Lomitapide Effectively Reduces Triglyceride (TG) Levels in Familial Chylomicronemia Syndrome (FCS)

Lead Author's Financial Disclosures A.C. has received consulting fees from Amryt. Study Funding Amryt Pharma. Background/Synopsis FCS is a rare autosomal recessive disorder caused by impaired lipoprotein lipase (LPL) function, resulting in elevated TG levels, intense abdominal pain, hepatosplenomegaly, and recurrent episodes of acute pancreatitis. Treatment requires a strict, extremely low-fat diet (<10% fat/day) to control TG levels <750-1000mg/dL, which does not fully control the disease. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that prevents assembly of triglycerides (TGs) into chylomicrons, in addition to very low-density lipoproteins and thereby reduces circulating levels of TGs. Objective/Purpose The LOCHNES study was designed to evaluate the efficacy and safety of lomitapide in FCS. Methods This open-label, single arm LOCHNES study of lomitapide in FCS, enrolled adult patients ≥18 years with genetically confirmed FCS, elevated fasting TG≥750mg/dL and a history of pancreatitis, across 3 Italian centres. Patients were administered escalating-doses of lomitapide to maximum tolerated dose (MTD) for 26 weeks. The primary endpoint was the percent change in TGs from baseline to week 26, with lomitapide in combination with other lipid lowering therapy. Results Eighteen patients were enrolled in the study (mean+/-SD: age 46.6+/-16.7y; body mass index 23.7+/-4.1kg/m2). Median baseline TG levels were 1804mg/dL (range 810-4151mg/dL). Lomitapide increased from standard starting dose 5mg/day at baseline to mean 32.8+/-17.8mg/day at week 26. Median TGs reduced to 305mg/dL (range 70-1818mg/dL) at week 26. This equates to a 70.5% reduction in median fasting triglyceride levels. At week 26, 13 patients achieved TGs ≤750mg/dL. Treatment with lomitapide was generally well tolerated with no patient discontinuations. Adverse events were mild to moderate and were mainly related to gastrointestinal tolerability (n=9) and ALT/AST enzyme elevations ≥3x upper limit of normal (n=4). Where available (n=13), liver MRI imaging revealed increases in hepatic fat in some patients (n=5/13), and three patients with a baseline hepatic fat >20% (range 22-30%), experienced increases to 30-50% hepatic fat at 26 weeks. No patient experienced an episode of acute pancreatitis or severe abdominal pain during lomitapide treatment. One patient who temporarily interrupted lomitapide treatment due to an episode of diarrhoea, experienced acute pancreatitis during the treatment interruption period. Conclusions Lomitapide is effective in reducing triglycerides in FCS and preventing the recurrence of acute pancreatitis in this pilot study. The extent of the benefit of lomitapide to patients with FCS should be further evaluated in a larger prospective clinical trial. A.C. has received consulting fees from Amryt. Amryt Pharma.