Lysosomal Acid Lipase Deficiency
Conditions
Keywords
Enzyme Replacement Therapy (ERT), Lysosomal Storage Disease, Late Onset Lysosomal Acid Lipase (LAL) Deficiency, Acid cholesteryl ester hydrolase deficiency, type 2, Acid lipase disease, Cholesterol ester hydrolase deficiency, LAL Deficiency, LIPA Deficiency, Wolman disease, Additional relevant MeSH terms:, Cholesterol Ester Storage Disease, Metabolic Diseases, Lipidoses, Lipid Metabolism, Inborn Errors, Metabolism, Inborn Errors, Genetic Diseases, Inborn, Lysosomal Storage Diseases, Lipid Metabolism Disorders, Infant, Newborn, Diseases
Brief summary
This study evaluated the safety and efficacy of sebelipase alfa in a broad population of participants with lysosomal acid lipase deficiency (LAL-D).
Detailed description
The primary objective of this study was to evaluate the safety of intravenous (IV) infusions of sebelipase alfa in a more broad population of LAL-D participants than previously studied. Such participants may have been excluded from enrollment in other studies of LAL-D because of age, disease progression, previous treatment by hematopoietic stem cell or liver transplantation, less common disease manifestations, or disease characteristics that would preclude participation in a placebo-controlled study. This open-label study included infants \>8 months, children, and adults. At least 4 participants in the study were to be between the age of 2 and 4 years. Eligible participants received sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) every other week (qow).
Interventions
DRUGSebelipase Alfa
IV infusion of sebelipase alfa
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
8 Months to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Participant was \>8 months of age at the time of dosing. 2. Confirmation of LAL-D diagnosis as determined by the central laboratory or, for participants with prior hematopoietic stem cell transplant or liver transplant, historical enzyme activity or molecular genetic testing confirming a diagnosis of LAL-D. 3. Participants \>8 months but \<4 years of age at Screening had at least 1 of the following documented clinical manifestations of LAL-D: * Dyslipidemia * Elevated transaminases * Impaired growth * Suspected malabsorption * Other clinical manifestation of LAL-D 4. Participants ≥4 years of age at Screening had at least 1 of the following documented clinical manifestations of LAL-D: * Evidence of advanced liver disease * Histologically confirmed disease recurrence in participants with past liver or hematopoietic transplant * Persistent dyslipidemia * Suspected malabsorption * Other clinical manifestation of LAL-D Key
Exclusion criteria
1. Participant had known causes of active liver disease other than LAL-D, which had not been adequately treated. 2. Participant received a hematopoietic stem cell or liver transplant \<2 years from the time of dosing. 3. Participant with co-morbidities other than complications due to LAL-D, which were irreversible or associated with a high mortality risk within 6 months or would interfere with study compliance or data interpretation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs) | Screening, Week 144 | The number of participants experiencing severe TEAEs is presented for participants who received sebelipase alfa in this open-label study. Adverse events (AEs) information was obtained at each scheduled contact with the participant (or participant's parent or legal guardian). An AE was defined as any untoward medical occurrence that did not require a causal relationship with study drug administration. An AE could have been any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the study drug, whether or not considered related to the study drug. Pre-existing conditions that worsened in severity during the study were reported as AEs. A summary of all serious and other non-serious AEs regardless of causality is located in the Reported AE module. Severity assessed using Clinical Data Interchange Standards Consortium Study Data Tabulation Model standard terminology v3.1.1. Data presented only according to age group, not dose of study drug received. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change In Serum Lipids From Baseline To Week 144 | Baseline, Week 144 | The effect of sebelipase alfa on lipid metabolism was evaluated by measuring the change from baseline to Week 144 in 4 serum lipids: low-density lipoprotein cholesterol (LDL-C); high-density lipoprotein cholesterol (HDL-C); non-HDL-C; triglycerides. Blood samples for these clinical laboratory tests were collected at scheduled time points and analyzed by a central laboratory. |
| Participants Testing Positive For Anti-drug Antibodies (ADAs) | Week 144 | The impact of ADAs on the safety and immunogenicity of sebelipase alfa was evaluated by testing for ADAs in participants who received sebelipase alfa in this open-label study. Blood samples for assessment were collected prior to study infusions at Week 2, Week 4, Week 8, Week 12, and every 12 weeks thereafter. Participants testing positive for ADAs were also tested for the presence of neutralizing antibodies that inhibited sebelipase alfa enzyme activity and/or cellular uptake. Any participant experiencing a moderate or severe infusion-associated reaction (IAR) was to have an additional assessment of ADAs at the next study visit (prior to study drug infusion); these participants were to also have serum samples collected at 1 to 2 hours after IAR onset and at the next study visit (prior to study drug infusion) for analysis of serum tryptase. The count of participants who became ADA positive and who tested positive for neutralizing antibodies are presented. |
| Percent Change In Body Mass Index (BMI)-For-Age Percentile From Baseline To Week 144 In Pediatric Participants | Baseline, Week 144 | To evaluate the effects of sebelipase alfa on growth parameters in pediatric participants (≤18 years old) presenting with evidence of growth delay, the percent change in the anthropometric parameter of BMI-for-age percentile from Baseline to Week 144 is reported. Anthropometric parameters were plotted on standard growth curves. When possible, historical data on growth parameters was also incorporated into the analyses. Percentiles and Z-scores for BMI-for-age were determined using standard growth charts appropriate to a participant's age on the date of the assessment: the World Health Organization standard growth chart for participants ≤2 years of age and the Centers for Disease Control standard growth chart for participants \>2 years of age. |
| Shift In Child-Pugh Status From Baseline To Week 144 | Baseline, Week 144 | In order to evaluate the effects of sebelipase alfa on liver function, the number of participants with a shift in Child-Pugh status from Baseline to Week 144 is reported. The status is based on the Child-Pugh score, which is used in clinical practice to assess prognosis in individuals with chronic liver disease. Laboratory data were used in derivation of the score by summing individual scores (scored 1-3, with 3 indicating most severe) from clinical laboratory test results and physical examinations, including total serum bilirubin, serum albumin, prothrombin time, ascites, and hepatic encephalopathy. The total score was used to determine the Child-Pugh status, reported as Class A (score of 5 or 6), Class B (score of 7 to 9), or Class C (score of 10 to 15). Higher scores and higher categories represented a worse outcome. Data reported as 1 of 2 types of shifts in class: No Change from Baseline; Decline from Baseline. |
Countries
Australia, Belgium, Brazil, Canada, Croatia, Denmark, Germany, Italy, Mexico, Netherlands, Russia, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total of 21 study centers were initiated in 15 countries, including Australia, Belgium, Brazil, Canada, Croatia, Denmark, Germany, Italy, Mexico, Netherlands, Russia, Spain, Turkey, United Kingdom (UK), and the United States. Seventeen study centers screened at least 1 participant in all of these countries, except the UK and the Netherlands.
Pre-assignment details
All participants began treatment with sebelipase alfa at a dose of 1 milligram/kilogram (mg/kg) every other week (qow). Individual participants could escalate/decrease their dose at any time during the study and only at the discretion of the Investigator and in consultation with the Sponsor. All 5 different doses are presented as Milestones below.
Participants by arm
| Arm | Count |
|---|---|
| Sebelipase Alfa Pediatric and adult participants initiated IV treatment with sebelipase alfa at a dose of 1 mg/kg qow. Participants were considered for a dose adjustment at the discretion of the Investigator and in consultation with the Sponsor. Dose escalation to 3 mg/kg qow was considered if pre-defined dose-escalation criteria were met. If these criteria continued to be met, a subsequent dose escalation to 3 mg/kg qw was considered. Dose decreases as low as 0.35 mg/kg qow were permitted based upon evidence of intolerance to sebelipase alfa treatment. Participants who completed the 96-week treatment period were permitted to continue receiving sebelipase alfa in an expanded treatment period for up to 48 weeks, pending local drug availability and study participation status. | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Liver Transplant | 0 | 1 | 0 |
| Overall Study | Pregnancy | 0 | 1 | 1 |
| Overall Study | Progressive Disease | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Sebelipase Alfa |
|---|---|
| Age, Continuous | 16.82 years STANDARD_DEVIATION 14.674 |
| Age, Customized >18 years | 9 Participants |
| Age, Customized 2 to <4 years | 6 Participants |
| Age, Customized 4 to 18 years | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Other | 4 Participants |
| Race/Ethnicity, Customized White | 27 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 31 | 0 / 2 | 0 / 11 | 0 / 4 |
| other Total, other adverse events | 0 / 1 | 30 / 31 | 0 / 2 | 10 / 11 | 4 / 4 |
| serious Total, serious adverse events | 0 / 1 | 8 / 31 | 0 / 2 | 3 / 11 | 0 / 4 |
Outcome results
Primary
Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs)
The number of participants experiencing severe TEAEs is presented for participants who received sebelipase alfa in this open-label study. Adverse events (AEs) information was obtained at each scheduled contact with the participant (or participant's parent or legal guardian). An AE was defined as any untoward medical occurrence that did not require a causal relationship with study drug administration. An AE could have been any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the study drug, whether or not considered related to the study drug. Pre-existing conditions that worsened in severity during the study were reported as AEs. A summary of all serious and other non-serious AEs regardless of causality is located in the Reported AE module. Severity assessed using Clinical Data Interchange Standards Consortium Study Data Tabulation Model standard terminology v3.1.1. Data presented only according to age group, not dose of study drug received.
Time frame: Screening, Week 144
Population: Full Analysis Set: All participants who received at least 1 infusion of sebelipase alfa. The full analysis set was used for analysis of safety and efficacy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2-<4 Years | Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs) | 1 Participants |
| 4-18 Years | Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs) | 1 Participants |
| >18 Years | Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
Secondary
Participants Testing Positive For Anti-drug Antibodies (ADAs)
The impact of ADAs on the safety and immunogenicity of sebelipase alfa was evaluated by testing for ADAs in participants who received sebelipase alfa in this open-label study. Blood samples for assessment were collected prior to study infusions at Week 2, Week 4, Week 8, Week 12, and every 12 weeks thereafter. Participants testing positive for ADAs were also tested for the presence of neutralizing antibodies that inhibited sebelipase alfa enzyme activity and/or cellular uptake. Any participant experiencing a moderate or severe infusion-associated reaction (IAR) was to have an additional assessment of ADAs at the next study visit (prior to study drug infusion); these participants were to also have serum samples collected at 1 to 2 hours after IAR onset and at the next study visit (prior to study drug infusion) for analysis of serum tryptase. The count of participants who became ADA positive and who tested positive for neutralizing antibodies are presented.
Time frame: Week 144
Population: Full Analysis Set: All participants who received at least 1 infusion of sebelipase alfa. The full analysis set was used for analysis of safety and efficacy.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 2-<4 Years | Participants Testing Positive For Anti-drug Antibodies (ADAs) | ADA Positive | 2 Participants |
| 2-<4 Years | Participants Testing Positive For Anti-drug Antibodies (ADAs) | Neutralizing Antibodies Positive | 0 Participants |
Secondary
Percent Change In Body Mass Index (BMI)-For-Age Percentile From Baseline To Week 144 In Pediatric Participants
To evaluate the effects of sebelipase alfa on growth parameters in pediatric participants (≤18 years old) presenting with evidence of growth delay, the percent change in the anthropometric parameter of BMI-for-age percentile from Baseline to Week 144 is reported. Anthropometric parameters were plotted on standard growth curves. When possible, historical data on growth parameters was also incorporated into the analyses. Percentiles and Z-scores for BMI-for-age were determined using standard growth charts appropriate to a participant's age on the date of the assessment: the World Health Organization standard growth chart for participants ≤2 years of age and the Centers for Disease Control standard growth chart for participants \>2 years of age.
Time frame: Baseline, Week 144
Population: Full Analysis Set: All pediatric participants who received at least 1 infusion of sebelipase alfa. The full analysis set was used for analysis of safety and efficacy.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2-<4 Years | Percent Change In Body Mass Index (BMI)-For-Age Percentile From Baseline To Week 144 In Pediatric Participants | 26.45 Percent Change | Standard Deviation 118.432 |
Secondary
Percent Change In Serum Lipids From Baseline To Week 144
The effect of sebelipase alfa on lipid metabolism was evaluated by measuring the change from baseline to Week 144 in 4 serum lipids: low-density lipoprotein cholesterol (LDL-C); high-density lipoprotein cholesterol (HDL-C); non-HDL-C; triglycerides. Blood samples for these clinical laboratory tests were collected at scheduled time points and analyzed by a central laboratory.
Time frame: Baseline, Week 144
Population: Full Analysis Set: All participants who received at least 1 infusion of sebelipase alfa. The full analysis set was used for analysis of safety and efficacy.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 2-<4 Years | Percent Change In Serum Lipids From Baseline To Week 144 | LDL-C | -37.5 Percent Change |
| 2-<4 Years | Percent Change In Serum Lipids From Baseline To Week 144 | HDL-C | 76.5 Percent Change |
| 2-<4 Years | Percent Change In Serum Lipids From Baseline To Week 144 | Non-HDL-C | -39.1 Percent Change |
| 2-<4 Years | Percent Change In Serum Lipids From Baseline To Week 144 | Triglycerides | -48.3 Percent Change |
| 4-18 Years | Percent Change In Serum Lipids From Baseline To Week 144 | Triglycerides | -15.8 Percent Change |
| 4-18 Years | Percent Change In Serum Lipids From Baseline To Week 144 | LDL-C | -29.2 Percent Change |
| 4-18 Years | Percent Change In Serum Lipids From Baseline To Week 144 | Non-HDL-C | -26.7 Percent Change |
| 4-18 Years | Percent Change In Serum Lipids From Baseline To Week 144 | HDL-C | 24.2 Percent Change |
| >18 Years | Percent Change In Serum Lipids From Baseline To Week 144 | Triglycerides | -22.0 Percent Change |
| >18 Years | Percent Change In Serum Lipids From Baseline To Week 144 | HDL-C | 6.1 Percent Change |
| >18 Years | Percent Change In Serum Lipids From Baseline To Week 144 | Non-HDL-C | -22.1 Percent Change |
| >18 Years | Percent Change In Serum Lipids From Baseline To Week 144 | LDL-C | -22.5 Percent Change |
Secondary
Shift In Child-Pugh Status From Baseline To Week 144
In order to evaluate the effects of sebelipase alfa on liver function, the number of participants with a shift in Child-Pugh status from Baseline to Week 144 is reported. The status is based on the Child-Pugh score, which is used in clinical practice to assess prognosis in individuals with chronic liver disease. Laboratory data were used in derivation of the score by summing individual scores (scored 1-3, with 3 indicating most severe) from clinical laboratory test results and physical examinations, including total serum bilirubin, serum albumin, prothrombin time, ascites, and hepatic encephalopathy. The total score was used to determine the Child-Pugh status, reported as Class A (score of 5 or 6), Class B (score of 7 to 9), or Class C (score of 10 to 15). Higher scores and higher categories represented a worse outcome. Data reported as 1 of 2 types of shifts in class: No Change from Baseline; Decline from Baseline.
Time frame: Baseline, Week 144
Population: Full Analysis Set: All participants who received at least 1 infusion of sebelipase alfa. The full analysis set was used for analysis of safety and efficacy.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 2-<4 Years | Shift In Child-Pugh Status From Baseline To Week 144 | No Change: B to B | 1 Participants |
| 2-<4 Years | Shift In Child-Pugh Status From Baseline To Week 144 | No Change: A to A | 16 Participants |
| 2-<4 Years | Shift In Child-Pugh Status From Baseline To Week 144 | Decline: A to B | 1 Participants |