Universität zu Köln

McGowan, Mary P., Tardif, Jean-Claude, Ceska, Richard ORCID: 0000-0002-2541-5179, Burgess, Lesley J., Soran, Handrean, Gouni-Berthold, Ioanna, Wagener, Gilbert and Chasan-Taber, Scott (2012). Randomized, Placebo-Controlled Trial of Mipomersen in Patients with Severe Hypercholesterolemia Receiving Maximally Tolerated Lipid-Lowering Therapy. PLoS One, 7 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Objectives: 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. Methods and Results: 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. Main outcome: 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%). Conclusion: 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. Trial Registration: ClinicalTrials.gov NCT00794664.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code McGowan, Mary P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tardif, Jean-Claude UNSPECIFIED UNSPECIFIED UNSPECIFIED Ceska, Richard UNSPECIFIED orcid.org/0000-0002-2541-5179 UNSPECIFIED Burgess, Lesley J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Soran, Handrean UNSPECIFIED UNSPECIFIED UNSPECIFIED Gouni-Berthold, Ioanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagener, Gilbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Chasan-Taber, Scott UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-478974
DOI:	10.1371/journal.pone.0049006
Journal or Publication Title:	PLoS One
Volume:	7
Number:	11
Date:	2012
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHEMISTRY STANDARDIZATION PROJECT; B SYNTHESIS INHIBITOR; APOLIPOPROTEIN-A-I; FAMILIAL HYPERCHOLESTEROLEMIA; DOUBLE-BLIND; INTERNATIONAL-FEDERATION; CARDIOVASCULAR RISK; LDL CHOLESTEROL; EFFICACY; STATIN Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47897