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

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: A Multicenter, Randomized, Placebo-Controlled Study of SBC-102 in Patients With Lysosomal Acid Lipase Deficiency

Brief Summary:

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.

Detailed Summary:

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 LAL
Sponsor: Alexion Pharmaceuticals

Current Primary Outcome: Percentage of Subjects Achieving Alanine Aminotransferase (ALT) Normalization [ Time Frame: Baseline to the end of the double-blind period (week 20) ]

Original Primary Outcome: 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 ]

Current Secondary Outcome:

• Percentage Change From Baseline in LDL-c [ Time Frame: Baseline to the end of the double-blind period (week 20) ]
  Relative reduction (percentage change from baseline) in LDL-c at the end of the double-blind period.
• Percentage Change From Baseline in Non-HDL-c [ Time Frame: Baseline to the end of the double-blind period (week 20) ]
  Relative reduction (percentage change from baseline) in non-high density lipoprotein cholesterol (non-HDL-c) at the end of the double-blind period
• Percentage of Subjects Achieving Aspartate Aminotransferase (AST) Normalization [ Time Frame: Baseline to the end of the double-blind period (week 20) ]
  The percentage of subjects with an abnormal baseline aspartate aminotransferase (AST; i.e., >ULN) who achieved AST normalization, based on age- and gender-specific normal ranges provided by the central laboratory performing the assay.
• Percentage Change From Baseline in Triglycerides [ Time Frame: Baseline to the end of the double-blind period (week 20) ]
  Relative reduction (percentage change from baseline) in triglycerides at the end of the double-blind period
• Percentage Change From Baseline in HDL-c [ Time Frame: Baseline to the end of the double-blind period (week 20) ]
  Relative increase (percentage change from baseline) in high density lipoprotein cholesterol (HDL-c) at the end of the double-blind period
• Percentage Change From Baseline in Liver Fat Content [ Time Frame: Baseline to the end of the double-blind period (week 20) ]
  Decrease in liver fat content, as assessed by magnetic resonance imaging (MRI), in the subset of subjects for whom imaging was performed
• Number of Subjects With Improvement in Liver Histology (Decrease of >5% in Hepatic Steatosis Score) [ Time Frame: Baseline to the end of the double-blind period (week 20) ]
  The number of subjects who had an improvement in hepatic histology (i.e., a decrease of >5% in hepatic steatosis score) from baseline to Week 20, as determined by blinded central review, in the subset of subjects for whom liver biopsy was performed.
• Percentage Change From Baseline in Liver Volume [ Time Frame: Baseline to the end of the double-blind period (week 20) ]
  Relative reduction (percentage change from baseline) in liver volume, as assessed by magnetic resonance imaging, in the subset of subjects for whom imaging was performed

Original Secondary Outcome:

• Relative change in LDL cholesterol [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• Relative change in non-HDL cholesterol [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• 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 ]
• Relative change in triglycerides [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• Relative change in HDL cholesterol [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• In the subset of subjects where performed, relative change in liver fat content [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• 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 ]
• In the subset of subjects where performed, relative change in liver volume [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• 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 ]
• Incidence of Adverse Events, Serious Adverse Events, and Infusion Related Reactions [ Time Frame: 20 weeks, 52 weeks and 78 weeks ]
• 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 ]
• Peak Plasma Concentration (Cmax) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 ]
• Time to maximum observed concentration (Tmax) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ]
• Area under the plasma concentration versus time curve (AUC) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ]
• Terminal elimination half-life (t1/2) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ]
• Clearance (CL) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ]
• Volume of distribution (Vd) of sebelipase alfa [ Time Frame: Week 0, 22 weeks and 52 weeks ]

Information By: Alexion Pharmaceuticals

Dates:
Date Received: December 17, 2012
Date Started: January 2013
Date Completion: January 2019
Last Updated: February 13, 2017
Last Verified: February 2017