Phase 1/2 Study of Vorinostat Therapy in Niemann-Pick Disease, Type C1

NCT02124083 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 14010214-CH-0102
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief 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. The causative genes NPC1 (about 95% of cases) and NPC2 (about 5% of cases) are involved in the intracellular trafficking of lipids and cholesterol. Mutations on either of these genes lead to progressive accumulation of unesterified cholesterol and other lipids in the central nervous system (CNS). Vorinostat is a histone deacetylase inhibitor that has been shown in vivo to increase mutant NPC1 protein levels and to reverse cellular accumulation of unesterified cholesterol. Vorinostat has been labeled by the FDA for treatment of cutaneous T-cell lymphoma. In this Phase I, non-randomized, open-label, single-center study, we plan to study whether Vorinostat can be repurposed to treat patients with NPC1. Our primary objective is to determine the safety and tolerability of Vorinostat in NPC1 disease. Our secondary objectives will be to determine biochemical efficacy of Vorinostat to increase expression of NPC1 protein and normalize lipid and protein biomarkers. This study will enroll up to 12 NPC1 patients and test the safety of two dose levels (200 and 400 mg). Drug will be administered on a 3 days on/4 days off schedule for 3 months at each dose level. Patients will be evaluated at the NIH Clinical Center at 0, 3 and 6 months. Safety will be assessed by adverse events (AEs), clinical laboratory tests and physical examinations. Biochemical efficacy will be assessed by measurement of serum and cerebral spinal fluid biomarkers. Clinical efficacy will be evaluated by audiologic testing, assessment ataxia, and swallowing studies.

Conditions

Neimann-Pick Disease

Keywords

Niemann Pick Disease, Type C1; Phase I, Phase 2; Vorinostat

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Tolerabilty of 200 mg Vorinostat in Niemann-Pick Disease, Type C1

  The number of Niemann-Pick Disease, type C1 patients completing 3 month 200 mg phase

  3 months

• Number of Participants With Tolerabilty of 400 mg Vorinostat in Niemann-Pick Disease, Type C1

  The number of Niemann-Pick Disease, type C1 patients completing 3 month 400 mg phase

  3 months

Secondary Outcomes (4)

• Biochemical Efficacy as Measured by Serum Cathepsin D

  6 months

• Biochemical Efficacy as Measured by Serum Cathepsin D

  Baseline

• Biochemical Efficacy as Measured by Serum LGALS3

  6 months

• Biochemical Efficacy as Measured by Serum LGALS3

  Baseline

Study Arms (1)

Vorinostat

EXPERIMENTAL

Trial participants were treated with Vorinostat (3 days on/4 days off regimen) to limit toxicity. Subjects were initially dosed with 200 mg (two 100 mg capsules) by mouth daily for three months, followed by dose escalation to 400 mg (four 100 mg capsules) by mouth daily for three months.

Drug: Vorinostat

Interventions

Vorinostat DRUG

Histone deactylase inhibitor

Vorinostat

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Aged greater than or equal to 18 and less than or equal to 60 years old at time of enrollment, either gender, and any ethnicity.
• Diagnosis of NPC1 based upon one of the following:
• Two NPC1 mutations;
• Positive filipin staining and at least one NPC1 mutation;
• Vertical supranuclear gaze palsy (VSNGP) in combination with either:
• One NPC1 mutation, or
• Positive filipin staining and no pathogenic NPC2 mutations.
• Patients with at least one neurological manifestation of NPC1. For example, but not limited to, hearing loss, vertical supranuclear gaze palsy, ataxia, dementia, dystonia, seizures, dysarthria, or dysphagia.
• A patient s cultured skin fibroblasts when treated with 10 M Vorinostat must exhibit a reduction in the filipin lysosomal storage organelle ratio equivalent to 75% of the response measured in NPC1 positive control fibroblasts.
• Ability to travel to the NIH Clinical Center repeatedly for evaluation and follow-up.
• If taking miglustat, the patient must have been taking a constant dose of the medication for no less than three months prior to baseline evaluation and must be willing to maintain that dose level for the duration of the trial.
• Willing to discontinue all non-prescription supplements, with the exception of an age-appropriate multivitamin.
• Women of reproductive age must be willing to use an effective method of contraception for the duration of the trial.
• Willing to participate in all aspects of trial design including serial blood and CSF collections.

You may not qualify if:

• Aged below 18 or above 60 years of age at enrollment in the trial.
• Severe manifestations of NPC1 that would interfere with the patient s ability to comply with the requirements of this protocol.
• Neurologically asymptomatic patients.
• Patients who have received any form of cyclodextrin or an HDACi in an attempt to treat NPC1.
• History of hypersensitivity reactions to Vorinostat or components of the formulation.
• Pregnancy or breastfeeding at any time during the study.
• Patients with suspected infection of the CNS or any systemic infection.
• Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1,500 per microliter.
• Thrombocytopenia defined as a platelet count less than 75,000 per microliter, or a history of greater than or equal to grade 2 thrombocytopenia (50,000-75,000 platelets/microliter).
• Prior use of anticoagulants or history/presence of a bleeding disorder.
• Hepatic laboratory parameters (aspartate aminotransferase (AST), alanine aminotransferase, (ALT)) greater than four-times upper limit of normal.
• Presence of anemia defined as two standard deviations below normal for age and gender.
• Serum creatinine level greater than 1.5 times the upper limit of normal.
• Proteinuria (1+ protein on urinalysis) Patient will not be excluded if urine protein/creatinine ratio is normal or if classified as benign by either patient's primary medical provider or upon obtaining a nephrology consult.
• Serum potassium or Magnesium outside of the normal laboratory range prior to initiation of vorinostat therapy.

Sponsors & Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): lead
• Washington University School of Medicine: collaborator
• Weill Medical College of Cornell University: collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Vanier MT. Niemann-Pick diseases. Handb Clin Neurol. 2013;113:1717-21. doi: 10.1016/B978-0-444-59565-2.00041-1.

  PMID: 23622394 BACKGROUND

• Ory DS. Niemann-Pick type C: a disorder of cellular cholesterol trafficking. Biochim Biophys Acta. 2000 Dec 15;1529(1-3):331-9. doi: 10.1016/s1388-1981(00)00158-x. No abstract available.

  PMID: 11111100 BACKGROUND

• Sevin M, Lesca G, Baumann N, Millat G, Lyon-Caen O, Vanier MT, Sedel F. The adult form of Niemann-Pick disease type C. Brain. 2007 Jan;130(Pt 1):120-33. doi: 10.1093/brain/awl260. Epub 2006 Sep 26.

  PMID: 17003072 BACKGROUND

• Garcia AA, Koperniku A, Ferreira JCB, Mochly-Rosen D. Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives. Trends Pharmacol Sci. 2021 Oct;42(10):829-844. doi: 10.1016/j.tips.2021.07.002. Epub 2021 Aug 10.

  PMID: 34389161 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C

Interventions

Vorinostat

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

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Results Point of Contact

• Title: Porter, Forbes
• Organization: National Institute of Child Health and Human Development

fdporter@mail.nih.gov

+1 301 435 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
• Restrictive Agreement: No

Study Design

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

Study Record Dates

• First Submitted: April 25, 2014
• First Posted: April 28, 2014
• Study Start: April 25, 2014
• Primary Completion: December 13, 2016
• Study Completion: December 13, 2016
• Last Updated: February 22, 2018
• Results First Posted: February 22, 2018

Record last verified: 2018-01-13

Locations

US (1)