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

• ClinicalTrials.gov Identifier: NCT01371825
• Recruitment Status: Completed
• First Posted: June 13, 2011
• Results First Posted: April 18, 2016
• Last Update Posted: January 30, 2019
• Sponsor: Alexion Pharmaceuticals
• Information provided by (Responsible Party): Alexion Pharmaceuticals

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Lysosomal Acid Lipase Deficiency; Wolman Disease	Drug: Sebelipase alfa (SBC-102)	Phase 2; Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 4, 2011
• Actual Primary Completion Date: January 3, 2018
• Actual Study Completion Date: January 3, 2018

Arms and Interventions

Arm

Intervention/treatment

Experimental: Open-Label Sebelipase Alfa; 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); 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.

Outcome Measures

Primary Outcome Measures :

1. Percentage Of Participants In The Primary Efficacy Analysis Set (PES) Surviving To 12 Months Of Age [ Time Frame: Month 12 ]
   The primary efficacy endpoint was the percentage of participants (%) in the PES who survived to at least 12 months of age.

Secondary Outcome Measures :

1. Percentage Of Participants Surviving Beyond 12 Months Of Age [ Time Frame: 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.
2. Median Age At Death [ Time Frame: 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.
3. Change From Baseline To Months 12, 24, 36, 48, And 60 In Weight For Age (WFA) Percentiles [ Time Frame: 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.
4. Number Of Participants With Stunting, Wasting, Or Underweight [ Time Frame: 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.
5. Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Transaminases (ALT And AST) [ Time Frame: 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).
6. Change From Baseline To Months 12, 24, 36, 48, And 60 In Serum Ferritin [ Time Frame: 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.
7. Number Of Participants Achieving And Maintaining Transfusion-free Hemoglobin Normalization [TFHN] [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: up to 24 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

Irvine, California, United States, 92697

Egypt

Cairo, Egypt, 11771

France

Grenoble, France, 38700

Paris, France, 75015

Ireland

Dublin, Ireland, 1

United Kingdom

London, United Kingdom, SE1 7EH

Manchester, United Kingdom, M13 9WL

Sponsors and Collaborators

Alexion Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Alexion Pharmaceuticals:

Study Protocol  [PDF] January 5, 2016

Statistical Analysis Plan  [PDF] March 7, 2014

More Information

Publications:

Jones SA, Rojas-Caro S, Quinn AG, Friedman M, Marulkar S, Ezgu F, Zaki O, Gargus JJ, Hughes J, Plantaz D, Vara R, Eckert S, Arnoux JB, Brassier A, Le Quan Sang KH, Valayannopoulos V. Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study. Orphanet J Rare Dis. 2017 Feb 8;12(1):25. doi: 10.1186/s13023-017-0587-3.

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01371825
• Obsolete Identifiers: NCT01473875
• Other Study ID Numbers: LAL-CL03
• First Posted: June 13, 2011
• Results First Posted: April 18, 2016
• Last Update Posted: January 30, 2019
• Last Verified: January 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Alexion Pharmaceuticals:

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

Additional relevant MeSH terms:

Wolman Disease; Failure to Thrive; Cholesterol Ester Storage Disease; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Infant, Newborn, Diseases; Lipid Metabolism Disorders; Metabolic Diseases