title: Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency.
abstract: OBJECTIVE
  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).
authors.affiliation: Ref Centre IEM, Necker-Enf Malades Hosp, IMAGINE Institute and Paris Descartes University, Paris, France.
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.affiliation: Department of Pediatrics, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
authors.forename: Vera
authors.initials: V
authors.lastname: Malinova
authors.affiliation: Department of Pediatrics, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Honzík
authors.affiliation: Department of Genetics and Genomic Sciences, The Mount Sinai School of Medicine, New York, NY, United States.
authors.forename: Manisha
authors.initials: M
authors.lastname: Balwani
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Breen
authors.affiliation: Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Deegan
authors.affiliation: Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, United States.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Enns
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Divisions of Endocrinology & Metabolism, University of California, San Francisco, CA, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
authors.affiliation: Divisions of Cardiology, University of California, San Francisco, CA, United States.
authors.forename: Eveline O
authors.initials: EO
authors.lastname: Stock
authors.affiliation: Synageva BioPharma Corp., Lexington, MA, United States.
authors.forename: Radhika
authors.initials: R
authors.lastname: Tripuraneni
authors.affiliation: Synageva BioPharma Corp., Lexington, MA, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Eckert
authors.affiliation: Synageva BioPharma Corp., Lexington, MA, United States.
authors.forename: Eugene
authors.initials: E
authors.lastname: Schneider
authors.affiliation: University of California, San Diego, CA, United States.
authors.forename: Gavin
authors.initials: G
authors.lastname: Hamilton
authors.affiliation: University of California, San Diego, CA, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Middleton
authors.affiliation: University of California, San Diego, CA, United States.
authors.forename: Claude
authors.initials: C
authors.lastname: Sirlin
authors.affiliation: Eureka Internal Medicine, Eureka, CA, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Kessler
authors.affiliation: Health Sciences North, Sudbury, Ontario, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bourdon
authors.affiliation: University of California, Davis Medical Center, Department of Pediatrics, Section of Genetics, Davis, CA, United States.
authors.forename: Simeon A
authors.initials: SA
authors.lastname: Boyadjiev
authors.affiliation: Salford Royal NHS Foundation Trust, Salford, UK.
authors.forename: Reena
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Leeds Institute of Cancer and Pathology, Leeds, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Twelves
authors.affiliation: University of Minnesota, Minneapolis, MN, United States.
authors.forename: Chester B
authors.initials: CB
authors.lastname: Whitley
authors.affiliation: Synageva BioPharma Corp., Lexington, MA, United States. Electronic address: Anthony.Quinn@synageva.com.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Quinn
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood; D008099:Liver / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D002787:Sterol Esterase / Q000008:administration & dosage* / Q000009:adverse effects / Q000172:deficiency; D015223:Wolman Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D055815:Young Adult
chemical_list: D008055:Lipids; D011994:Recombinant Proteins; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C503451:LIPA protein, human; D002787:Sterol Esterase
keywords: Dyslipidemia; Enzyme replacement; Fatty liver; Hepatomegaly; Lysosomal storage