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 (1 mg/kg or 3 mg/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).
Bibliographical noteFunding Information:
This study was supported by Synageva BioPharma Corp. A portion of this work was also supported in part by grant UL1TR000067 from the National Center for Advancing Translational Sciences , National Institutes of Health to the Mount Sinai School of Medicine and by research project PRVOUK-P24/LF1/3 to TH. The NIHR supports the Leeds Clinical Research Facility.
© 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Copyright 2017 Elsevier B.V., All rights reserved.
- Enzyme replacement
- Fatty liver
- Lysosomal storage