Journal Article

Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study

Blom, Dirk J, Propert, Kathleen J, Sasiela, William J, Stefanutti, Claudia, Rader, Daniel J, Meagher, Emma A, Averna, Maurizio R, Gaudet, Daniel, Du Plessis, Anna ME, Shah, Prediman K, Bloedon, LeAnne T, Marais, A David, Sirtori, Cesare R, Vigna, Giovanni B, Hegele, Robert A, du Toit Theron, Hendrik, Cuchel, Marina

2013

Overview

Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease. We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI −57 to −31; p<0·0001) at week 56 and 38% (–52 to −24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.

• Publisher: Elsevier Ltd,Elsevier,Elsevier Limited
• Subject: adults / Benzimidazoles - adverse effects / Benzimidazoles - therapeutic use / Biological and medical sciences / Canada / Cardiovascular disease / Carrier Proteins - antagonists & inhibitors / Cholesterol / Cholesterol, LDL - blood / Disorders of blood lipids. Hyperlipoproteinemia / Drug therapy / drugs / Female / gastrointestinal system / General aspects / homozygosity / Homozygote / Humans / hypercholesterolemia / Hyperlipoproteinemia Type II - blood / Hyperlipoproteinemia Type II - drug therapy / Hyperlipoproteinemia Type II - genetics / Internal Medicine / Italy / linear models / liver / low density lipoprotein cholesterol / Male / Medical sciences / men / Metabolic diseases / Mutation / patients / product development / Proteins / Safety / safety assessment / South Africa / therapeutics / triacylglycerols / United States / women