Clinical trial NCT02193867: Clinical Study In Infants With Rapidly Progressive Lysosomal Acid Lipase Deficiency
Official title: A Phase 2, Open Label, Multicenter Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Sebelipase Alfa in Infants With Rapidly Progressive Lysosomal Acid Lipase Deficiency
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Lysosomal Acid Lipase Deficiency
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
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2014-07-18
Enrollment: 10
Sex: ALL
Maximum age (years): 8
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This was an open-label, repeat-dose, study of sebelipase alfa in infants with rapidly progressive lysosomal acid lipase deficiency (LAL-D). Eligible participants received once-weekly infusions of sebelipase alfa for up to 3 years.

Detailed description: Lysosomal acid lipase deficiency is a rare autosomal recessive lipid storage disorder that is caused by a marked decrease or complete absence of the LAL enzyme, leading to the accumulation of lipids, predominately cholesteryl esters and triglycerides, in various tissues and cell types. In the liver, accumulation of lipids in hepatocytes and macrophages leads to hepatomegaly, fibrosis, cirrhosis, liver dysfunction, and hepatic failure. In the small intestine, lipid-laden macrophage accumulation in the lamina propria leads to profound malabsorption.

Lysosomal acid lipase deficiency presenting in infancy is an extremely rare form of the disease characterized by profound malabsorption, growth failure, and hepatic failure that is usually fatal within the first 6 months of life.

Eligibility criteria: Inclusion Criteria:

1. Participant's parent or legal guardian (if applicable) consent to participation in the study
2. Confirmation of documented decreased LAL activity relative to the normal range of the lab performing the assay or confirmation of LAL-D diagnosis as determined by a Sponsor-approved central laboratory
3. Substantial clinical concerns, in the opinion of Investigator and Sponsor, of rapid disease progression requiring urgent medical intervention including, but not restricted to the following:

   * Marked abdominal distension and hepatomegaly
   * Failure to thrive
   * Disturbance of coagulation
   * Severe anemia
   * Sibling with rapidly progressive course of LAL-D

Exclusion Criteria:

1. Clinically important concurrent disease
2. Participant was \> 8 months of age at the time of first dosing
3. Participant received an investigational medicinal product other than sebelipase alfa within 14 days prior to the first dose of sebelipase alfa in this study
4. Myeloablative preparation, or other systemic pre-transplant conditioning, for hematopoietic stem cell or liver transplantation
5. Previous hematopoietic stem cell or liver transplant
6. Known hypersensitivity to eggs

Primary outcomes:
measure: Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs)
timeFrame: Screening through Month 37
Secondary outcomes:
measure: Percentage Of Participants Surviving To 12, 18, 24, And 36 Months Of Age
timeFrame: Baseline through Month 12, Month 18, Month 24, and Month 36
measure: Median Age At Death
timeFrame: Baseline through Month 36
measure: Change From Baseline In Percentiles For Weight For Age (WFA) At 12, 24, And 36 Months
timeFrame: Baseline, Month 12, Month 24, and Month 36
measure: Number Of Participants With Stunting, Wasting, Or Underweight At Baseline, 12, 24, And 36 Months
timeFrame: Baseline to Month 12, Month 24, and Month 36
measure: Change From Baseline In Serum Transaminases (ALT And AST) At Month 12, 24, And 36
timeFrame: Baseline, Month 12, Month 24, and Month 36
measure: Change From Baseline In Serum Ferritin At Month 12, 24, And 36
timeFrame: Baseline, Month 12, Month 24, and Month 36
measure: Number Of Participants Achieving And Maintaining Transfusion-free Hemoglobin Normalization (TFHN)
timeFrame: Baseline through Month 36
Other outcomes:
Locations:
city: Phoenix
country: United States
state: Arizona
city: Kuopio
country: Finland
city: Naples
country: Italy
city: Birmingham
country: United Kingdom
city: Manchester
country: United Kingdom
Study officials:
References:
citation: Balwani M, Breen C, Enns GM, Deegan PB, Honzik T, Jones S, Kane JP, Malinova V, Sharma R, Stock EO, Valayannopoulos V, Wraith JE, Burg J, Eckert S, Schneider E, Quinn AG. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Hepatology. 2013 Sep;58(3):950-7. doi: 10.1002/hep.26289. Epub 2013 Mar 28.
citation: Jones SA, Valayannopoulos V, Schneider E, Eckert S, Banikazemi M, Bialer M, Cederbaum S, Chan A, Dhawan A, Di Rocco M, Domm J, Enns GM, Finegold D, Gargus JJ, Guardamagna O, Hendriksz C, Mahmoud IG, Raiman J, Selim LA, Whitley CB, Zaki O, Quinn AG. Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants. Genet Med. 2016 May;18(5):452-8. doi: 10.1038/gim.2015.108. Epub 2015 Aug 27.
citation: 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.