Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease.
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).


CONCLUSIONS
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.
Department of Genetics and Genomic Sciences, The Mount Sinai School of Medicine, New York, NY, USA.
Manisha
M
Balwani
Catherine
C
Breen
Gregory M
GM
Enns
Patrick B
PB
Deegan
Tomas
T
Honzík
Simon
S
Jones
John P
JP
Kane
Vera
V
Malinova
Reena
R
Sharma
Eveline O
EO
Stock
Vassili
V
Valayannopoulos
J Edmond
JE
Wraith
Jennifer
J
Burg
Stephen
S
Eckert
Eugene
E
Schneider
Anthony G
AG
Quinn
D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015217:Cholesterol Ester Storage Disease / Q000097:blood / Q000188:drug therapy*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002787:Sterol Esterase / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D011994:Recombinant Proteins; D014280:Triglycerides; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002787:Sterol Esterase