Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia : a single-arm, open-label, phase 3 study
Cuchel, Marina; Meagher, Emma A.; Theron, Hendrik Du Toit; Blom, Dirk J.; Marais, A. David; Hegele, Robert A.; Averna, Maurizio R.; Sirtori, Cesare R.; Shah, Prediman K.; Gaudet, Daniel; Stefanutti, Claudia; Vigna, Giovanni B.; Du Plessis, Anna M.E.; Propert, Kathleen J.; Sasiela, William J.; Bloeden, LeAnne T.; Rader, Daniel J.
BACKGROUND Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We
aimed to assess the effi cacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults
with this disease.
METHODS 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.
FINDINGS 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
effi cacy 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 fi ve 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.
Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of
homozygous familial hypercholesterolaemia.