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J Hepatol. 2014 Nov;61(5):1135-42. doi: 10.1016/j.jhep.2014.06.022. Epub 2014 Jun 30.

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

Author information

1
Ref Centre IEM, Necker-Enf Malades Hosp, IMAGINE Institute and Paris Descartes University, Paris, France.
2
Department of Pediatrics, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
3
Department of Genetics and Genomic Sciences, The Mount Sinai School of Medicine, New York, NY, United States.
4
Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.
5
Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
6
Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, United States.
7
Divisions of Endocrinology & Metabolism, University of California, San Francisco, CA, United States.
8
Divisions of Cardiology, University of California, San Francisco, CA, United States.
9
Synageva BioPharma Corp., Lexington, MA, United States.
10
University of California, San Diego, CA, United States.
11
Eureka Internal Medicine, Eureka, CA, United States.
12
Health Sciences North, Sudbury, Ontario, Canada.
13
University of California, Davis Medical Center, Department of Pediatrics, Section of Genetics, Davis, CA, United States.
14
Salford Royal NHS Foundation Trust, Salford, UK.
15
Leeds Institute of Cancer and Pathology, Leeds, UK.
16
University of Minnesota, Minneapolis, MN, United States.
17
Synageva BioPharma Corp., Lexington, MA, United States. Electronic address: Anthony.Quinn@synageva.com.

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

PMID:
24993530
PMCID:
PMC4203712
DOI:
10.1016/j.jhep.2014.06.022
[Indexed for MEDLINE]
Free PMC Article

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