Lorraine L. Janeczko, MPH
Pradigastat may offer several benefits to patients with familial chylomicronemia syndrome (FCS). In patients with FCS, pradigastat appears to help reduce fasting plasma triglygerides (TGs), reduce pancreatitis risk, decrease total bile acid, and be safe and well tolerated, although precautions may be necessary to prevent problems such as diarrhea, according to results of 1 study presented in 3 posters at the National Lipid Association Scientific Sessions, June 11-14, 2015, in Chicago, Illinois.1-3
FCS, also called familial lipoprotein lipase (LDL) deficiency, or hyperlipoproteinemia type 1, is a rare genetic disorder involving the accumulation of chylomicrons in plasma and extreme hypertriglyceridemia, usually due to the loss of activity of LPL, the enzyme necessary for metabolizing of triglyceride (TG)-rich lipoproteins.4
FCS is associated with a greater than 300-fold increased risk of developing acute pancreatitis compared with normal controls. This can be severe and life-threatening, and is one of the disorder’s most serious complications. Reducing plasma TG levels is thought to be a way to decrease the risk of pancreatitis in FCS.
In the United States at this time, patients with FCS have no medication that can effectively improve their fasting plasma TG.
Pradigastat is a potent selective inhibitor of the enzyme diacylglycerol acyltransferase-1 (DGAT1), which catalyzes the final step in TG synthesis.
Co-investigator Dr. Deborah Keefe, MD, MPH, of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, and her colleagues studied 45 patients with FCS in 13 centers in 8 countries over 52 weeks. Participants were assigned to 20 mg or 40 mg of pradigastat or placebo while consuming a low-fat diet.
In an interview with Rare Disease Report
, Dr. Keefe said:
“This is a disease with recurrent pancreatitis that has very severe effects on people’s lives. It is also very difficult for people with this disorder to live in our society. Fat is a very important part of our diet, is found in all prepared foods, and we cook with fat. This causes a huge problem for patients, their families and friends, because limiting their dietary fat intake to only 10% to 15% is
difficult. Yet, it is currently the only treatment we have for this disease in the US.”
“As the usual treatment for this disease is a low-fat diet, the loss of effect in our study may have been due to the fact that patients tended to eat more fat after they had been in the study for a while.”
“This study in 8 countries over 52 weeks was large. Given the rarity of the disease – with an incidence of only about 1 in one million – finding 45 patients was difficult.”
“The findings were as we expected. Pradigastat did lower triglycerides in this population, which was particularly pronounced for the first 16 weeks of therapy. In the high-dose group, we also saw a decreased incidence of pancreatitis.”
“The drug was generally found to be reasonably well tolerated, although there was an incidence of diarrhea associated with higher fat intake. In general, the drug had favorable effects on lipids, and in particular, lower triglycerides, which seemed to alleviate the pancreatitis.”
In the study patients with FCS, 40 mg of the drug was shown to be superior to placebo in reducing fasting plasma TG at 12 weeks; however, this effect diminished after 16 weeks and was no longer significant from weeks 20 through 52. Pradigastat 40 mg was associated with a significant reduction in non–high-density lipoprotein (HDL) cholesterol only to week 16. In the pradigastat 40-mg group, no confirmed pancreatitis events were seen over 52 weeks.
Pradigastat was generally safe and well tolerated at 20 mg and 40 mg, but gastrointestinal complaints, especially diarrhea, were common.
Despite changes in TG and other lipid profiles and an increase in fat intake from baseline, the fecal total bile acid, deoxycholic acid (DCA
), and lithocholic acid (LCA
) concentrations and content did not increase after 52 weeks of treatment with either dosage of the drug. Pradigastat treatment was also associated with a decrease in total bile acid, DCA, and LCA, compared with placebo.
Dr. Keefe added:
“We did have a long-term follow-up study for these patients that that we will be closing out soon, but otherwise there are no further studies planned
1. Gaudet D, Bernelot-Moens S, Zhou Y, et al. Pradigastat, a diacylglycerol acyltransferase 1 inhibitor, reduces fasting triglyceride levels in familial chylomicronemia. Presented at: the National Lipid Association Scientific Sessions; June 11-14, 2015; Chicago, IL. Abstract 152.
2. Stroes ESG, Keefe D, Bernelot-Moens S, et al. The diacylglycerol acyltransferase 1 inhibitor, pradigastat, was well tolerated in a 52-week clinical trial in FCS patients. Presented at: the National Lipid Association Scientific Sessions; June 11-14, 2015; Chicago, IL. Abstract 153.
3. Zhou Y, Gaudet D, Stroes ESG, et al. Pradigastat did not increase fecal bile acids in patients with familial chylomicronemia syndrome after 52 weeks. Presented at: the National Lipid Association Scientific Sessions; June 11-14, 2015; Chicago, IL. Abstract 160.
4. A Genetic Disorder Causing Build Up Of Triglycerides And Chylomicrons. http://fcs.raredr.com/. Accessed June 13, 2015.