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

NCT01757184 | Completed Phase 3 Results DMC

• 1 other identifier: LAL-CL02
• Study Type: interventional
• Target: 66
• Locations: 15 countries
• Sites: 40

Brief Summary

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.

Conditions

Lysosomal Acid Lipase Deficiency

Keywords

Enzyme replacement therapy (ERT); Lysosomal storage disease; Late-onset lysosomal acid lipase deficiency (LAL-D); Acid cholesteryl ester hydrolase deficiency, type 2; Acid lipase disease; Cholesterol ester hydrolase deficiency; LAL-D; LIPA deficiency; Wolman disease; Cholesterol ester storage disease (CESD)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C)

  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)

  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

  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

  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)

  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).

Study Arms (4)

Double-blind Sebelipase Alfa

EXPERIMENTAL

Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow for 20 weeks.

Drug: Sebelipase Alfa

Double-blind Placebo

PLACEBO COMPARATOR

Double-blind Period: IV infusions of matched placebo administered qow for 20 weeks.

Drug: Placebo

Open-label Sebelipase Alfa/Sebelipase Alfa

EXPERIMENTAL

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

Open-label Placebo/Sebelipase Alfa

EXPERIMENTAL

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

Interventions

Sebelipase Alfa DRUG

IV infusions of sebelipase alfa

Also known as: SBC-102

Double-blind Sebelipase Alfa; Open-label Placebo/Sebelipase Alfa; Open-label Sebelipase Alfa/Sebelipase Alfa

Placebo DRUG

IV infusions of matched placebo

Double-blind Placebo

Eligibility Criteria

• Age: 4 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Alexion Pharmaceuticals, Inc.: lead

Study Sites (40)

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Tucson, Arizona, 85724, United States

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Palo Alto, California, 94304, United States

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San Francisco, California, 94143-0214, United States

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Wilmington, Delaware, 19803, United States

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Chicago, Illinois, 60611-2605, United States

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Boston, Massachusetts, 02115, United States

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Buffalo, New York, 14222, United States

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Manhasset, New York, 11030, United States

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New York, New York, 10029, United States

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Cincinnati, Ohio, 45229, United States

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Philadelphia, Pennsylvania, 19104, United States

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Córdoba, Argentina

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Brisbane, Australia

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New Lambton, Australia

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Parkville, Australia

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Perth, Australia

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Zagreb, Croatia

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Olomouc, Czechia

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Prague, Czechia

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Paris, France

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Vandœuvre-lès-Nancy, France

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Freiburg im Breisgau, Germany

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Mainz, Germany

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Munich, Germany

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Bergamo, Italy

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Genoa, Italy

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Padua, Italy

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Tokyo, Japan

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Tottori, Japan

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Mexico City, Mexico

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Warsaw, Poland

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Moscow, Russia

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Elche, Spain

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Madrid, Spain

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Oviedo, Spain

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Ankara, Turkey (Türkiye)

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Izmir, Turkey (Türkiye)

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Cambridge, United Kingdom

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London, United Kingdom

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Plymouth, United Kingdom

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Related Publications (4)

• 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.

  PMID: 29628368 BACKGROUND

• 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.

  PMID: 26352813 BACKGROUND

• 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.

  PMID: 34774639 DERIVED

• 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.

  PMID: 24993530 DERIVED

MeSH Terms

Conditions

Wolman Disease; Lysosomal Storage Diseases; Cholesterol Ester Storage Disease

Interventions

Sebelipase alfa

Condition Hierarchy (Ancestors)

Lipidoses; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Alexion Pharmaceuticals, Inc.
• Organization: Alexion Pharmaceuticals, Inc.

clinicaltrials@alexion.com

855-752-2356

Study Officials

• Florian Abel, MD

  Alexion Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2012
• First Posted: December 28, 2012
• Study Start: January 22, 2013
• Primary Completion: May 30, 2014
• Study Completion: December 11, 2018
• Last Updated: December 29, 2020
• Results First Posted: April 18, 2016

Record last verified: 2020-12

Locations

CR (1); DE (3); AR (1); GB (3); IT (3); ES (3); ME (1); CZ (2); FR (2); AU (4); US (11); TU (2); JP (2); PL (1); RU (1)