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

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.