Phase 1/2a Study of 2-Hydroxypropyl-Beta-Cyclodextrin Therapy for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C
Niemann-Pick disease, type C (NPC) is a lethal, autosomal recessive, lysosomal storage disorder characterized by neurodegeneration in early childhood and death in adolescence. NPC results from mutation of either the Niemann-Pick C1 disease (NPC1) (\ 95% of cases) or NPC2 genes. NPC is characterized by the endolysosomal storage of unesterified cholesterol and lipids in both the central nervous system and peripheral tissues such as the liver. Individuals with NPC demonstrate progressive central nervous system decline including inability to coordinate balance, gait, extremity and eye movements. Acute liver disease in the newborn/infant period is frequently observed, but subsequently resolves. However, chronic, sub-clinical liver disease persists. Intrathecal 2-Hydroxypropyl-β-Cyclodextrin (HP-β-CD, VTS-270), also known as adrabetadex, has proven effective in reducing the signs and prolonging life in animal models and Phase 1/2a data support efficacy in NPC1 patients. Adrabetadex (VTS-270) also has been shown to be effective in treating liver disease in the NPC1 cat. This Phase 1/2a, open-label, multiple ascending dose trial will evaluate whether adrabetadex (VTS-270) administered intravenously is effective in treating acute liver disease in NPC1 infants.
• Age 0 to 6 months of age at time of enrollment, both genders, and any race/ethnicity.
• Diagnosis of NPC (either NPC1 or NPC2) based upon meeting any of the two following conditions:
• A. Two variants classified as pathogenic or likely pathogenic in NPC1/NPC2 on clinical laboratory testing, or B. One variant classified as pathogenic or likely pathogenic on clinical laboratory testing and a positive NPC biochemical marker (oxysterol or bile acid biomarker or PPCS/Lyso509) test, if acid sphingomyelinase deficiency and cholesterol ester storage disease have been excluded either by clinical molecular testing of the SMPD1 and LIPA genes or by clinical biochemical assay for acid sphingomyelinase and lysosomal acid lipase enzymes (or a combination of enzymatic and molecular testing).
• Variants will be interpreted using the American College of Medical Genetics guidelines for the interpretation of sequence variants (2015) and testing must be performed by a CLIA-certified laboratory.
• Subjects with evidence of NPC-related liver disease as defined by direct bilirubin (DB) \>2mg/dL or DB/total bilirubin ratio \>0.2.
• Ability to travel to a research site.
• Willing to participate in all aspects of trial design including serial blood collections.
• Parent / guardian must provide written informed consent to participate in the study. Because of the age range intended for inclusion, assent will not possible.