safety, tolerability and pharmacokinetics of sbc-102 (sebelipase alfa) in adult participants with lysosomal acid lipase deficiency

Conditions: Cholesterol Ester Storage Disease(CESD); Lysosomal Acid Lipase Deficiency; LAL-Deficiency

Summary: this was the first clinical study of sbc-102 (sebelipase alfa) for the treatment of lysosomal acid lipase (lal) deficiency. it was an open-label dose escalation study in adult participants with liver dysfunction due to lal deficiency and was designed to examine 3 doses of sebelipase alfa. the targeted number for this study was 9 evaluable participants.

the study was composed of a screening period, a treatment period, and a post-treatment follow-up period (including an end of study visit). participants who successfully completed screening assessments to determine study eligibility were allocated to 3 sequential cohorts (0.35, 1, or 3 milligrams/kilogram \[mg/kg\]). within each cohort, one participant was initially dosed and, if sebelipase alfa was deemed safe and well tolerated in this participant (based on at least 24 hours of monitoring), dosing was allowed to be initiated for the remaining participants in the cohort. initiation of dosing in the next cohort occurred only after all participants in the preceding cohort had been monitored for at least 5 days after the second infusion, without any evidence of significant safety signals, and an independent safety committee had reviewed the cumulative safety data and provided their recommendation on the acceptability of beginning dosing in the next cohort. cholesteryl ester storage disease (cesd) is the late onset phenotype for lal deficiency, a lysosomal storage disorder, which also has an early onset phenotype known as wolman disease that primarily affects infants. cesd can present in childhood but often goes unrecognized until adulthood when the underlying pathology is advanced. many of the signs and symptoms are common to participants with other liver conditions. cesd is an autosomal recessive genetic condition and is characterized by hepatomegaly, persistently abnormal liver function tests and type ii hyperlipidemia. splenomegaly and evidence of mild hypersplenism may affect some participants. untreated, cesd may lead to fibrosis, cirrhosis, liver failure and death.

Eligibility criteria:
inclusion criteria: * male or female participants ≥ 18 and ≤ 65 years of age * documented decreased lal activity * evidence of liver involvement exclusion criteria: * clinically significant concurrent disease, serious inter-current illness, concomitant medications or other extenuating circumstances * clinically significant abnormal values on laboratory screening tests, other than liver function or lipid panel tests * aspartate aminotransferase and/or alanine aminotransferase persistently elevated \> 3x upper limit of normal at screening * previous hemopoietic bone marrow or liver transplant * current history of alcohol abuse

Keywords: enzyme replacement therapy (ert) lysosomal storage disease late onset lysosomal acid lipase (lal) deficiency acid cholesteryl ester hydrolase deficiency, type 2 acid lipase disease cholesterol ester hydrolase deficiency lal deficiency lipa deficiency wolman disease