Homozygous familial hypercholesterolaemia (HoFH) is a genetic disease characterised by high plasma levels of low-density lipoprotein (LDL) and total cholesterol. It is caused by a loss-of-function mutation on both alleles of the LDL receptor, resulting in inhibition of LDL uptake from the circulation. Statins are an insufficiently effective therapy for HoFH; the LDL receptor up-regulation that statins effect is insufficient to compensate for the abnormal LDL receptor's reduced activity.
Lomitapide lowers cholesterol by interfering in the production of very-low-density lipoprotein (VLDL) in the liver. Specifically, lomitapide inhibits microsomal triglyceride transfer protein (MTP), which is involved in the loading of triglyceride onto apolipoprotein B100 during VLDL assembly in the liver. Since VLDL is converted to LDL in the circulation, the reduced output of VLDL results in a concomitant decrease in plasma LDL levels. VLDL-mediated triglyceride secretion is also reduced.
Ninety percent of patients treated with lomitapide experiencegastrointestinal side-effects, including diarrhoea, nausea, dyspepsia, vomiting, pain, discomfort, bloating of the abdomen, constipation, and flatulence. Elevated liver aminotransferase levels are also common and require regular monitoring of hepatic function. Side-effects are reduced in patients following a low-fat diet. Inhibition of VLDL-mediated triglyceride secretion can lead to accumulation of triglycerides in the liver.