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 .

Figures

Figure 1

Fasting triglyceride levels during the treatment with pradigastat at different doses. Footnote: Data presented as geometric mean ± standard error of mean (SEM).

Figure 2

Postprandial plasma triglyceride levels during the treatment with pradigastat at different doses. Footnote: Data presented as geometric mean ± standard error of mean (SEM). Percentage change compared with the 10 mg dose for postprandial TG AUC0–9 are shown by ‘↓’. TG, triglycerides; AUC0–9, area under curve over 0 to 9 hours of meal tolerance test. Panel A = TG concentration/time profile over 9 hours, Panel B = TG AUC0-9.

Figure 3

Dose comparison of fasting and postprandial apolipoprotein B48 levels. Footnote: Original ApoB48 values were expressed in ng/L for fasting and postprandial peak, and h*ng/mL for postprandial AUC0–9. This figure shows the Geometric least squares mean ratio of the end of treatment for each of the three dose levels to baseline. Percentage change compared with the 10 mg dose are shown by ‘↓’; * p < 0.05.

Figure 4

Pradigastat plasma concentration-time profile. Footnote: Data presented as mean ± standard deviation.

Figure 5

Study design.