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

Phase 3

Completed

Conditions: Lysosomal Acid Lipase Deficiency

Interventions: Drug: Placebo
Drug: Sebelipase Alfa

Registration Number: NCT01757184

Lead Sponsor: Alexion Pharmaceuticals, Inc.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 66

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Double-blind Placebo	Placebo	Double-blind Period: IV infusions of matched placebo administered qow for 20 weeks.
Double-blind Sebelipase Alfa	Sebelipase Alfa	Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow for 20 weeks.
Open-label Sebelipase Alfa/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.
Open-label Placebo/Sebelipase Alfa	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.

Primary Outcome Measures

Name	Time	Method
Percentage Of Participants Achieving Alanine 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)	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.

Secondary Outcome Measures

Name	Time	Method
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).	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.
Percent Change From Baseline In Liver Fat Content	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).	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.
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).	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.
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).	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.
Participants With Improvement In Liver Histopathology (Decrease Of > 5% In Hepatic Steatosis Score)	Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline up to Week 52.	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.
Percent Change From Baseline In Liver Volume	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).	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.
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).	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.
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).	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.