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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. CONCLUSION:The novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease. TRIAL REGISTRATION:ClinicalTrials.gov identifier NCT01146522 .

SUBMITTER: Meyers CD

PROVIDER: S-EPMC4337059 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome.

Meyers Charles Daniel CD Tremblay Karine K Amer Ahmed A Chen Jin J Jiang Liewen L Gaudet Daniel D

Lipids in health and disease 20150218

<h4>Background</h4>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 wit ...[more]

PMID: 25889044

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Project description:BACKGROUND:Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by persistent extreme hypertriglyceridemia as a result of lipoprotein lipase deficiency. Canada is an important region for FCS research due to the high prevalence rates. The burden of illness and quality of life of Canadian patients, however, have been inadequately addressed in the literature. OBJECTIVE:To understand the burden of illness of FCS on Canadian patients' lives. METHODS:IN-FOCUS is a global web-based survey open to patients with FCS, including patients in Canada. This survey captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions. RESULTS:A total of 37 Canadian patients completed the IN-FOCUS survey. Patients saw a mean of 4 physicians before their FCS diagnosis despite 89% reporting an FCS family history. Patients experience multiple physical, emotional, and cognitive symptoms in addition to FCS-related comorbidities. Notably, 35% of those who answered the survey have experienced acute pancreatitis, averaging 14 lifetime episodes per patient. In the preceding 12?months, 46% of patients had an FCS-related hospitalization, averaging 3 nights' stay. All respondents restricted fat intake, with 27% following an extremely low-fat diet. Despite this, 100% of patients reported fasting TG levels above the normal range. FCS impacted career choice in nearly all patients (97%) and employment status in all patients who were employed part time, disabled, or homemakers, causing many (>?75%) to choose careers below their level of abilities. Furthermore, 2/3 of patients reported FCS had a significant impact on their decision regarding whether to have children. Most report significant interference with their emotional/mental well-being, social relationships, and the majority were concerned about the long-term impact of FCS on their health (89%). CONCLUSIONS:This study provides the first and largest study to investigate the multi-faceted psychosocial and cognitive impacts of FCS on patients. Canadian patients with FCS experience significant multi-faceted burdens that diminish their quality of life, employment opportunities, social relationships, and mental/emotional well-being. These results highlight the need for greater disease awareness, improved clinical diagnosis, broader clinical management for heterogenous symptoms, and more effective treatment options for FCS.

Dataset Information

Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome.

Publications

Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome.

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