Document Detail

Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease.
MedLine Citation:
PMID:  23348766     Owner:  NLM     Status:  MEDLINE    
Cholesteryl ester storage disease (CESD), an inherited deficiency of lysosomal acid lipase (LAL), is an underappreciated cause of progressive liver disease with no approved therapy. Presenting features include dyslipidemia, elevated transaminases, and hepatomegaly. To assess the clinical effects and safety of the recombinant human LAL, sebelipase alfa, nine patients received four once-weekly infusions (0.35, 1, or 3 mg·kg(-1) ) in LAL-CL01, which is the first human study of this investigational agent. Patients completing LAL-CL01 were eligible to enroll in the extension study (LAL-CL04) in which they again received four once-weekly infusions of sebelipase alfa (0.35, 1, or 3 mg·kg(-1) ) before transitioning to long-term every-other-week infusions (1 or 3 mg·kg(-1) ). Sebelipase alfa was well tolerated, with mostly mild adverse events unrelated to sebelipase alfa. No antidrug antibodies were detected. Transaminases decreased in patients in LAL-CL01 and increased between studies. In seven patients receiving ongoing sebelipase alfa treatment in LAL-CL04, the mean ± standard deviation (SD) decreases for alanine transaminase and aspartate aminotransferase at week 12 compared to the baseline values in LAL-CL01 were 46 ± 21 U/L (-52%) and 21 ± 14 U/L (-36%), respectively (P ≤ 0.05). Through week 12 of LAL-CL04, these seven patients also showed mean decreases from baseline in total cholesterol of 44 ± 41 mg/dL (-22%; P = 0.047), low density lipoprotein-cholesterol of 29 ± 31 mg/dL (-27%; P = 0.078), and triglycerides of 50 ± 38 mg/dL (-28%, P = 0.016) and increases in high density lipoprotein-cholesterol of 5 mg/dL (15%; P = 0.016). Conclusion: These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with CESD is well tolerated, rapidly decreases serum transaminases, and that these improvements are sustained with long-term dosing and are accompanied by improvements in serum lipid profile.
Manisha Balwani; Catherine Breen; Gregory M Enns; Patrick B Deegan; Tomas Honzík; Simon Jones; John P Kane; Vera Malinova; Reena Sharma; Eveline O Stock; Vassili Valayannopoulos; J Edmond Wraith; Jennifer Burg; Stephen Eckert; Eugene Schneider; Anthony G Quinn
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Publication Detail:
Type:  Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Multicenter Study; Research Support, N.I.H., Extramural     Date:  2013-03-28
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  58     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-09-02     Completed Date:  2014-02-13     Revised Date:  2014-04-10    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  950-7     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Association for the Study of Liver Diseases.
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MeSH Terms
Alanine Transaminase / metabolism
Aspartate Aminotransferases / metabolism
Cholesterol Ester Storage Disease / blood,  drug therapy*
Cholesterol, HDL / blood
Cholesterol, LDL / blood
Dose-Response Relationship, Drug
Liver / metabolism
Middle Aged
Recombinant Proteins / adverse effects*,  pharmacokinetics,  therapeutic use*
Sterol Esterase / adverse effects*,  pharmacokinetics,  therapeutic use*
Treatment Outcome
Triglycerides / blood
Grant Support
Reg. No./Substance:
0/Cholesterol, HDL; 0/Cholesterol, LDL; 0/Recombinant Proteins; 0/Triglycerides; EC Aminotransferases; EC Transaminase; EC Esterase
Comment In:
Hepatology. 2013 Sep;58(3):850-2   [PMID:  23471861 ]

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