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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Cholesterol Ester Storage Disease (CESD); Lysosomal Acid Lipase Deficiency	Drug: SBC-102 [sebelipase alfa] (1 mg/kg); Drug: Placebo	Phase 3

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	66 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Multicenter, Randomized, Placebo-Controlled Study of SBC-102 in Patients With Lysosomal Acid Lipase Deficiency
Study Start Date :	January 2013
Estimated Primary Completion Date :	January 2019
Estimated Study Completion Date :	January 2019

Arms and Interventions

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

Outcome Measures

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Primary Outcome Measures :

1. Percentage of Subjects Achieving Alanine Aminotransferase (ALT) Normalization [ Time Frame: Baseline to the end of the double-blind period (week 20) ]
   The primary efficacy endpoint was the percentage of subjects who achieve alanine aminotransferase (ALT) normalization (i.e., ALT below the age- and gender-specific upper limit of normal provided by the central laboratory performing the assay) at the end of the double-blind treatment period (i.e., the last double-blind assessment), relative to placebo.

Secondary Outcome Measures :

1. 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.
2. 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
3. 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.
4. 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
5. 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
6. 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
7. 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.
8. 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

Eligibility Criteria

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Ages Eligible for Study:	4 Years and older (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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  Show 54 Study Locations

Sponsors and Collaborators

Alexion Pharmaceuticals

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications:

Balwani M, Breen C, Enns GM, Deegan PB, Honzík T, Jones S, Kane JP, Malinova V, Sharma R, Stock EO, Valayannopoulos V, Wraith JE, Burg J, Eckert S, Schneider E, Quinn AG. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Hepatology. 2013 Sep;58(3):950-7. doi: 10.1002/hep.26289. Epub 2013 Mar 28.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wilson DP, Friedman M, Marulkar S, Hamby T, Bruckert E. Sebelipase alfa improves atherogenic biomarkers in adults and children with lysosomal acid lipase deficiency. J Clin Lipidol. 2018 Mar 9. pii: S1933-2874(18)30147-8. doi: 10.1016/j.jacl.2018.02.020. [Epub ahead of print]

Burton BK, Balwani M, Feillet F, Barić I, Burrow TA, Camarena Grande C, Coker M, Consuelo-Sánchez A, Deegan P, Di Rocco M, Enns GM, Erbe R, Ezgu F, Ficicioglu C, Furuya KN, Kane J, Laukaitis C, Mengel E, Neilan EG, Nightingale S, Peters H, Scarpa M, Schwab KO, Smolka V, Valayannopoulos V, Wood M, Goodman Z, Yang Y, Eckert S, Rojas-Caro S, Quinn AG. A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency. N Engl J Med. 2015 Sep 10;373(11):1010-20. doi: 10.1056/NEJMoa1501365.

Valayannopoulos V, Malinova V, Honzík T, Balwani M, Breen C, Deegan PB, Enns GM, Jones SA, Kane JP, Stock EO, Tripuraneni R, Eckert S, Schneider E, Hamilton G, Middleton MS, Sirlin C, Kessler B, Bourdon C, Boyadjiev SA, Sharma R, Twelves C, Whitley CB, Quinn AG. Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency. J Hepatol. 2014 Nov;61(5):1135-42. doi: 10.1016/j.jhep.2014.06.022. Epub 2014 Jun 30.

Responsible Party:	Alexion Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT01757184 History of Changes
Other Study ID Numbers:	LAL-CL02
First Posted:	December 28, 2012
Results First Posted:	April 18, 2016
Last Update Posted:	March 20, 2017
Last Verified:	February 2017

Keywords provided by Alexion Pharmaceuticals:

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

Additional relevant MeSH terms:

Wolman Disease; Cholesterol Ester Storage Disease; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors	Genetic Diseases, Inborn; Lysosomal Storage Diseases; Infant, Newborn, Diseases; Lipid Metabolism Disorders; Metabolic Diseases