A Multicenter Study of SBC-102 (Sebelipase Alfa) in Patients With Lysosomal Acid Lipase Deficiency/ ARISE (Acid Lipase Replacement Investigating Safety and Efficacy)

• Proportion of subjects who achieve ALT normalization (i.e., ALT below the age- and gender-specific upper limit of normal provided by the central laboratory performing the assay) relative to placebo [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  

• Relative change in LDL cholesterol [ Time Frame: 20 weeks, 52 weeks and 78 weeks ] [ Designated as safety issue: No ]
  
• Relative change in non-HDL cholesterol [ Time Frame: 20 weeks, 52 weeks and 78 weeks ] [ Designated as safety issue: No ]
  
• Proportion of subjects with an abnormal baseline AST (i.e., >ULN) who achieve normalization of AST, based on age- and gender-specific normal ranges provided by the central laboratory performing this assay [ Time Frame: 20 weeks, 52 weeks and 78 weeks ] [ Designated as safety issue: No ]
  
• Relative change in triglycerides [ Time Frame: 20 weeks, 52 weeks and 78 weeks ] [ Designated as safety issue: No ]
  
• Relative change in HDL cholesterol [ Time Frame: 20 weeks, 52 weeks and 78 weeks ] [ Designated as safety issue: No ]
  
• In the subset of subjects where performed, relative change in liver fat content [ Time Frame: 20 weeks, 52 weeks and 78 weeks ] [ Designated as safety issue: No ]
  
• In the subset of subjects where performed, proportion of subjects who show improvement in liver histopathology [ Time Frame: 20 weeks, 52 weeks and 78 weeks ] [ Designated as safety issue: No ]
  
• In the subset of subjects where performed, relative change in liver volume [ Time Frame: 20 weeks, 52 weeks and 78 weeks ] [ Designated as safety issue: No ]
  
• Proportion of subjects who achieve ALT normalization (i.e., ALT below the age- and gender-specific upper limit of normal provided by the central laboratory performing the assay) [ Time Frame: 52 weeks and 78 weeks ] [ Designated as safety issue: No ]
  
• Incidence of Adverse Events, Serious Adverse Events, and Infusion Related Reactions [ Time Frame: 20 weeks, 52 weeks and 78 weeks ] [ Designated as safety issue: Yes ]
  
• Characterization of Anti-Drug Antibodies (ADAs), including seroconversion rate, time to seroconversion, ADA titer by time point, peak ADA titer, time to peak ADA titer, and tolerization [ Time Frame: 20 weeks, 52 weeks and 78 weeks ] [ Designated as safety issue: Yes ]
  
• Peak Plasma Concentration (Cmax) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 ] [ Designated as safety issue: No ]
  
• Time to maximum observed concentration (Tmax) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ] [ Designated as safety issue: No ]
  
• Area under the plasma concentration versus time curve (AUC) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ] [ Designated as safety issue: No ]
  
• Terminal elimination half-life (t1/2) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ] [ Designated as safety issue: No ]
  
• Clearance (CL) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ] [ Designated as safety issue: No ]
  
• Volume of distribution (Vd) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ] [ Designated as safety issue: No ]
  

Lysosomal Acid Lipase Deficiency (LALD) is a genetic disease which is characterized by abnormal lipid accumulation in many parts of the body due to a marked decrease in activity of the enzyme lysosomal acid lipase (LAL). Although a single disease, LALD presents with two major forms: early onset and late onset. Early onset LALD, also known as Wolman Disease, is characterized by severe malabsorption, growth failure, and hepatic failure and is usually fatal within the first year of life.

The late onset form of the disease, also known as Cholesteryl Ester Storage Disease (CESD), occurs in both children and adults and is an under-appreciated cause of fatty liver with prominent microvesicular steatosis and cirrhosis. Although the natural history of the disease has not been well studied, serious liver complications are frequently described including early death and liver transplantation. Other complications includes premature atherosclerosis (hardening of arteries) associated with high levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, often called the "bad" cholesterol. The levels of triglycerides can also be high and the levels of high-density lipoprotein (HDL) cholesterol (the "good" cholesterol) are typically low.

Current treatments mainly focus on control of the lipid abnormalities through diet and the use of lipid lowering medications. New treatments are needed for patients with LALD as current treatments only address some aspects of the disease and disease progression to cirrhosis still occurs. In pre-clinical studies and studies in patients with LALD, treatment with SBC-102 (sebelipase alfa) has been shown to produce improvements in markers of liver damage and in the lipid abnormalities. The purpose of this study is to examine the effects of using SBC-102 to treat late onset LALD (CESD) through a placebo-controlled, randomized, double-blinded study in both affected children and adults.