Combined Intrathecal and Intravenous VTS-270 Therapy for Liver and Neurological Disease Associated With 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. NPC
results from mutation of either the NPC1 (approximately 95% of cases) or NPC2 genes.
Biochemically, 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 cerebellar ataxia and dementia. Acute
cholestatic liver disease is frequently observed in the neonatal/infantile period but
subsequently resolves. However, chronic, sub-clinical liver disease persists. Intrathecal
2-hydroxypropyl-beta-cyclodextrin (HPbetaCD, VTS-270) has proven effective in reducing signs
and prolonging life in NPC1 animal models, and Phase 1/2a data support efficacy in NPC1
patients. Parenteral administration of VTS-270 has also been shown to be effective in
treating liver disease in the NPC1 cat.

In this Phase 1/2a, open-label, randomized, parallel dose, single-center study, we will
examine whether VTS-270 can be used to treat chronic subacute liver disease in NPC1 patients.
Our primary objective is to determine the safety and tolerability of intravenous VTS-270 in
NPC1 disease. Secondary objectives will be to evaluate the efficacy of VTS-270 to reduce
plasma cholestane-3beta,5alpha,6beta-triol, an NPC1-specific pharmacodynamic biomarker, and
to normalize the degree of liver injury. Exploratory testing will include lipid and protein
biomarkers. This study will evaluate three dose levels (500, 1000 and 1500 mg/kg)
administered monthly for twelve months. Safety will be assessed by adverse event recording,
clinical laboratory testing and physical examination. Clinical efficacy will be evaluated by
assessment of liver chemistries, determination of liver size, and changes in liver
histopathology. Biochemical efficacy will be assessed by measurement of plasma
cholestane-3beta,5alpha,6beta-triol and other biomarkers.

- INCLUSION CRITERIA:

1. Age greater than or equal to 3 and less than or equal to 60 years old at time of
enrollment

2. Diagnosis of NPC1 based upon one of the following:

A. Two NPC1 mutations

B. Biochemical Positive for NPC (oxysterol/bile acid and sphingomyelinase levels
consistent with a diagnosis of NPC) and one NPC1 mutation

C. Biochemical Positive for NPC (oxysterol/bile acid and sphingomyelinase levels
consistent with a diagnosis of NPC) and no NPC2 mutations and at least one
neurological sign/symptom consistent with NPC1

3. Evidence of NPC1-related liver disease as defined by one of the following:

A. Plasma aspartate aminotransferase (AST) greater than or equal to 1.5-times
age-appropriate upper limit of normal

B. Plasma aspartate aminotransferase (AST) greater than or equal to 1.25-times
age-appropriate upper limit of normal and plasma alanine aminotransferase (ALT) >
1.25-times age-appropriate upper limit of normal

C. Plasma aspartate aminotransferase (AST) greater than or equal to 1.25-times
age-appropriate upper limit of normal and AST/ALT ratio greater than or equal to
2.0

4. Ability to travel to the NIH Clinical Center repeatedly for evaluation and
follow-up.

5. Willingness to discontinue all non-prescription supplements, except for an
age-appropriate multivitamin/mineral supplement.

6. Willingness to discontinue miglustat (Zavesca) one month prior and for the
duration of the trial.

7. Women of reproductive age must be willing to use an effective method of
contraception for the duration of the trial if sexually active.

8. Willingness to participate in all aspects of the IV trial

EXCLUSION CRITERIA:

1. Age <3 or > 60 years of age at time of enrollment in the trial.

2. Subjects who have received any form of parenteral cyclodextrin, an HDAC inhibitor, or
an experimental therapy for NPC in the prior six months. Prior Intrathecal VTS-270
treatment is allowed.

3. History of hypersensitivity reactions to cyclodextrin or components of the
formulation.

4. Pregnancy or breastfeeding.

5. Any systemic infection at the time of enrollment.

6. Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1,000 per
microliter. Subjects with benign cyclic/ethnic neutropenia may be enrolled if not
clinically symptomatic.

7. Thrombocytopenia defined as a platelet count less than 75,000 per microliter.

8. Established history of a chronic clotting or bleeding disorder.

9. Use of anticoagulants within 3 months of enrollment

10. AST or ALT greater than 10-times age-appropriate upper limit of normal at the time of
screening. Individuals with AST and ALT greater than 4-times age-appropriate upper
limit of normal will be excluded if they have reasonable clinical evidence for another
underlying pathology (e.g. exposure to hepatotoxic drugs, viral infections).

11. Presence of anemia defined as two standard deviations below normal for age and gender.

12. Serum creatinine level greater than 1.5 times the age-appropriate upper limit of
normal.

13. Hematuria on a single urinalysis, as defined by the American Urological Association
(AUA) as five or more red blood cells per high-power field on microscopic evaluation
of urinary sediment from a properly collected urinalysis specimen. The patient will
not be excluded if two subsequent urine specimens are negative for hematuria as
defined by the AUA.

14. Proteinuria (1+ protein on repeat urinalysis) unless evaluated and classified as
benign.

15. Active pulmonary disease, oxygen requirement or clinically significant history of
decreased blood oxygen saturation (SaO2 <95% on room air), pulmonary therapy, daily
use of a cough assist device or pulmonary vest, requiring active suction, or with a
tracheostomy.

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

1. Unstable frequency, type or duration of seizures. Quantified by a seizure log
over one month prior to enrollment.

2. Subject requiring antiepileptic medication changes (other than dose adjustments
for weight) in the month prior to enrollment.

17. 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.

Additional exclusion criteria for intrathecal VTS-270

1. Neurologically asymptomatic. Determination made by the investigators based on history,
neurological exam and consultant input.

2. Suspected infection of the central nervous system

3. Spinal deformity that would impact the ability to perform a lumbar puncture

4. Skin infection in the lumbar region

5. Prior use of anticoagulants or a bleeding disorder with increased risk of clinical
bleeding.

6. Patients unable to complete a behavioral audiological evaluation including pure-tone
threshold assessment (500 Hz to 8000 Hz). In consultation with the medical monitor and
audiologists, a sedated ABR may be utilized to monitor ototoxicity if the participant
is being sedated to receive IT VTS-270.

7. 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.