Study of IV VTS-270 for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C

Conditions:Neurology, Neurology, Gastrointestinal
Therapuetic Areas:Gastroenterology, Neurology
Age Range:Any
Start Date:February 22, 2019
End Date:February 2022
Contact:Daniel S Ory, MD

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Phase 1/2a Study of 2-Hydroxypropyl-Beta-Cyclodextrin Therapy for Infantile Liver Disease Associated With Niemann-Pick Disease, Type C

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 Niemann-Pick C1 disease (NPC1) (~95% of cases) or NPC2
genes. 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 central nervous system decline including
inability to coordinate balance, gait, extremity and eye movements. Acute liver disease in
the newborn/infant period is frequently observed, but subsequently resolves. However,
chronic, sub-clinical liver disease persists. Intrathecal 2-Hydroxypropyl-β-Cyclodextrin
(HP-β-CD, VTS-270) has proven effective in reducing the signs and prolonging life in animal
models and Phase 1/2a data support efficacy in NPC1 patients. VTS-270 also has been shown to
be effective in treating liver disease in the NPC1 cat.

This Phase 1/2a, open-label, multiple ascending dose trial will evaluate whether VTS-270
administered intravenously is effective in treating acute liver disease in NPC1 infants.

In the first phase of the study, infants will be treated for a total of 6 weeks, treated
twice weekly. Infants will be admitted to the Neonatal Intensive Care Unit (NICU) for the
first week of treatment. Procedures during the first week of the study will include blood
draws for genetic testing, clinical and research blood draws, urine collection, abdominal
ultrasound, peripheral inserted central catheter (PICC) placement, hearing screening, and the
first two IV VTS-270 infusions through the PICC line. Weeks 2-6 will occur on an outpatient
basis. During week 2-6, the infant will receive 2 doses per week of VTS-270 with blood draws
and urine collection during weeks 2, 4, and 6. PICC line will be removed after final

Subjects who demonstrate statistically significant reduction either in the glycine-conjugated
trihydroxycholanic acid biomarker or serum bilirubin (direct bilirubin or direct bilirubin:
total bilirubin ratio) will be allowed to crossover into the second phase of the study, an
open label phase of six months duration in which IV VTS-270 will be administered monthly for
a total of six doses. Month 1-6 procedures will occur on an outpatient basis. Procedures
during the second phase include a monthly intravenous line placement. After each monthly
visit, the intravenous line will be removed.

Inclusion Criteria:


1. Age 0 to 6 months of age at time of enrollment, both genders, and any

2. Diagnosis of NPC (either NPC1 or NPC2) based upon meeting any of the three
following conditions: A. Two NPC1/NPC2 mutations, or B. One NPC1/NPC2 mutation
and positive oxysterol or bile acid biomarker test, or C. Positive oxysterol or
bile acid biomarker test, and normal sphingomyelinase activity

3. Subjects with evidence of NPC-related liver disease as defined by direct
bilirubin (DB) >2mg/dL or DB/total bilirubin ratio >0.2.

4. Ability to travel to a research site.

5. Willing to participate in all aspects of trial design including serial blood

6. Parent/guardian must provide written informed consent to participate in the
study. Because of the age range intended for inclusion, assent will not be

Exclusion Criteria:

1. Age ≥ 6 months at time of enrollment in the trial.

2. Prematurity ( ≤ 37 weeks EGA).

3. Subjects with suspected infection of the central nervous system (CNS) or any systemic

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

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

6. Functional cardiac malformation.

7. History of neonatal encephalopathy

8. Subjects, 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

9. Concurrent participation in another investigational drug trial.

10. Unstable medical condition that precludes travel to one of the study sites.

11. Imminent expiration (within 2 weeks) in the opinion of the subject's primary

12. History of renal disease or evidence of acute kidney injury defined as serum
creatinine greater than 1.5 mg/dL or an increase of at least 0.2-0.3 mg/dL per day.
We found this trial at
Saint Louis, Missouri 63110
Principal Investigator: Daniel S Ory, MD
Phone: 314-362-8737
Saint Louis, MO
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