Combined Intrathecal and Intravenous VTS-270 Therapy for Liver and Neurological Disease Associated With Niemann-Pick Disease, Type C1

NCT03887533 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 19002819-CH-0028
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

Background: For people who have Niemann-Pick disease, type C1 (NPC1), cholesterol and other fats have trouble moving out of liver and other tissue cells. This makes the cells sick. Researchers want to find out if a drug called VTS-270 can help. Objective: To test if VTS-270 is safe and effective in treating chronic liver disease associated with NPC1. Eligibility: People ages 3-60 with NPC1 Design: Participants may be screened by phone or under another protocol. Participants will have visits once a month for 12 months. If they have intrathecal injections, the study may last 15 months or more. The first visit will last about 5 days. Others will last 2-3 days. Participants will get VTS-270 injected into a vein at each visit. They can also choose to have intrathecal injections. These are like spinal taps. Some visits will also include: Physical exam Urine tests Blood tests. A small tube or needle will be inserted into the participants vein to collect blood. The small tube will also be used to give the VTS-270. Hearing tests: For one test, participants will have electrodes taped to their head. These will record brain waves. Breathing tests Ultrasound of abdomen: Sounds waves will take pictures of the participant s body. Chest x-ray: This is a picture of the lungs.

Conditions

Niemann-Pick Disease, Type C1

Keywords

2-Hydroxypropyl-B-Cyclodextrin

Outcome Measures

Primary Outcomes (4)

• Participants With Adverse Events by Grade

  Adverse events (AEs) were used to determine safety and assess safety of intravenous VTS-270 in subjects with Niemann-Pick Disease, type C1. Assessment of safety was made by evaluation of summary statistics of adverse events and unanticipated problems. AEs were assessed using CTCAE version 5.0 grades 1-5. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL\*. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL\*\*. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE

  18 months

• Participants With Reduction in Plasma Cholestane-3β

  Efficacy of IV VTS-270 in treating chronic liver disease associated with Niemann-Pick Disease, type C1 as measured by reduction in plasma cholestane-3β, an NPC1-specific pharmacodynamic biomarker

  Assessed at baseline and at 52 weeks

• Participants With Reduction in Plasma Bile Acid B (5α)

  Efficacy of IV VTS-270 in treating chronic liver disease associated with Niemann-Pick Disease, type C1 as measured by reduction in bile acid B (5α), an NPC1-specific pharmacodynamic biomarker

  Assessed at baseline and at 52 weeks

• Participants With Reduction in C-Triol (6β-triol)

  Efficacy of IV VTS-270 in treating chronic liver disease associated with Niemann-Pick Disease, type C1 as measured by reduction in C-Triol (6β-triol), an NPC1-specific pharmacodynamic biomarker

  Assessed at baseline and at 52 weeks

Secondary Outcomes (3)

• Participants With Reduction in Liver Stiffness (kPa)

  Assessed at baseline and at 52 weeks

• Participants With Reduction in Alanine Aminotransferase Level

  Assessed at baseline and at 52 weeks

• Participants With Reduction in Aspartate Aminotransferase

  Assessed at baseline and at 52 weeks

Study Arms (2)

VTS-270 at 500 mg/kg

EXPERIMENTAL

Participant received dose of 500 mg/kg of intravenous VTS-270 administered over 2 hours monthly for 12 months. Participant also received 900 mg intrathecal VTS-270 therapy monthly for 18 months.

Drug: VTS-270

VTS-270 at 1000 mg/kg

EXPERIMENTAL

Participant received 1000 mg/kg of intravenous VTS-270 over 4 hours monthly for 12 months. Participant also received 900 mg intrathecal VTS-270 therapy monthly for 18 months.

Drug: VTS-270

Interventions

VTS-270 DRUG

Intravenous VTS-270 was administered on a monthly dosing schedule for 12 months. Each participant received one of two doses (500 or 1000mg/kg). Participants also received monthly 900 mg intrathecal VTS-270 therapy.

VTS-270 at 1000 mg/kg; VTS-270 at 500 mg/kg

Eligibility Criteria

• Age: 3 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age greater than or equal to 3 and less than or equal to 60 years old at time of enrollment
• Diagnosis of NPC1 based upon one of the following:
• A. Two NPC1 mutations
• B. Biochemical Positive for NPC (oxysterol/bile acid and sphingomyelinase levels consistent with a diagnosis of NPC) and one NPC1 mutation
• NPC1 mutations will be interpreted using standards established for the interpretation of sequence variants \[33\].
• Oxysterol/Bile Acid testing refers to cholestane-3beta,5 ,6beta-triol \[7, 8\] or 3beta,5alpha,6beta-trihydroxycholanic acid and its glycine conjugate \[34\].
• Evidence of NPC1-related liver disease as defined by one of the following:
• A. Abnormal liver chemistries as defined by one of the following:
• i. Plasma aspartate aminotransferase (AST) greater than or equal to 1.5-times age-appropriate upper limit of normal
• ii. Plasma aspartate aminotransferase (AST) greater than or equal to 1.25-times age-appropriate upper limit of normal and plasma alanine aminotransferase (ALT) \> 1.25-times age-appropriate upper limit of normal
• iii. Plasma aspartate aminotransferase (AST) greater than or equal to 1.25-times age-appropriate upper limit of normal and AST/ALT ratio greater than or equal to 2.0 AND Abnormal liver chemistries as defined above at least 8 weeks apart.
• B. Abnormal Liver Ultrasound\* defined as one of the following:
• Intraparenchymal echogenic bands consistent with fibrosis
• Abnormal liver echogenicity with AST or ALT above the upper limit of normal.
• Hepatomegaly with AST or ALT above the upper limit of normal.

You may not qualify if:

• Age \<3 or \> 60 years of age at time of enrollment in the trial.
• Subjects who have received any form of parenteral cyclodextrin, an HDAC inhibitor, or an experimental therapy for NPC in the prior six months. Prior Intrathecal VTS-270 treatment is allowed.
• History of hypersensitivity reactions to cyclodextrin or components of the formulation.
• Pregnancy or breastfeeding. Females of childbearing potential unwilling to utilize a highly effective form of contraception (i.e., barrier method with spermicide, intrauterine device, steroidal contraceptive in conjunction with a barrier method, or abstinence if it is the patient s baseline preference) for the duration of the study and for 30 days after participation.
• Any systemic infection at the time of enrollment.
• Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1,500 per microliter. Subjects with benign cyclic/ethnic neutropenia may be enrolled if not clinically symptomatic.
• Thrombocytopenia defined as a platelet count less than 75,000 per microliter.
• Established history of a chronic clotting or bleeding disorder.
• Use of anticoagulants within 3 months of enrollment
• Severe or acute liver disease as defined by one of the following:
• A. AST or ALT greater than 10-times age-appropriate upper limit of normal
• B. Jaundice or right upper quadrant pain
• C. International Normalized Ratio (INR) \>1.8
• Individuals with AST and ALT greater than 4-times the age-appropriate upper limit of normal will be excluded if they have a positive NIH Clinical Center Viral Markers Hepatitis Screen (HBsAG, anti-HCV and Anti-HAV IgM). This screening test will not be obtained unless AST and ALT are elevated. An equivalent panel from another laboratory may be used if this elevation is noted on screening. Individuals excluded under this criterion may be rescreened after the acute pathology resolves (e.g. Hepatitis A infection).
• Presence of anemia defined as two standard deviations below normal for age and gender.

Sponsors & Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010 Jun 3;5:16. doi: 10.1186/1750-1172-5-16.

  PMID: 20525256 BACKGROUND

• Porter FD, Scherrer DE, Lanier MH, Langmade SJ, Molugu V, Gale SE, Olzeski D, Sidhu R, Dietzen DJ, Fu R, Wassif CA, Yanjanin NM, Marso SP, House J, Vite C, Schaffer JE, Ory DS. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med. 2010 Nov 3;2(56):56ra81. doi: 10.1126/scitranslmed.3001417.

  PMID: 21048217 BACKGROUND

• Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, Berry-Kravis E, Davidson CD, Bianconi S, Keener LA, Rao R, Soldatos A, Sidhu R, Walters KA, Xu X, Thurm A, Solomon B, Pavan WJ, Machielse BN, Kao M, Silber SA, McKew JC, Brewer CC, Vite CH, Walkley SU, Austin CP, Porter FD. Intrathecal 2-hydroxypropyl-beta-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial. Lancet. 2017 Oct 14;390(10104):1758-1768. doi: 10.1016/S0140-6736(17)31465-4. Epub 2017 Aug 10.

  PMID: 28803710 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Niemann-Pick Disease, Type C

Condition Hierarchy (Ancestors)

Niemann-Pick Diseases; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Limitations and Caveats

Enrollment was poor due to COVID-19 pandemic

Results Point of Contact

• Title: Dr. Forbes Porter
• Organization: National Institute of Child Health and Human Development (NICHD)

fdporter@mail.nih.gov

301-435-4432

Study Officials

• Forbes D Porter, M.D.

  Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 22, 2019
• First Posted: March 25, 2019
• Study Start: January 6, 2020
• Primary Completion: October 25, 2021
• Study Completion: October 25, 2021
• Last Updated: August 30, 2022
• Results First Posted: August 30, 2022

Record last verified: 2021-10

Locations

US (1)