Phase 1/2 Study of Vorinostat Therapy in Niemann-Pick Disease, Type C1
Status:
Completed
Trial end date:
2016-12-13
Target enrollment:
Participant gender:
Summary
Niemann-Pick disease type C (NPC) is a lethal, autosomal recessive, lysosomal storage
disorder characterized by neurodegeneration in early childhood and death in adolescence. The
causative genes NPC1 (about 95% of cases) and NPC2 (about 5% of cases) are involved in the
intracellular trafficking of lipids and cholesterol. Mutations on either of these genes lead
to progressive accumulation of unesterified cholesterol and other lipids in the central
nervous system (CNS). Vorinostat is a histone deacetylase inhibitor that has been shown in
vivo to increase mutant NPC1 protein levels and to reverse cellular accumulation of
unesterified cholesterol. Vorinostat has been labeled by the FDA for treatment of cutaneous
T-cell lymphoma. In this Phase I, non-randomized, open-label, single-center study, we plan to
study whether Vorinostat can be repurposed to treat patients with NPC1. Our primary objective
is to determine the safety and tolerability of Vorinostat in NPC1 disease. Our secondary
objectives will be to determine biochemical efficacy of Vorinostat to increase expression of
NPC1 protein and normalize lipid and protein biomarkers. This study will enroll up to 12 NPC1
patients and test the safety of two dose levels (200 and 400 mg). Drug will be administered
on a 3 days on/4 days off schedule for 3 months at each dose level. Patients will be
evaluated at the NIH Clinical Center at 0, 3 and 6 months. Safety will be assessed by adverse
events (AEs), clinical laboratory tests and physical examinations. Biochemical efficacy will
be assessed by measurement of serum and cerebral spinal fluid biomarkers. Clinical efficacy
will be evaluated by audiologic testing, assessment ataxia, and swallowing studies.
Phase:
Phase 1/Phase 2
Details
Lead Sponsor:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Collaborators:
Washington University School of Medicine Weill Medical College of Cornell University