title: Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome.
abstract: BACKGROUND
  Familial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS.
  
  
  METHODS
  Six FCS patients were enrolled in an open-label clinical study. Following a 1-week very low fat diet run-in period patients underwent baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 & 10 mg, respectively). Treatment periods were separated by washout periods of ≥4 weeks. Fasting TG levels were assessed weekly through the treatment periods. Postprandial TGs, ApoB48 and lipoprotein lipid content were also monitored.
  
  
  RESULTS
  Following once daily oral dosing, steady-state exposure was reached by Day 14. There was an approximately dose proportional increase in pradigastat exposure at studied doses. Pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting triglyceride over 21 days of treatment. The reduction in fasting TG was almost entirely accounted for by a reduction in chylomicron TG. Pradigastat treatment also led to substantial reductions in postprandial TG as well as apo48 (both fasting and postprandial). Pradigastat was safe and well tolerated, with only mild, transient gastrointestinal adverse events.
  
  
  CONCLUSIONS
  The novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier NCT01146522 .
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, USA. dan.meyers@novartis.com.
authors.forename: Charles Daniel
authors.initials: CD
authors.lastname: Meyers
authors.affiliation: Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada. karine.tremblay@ecogene21.org.
authors.forename: Karine
authors.initials: K
authors.lastname: Tremblay
authors.affiliation: Novartis Institutes for Biomedical Research, East Hanover, NJ, USA. ahmed.amer@novartis.com.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Amer
authors.affiliation: Novartis Institutes for Biomedical Research, East Hanover, NJ, USA. jin.chen@novartis.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, USA. liewen.jiang@novartis.com.
authors.forename: Liewen
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada. daniel.gaudet@umontreal.ca.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
mesh_terms: D000085:Acetates / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000627:therapeutic use*; D053283:Apolipoprotein B-48 / Q000097:blood*; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D014280:Triglycerides / Q000097:blood*
chemical_list: D000085:Acetates; D000631:Aminopyridines; D053283:Apolipoprotein B-48; D014280:Triglycerides; C000594809:pradigastat; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase