bms201038 and Hypertriglyceridemia

Severe genetic forms of hypertriglyceridemia carry a risk of life-threatening pancreatitis and lack available effective treatments. Lomitapide is a microsomal triglyceride transfer protein inhibitor currently approved for treatment of homozygous familial hypercholesterolemia that may be useful in the management of severe hypertriglyceridemia. Areas covered: Published trials of lomitapide that reported plasma triglyceride response were reviewed, as was a case report of a patient with hypertriglyceridemia who was treated for 13 years with lomitapide. ClinicalTrials.gov was also reviewed for any unpublished results and ongoing trials. Expert opinion: Lomitapide demonstrates effective triglyceride lowering and may be a useful treatment for patients with genetic hypertriglyceridemia and recurrent acute pancreatitis who are refractory to traditional treatment. However, long term hepatic safety may be a concern and direct clinical trial-level data are lacking for this indication.

Topics: Animals; Anticholesteremic Agents; Benzimidazoles; Female; Humans; Hypertriglyceridemia; Pancreatitis; Treatment Outcome

Aegerion Pharmaceuticals is developing lomitapide, a small-molecule, microsomal triglyceride transfer protein (MTP) inhibitor, for the treatment of both familial and primary hypercholesterolemia. Oral, once-daily lomitapide will be targeted at patients resistant to HMG-CoA reductase inhibitors (statins) either due to abnormalities in liver function or to discontinuation because of muscle pain. An oral formulation of lomitapide is in phase III development for homozygous familial hypercholesterolemia (hyperlipoproteinemia type IIa) in the US, Canada, Italy, and South Africa. This review discusses the key development milestones and therapeutic trials of this drug.

Topics: Animals; Anticholesteremic Agents; Benzimidazoles; Carrier Proteins; Drugs, Investigational; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type I; Hyperlipoproteinemia Type II; Hypertriglyceridemia; Hypolipidemic Agents

Several new or emerging drugs for dyslipidemia owe their existence, in part, to human genetic evidence, such as observations in families with rare genetic disorders or in Mendelian randomization studies. Much effort has been directed to agents that reduce LDL (low-density lipoprotein) cholesterol, triglyceride, and Lp[a] (lipoprotein[a]), with some sustained programs on agents to raise HDL (high-density lipoprotein) cholesterol. Lomitapide, mipomersen, AAV8.TBG.hLDLR, inclisiran, bempedoic acid, and gemcabene primarily target LDL cholesterol. Alipogene tiparvovec, pradigastat, and volanesorsen primarily target elevated triglycerides, whereas evinacumab and IONIS-ANGPTL3-L

Topics: Antibodies, Monoclonal; Anticholesteremic Agents; Benzimidazoles; Caproates; Cholesterol, HDL; Cholesterol, LDL; Diacylglycerol O-Acyltransferase; Dicarboxylic Acids; Dyslipidemias; Ezetimibe; Fatty Acids; Genetic Therapy; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Lipoprotein(a); Oligonucleotides; RNA, Small Interfering

Recurrent pancreatitis is a potentially fatal complication of severe hypertriglyceridemia. Genetic defects and lifestyle risk factors may render this condition unresponsive to current treatments.. We report this first case of long-term management of intractable near-fatal recurrent pancreatitis secondary to severe hypertriglyceridemia by a novel use of lomitapide, an inhibitor of microsomal triglyceride transfer protein, recently approved for treatment of familial homozygous hypercholesterolemia. The patient had been hospitalized many times for pancreatitis since age 15 years. Her serum triglyceride level averaged 3900 mg/dL while she received therapy with approved lipid drugs. She is homozygous for a coding mutation (P234L) in lipoprotein lipase, leaving her unable to metabolize triglycerides in chylomicrons and very low density lipoproteins (VLDL). Lomitapide reduces the secretion of chylomicrons and VLDL. Lomitapide, which was started when she was 44 years old after near-fatal pancreatitis, lowered her fasting triglyceride level from greater than 3000 mg/dL to a mean (SD) of 903 (870) mg/dL while she received 30 mg/d and to 524 (265) mg/dL while she received 40 mg/d; eliminated chronic abdominal pain; and prevented pancreatitis. However, fatty liver, present before treatment, progressed to steatohepatitis and fibrosis after 12 to 13 years.. Lomitapide prevented pancreatitis in severe intractable hypertriglyceridemia but at a potential long-term cost of hepatotoxicity.

Topics: Adult; Anticholesteremic Agents; Benzimidazoles; Female; Humans; Hypertriglyceridemia; Pancreatitis, Chronic; Pregnancy; Recurrence; Treatment Outcome