Fast track — ArticlesMipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial
Introduction
Homozygous familial hypercholesterolaemia is characterised by very high LDL cholesterol concentrations (usually >13 mmol/L), cutaneous and tendinous xanthomata, and early cardiovascular disease, and untreated patients rarely survive beyond the age of 30 years.1, 2 The genetic basis of this autosomal codominant disorder is distinguished by loss-of-function mutations in both LDL-receptor gene loci, resulting in reduced uptake and clearance of circulating LDL cholesterol by the liver. 1, 2
Because LDL receptors are not functional in patients with homozygous familial hypercholesterolaemia, conventional lipid-lowering drugs such as statins, which act mainly by up-regulating hepatic LDL receptors, result in insufficient reductions in LDL cholesterol concentrations, even when these agents are administered at maximum doses.2, 3 LDL apheresis seems to increase survival but is expensive, invasive, and not universally available.4, 5 Portocaval shunting can be complicated by hepatic encephalopathy, and liver transplantation is restricted by few donor organs and the complications of long-term immunosuppression.6, 7
Since patients with this disease are unable to effectively clear LDL particles, therapy aimed to reduce LDL production is an attractive option. Apolipoprotein B is an essential structural and receptor-binding component of all atherogenic lipoproteins, including LDL.8 Atherogenic lipoproteins of hepatic origin carry one molecule of apolipoprotein B100 per lipoprotein particle, whereas apolipoprotein B48, a truncated form of apolipoprotein B100, is found in chylomicrons synthesised in the intestine.8 Inhibition of microsomal triglyceride transfer protein (MTP), which is responsible for transferring lipid onto apolipoprotein B in the intestine and liver, reduces the production of lipoproteins containing apolipoprotein B in homozygous familial hypercholesterolaemia.9, 10, 11 However, at therapeutically effective doses in patients with this disease, MTP inhibition causes substantial rises in serum aminotransferase concentrations and hepatic fat accumulation. Moreover, this treatment is complicated by gastrointestinal side-effects owing to inhibition of intestinal chylomicron production and subsequent fat malabsorption.9
Hepatic lipoprotein production can be specifically reduced by directly targeting apolipoprotein B100. Mipomersen is a second-generation antisense oligonucleotide that is designed to inhibit apolipoprotein B100 protein synthesis.12 Mipomersen binding to the mRNA sequence encoding apolipoprotein B results in degradation of the apolipoprotein B mRNA by ribonuclease H, an endoribonuclease that specifically hydrolyses the phosphodiester bonds of RNA when hybridised to DNA, thereby inhibiting translation of the apolipoprotein B protein, and effectively reducing concentrations of apolipoprotein B100.
Studies in animals and in healthy volunteers with mild hypercholesterolaemia have shown that mipomersen results in substantial reductions in plasma concentrations of both apolipoprotein B and LDL cholesterol.13, 14 In preclinical studies, mipomersen predominantly distributes to the liver rather than the intestine, leading to functional specificity for apolipoprotein B100 synthesis in the liver rather than apolipoprotein B48 synthesis in the intestine.15 This finding is consistent with previous clinical studies that have not shown evidence of intestinal fat malabsorption.14 In phase 2 studies, mipomersen produced dose-dependent lipid-lowering effects, including reductions in concentrations of apolipoprotein B, LDL cholesterol, non-HDL cholesterol, and triglycerides in patients with varying extents of hyperlipidaemia, including heterozygous and homozygous familial hypercholesterolaemia, on a background of statins and other conventional lipid-lowering drugs.11, 16, 17
This study aimed to assess the efficacy and safety of mipomersen 200 mg per week, when added to existing lipid-lowering treatment in patients with homozygous familial hypercholesterolaemia.
Section snippets
Study design and participants
This randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial was undertaken in nine lipid clinics in seven countries (Brazil, Canada, Singapore, South Africa, Taiwan, the UK, and the USA) between September, 2007, and April, 2009. Participants were patients of either sex aged 12 years and older, with genetic confirmation of homozygous familial hypercholesterolaemia or a clinical diagnosis based on an untreated LDL cholesterol concentration greater than 13 mmol/L
Results
61 patients were screened and 51 were enrolled (34 mipomersen, 17 placebo; figure 1). 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Reasons for withdrawal from the mipomersen group were: injection-site reactions (n=2); rash (n=1); ALT increase (n=1); non-compliance (n=1); and consent withdrawn (n=1). 39 patients joined the open-label extension study, whereas six declined and completed the post-treatment follow-up period. Mean treatment duration was 176 days (SD
Discussion
Findings from this study have shown that weekly treatment with 200 mg mipomersen, an antisense oligonucleotide inhibitor of apolipoprotein B synthesis, effectively lowered LDL cholesterol concentration by a mean of 25% in a large cohort of patients with homozygous familial hypercholesterolaemia who were already receiving lipid-lowering drugs, including high-dose statins. Concomitant significant reductions were also noted in concentrations of apolipoprotein B, non-HDL cholesterol, VLDL
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