Phase 1/2 Study of Vorinostat Therapy in Niemann-Pick Disease, Type C1
Condition: Neimann-Pick Disease
MeSH terms: Pick Disease of the Brain; Aphasia, Primary Progressive; Frontotemporal Dementia; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Detailed description: 
      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.
    

Intervention name(s): Vorinostat
Intervention type(s): Drug
Intervention description(s): Histone deactylase inhibitor
Intervention MeSH terms: Vorinostat
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Niemann Pick Disease, Type C1; Phase I, Phase 2; Vorinostat