Patient case: 11-year-old male with Peutz-Jeghers syndrome; genetic feature: STK11

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

Summary: 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.

Detailed description: 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 infusion.
  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.

Eligibility: Inclusion Criteria:
  1. Age 0 to 6 months of age at time of enrollment, both genders, and any race/ethnicity.
  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 a positive NPC biochemical marker (oxysterol or bile acid biomarker) test
  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 collections.
  6. Parent / guardian must provide written informed consent to participate in the study. Because of the age range intended for inclusion, assent will not possible.
  Exclusion Criteria:
  1. Age ≥ 6 months at time of enrollment in the trial.
  2. A medical condition (such as clinically significant bleeding diathesis or evidence of immune suppression) that in the opinion of the investigator precludes placement of an intravenous catheter
  3. An absolute neutrophil count (ANC) of less than 1,500 per microliter.
  4. A platelet count less than 75,000 per microliter.
  5. History of severe neonatal encephalopathy, per SIBEN (Score of the Iberoamerican Society of Neonatology) including level of consciousness as stupor/coma, absent spontaneous activity, decerebrate posture, flaccid tone, absent suck, absent moro, diverted/nonreactive pupils, lack of heart rate variability, apnea, and infrequent seizures..6. 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 participation.
  7. Concurrent participation in another investigational drug trial.
  8. 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.

Relevance to patient case: not relevant