Long-Term Efficacy and Safety of the Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide in Patients With Homozygous Familial Hypercholesterolemia

omozygous familial hypercholesterolemia is a genetic disorder characterized by low-density lipoprotein (LDL)-receptor dysfunction, markedly elevated levels of LDL-cholesterol (LDL-C) and premature atherosclerosis.Patients are often poorly responsive to conventional lipid-lowering therapies that upregulate LDL-receptor expression. 1 Lomitapide inhibits microsomal triglyceride transfer protein, which lipidates nascent apolipoprotein (apo)B-containing lipoproteins.In a pivotal 78-week openlabel trial, lomitapide, titrated to the maximal tolerable dose, decreased LDL-C by 50% at the end of the efficacy phase (week 26) in patients with homozygous familial hypercholesterolemia. 2 The principal adverse events included gastrointestinal disturbances, hepatic enzyme elevations, and increased liver fat.Here we provide additional long-term efficacy and safety data, including an exploratory analysis of the potential metabolic consequences of hepatic fat accumulation from an extension trial (NCT00943306).Patients continued on lomitapide at the maximally tolerated dose until transition to commercial or compassionate lomitapide.Lipid-lowering therapies, including apheresis, could be modified at the investigator's discretion if LDL-C was <100 mg/dL.Both studies received institutional review board and regulatory approval, and all participants provided informed consent.Significance of the percent changes from baseline was assessed using a mixed linear model; correlations were assessed with Pearson correlation.Nineteen (mean age, 30.4 years; 10 male/9 female) of the 23 patients who completed the pivotal trial enrolled in the extension trial, and 17 completed week 126 (78 weeks pivotal + 48 weeks extension) assessments (primary efficacy end point).Three patients discontinued prematurely (relocation, elevated transaminases and excess alcohol, sudden cardiac death).The median lomitapide dose remained mostly consistent at 40 mg (range, 20-60 mg) from week 36 in the pivotal study to week 282 in the extension trial.Overall, the median treatment duration with lomitapide across both trials was 5.1 years (range, 2.1-5.7 years).Among the 17 patients who completed week 126, LDL-C decreased from 356±127 mg/dL at baseline to 189±120 mg/dL at week 126, a mean percent change of -45.5% (95% confidence interval [CI], -61.6 to -29.4; P<0.001).LDL-C reduction was maintained for the duration of the extension trial (P<0.001; Figure , A).From baseline through week 246, a total of 14 (74%) patients achieved LDL-C <100 mg/dL, and 11 (58%) patients achieved LDL-C <70 mg/dL on at least 1 occasion.LDL-C reduction was independent of residual LDL-receptor functionality.The most common adverse events reported were gastrointestinal, including diarrhea, nausea, dyspepsia, and vomiting.For most drug-related adverse events, the incidence was lower in the extension trial compared with the pivotal trial (42.1% versus 84.2%).Major adverse cardiovascular events occurred in 2 patients (sudden cardiac death and coronary artery bypass graft).

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