Clinical trial NCT01757184: Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) in Participants With Lysosomal Acid Lipase Deficiency
Official title: A Multicenter, Randomized, Placebo-controlled Study of SBC-102 in Patients With Lysosomal Acid Lipase Deficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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)
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2012-12-28
Enrollment: 66
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage Of Participants Achieving Alanine Aminotransferase Normalization
timeFrame: 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:
measure: Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C)
timeFrame: 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).
measure: Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C)
timeFrame: 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).
measure: Percentage Of Participants Achieving Aspartate Aminotransferase Normalization
timeFrame: 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).
measure: Percent Change From Baseline In Triglycerides
timeFrame: 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).
measure: Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C)
timeFrame: 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).
measure: Percent Change From Baseline In Liver Fat Content
timeFrame: 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).
measure: Participants With Improvement In Liver Histopathology (Decrease Of > 5% In Hepatic Steatosis Score)
timeFrame: Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline up to Week 52.
measure: Percent Change From Baseline In Liver Volume
timeFrame: 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).
Other outcomes:
Locations:
city: Tucson
country: United States
state: Arizona
city: Palo Alto
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Wilmington
country: United States
state: Delaware
city: Chicago
country: United States
state: Illinois
city: Boston
country: United States
state: Massachusetts
city: Buffalo
country: United States
state: New York
city: Manhasset
country: United States
state: New York
city: New York
country: United States
state: New York
city: Cincinnati
country: United States
state: Ohio
city: Philadelphia
country: United States
state: Pennsylvania
city: Córdoba
country: Argentina
city: Brisbane
country: Australia
city: New Lambton
country: Australia
city: Parkville
country: Australia
city: Perth
country: Australia
city: Zagreb
country: Croatia
city: Olomouc
country: Czechia
city: Prague
country: Czechia
city: Paris
country: France
city: Vandoeuvre les Nancy
country: France
city: Freiburg
country: Germany
city: Mainz
country: Germany
city: Munich
country: Germany
city: Bergamo
country: Italy
city: Genoa
country: Italy
city: Padova
country: Italy
city: Tokyo
country: Japan
city: Tottori
country: Japan
city: Mexico City
country: Mexico
city: Warsaw
country: Poland
city: Moscow
country: Russian Federation
city: Elche
country: Spain
city: Madrid
country: Spain
city: Oviedo
country: Spain
city: Ankara
country: Turkey
city: Izmir
country: Turkey
city: Cambridge
country: United Kingdom
city: London
country: United Kingdom
city: Plymouth
country: United Kingdom
Study officials:
affiliation: Alexion Pharmaceuticals, Inc.
name: Florian Abel, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.