Study of VTS-270 (2-hydroxypropyl-β-cyclodextrin) to Treat Niemann-Pick Type C1 (NPC1) Disease

Non-clinical studies and a Phase 1 clinical trial suggest that intrathecal administration of
2-hydroxypropyl- β-cyclodextrin (VTS-270) in patients with neurologic manifestations of
Niemann-Pick Type C1 (NPC1) disease has the potential to slow the rate of progression of
their neurologic disease.

Niemann-Pick Type C1 (NPC1) disease is a rare, neurodegenerative, inherited, autosomal
recessive lysosomal lipid storage disorder primarily in children and teenagers. The disease
is characterized by the inability to properly metabolize cholesterol and other lipids within
the cell due to mutations in the NPC1 gene causing unesterified cholesterol to accumulate in
the brain, liver and spleen.

This study is a multicenter, multinational, prospective, randomized, double-blind,
sham-controlled, 3-part, efficacy and safety trial of VTS-270, administered by the lumbar
intrathecal route (IT) every 2 weeks, with a planned enrollment of approximately 51 subjects
with NPC1 disease. The study will be conducted in three parts: Parts A, B, and C.

Part A will evaluate 3 different dose levels of VTS-270 in 9 subjects and 3 sham control
subjects to determine the dose level for Parts B and C.

Part B will evaluate the safety and efficacy of the dose selected from Part A compared to
sham control in 51 subjects, including the 12 subjects from Part A.

Part C will be an open-label extension phase of the study to subjects who either complete
Part B or are subjects in Part B who have met rescue therapy criteria.

Subjects in Part C will receive treatment with VTS-270 until the product is licensed or the
program is terminated.

Key Inclusion Criteria:

Parts A and B:

1. Onset of neurological symptoms prior to 15 years of age.

2. Confirmed diagnosis of NPC1 determined by either:

- Two NPC1 mutations;

- Positive filipin staining and at least one NPC1 mutation;

- c. Vertical supranuclear gaze palsy (VSNGP) in combination with either: one NPC1
mutation, OR positive filipin staining or oxysterol levels consistent with NPC
disease and no Niemann-Pick Type C2 (NPC2) Disease mutations.

3. Subject or parent/guardian must provide written informed consent and assent (for
minors).

4. Ability to undergo a lumbar puncture (LP) and IT drug administration under conscious
sedation or general anesthesia.

5. An NPC Clinical Severity Scale Score of 1 through 4, inclusive, in two or more of the
following on the NPC Severity Scale components: ambulation, fine motor skills, or
swallowing and a score of 0 through 4 on the cognition component.

6. Total NPC Clinical Severity Scale Score of 10 or greater.

7. If taking miglustat, must have been on a stable dose for past 3 months and be willing
to remain on a stable dose.

8. Subjects with adequately controlled seizures may qualify for enrollment. Subjects with
a history of seizures should have a stable pattern of seizure activity and be on a
stable dose and regimen of anti epileptic medication during the 3 months prior to
screening without change in dose in regimen up to and including Study Day 0.

9. Agree to discontinue all non-prescription supplements such as Coenzyme Q10, curcumin,
cinnamon, fish oil supplements, high dose vitamin D (>500 milli-International unit
(mIU)/day), acetylleucine, or gingko biloba at least 1 month prior to first dose
(Study Day 0).

10. Agree to discontinue any other investigational treatments for NPC including vorinostat
or arimoclomol at least 3 months prior to first dose (Study Day 0).

11. Females of child-bearing potential (not surgically sterile) must use a medically
acceptable method of contraception and must agree to continue use of this method for
the duration of the study and for 30 days after participation in the study.

Part C:

1. Subject has completed Part B, or meets the criteria for the Rescue Option.

Key Exclusion Criteria:

1. Exclusion criteria as assessed by NPC Clinical Severity Scale:

- Unable to walk, wheelchair dependent (ambulation NPC score=5)

- Needs a nasogastric tube to overcome swallowing difficulties (swallowing NPC
score=5) Note: Nasogastric or gastric tube use for supplemental feeding or
medication administration is permitted and will not exclude a subject from the
trial.

- Severe dysmetria (fine motor NPC score=5)

- Minimal cognitive function (cognition NPC score=5).

2. Body weight < 15 kg.

3. Prior treatment with intravenous 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) for NPC1
disease, unless the subject has undergone a minimum 3-month washout period prior to
Study Day 0. Note: Any prior IT administration of HP-β-CD will exclude a subject from
enrollment.

4. Subjects on antipsychotics for treatment of psychosis. Note: Use of antipsychotic
medication for treatment of other disorders (e.g., Attention Deficit Hyperactivity
Disorder) will not exclude a subject from this trial.

5. History of hypersensitivity reactions to any product containing
2-hydroxypropyl-β-cyclodextrin (HP-β-CD).

6. Spinal deformity that could impact the ability to perform a lumbar puncture.

7. Skin infection in the lumbar region within 2 months of study entry.

8. Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1.5 X 10^9/L.

9. Thrombocytopenia (platelet count of less than 75 X 10^9/L).

10. Activated partial thromboplastin time (aPTT) or prothrombin time (PT) prolonged by >
1.5 times the upper limit of normal (ULN) or known history of a bleeding disorder.

11. Status epilepticus occurring within 3 months of screening and/or seizure frequency
that cannot be quantified.

12. Evidence of obstructive hydrocephalus or normal pressure hydrocephalus.

13. Recent use of anticoagulants [in past 2 weeks prior to first dose (Study Day 0); re:
lumbar puncture safety].

14. Subjects unable to comply with the study procedures or with a clinical disease or
laboratory abnormality that in the opinion of the investigator would potentially
increase the risk of participation.