blood / Clinical trials / Coronary heart disease / Diabetes / Drug dosages / Fatty liver / Female / Heart / Heart diseases / High density lipoprotein / Humans / Hypercholesterolemia / Hypercholesterolemia - drug therapy / Lipids / Lipoprotein A / Lipoproteins / Low density lipoprotein / Low density lipoproteins / Male / Medicine / Oligodeoxyribonucleotides, Antisense - administration & dosage / Oligodeoxyribonucleotides, Antisense - adverse effects / Oligodeoxyribonucleotides, Antisense - therapeutic use / Oligonucleotides - administration & dosage / Oligonucleotides - adverse effects / Oligonucleotides - therapeutic use / Patients / Pharmacology / Preventive medicine / Randomization / Reduction / Reference materials / Schedules / Side effects / Statins / Statistical analysis / Steatosis / Therapy / Transaminase / Treatment Outcome