Phase 1/2 Study of Vorinostat Therapy in Niemann-Pick Disease, Type C1

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.

-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 exclusion criteria
will not apply to a female currently menstruating who has no history of renal disease
or other evidence of renal impairment (eg hypertension, serum creatinine above upper
limit of normal, history of renal disease). Urinalyis will be repeated after menses
has ended and drug discontinued if hematuria persists. Efforts will be made to avoid
menses in scheduling the initial admission.

15. Proteinuria (1+ protein on urinalysis) Patient will not be excluded if urine
protein/creatinine ratio is normal or if classified as benign by either patient's
primary medical provider or upon obtaining a nephrology consult.

16. Serum potassium or Magnesium outside of the normal laboratory range prior to
initiation of vorinostat therapy.

17. Diabetes or a fasting glucose greater than 106 mg/dl.

18. Active pulmonary disease, oxygen requirement or clinically significant history of
decreased blood oxygen saturation, pulmonary therapy, or requiring active suction.

19. Patients with uncontrolled seizures per either of the criteria below.

1. Unstable frequency, type or duration of seizures. Quantified by a seizure log
over the two months prior to enrollment.

2. Patients requiring antiepileptic medication changes (other than dose adjustments
for weight) in the two months prior to enrollment, or requiring three or more
antiepileptic medications to control seizures.

20. Use of another HDAC inhibitor or compounds with established HDAC inhibitory activity,
including valproic acid, unless discontinued at least 2 months prior to enrollment.

21. History of a thromboembolic event (such as DVT or Pulmonary embolism).

22. Patients, who in the opinion of the investigators, are unable to comply with the
protocol or have specific health concerns that would potentially increase the risk of
participation.