Neimann-Pick Disease
Conditions
Keywords
Niemann Pick Disease, Type C1, Phase I, Phase 2, Vorinostat
Brief 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.
Interventions
DRUGVorinostat
Histone deactylase inhibitor
Sponsors
Washington University School of Medicine
Weill Medical College of Cornell University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
-INCLUSION CRITERIA: 1. Aged greater than or equal to 18 and less than or equal to 60 years old at time of enrollment, either gender, and any ethnicity. 2. Diagnosis of NPC1 based upon one of the following: * Two NPC1 mutations; * Positive filipin staining and at least one NPC1 mutation; * Vertical supranuclear gaze palsy (VSNGP) in combination with either: * One NPC1 mutation, or * Positive filipin staining and no pathogenic NPC2 mutations. 3. Patients with at least one neurological manifestation of NPC1. For example, but not limited to, hearing loss, vertical supranuclear gaze palsy, ataxia, dementia, dystonia, seizures, dysarthria, or dysphagia. 4. A patient s cultured skin fibroblasts when treated with 10 M Vorinostat must exhibit a reduction in the filipin lysosomal storage organelle ratio equivalent to 75% of the response measured in NPC1 positive control fibroblasts. 5. Ability to travel to the NIH Clinical Center repeatedly for evaluation and follow-up. 6. If taking miglustat, the patient must have been taking a constant dose of the medication for no less than three months prior to baseline evaluation and must be willing to maintain that dose level for the duration of the trial. 7. Willing to discontinue all non-prescription supplements, with the exception of an age-appropriate multivitamin. 8. Women of reproductive age must be willing to use an effective method of contraception for the duration of the trial. 9. Willing to participate in all aspects of trial design including serial blood and CSF collections.
Exclusion criteria
1. Aged below 18 or above 60 years of age at enrollment in the trial. 2. Severe manifestations of NPC1 that would interfere with the patient s ability to comply with the requirements of this protocol. 3. Neurologically asymptomatic patients. 4. Patients who have received any form of cyclodextrin or an HDACi in an attempt to treat NPC1. 5. History of hypersensitivity reactions to Vorinostat or components of the formulation. 6. Pregnancy or breastfeeding at any time during the study. 7. Patients with suspected infection of the CNS or any systemic infection. 8. Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1,500 per microliter. 9. Thrombocytopenia defined as a platelet count less than 75,000 per microliter, or a history of greater than or equal to grade 2 thrombocytopenia (50,000-75,000 platelets/microliter). 10. Prior use of anticoagulants or history/presence of a bleeding disorder. 11. Hepatic laboratory parameters (aspartate aminotransferase (AST), alanine aminotransferase, (ALT)) greater than four-times upper limit of normal. 12. Presence of anemia defined as two standard deviations below normal for age and gender. 13. Serum creatinine level greater than 1.5 times the upper limit of normal. 14. Hematuria (greater than15 RBC/mcL or positive hemoglobin). This
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Tolerabilty of 200 mg Vorinostat in Niemann-Pick Disease, Type C1 | 3 months | The number of Niemann-Pick Disease, type C1 patients completing 3 month 200 mg phase |
| Number of Participants With Tolerabilty of 400 mg Vorinostat in Niemann-Pick Disease, Type C1 | 3 months | The number of Niemann-Pick Disease, type C1 patients completing 3 month 400 mg phase |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biochemical Efficacy as Measured by Serum Cathepsin D | 6 months | Serum concentration of Cathepsin D. Cathepsin D is an aspartyl protease involved in protein catabolism and tissue remodeling. Cathepsin D normal range = 220-515 ng/ml. |
| Biochemical Efficacy as Measured by Serum LGALS3 | 6 months | Serum concentration of LGALS3 (galectin-3). Galectin-3 is a carbohydrate-binding lectin whose expression is associated with inflammatory cells including macrophages, neutrophils, and mast cells. LGALS3 normal range = 1.4-5.3 ng/ml. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat Trial participants were treated with Vorinostat (3 days on/4 days off regimen) to limit toxicity. Subjects were initially dosed with 200 mg (two 100 mg capsules) by mouth daily for three months, followed by dose escalation to 400 mg (four 100 mg capsules) by mouth daily for three months. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Vorinostat |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 11 / 12 |
| serious Total, serious adverse events | 5 / 12 |
Outcome results
Primary
Number of Participants With Tolerabilty of 200 mg Vorinostat in Niemann-Pick Disease, Type C1
The number of Niemann-Pick Disease, type C1 patients completing 3 month 200 mg phase
Time frame: 3 months
Population: All participants who started study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat | Number of Participants With Tolerabilty of 200 mg Vorinostat in Niemann-Pick Disease, Type C1 | 12 Participants |
Primary
Number of Participants With Tolerabilty of 400 mg Vorinostat in Niemann-Pick Disease, Type C1
The number of Niemann-Pick Disease, type C1 patients completing 3 month 400 mg phase
Time frame: 3 months
Population: All participants completing 200 mg phase and starting 400 mg phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat | Number of Participants With Tolerabilty of 400 mg Vorinostat in Niemann-Pick Disease, Type C1 | 11 Participants |
Secondary
Biochemical Efficacy as Measured by Serum Cathepsin D
Serum concentration of Cathepsin D. Cathepsin D is an aspartyl protease involved in protein catabolism and tissue remodeling. Cathepsin D normal range = 220-515 ng/ml.
Time frame: 6 months
Population: All participants completing both 200 and 400 mg phases
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vorinostat | Biochemical Efficacy as Measured by Serum Cathepsin D | 625.3 ng/mL | Standard Deviation 183.8 |
Secondary
Biochemical Efficacy as Measured by Serum Cathepsin D
Serum concentration of Cathepsin D. Cathepsin D is an aspartyl protease involved in protein catabolism and tissue remodeling. Cathepsin D normal range = 220-515 ng/ml.
Time frame: Baseline
Population: All participants who started study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vorinostat | Biochemical Efficacy as Measured by Serum Cathepsin D | 648.2 ng/mL | Standard Deviation 266 |
Secondary
Biochemical Efficacy as Measured by Serum LGALS3
Serum concentration of LGALS3 (galectin-3). Galectin-3 is a carbohydrate-binding lectin whose expression is associated with inflammatory cells including macrophages, neutrophils, and mast cells. LGALS3 normal range = 1.4-5.3 ng/ml.
Time frame: 6 months
Population: All participants completing both 200 and 400 mg phases
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vorinostat | Biochemical Efficacy as Measured by Serum LGALS3 | 6.565 ng/mL | Standard Deviation 4.775 |
Secondary
Biochemical Efficacy as Measured by Serum LGALS3
Serum concentration of LGALS3 (galectin-3). Galectin-3 is a carbohydrate-binding lectin whose expression is associated with inflammatory cells including macrophages, neutrophils, and mast cells. LGALS3 normal range = 1.4-5.3 ng/ml.
Time frame: Baseline
Population: All participants who started study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vorinostat | Biochemical Efficacy as Measured by Serum LGALS3 | 6.667 ng/mL | Standard Deviation 2.303 |