Efficacy and Safety of a Microsomal Triglyceride Transfer Protein Inhibitor in Homozygous Familial Hypercholesterolemia

By M. Cuchel, E. Meagher, Hendrik Du Toit Theron, D. Blom, A. Marais, R. Hegele, Maurizio Averna, C. Sirtori, Prediman K. Shah, D. Gaudet and 7 more. The Lancet, 2012

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Background Patients with homozygous familial hypercholesterolemia (HoFH) respond inadequately to existing drugs. We conducted a phase 3 study to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with HoFH. Methods Twenty-nine subjects enrolled into a single-arm, open-label study and maintained current lipid lowering therapy from six weeks before baseline through at least week 26. Lomitapide dose was escalated based on safety and tolerability from 5 mg to a maximum of 60 mg/day. The primary endpoint was mean percent change from baseline in LDL-C at week 26, after which patients remained on lomitapide through week 78 for safety assessment. Findings Twenty-three subjects completed weeks 26 and 78. The median dose of lomitapide was 40 mg/day. LDL-C was reduced by 50% from baseline at week 26 (4·3 ± 2·5 mmol/L vs. 8·7 ± 2·9 mmol/L, p<0.0001). Eight subjects achieved LDL-C <2·6 mmol/L at this time point. LDL-C was reduced by 44% at week 56 and 38% at week 78 (p<0.0001 for both). Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase > 5× ULN that resolved after dose reduction or temporary interruption of lomitapide. No subject permanently discontinued treatment due to liver abnormalities. Liver fat content assessed by nuclear magnetic resonance spectroscopy (NMRS; n=20) was 1·0 ± 1·3 % at baseline, 8·6 ± 8·1% at week 26 and remained stable up to week 78 (8·3± 5·3%). Interpretation These data demonstrate that lomitapide had a robust and durable efficacy in lowering LDL-C in patients with HoFH with an acceptable safety and tolerability profile.

Subfields: Endocrinology, Diabetes and Metabolism, Surgery

View Paper: https://www.semanticscholar.org/paper/be4c33fb7141e386bda9c284279062c35f74b06e

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