Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) in Participants With Lysosomal Acid Lipase Deficiency (ARISE)

A Multicenter, Randomized, Placebo-controlled Study of SBC-102 in Patients With Lysosomal Acid Lipase Deficiency

This Phase 3 study evaluated the efficacy and safety of 1 milligram/kilogram (mg/kg) intravenous (IV) infusions of SBC-102 (sebelipase alfa) administered every other week (qow) in participants with late onset lysosomal acid lipase deficiency (LAL-D) (cholesteryl ester storage disease [CESD]).

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

Study Overview

• Status: Completed
• Conditions: Lysosomal Acid Lipase Deficiency
• Intervention / Treatment: Drug: Sebelipase Alfa; Drug: Placebo

Detailed Description

Lysosomal acid lipase deficiency (LAL-D) is a genetic disease 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).

The LAL-D disease spectrum ranges from a presentation in infants that is rapidly progressive to a presentation that occurs in childhood, adolescence, or less frequently, in adulthood in which the rate of disease progression is more variable. Irrespective of where a patient is on the disease spectrum, LAL-D is associated with significant burden of disease and a shortened life expectancy in some patients.

The non-infantile onset form of the disease, also known as CESD, occurs in both children and adults and is an under-appreciated cause of fatty liver with prominent microvesicular steatosis, fibrosis, and cirrhosis. Although the natural history of the disease has not been well studied, serious complications are frequently described, including early death, liver transplantation, or cardiovascular accidents. Other complications include 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.

In the past, treatments mainly focused on control of the lipid abnormalities through diet and the use of lipid-lowering medications, which only address some aspects of the disease, while progression to fibrosis and cirrhosis may still occur. In preclinical studies and clinical studies in participants with LAL-D, treatment with SBC-102 (sebelipase alfa, Kanuma®) has been shown to produce improvements in markers of liver damage and in the lipid abnormalities. The purpose of this study was to examine the effects of using SBC-102 to treat LAL-D through a placebo-controlled, randomized, double-blinded study in children and adults.

This multicenter, randomized, double-blind, placebo-controlled study involving 66 participants evaluated the safety and efficacy of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg/kg of body weight qow). The study included a 20-week placebo-controlled period followed by open-label treatment periods for all participants. The primary end-point was normalization of the alanine aminotransferase level. Secondary end-points included additional disease-related efficacy and safety assessments.

Final study results have not been published in a peer-reviewed journal.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Córdoba, Argentina
• Australia
  • Brisbane, Australia
  • New Lambton, Australia
  • Parkville, Australia
  • Perth, Australia
• Croatia
  • Zagreb, Croatia
• Czechia
  • Olomouc, Czechia
  • Prague, Czechia
• France
  • Paris, France
  • Vandoeuvre les Nancy, France
• Germany
  • Freiburg, Germany
  • Mainz, Germany
  • Munich, Germany
• Italy
  • Bergamo, Italy
  • Genoa, Italy
  • Padova, Italy
• Japan
  • Tokyo, Japan
  • Tottori, Japan
• Mexico
  • Mexico City, Mexico
• Poland
  • Warsaw, Poland
• Russian Federation
  • Moscow, Russian Federation
• Spain
  • Elche, Spain
  • Madrid, Spain
  • Oviedo, Spain
• Turkey
  • Ankara, Turkey
  • Izmir, Turkey
• United Kingdom
  • Cambridge, United Kingdom
  • London, United Kingdom
  • Plymouth, United Kingdom
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
  • California
    • Palo Alto, California, United States, 94304
    • San Francisco, California, United States, 94143-0214
  • Delaware
    • Wilmington, Delaware, United States, 19803
  • Illinois
    • Chicago, Illinois, United States, 60611-2605
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
  • New York
    • Buffalo, New York, United States, 14222
    • Manhasset, New York, United States, 11030
    • New York, New York, United States, 10029
  • Ohio
    • Cincinnati, Ohio, United States, 45229
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participant and/or participant's parent or legal guardian provided informed consent.
• Participant was ≥ 4 years of age on the date of informed consent.
• Deficiency of LAL enzyme activity confirmed by dried blood spot testing at screening.
• Alanine aminotransferase ≥ 1.5x upper limit of normal on 2 consecutive screening measurements obtained at least 1 week apart.
• Female participants of childbearing potential must not have been pregnant or breastfeeding and must have agreed to use a medically acceptable method of preventing contraception from screening until 4 weeks after the last dose of study drug.
• Participant receiving lipid-lowering therapies must have been on a stable dose of the medication for at least 6 weeks prior to randomization and was willing to remain on a stable dose for at least the first 32 weeks of treatment in the study.
• Participant receiving medications for the treatment of nonalcoholic fatty liver disease must have been on a stable dose for at least 16 weeks prior to randomization and was willing to remain on a stable dose for at least the first 32 weeks of treatment in the study.

Exclusion Criteria:

• Severe hepatic dysfunction (Child-Pugh Class C).
• Other medical conditions or comorbidities, which, in the opinion of the Investigator, would have interfered 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: Participants receiving maintenance therapy with low-dose oral, intranasal, topical, or inhaled corticosteroids were considered eligible for the study).
• Known hypersensitivity to eggs.
• Participated in a study employing an investigational medicinal product within 4 weeks prior to randomization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Double-blind Sebelipase Alfa; Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow for 20 weeks.	Drug: Sebelipase Alfa; IV infusions of sebelipase alfa; Other Names: SBC-102
Placebo Comparator: Double-blind Placebo; Double-blind Period: IV infusions of matched placebo administered qow for 20 weeks.	Drug: Placebo; IV infusions of matched placebo
Experimental: Open-label Sebelipase Alfa/Sebelipase Alfa; Participants who were randomized to receive sebelipase alfa during the Double-blind Period and received sebelipase alfa in the Open-label Period. All participants received sebelipase alfa at a dose of 1 mg/kg qow, irrespective of treatment received in the Double-blind Period. Dose modifications were permitted during the Open-label Period.	Drug: Sebelipase Alfa; IV infusions of sebelipase alfa; Other Names: SBC-102
Experimental: Open-label Placebo/Sebelipase Alfa; Participants who were randomized to receive placebo during the Double-blind Period and received sebelipase alfa in the Open-label Period. All participants received sebelipase alfa at a dose of 1 mg/kg qow, irrespective of treatment received in the Double-blind Period. Dose modifications were permitted during the Open-label Period.	Drug: Sebelipase Alfa; IV infusions of sebelipase alfa; Other Names: SBC-102

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Of Participants Achieving Alanine Aminotransferase Normalization	Alanine aminotransferase (ALT) normalization was defined as an abnormal baseline value (ALT > the age- and gender-specific upper limit of normal [ULN] provided by the central laboratory performing the assay) that becomes normal (< ULN). Alanine aminotransferase normalization was evaluated at the end of the Double-blind Period (the last double-blind assessment) and at the end of the Open-label Period (last open-label assessment). Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.	Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C)	Relative reduction (percentage change from baseline) in LDL-C, as assessed by laboratory measurements was evaluated at the end of the Double-blind Period and at the end of the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.	Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C)	Relative reduction (percent change from baseline) in non-HDL-C, as assessed by laboratory measurements, was evaluated at the end of the Double-blind Period and the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.	Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
Percentage Of Participants Achieving Aspartate Aminotransferase Normalization	Aspartate aminotransferase (AST) normalization was defined as an abnormal baseline value (AST > the age- and gender-specific ULN provided by the central laboratory performing the assay) that becomes normal (< ULN). AST normalization was evaluated at the end of the Double-blind Period (the last Double-blind assessment) and at the end of the Open-label Period (last open-label assessment). Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.	Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
Percent Change From Baseline In Triglycerides	Relative reduction (percent change from baseline) in triglycerides, as assessed by laboratory measurements, was evaluated at the end of the Double-blind Period and the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.	Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C)	Relative increase (percent change from baseline) in HDL-C, assessed by laboratory measurements, was evaluated at the end of the Double-blind Period and the Open-label Period. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.	Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
Percent Change From Baseline In Liver Fat Content	Decrease in liver fat content, as assessed by magnetic resonance imaging (MRI), was evaluated in participants for whom imaging was performed. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.	Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).
Participants With Improvement In Liver Histopathology (Decrease Of > 5% In Hepatic Steatosis Score)	The number of participants who had an improvement in hepatic histopathology (defined as a decrease of > 5% in hepatic steatosis score, assessed by morphometry), as determined by blinded central pathologist review, in the participants for whom liver biopsy was performed. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group.	Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline up to Week 52.
Percent Change From Baseline In Liver Volume	Relative reduction (percent change from baseline) in liver volume, as assessed by MRI, was evaluated in participants for whom imaging was performed. Baseline for the Open-label Period was defined relative to the first infusion of sebelipase alfa, which occurred at Week 0 for participants in the sebelipase alfa/sebelipase alfa group and Week 22 for participants in the placebo/sebelipase alfa group. The last open-label assessment varied by participant, depending on whether a participant completed treatment through Week 256 or discontinued prior to this timepoint to transition out of clinical study settings.	Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals
• Investigators: Study Director: Florian Abel, MD, Alexion Pharmaceuticals

Publications and helpful links

General Publications

• 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 May-Jun;12(3):604-614. doi: 10.1016/j.jacl.2018.02.020. Epub 2018 Mar 9.
• Burton BK, Balwani M, Feillet F, Baric I, Burrow TA, Camarena Grande C, Coker M, Consuelo-Sanchez 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.
• Burton BK, Feillet F, Furuya KN, Marulkar S, Balwani M. Sebelipase alfa in children and adults with lysosomal acid lipase deficiency: Final results of the ARISE study. J Hepatol. 2022 Mar;76(3):577-587. doi: 10.1016/j.jhep.2021.10.026. Epub 2021 Nov 10.
• Valayannopoulos V, Malinova V, Honzik 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2013
• Primary Completion (Actual): May 30, 2014
• Study Completion (Actual): December 11, 2018

Study Registration Dates

• First Submitted: December 17, 2012
• First Submitted That Met QC Criteria: December 27, 2012
• First Posted (Estimate): December 28, 2012

Study Record Updates

• Last Update Posted (Actual): December 29, 2020
• Last Update Submitted That Met QC Criteria: December 2, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Acid cholesteryl ester hydrolase deficiency, type 2; Acid lipase disease; Cholesterol ester hydrolase deficiency; Wolman disease; Lysosomal storage disease; Enzyme replacement therapy (ERT); Late-onset lysosomal acid lipase deficiency (LAL-D); LAL-D; LIPA deficiency; Cholesterol ester storage disease (CESD)
• Additional Relevant MeSH Terms: Metabolic Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Lipidoses; Lipid Metabolism, Inborn Errors; Cholesterol Ester Storage Disease; Wolman Disease
• Other Study ID Numbers: LAL-CL02