Lysosomal Acid Lipase Deficiency
Conditions
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)
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.
Interventions
DRUGSebelipase Alfa
IV infusions of sebelipase alfa
DRUGPlacebo
IV infusions of matched placebo
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 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. |
| 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 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. |
Countries
Argentina, Australia, Croatia, Czechia, France, Germany, Italy, Japan, Mexico, Poland, Russia, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total of 56 study centers located in 17 countries were initiated in this study. Participants were enrolled and treated at 41 centers in 15 countries, including 35 primary centers where participants initiated treatment and 6 qualified local medical centers where participants who were medically stable were transferred for long-term treatment.
Pre-assignment details
To assess eligibility, participants were screened for a period of up to 6 weeks prior to enrollment in the study. A total of 86 participants were screened. Six of these participants underwent rescreening (of which 2 were eligible for the study). In total, 66 participants were eligible for the study and 20 participants were screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Double-Blind Sebelipase Alfa Double-blind Period: IV infusions of sebelipase alfa at a dose of 1 mg/kg administered qow. | 36 |
| Double-Blind Placebo Double-blind Period: IV infusions of placebo administered qow. | 30 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind Period | Adverse Event | 1 | 0 | 0 | 0 |
| Open-label Period | Discontinued by Sponsor | 0 | 0 | 1 | 2 |
| Open-label Period | Lost to Follow-up | 0 | 0 | 2 | 0 |
| Open-label Period | Withdrawal by Subject | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Double-Blind Sebelipase Alfa | Double-Blind Placebo | Total |
|---|---|---|---|
| Age, Continuous | 17.39 years STANDARD_DEVIATION 11.529 | 15.70 years STANDARD_DEVIATION 10.283 | 16.62 years STANDARD_DEVIATION 10.93 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 4 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 26 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) White | 27 Participants | 28 Participants | 55 Participants |
| Sex: Female, Male Female | 18 Participants | 15 Participants | 33 Participants |
| Sex: Female, Male Male | 18 Participants | 15 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 30 | 0 / 36 | 0 / 30 |
| other Total, other adverse events | 31 / 36 | 28 / 30 | 35 / 36 | 29 / 30 |
| serious Total, serious adverse events | 2 / 36 | 1 / 30 | 6 / 36 | 5 / 30 |
Outcome results
Primary
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.
Time frame: 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)
Population: Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa or placebo).~Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Sebelipase Alfa | Percentage Of Participants Achieving Alanine Aminotransferase Normalization | 31 percentage of participants |
| Double-blind Placebo | Percentage Of Participants Achieving Alanine Aminotransferase Normalization | 7 percentage of participants |
| Open-label Sebelipase Alfa/Sebelipase Alfa | Percentage Of Participants Achieving Alanine Aminotransferase Normalization | 56 percentage of participants |
| Open-label Placebo/Sebelipase Alfa | Percentage Of Participants Achieving Alanine Aminotransferase Normalization | 37 percentage of participants |
Comparison: A sample size of 50 randomized participants (approximately 25 participants per treatment group) provided 97% power to detect a statistically significant difference between sebelipase alfa and placebo, using Fisher's exact test at α=0.05.p-value: 0.0271Fisher Exact
Secondary
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.
Time frame: Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline up to Week 52.
Population: Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa or placebo).~Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Sebelipase Alfa | Participants With Improvement In Liver Histopathology (Decrease Of > 5% In Hepatic Steatosis Score) | 10 participants |
| Double-blind Placebo | Participants With Improvement In Liver Histopathology (Decrease Of > 5% In Hepatic Steatosis Score) | 4 participants |
| Open-label Sebelipase Alfa/Sebelipase Alfa | Participants With Improvement In Liver Histopathology (Decrease Of > 5% In Hepatic Steatosis Score) | 7 participants |
| Open-label Placebo/Sebelipase Alfa | Participants With Improvement In Liver Histopathology (Decrease Of > 5% In Hepatic Steatosis Score) | 4 participants |
p-value: 0.4216Fisher Exact
Secondary
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.
Time frame: 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).
Population: Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa or placebo).~Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Sebelipase Alfa | Percentage Of Participants Achieving Aspartate Aminotransferase Normalization | 42 percentage of participants |
| Double-blind Placebo | Percentage Of Participants Achieving Aspartate Aminotransferase Normalization | 3 percentage of participants |
| Open-label Sebelipase Alfa/Sebelipase Alfa | Percentage Of Participants Achieving Aspartate Aminotransferase Normalization | 69 percentage of participants |
| Open-label Placebo/Sebelipase Alfa | Percentage Of Participants Achieving Aspartate Aminotransferase Normalization | 62 percentage of participants |
p-value: 0.0003Fisher Exact
Secondary
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.
Time frame: 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).
Population: Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa or placebo).~Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Sebelipase Alfa | Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C) | 19.57 percent change | Standard Deviation 16.833 |
| Double-blind Placebo | Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C) | -0.29 percent change | Standard Deviation 12.36 |
| Open-label Sebelipase Alfa/Sebelipase Alfa | Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C) | 31.65 percent change | Standard Deviation 28.971 |
| Open-label Placebo/Sebelipase Alfa | Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C) | 34.78 percent change | Standard Deviation 29.927 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: 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).
Population: Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa or placebo).~Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Sebelipase Alfa | Percent Change From Baseline In Liver Fat Content | -31.98 percent change | Standard Deviation 26.763 |
| Double-blind Placebo | Percent Change From Baseline In Liver Fat Content | -4.21 percent change | Standard Deviation 15.559 |
| Open-label Sebelipase Alfa/Sebelipase Alfa | Percent Change From Baseline In Liver Fat Content | -9.89 percent change | Standard Deviation 32.892 |
| Open-label Placebo/Sebelipase Alfa | Percent Change From Baseline In Liver Fat Content | -0.93 percent change | Standard Deviation 37.233 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: 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).
Population: Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa or placebo).~Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Sebelipase Alfa | Percent Change From Baseline In Liver Volume | -10.28 percent change | Standard Deviation 10.51 |
| Double-blind Placebo | Percent Change From Baseline In Liver Volume | -2.66 percent change | Standard Deviation 10.107 |
| Open-label Sebelipase Alfa/Sebelipase Alfa | Percent Change From Baseline In Liver Volume | -24.04 percent change | Standard Deviation 15.792 |
| Open-label Placebo/Sebelipase Alfa | Percent Change From Baseline In Liver Volume | -21.55 percent change | Standard Deviation 11.727 |
p-value: 0.0068Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: 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).
Population: Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa or placebo).~Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Sebelipase Alfa | Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C) | -28.42 percent change | Standard Deviation 22.304 |
| Double-blind Placebo | Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C) | -6.25 percent change | Standard Deviation 13.015 |
| Open-label Sebelipase Alfa/Sebelipase Alfa | Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C) | -19.74 percent change | Standard Deviation 33.262 |
| Open-label Placebo/Sebelipase Alfa | Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C) | -18.09 percent change | Standard Deviation 33.685 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: 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).
Population: Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa or placebo).~Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Sebelipase Alfa | Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C) | -27.97 percent change | Standard Deviation 18.612 |
| Double-blind Placebo | Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C) | -6.94 percent change | Standard Deviation 10.922 |
| Open-label Sebelipase Alfa/Sebelipase Alfa | Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C) | -19.75 percent change | Standard Deviation 26.875 |
| Open-label Placebo/Sebelipase Alfa | Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C) | -18.34 percent change | Standard Deviation 29.177 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: 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).
Population: Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa or placebo).~Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Sebelipase Alfa | Percent Change From Baseline In Triglycerides | -25.45 percent change | Standard Deviation 29.411 |
| Double-blind Placebo | Percent Change From Baseline In Triglycerides | -11.14 percent change | Standard Deviation 28.827 |
| Open-label Sebelipase Alfa/Sebelipase Alfa | Percent Change From Baseline In Triglycerides | -11.87 percent change | Standard Deviation 34.58 |
| Open-label Placebo/Sebelipase Alfa | Percent Change From Baseline In Triglycerides | -19.63 percent change | Standard Deviation 27.066 |
p-value: 0.0375Wilcoxon (Mann-Whitney)