Lysosomal Acid Lipase Deficiency, Wolman Disease
Conditions
Keywords
LIPA, Wolman Disease, Wolman Phenotype, Acid Lipase Deficiency, Acid Cholesteryl Hydrolase, Acid Lipase Disease Deficiency, type 2, Cholesteryl Ester Storage Disease (CESD), Cholesteryl Ester Hydrolase Deficiency, Early Onset Lysosomal Acid Lipase Deficiency (Wolman Disease), LAL Deficiency, Late Onset Lysosomal Acid Lipase Deficiency (CESD), Wolman Disease (early onset LAL Deficiency), Related Disorders:, Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH), Alcoholic Liver Disease, Cryptogenic Cirrhosis, Niemann-Pick Disease (NPD) Type C, Chanarin Dorfman Syndrome
Brief summary
This was an open-label, repeat-dose, intra-participant dose-escalation study of SBC-102 (sebelipase alfa) in children with growth failure due to lysosomal acid lipase (LAL) Deficiency. Eligible participants received once-weekly (qw) infusions of sebelipase alfa for up to 5 years.
Detailed description
LAL Deficiency is a rare autosomal-recessive lipid storage disorder that is caused by a marked decrease or almost complete absence of LAL, leading to the accumulation of lipids, predominately cholesteryl esters and triglycerides, in various tissues and cell types. In the liver, accumulation of lipids leads to hepatomegaly, liver dysfunction, and hepatic failure. Although a single disease, LAL Deficiency presents as a clinical continuum with 2 major phenotypes, Cholesteryl Ester Storage Disease (CESD) and Wolman Disease. Early-onset LAL Deficiency (Wolman Disease) is extremely rare, with an estimated incidence of less than 2 lives per million. It is characterized by profound malabsorption, growth failure, and hepatic failure, and is usually fatal in the first year of life.
Interventions
DRUGSebelipase alfa (SBC-102)
Sebelipase alfa is a recombinant human lysosomal acid lipase enzyme. The investigational medicinal product is an enzyme replacement therapy intended for treatment of participants with LAL Deficiency. Dosing occurred qw for up to 5 years.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 24 Months
Healthy volunteers
No
Inclusion criteria
* Participant's parent or legal guardian provided written informed consent/permission prior to any study procedures. * Male or female child with documented decreased LAL activity relative to the normal range of the laboratory performing the assay or documented result of molecular genetic testing (2 mutations) confirming a diagnosis. * Growth failure with onset before 6 months of age.
Exclusion criteria
* Clinically important concurrent disease or comorbidities. * Had received an investigational product other than sebelipase alfa within 14 days prior to the first dose. * Participant was older than 24 months of age. * Myeloablative preparation, or other systemic pre-transplant conditioning, for hematopoietic stem cell or liver transplant. * Previous hematopoietic stem cell or liver transplant. * Known hypersensitivity to eggs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Of Participants In The Primary Efficacy Analysis Set (PES) Surviving To 12 Months Of Age | Month 12 | The primary efficacy endpoint was the percentage of participants (%) in the PES who survived to at least 12 months of age. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Age At Death | Baseline to Week 260 | Participants in the PES who died during the study, including 3 participants who died after having received between 1 and 4 infusions of sebelipase alfa and 1 participant who died after approximately 40 weeks on treatment. |
| Change From Baseline To Months 12, 24, 36, 48, And 60 In Weight For Age (WFA) Percentiles | Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60 | Baseline is defined as the last measurement prior to the first infusion of sebelipase alfa. |
| Number Of Participants With Stunting, Wasting, Or Underweight | Baseline to Month 12, Month 24, Month 36, Month 48, and Month 60 | The number of participants who met criteria for the following dichotomous indicators of under nutrition were reported. These indicators included the following: * Stunting was defined as at least 2 standard deviations below the median for length-for-age/height-for-age; * Wasting was defined as wasting at least 2 standard deviations below the median for weight-for-length/weight-for-height; and * Underweight was defined as at least 2 standard deviations below the median for WFA. |
| Percentage Of Participants Surviving Beyond 12 Months Of Age | Baseline to Month 18, Month 24, Month 36, Month 48, and Month 60 | The percentage of participants in the PES who survived to at least 18 months of age. |
| Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Ferritin | Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60 | The median change in serum ferritin from Baseline to Months 12, 24, 36, 48, and 60 is presented. |
| Number Of Participants Achieving And Maintaining Transfusion-free Hemoglobin Normalization [TFHN] | Baseline to Month 60 | The number of participants achieving and maintaining TFHN are presented. For TFHN to be achieved, the participant must a) have had 2 post-baseline measurements of hemoglobin at least 4 weeks apart that were both above the age-adjusted lower limit of normal; b) have had no known additional measurements of hemoglobin that were below the age-adjusted lower limit of normal during the (minimum) 4-week period; and c) have had no transfusions during the (minimum) 4-week period, and also no transfusions for 2 weeks prior to the first hemoglobin measurement in the (minimum) 4-week period. For TFHN to be maintained, the participant must have been transfusion-free beginning at Week 6 and had all hemoglobin assessments above the lower limit of normal beginning in Week 8 and lasting at least 13 weeks. |
| Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) | Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60 | Change from Baseline to Months 12, 24, 36, 48, and 60 for alanine aminotransferase (ALT) and aspartate aminotransferase (AST). |
Countries
Egypt, France, Ireland, United Kingdom, United States
Participant flow
Recruitment details
A total of 8 centers participated in this study in the United Kingdom (UK), United States (US), France, Turkey, Ireland, and Egypt.
Pre-assignment details
To assess eligibility, participants were screened for a period of up to 3 weeks prior to enrollment. 11 participants were screened, and 2 participants died during screening. The other 9 participants, all of whom were ≤8 months of age on the date of enrollment, met all eligibility criteria and were enrolled, treated, and analyzed.
Participants by arm
| Arm | Count |
|---|---|
| Open-Label Sebelipase Alfa Participants received IV infusions of sebelipase alfa during the open-label treatment. Participants initially received 0.35 mg/kg qw and escalated to 1 mg/kg qw after demonstrating acceptable safety and tolerability during at least 2 infusions. One participant initiated treatment under a Temporary Use Authorization prior to enrollment, wherein the participant's dose was gradually escalated from 0.2 to 1 mg/kg over 4 weeks; the participant started the study at this dose. Participants on treatment for 96 weeks and on stable qw dosing for 24 weeks could be switched to a qow dosing schedule. In the event of protocol-defined disease progression at any time during treatment, a participant could receive a dose increase from 1 to 3 mg/kg qw and, if necessary, a dose increase to 5 mg/kg qw with Safety Committee approval. Participants dosed qow who met dose-escalation criteria were reverted to qw dosing or escalated to 1 or 3 mg/kg qow. | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 4 |
Baseline characteristics
| Characteristic | Open-Label Sebelipase Alfa |
|---|---|
| Age, Categorical <=18 years | 9 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 3.41 months |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 9 / 9 |
Outcome results
Primary
Percentage Of Participants In The Primary Efficacy Analysis Set (PES) Surviving To 12 Months Of Age
The primary efficacy endpoint was the percentage of participants (%) in the PES who survived to at least 12 months of age.
Time frame: Month 12
Population: The PES included participants who received any amount of sebelipase alfa and who were ≤8 months of age on the date of their first infusion of sebelipase alfa. All 9 participants were included in the PES.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open-Label Sebelipase Alfa | Percentage Of Participants In The Primary Efficacy Analysis Set (PES) Surviving To 12 Months Of Age | 67 Percentage of participants |
Secondary
Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Ferritin
The median change in serum ferritin from Baseline to Months 12, 24, 36, 48, and 60 is presented.
Time frame: Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60
Population: The PES included participants who received any amount of sebelipase alfa and who were ≤8 months of age on the date of their first infusion of sebelipase alfa. All 9 participants were included in the PES.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Ferritin | Month 12 | -294.40 micrograms/Liter (µg/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Ferritin | Month 24 | -239.00 micrograms/Liter (µg/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Ferritin | Month 36 | -262.95 micrograms/Liter (µg/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Ferritin | Month 48 | -268.00 micrograms/Liter (µg/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Ferritin | Month 60 | -213.00 micrograms/Liter (µg/L) |
Secondary
Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST)
Change from Baseline to Months 12, 24, 36, 48, and 60 for alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
Time frame: Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60
Population: The PES included participants who received any amount of sebelipase alfa and who were ≤8 months of age on the date of their first infusion of sebelipase alfa. All 9 participants were included in the PES.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) | ALT, Month 12 | -13.50 units/Liter (U/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) | ALT, Month 24 | -5.00 units/Liter (U/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) | ALT, Month 36 | -4.00 units/Liter (U/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) | ALT, Month 48 | -27.50 units/Liter (U/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) | ALT, Month 60 | -27.00 units/Liter (U/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) | AST, Month 12 | -43.50 units/Liter (U/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) | AST, Month 24 | -30.00 units/Liter (U/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) | AST, Month 36 | -33.00 units/Liter (U/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) | AST, Month 48 | -51.00 units/Liter (U/L) |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) | AST, Month 60 | -40.00 units/Liter (U/L) |
Secondary
Change From Baseline To Months 12, 24, 36, 48, And 60 In Weight For Age (WFA) Percentiles
Baseline is defined as the last measurement prior to the first infusion of sebelipase alfa.
Time frame: Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60
Population: The PES included participants who received any amount of sebelipase alfa and who were ≤8 months of age on the date of their first infusion of sebelipase alfa. All 9 participants were included in the PES.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Weight For Age (WFA) Percentiles | Month 12 | 7.469 WFA Percentile |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Weight For Age (WFA) Percentiles | Month 24 | 21.787 WFA Percentile |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Weight For Age (WFA) Percentiles | Month 36 | 14.037 WFA Percentile |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Weight For Age (WFA) Percentiles | Month 48 | 15.770 WFA Percentile |
| Open-Label Sebelipase Alfa | Change From Baseline To Months 12, 24, 36, 48, And 60 In Weight For Age (WFA) Percentiles | Month 60 | 19.869 WFA Percentile |
Secondary
Median Age At Death
Participants in the PES who died during the study, including 3 participants who died after having received between 1 and 4 infusions of sebelipase alfa and 1 participant who died after approximately 40 weeks on treatment.
Time frame: Baseline to Week 260
Population: Participants in the PES who died during the study were included in this analysis. The PES included all 9 participants who received any amount of sebelipase alfa and who were ≤8 months of age on the date of their first infusion of sebelipase alfa.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open-Label Sebelipase Alfa | Median Age At Death | 3.63 months |
Secondary
Number Of Participants Achieving And Maintaining Transfusion-free Hemoglobin Normalization [TFHN]
The number of participants achieving and maintaining TFHN are presented. For TFHN to be achieved, the participant must a) have had 2 post-baseline measurements of hemoglobin at least 4 weeks apart that were both above the age-adjusted lower limit of normal; b) have had no known additional measurements of hemoglobin that were below the age-adjusted lower limit of normal during the (minimum) 4-week period; and c) have had no transfusions during the (minimum) 4-week period, and also no transfusions for 2 weeks prior to the first hemoglobin measurement in the (minimum) 4-week period. For TFHN to be maintained, the participant must have been transfusion-free beginning at Week 6 and had all hemoglobin assessments above the lower limit of normal beginning in Week 8 and lasting at least 13 weeks.
Time frame: Baseline to Month 60
Population: Participants in the PES who received treatment with sebelipase alfa for at least 4 weeks (and could therefore be assessed for short-term TFHN). The PES included participants who received any amount of sebelipase alfa and who were ≤ 8 months of age on the date of their first infusion of sebelipase alfa.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open-Label Sebelipase Alfa | Number Of Participants Achieving And Maintaining Transfusion-free Hemoglobin Normalization [TFHN] | Achieved TFHN | 6 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants Achieving And Maintaining Transfusion-free Hemoglobin Normalization [TFHN] | Maintained TFHN | 2 Participants |
Secondary
Number Of Participants With Stunting, Wasting, Or Underweight
The number of participants who met criteria for the following dichotomous indicators of under nutrition were reported. These indicators included the following: * Stunting was defined as at least 2 standard deviations below the median for length-for-age/height-for-age; * Wasting was defined as wasting at least 2 standard deviations below the median for weight-for-length/weight-for-height; and * Underweight was defined as at least 2 standard deviations below the median for WFA.
Time frame: Baseline to Month 12, Month 24, Month 36, Month 48, and Month 60
Population: The PES included participants who received any amount of sebelipase alfa and who were ≤8 months of age on the date of their first infusion of sebelipase alfa. All 9 participants were included in the PES.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Stunting, Baseline | 4 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Stunting, Month 12 | 1 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Stunting, Month 24 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Stunting, Month 36 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Stunting, Month 48 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Stunting, Month 60 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Wasting, Baseline | 2 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Wasting, Month 12 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Wasting, Month 24 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Wasting, Month 36 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Wasting, Month 48 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Wasting, Month 60 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Underweight, Baseline | 2 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Underweight, Month 12 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Underweight, Month 24 | 1 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Underweight, Month 36 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Underweight, Month 48 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | Underweight, Month 60 | 0 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | No Stunting, Wasting, or Underweight, Baseline | 4 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | No Stunting, Wasting, or Underweight, Month 12 | 3 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | No Stunting, Wasting, or Underweight, Month 24 | 4 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | No Stunting, Wasting, or Underweight, Month 36 | 5 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | No Stunting, Wasting, or Underweight, Month 48 | 5 Participants |
| Open-Label Sebelipase Alfa | Number Of Participants With Stunting, Wasting, Or Underweight | No Stunting, Wasting, or Underweight, Month 60 | 5 Participants |
Secondary
Percentage Of Participants Surviving Beyond 12 Months Of Age
The percentage of participants in the PES who survived to at least 18 months of age.
Time frame: Baseline to Month 18, Month 24, Month 36, Month 48, and Month 60
Population: Evaluable participants in the PES, which included participants who received any amount of sebelipase alfa and who were ≤ 8 months of age on the date of their first infusion of sebelipase alfa. There were 2 non-evaluable participants at Month 60, defined as participants who were alive, still in the study, and had not yet reached 60 months of age.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Open-Label Sebelipase Alfa | Percentage Of Participants Surviving Beyond 12 Months Of Age | Survival Through 18 Months of Age | 56 Percentage of participants |
| Open-Label Sebelipase Alfa | Percentage Of Participants Surviving Beyond 12 Months Of Age | Survival Through 24 Months of Age | 56 Percentage of participants |
| Open-Label Sebelipase Alfa | Percentage Of Participants Surviving Beyond 12 Months Of Age | Survival Through 36 Months of Age | 56 Percentage of participants |
| Open-Label Sebelipase Alfa | Percentage Of Participants Surviving Beyond 12 Months Of Age | Survival Through 48 Months of Age | 56 Percentage of participants |
| Open-Label Sebelipase Alfa | Percentage Of Participants Surviving Beyond 12 Months Of Age | Survival Through 60 Months of Age | 43 Percentage of participants |