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

• Published in: The Lancet (British edition) Vol. 375; no. 9719; pp. 998 - 1006
• Main Authors: Raal, Frederick J, Prof, Santos, Raul D, MD, Blom, Dirk J, MD, Marais, A David, Prof, Charng, Min-Ji, MD, Cromwell, William C, MD, Lachmann, Robin H, MRCP, Gaudet, Daniel, MD, Tan, Ju L, MB BS, Chasan-Taber, Scott, PhD, Tribble, Diane L, PhD, Flaim, JoAnn D, PhD, Crooke, Stanley T, MD
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 20-03-2010; Elsevier; Elsevier Limited
• Subjects: Adult; Alanine Transaminase - metabolism; Anticholesteremic Agents - adverse effects; Anticholesteremic Agents - therapeutic use; Apolipoprotein B-100 - antagonists & inhibitors; Apolipoprotein B-100 - biosynthesis; Biological and medical sciences; Cardiovascular disease; Cholesterol; Cholesterol, LDL - blood; Clinical medicine; Conferences; Corporate sponsorship; Disorders of blood lipids. Hyperlipoproteinemia; Double-Blind Method; Drugs; Female; Gene loci; General aspects; Heart failure; Homozygote; Humans; Hyperlipoproteinemia Type II - blood; Hyperlipoproteinemia Type II - drug therapy; Hyperlipoproteinemia Type II - genetics; Hyperlipoproteinemia Type II - metabolism; Hypothyroidism; Internal Medicine; Lipids - analysis; Liver - metabolism; Male; Medical sciences; Metabolic diseases; Oligonucleotides - adverse effects; Oligonucleotides - therapeutic use; Oligonucleotides, Antisense - adverse effects; Oligonucleotides, Antisense - therapeutic use; Pharmaceuticals; Statins; Stock options; Studies; Travel & entertainment expenses; Human; Metabolic diseases; Cholesterol LDL; Lipids; Patient; Hyperlipoproteinemia; Concentration; Lipoprotein; Homozygosity; Randomized controlled trial; Genetic disease; Apolipoprotein B; Medicine; Hypercholesterolemia; Synthesis; Double blind study; Clinical trial; Inhibitor; Dyslipemia
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(10)60284-X

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.