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

• 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 ]

This Phase 3 study will evaluate the efficacy and safety of 1 mg/kg IV infusions of SBC-102 (sebelipase alfa) administered every other week in patients with late onset lysosomal acid lipase (LAL) deficiency (cholesteryl ester storage disease).

Late onset LAL Deficiency is an underappreciated cause of cirrhosis, liver failure and dyslipidemia. There is currently no standard treatment for LAL Deficiency other than supportive care. Enzyme replacement therapy (ERT) may be a potential new treatment option for LAL Deficiency patients.

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.

• Cholesterol Ester Storage Disease (CESD)
• Lysosomal Acid Lipase Deficiency

• Drug: SBC-102 [sebelipase alfa] (1 mg/kg)
• Drug: Placebo

• Experimental: SBC-102 [sebelipase alfa]
  Every other week IV infusions of SBC-102
  Intervention: Drug: SBC-102 [sebelipase alfa] (1 mg/kg)
• Placebo Comparator: Placebo
  Every other week infusions of placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

• Subject and/or subject's parent or legal guardian provides informed consent
• Subject is ≥4 years of age
• Deficiency of LAL enzyme activity confirmed by dried blood spot (DBS) testing at screening
• ALT ≥1.5x ULN
• Female subjects of childbearing potential must not be pregnant or breastfeeding
• Subjects receiving lipid-lowering therapies must be on a stable dose of the medication
• Subjects receiving medications for the treatment of non-alcoholic fatty liver disease must be on a stable dose

Exclusion Criteria:

• Severe hepatic dysfunction (Child-Pugh Class C)
• Other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation
• Previous hematopoietic or liver transplant procedure
• Received treatment with high-dose corticosteroids (acute or chronic) within 26 weeks. (Note: Subjects receiving maintenance therapy with low-dose oral, intranasal, topical, or inhaled corticosteroids are considered eligible for the study)
• Known hypersensitivity to eggs
• Participated in a study employing an investigational medicinal product within 4 weeks prior to randomization