TY - JOUR
T1 - Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency
AU - Valayannopoulos, Vassili
AU - Malinova, Vera
AU - Honzík, Tomas
AU - Balwani, Manisha
AU - Breen, Catherine
AU - Deegan, Patrick B.
AU - Enns, Gregory M.
AU - Jones, Simon A.
AU - Kane, John P.
AU - Stock, Eveline O.
AU - Tripuraneni, Radhika
AU - Eckert, Stephen
AU - Schneider, Eugene
AU - Hamilton, Gavin
AU - Middleton, Michael S.
AU - Sirlin, Claude
AU - Kessler, Bruce
AU - Bourdon, Christopher
AU - Boyadjiev, Simeon A.
AU - Sharma, Reena
AU - Twelves, Chris
AU - Whitley, Chester B.
AU - Quinn, Anthony G.
N1 - Publisher Copyright:
© 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2014
Y1 - 2014
N2 - 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).
AB - 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).
KW - Dyslipidemia
KW - Enzyme replacement
KW - Fatty liver
KW - Hepatomegaly
KW - Lysosomal storage
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U2 - 10.1016/j.jhep.2014.06.022
DO - 10.1016/j.jhep.2014.06.022
M3 - Article
C2 - 24993530
AN - SCOPUS:84921498525
SN - 0168-8278
VL - 61
SP - 1135
EP - 1142
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 5
ER -