Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Sebelipase Alfa in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open Label, Multicenter, Dose Escalation Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of SBC-102 (Sebelipase Alfa) in Children With Growth Failure Due to Lysosomal Acid Lipase Deficiency

Conditions
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Lysosomal Acid Lipase Deficiency, Wolman Disease

Intervention / Treatment
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* Drug: Sebelipase alfa (SBC-102)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 24 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label Sebelipase Alfa<br>Participants received intravenous (IV) infusions of sebelipase alfa during the open-label treatment. Participants initially received 0.35 milligrams (mg)/kilogram (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 an every other week (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. | Drug: Sebelipase alfa (SBC-102)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to Month 18, Month 24, Month 36, Month 48, and Month 60 | 
| 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. | Baseline to Week 260 | 
| 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. | Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60 | 
| 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. | Baseline to Month 12, Month 24, Month 36, Month 48, and Month 60 | 
| 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). | Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60 | 
| 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. | Baseline, Month 12, Month 24, Month 36, Month 48, and Month 60 | 
| 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. | Baseline to Month 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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