Elsevier

The Lancet

Volume 375, Issue 9719, 20–26 March 2010, Pages 998-1006
The Lancet

Fast track — Articles
Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(10)60284-XGet rights and content

Summary

Background

Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease.

Methods

This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confirmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight (<50 kg vs ≥50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00607373.

Findings

34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11·4 mmol/L (SD 3·6) in the mipomersen group and 10·4 mmol/L (3·7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (−24·7%, 95% CI −31·6 to −17·7) than with placebo (−3·3%, −12·1 to 5·5; p=0·0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal.

Interpretation

Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins.

Funding

ISIS Pharmaceuticals and Genzyme Corporation.

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

References (31)

  • C Gagne et al.

    Efficacy and safety of ezetimibe co administered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia

    Circulation

    (2002)
  • BS Sachais et al.

    Long-term effects of LDL apheresis in patients with severe hypercholesterolemia

    J Clin Apher

    (2005)
  • MH Moghadasian et al.

    Surgical management of dyslipidemia: clinical and experimental evidence

    J Invest Surg

    (2001)
  • M Cuchel et al.

    Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia

    N Engl J Med

    (2007)
  • FF Samaha et al.

    Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia

    Nat Clin Pract Cardiovasc Med

    (2008)
  • Cited by (796)

    • Advances in familial hypercholesterolemia

      2024, Advances in Clinical Chemistry
    • Recent applications of RNA therapeutic in clinics

      2024, Progress in Molecular Biology and Translational Science
    View all citing articles on Scopus
    View full text