Hydroxypropyl Beta Cyclodextrin for Niemann-Pick Type C1 Disease

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). The National Institutes of Health (NIH) Therapeutics for Rare and
Neglected Diseases (TRND) program is developing 2-hydroxypropyl-Beta-cyclodextrin
(HP-Beta-CD) for the treatment of patients with Niemann-Pick disease type C1 (NPC1) to slow
progression of symptoms of the disease. In this Phase 1, non-randomized, open-label,
single-center, study, we propose to administer HP-Beta-CD intrathecally via lumbar injection
to drug naive cohorts of 3 patients at doses of 200 mg escalated to 300, 400 mg and 900 mg.
Subsequent dose escalations may occur in increments of up to 300 mg. The objectives of this
study are to assess the safety, tolerability, feasibility, and pharmacokinetics (PK) of
intrathecally (IT) administered HP-Beta-CD to NPC1 patients, to determine an active dose of
HP-Beta-CD as measured by changes in plasma 24-(S) hydroxycholesterol (24(S)-HC)
concentration, and to evaluate the use of biomarkers and potential clinical outcomes of
NPC1. All patients in the cohort will receive HP-Beta-CD (n = 3) once monthly for at least
two doses, and the decision to dose-escalate will be based on safety and on biochemical
data. Safety will be assessed by adverse events (AEs), audiologic evaluation, clinical
laboratory tests, vital signs, physical examinations, chest X-rays and electrocardiograms
(ECGs). Biochemical efficacy will be measured by change from baseline in plasma 24(S)-HC. PK
will be assessed for plasma HP-Beta-CD.

- INCLUSION CRITERIA:

1. Aged greater than or equal to 2 and less than or equal to 25 years old at time
of enrollment, either gender and any ethnicity.

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

1. Two NPC1 mutations;

2. Positive filipin staining and at least one NPC1 mutation;

3. Vertical supranuclear gaze palsy (VSNGP) in combination with either:

i. One NPC1 mutation, or

ii. Positive filipin staining and no Niemann-Pick Type 2 (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. Ability to travel to the National Institutes of Health Clinical Center (NIH CC)
repeatedly for evaluation and follow-up.

5. If taking miglustat, the patient must have been taking a constant dose of the
medication for no less than 3 months prior to baseline evaluation and must be
willing to maintain that dose level for the duration of the trial.

6. Willing to discontinue all non-prescription supplements, with the exception of
an age-appropriate multivitamin.

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

8. Willing to participate in all aspects of trial design including serial blood and
cerebrospinal fluid (CSF) collections.

EXCLUSION CRITERIA:

1. Aged below 2 or above 25 years of age at enrollment in the trial.

2. Subjects will be excluded if their weight would result in an endotoxin level
that would exceed 0.2 EU/kg for either the saline or drug dosing.

3. Severe manifestations of NPC1 that would interfere with the patient's ability to
comply with the requirements of this protocol.

4. Neurologically asymptomatic patients.

5. Patients who have received any form of cyclodextrin in an attempt to treat NPC1.
Treatment with another drug preparation for another medical indication that
contains cyclodextrin as an excipient, will not exclude a patient.

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

7. Pregnancy or breastfeeding at any time during the study.

8. Patients with suspected infection of the CNS or any systemic infection.

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

10. Skin infection in the lumbar region

11. Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1,500.

12. Thrombocytopenia (a platelet count of less than 75,000 per cubic millimeter).

13. Evidence of disturbed circulation of CSF.

14. Contraindication for anesthesia.

15. Prior use of anticoagulants or history/presence of a bleeding disorder with
increased risk of clinical bleeding or an international normalized ratio (INR)
greater than 2.

16. Patients with clinical evidence of acute liver disease having symptoms of
jaundice or right upper quadrant pain.

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

18. For subjects 18 years of age and older, the epidermal growth factor receptor
(eGFR) is automatically calculated and reported by the NIH CC laboratory
utilizing the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
Creatinine 2009 equation. We will exclude subjects greater than or equal to 18
years of age if eGFR is less than or equal to 60 mL/min/1.73 m2. For subjects <
18

12 years of age, we will utilize the national kidney disease education program
(NKDEP) calculator
(http://www.nkdep.nih.gov/lab-evaluation/gfr-calculators/children-conventional-unit.shtml). Results are reported as > 75 mL/min/1.73 m2 or lower. We will exclude subjects < 18 years of age if eGFR is less than or equal to 75 15 mL/min/1.73 m2

19. Hematuria on a single urinalysis, as defined by the American Urological
Association (AUA) as five or more red blood cells per high-power field (or > 25/micro
L) on microscopic evaluation of urinary sediment from a properly collected urinalysis
specimen. The patient will not be excluded if 2 subsequent urine specimens are
negative for hematuria as defined by the AUA.

20. Proteinuria (1+ protein on urinalysis) unless evaluated and classified as benign
by patient s primary medical provider or by NIH nephrology consult or in the context
of normal urine protein creatinine ratio and in the absence of clinical symptoms
(edema, hypertension).

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

22. Patients unable to complete a behavioral audiologic evaluation including
pure-tone threshold assessment (500 Hz to 8000 Hz) to monitor for ototoxicity and for
whom otoacoustic emissions (OAEs) cannot be reliably obtained at baseline.

23. Patients with ongoing seizures, that are not stable in frequency, type or
duration over a 2 month period prior to enrollment, requiring change in dose of
antiepileptic medication (other than adjustment for weight) over a 2 month period
prior to enrollment, or requiring 3 or more antiepileptic medications to control
seizures.

24. 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.