Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency

Abstract

Background & aims: Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase.

Methods: Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals.

Results: 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected.

Conclusions: Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

Keywords: Dyslipidemia; Enzyme replacement; Fatty liver; Hepatomegaly; Lysosomal storage.

Conflict of interest statement

Conflict of interest:

Synageva BioPharma Corp. is the manufacturer of sebelipase alfa and conducted the statistical analysis. All authors had access to the study data, reviewed early and final drafts of the manuscript, and were fully responsible for the content and all editorial decisions related to this manuscript.

Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Figures

Figure 1

Flow chart diagram of the LAL-CL01 and LAL-CL04 study designs

Figure 2

Mean hepatic transaminases (U/L) in LAL-CL04 study (n=8) ALT alanine transaminase; AST aspartate aminotransferase Note: all one-week-post-infusion laboratory data are presented one week after the Week 24 visit.

Figure 3

Mean percent change from LAL-CL01 baseline for serum lipids in LAL-CL04 study (n=8) HDL High-density lipoprotein-cholesterol; LDL Low density lipoprotein-cholesterol; Trig Triglycerides Note: all one-week-post-infusion laboratory data are presented one week after the Week 24 visit.

Figure 4

Absolute LDL values over time (n=8)

Figure 5

Change in liver volume and hepatic PDFF in LAL-CL04