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Sponsors and Collaborators: |
ExSAR Corporation University Hospitals of Cleveland New York University School of Medicine The Hospital for Sick Children |
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Information provided by: | FDA Office of Orphan Products Development |
ClinicalTrials.gov Identifier: | NCT00679744 |
Adult Tay-Sachs disease and Sandhoff diseases are caused by deficiency of an enzyme called β-hexosaminidase A, or Hex A in short. This enzyme is located in a particular cellular component, called lysosomes, inside the brain cells. The reason that Hex A of patients with Adult Tay-Sachs disease or Sandhoff disease is deficient is because this enzyme had gone through mutation, resulting in it not working very well. In healthy people, Hex A efficiently breaks down GM2-ganglioside, which is a by-product from cells of our body. However, patients with Adult Tay-Sachs disease or Sandhoff disease cannot efficiently break down GM2-ganglioside in the body. Therefore, these patients have high levels of this by-product in the brain cells, which causes the brain to be unable to function normally.
There is a drug called Pyrimethamine. This drug is used by doctors to treat specific types of infections called malaria and toxoplasmosis. Our laboratory test tube studies have shown that Pyrimethamine can help the Hex A enzyme to function in a normal manner. If Hex A can function normally in presence of Pyrimethamine, this drug should be able restore the brain malfunction of these patients since Hex A can now efficiently break down GM2-ganglioside with Pyrimethamine treatment.
Although results from laboratory test tube studies are promising and Pyrimethamine should theoretically restore brain function of these patients, we do not know if Pyrimethamine is safe or if it would actually work in patients. This study is the first study (a Phase I study) of testing Pyrimethamine to treat Adult Tay-Sachs and Sandhoff diseases. The objective of this study is to see if Pyrimethamine is safe in these patients and to see if it can restore the brain function of these patients.
Condition | Intervention | Phase |
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G(M2) Ganglioside Tay-Sachs Disease Ganglioside Sandhoff Disease Ganglioside |
Drug: Pyrimethamine |
Phase I |
Study Type: | Interventional |
Study Design: | Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Dose Comparison, Factorial Assignment, Safety/Efficacy Study |
Official Title: | A Dose-Escalated, Double-Blind, Placebo-Controlled, Randomized Phase I Clinical Trial of Pyrimethamine in Patients Affected With Chronic GM2 Gangliosidosis (Tay-Sachs or Sandhoff Variants) |
Estimated Enrollment: | 20 |
Study Start Date: | May 2008 |
Estimated Study Completion Date: | March 2010 |
Estimated Primary Completion Date: | March 2010 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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4 dose levels: Active Comparator
Pyrimethamine at 6.25, 12.5, 25 and 37.5 mg/day will be evaluated sequentially, starting from 6.25 mg/day. Escalation from 6.25 mg/day to 12.5 mg/day, and from 12.5 mg/day to 25 mg/day, will not perform until all patients in the previous dose cohort have been treated for 4 weeks and until results obtained 4 weeks after treatment initiation do not reveal toxicity. Additionally, escalation from 25 mg/day to 37.5 mg/day will not perform until all patients in the 25-mg/day cohort have been treated for 8 weeks, and until results obtained 4 weeks after the 8-week treatment do not reveal toxicity. Dose escalation is considered complete, if 2 patients experience a Grade 3 Adverse Event (AE) or if 1 patient experiences a Grade 4 AE at a particular cohort.
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Drug: Pyrimethamine
Pyrimethamine will be given PO once daily for 8 consecutive weeks.
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Adult Tay-Sachs (TSD) and Sandhoff disease (SD) result from a deficiency of lysosomal heterodimeric β-hexosaminidase A (Hex A, αβ). These disorders are characterized by progressive neurological deterioration that mainly affects motor, cerebral and spinocerebellar function. They affect fewer than 1000 people in the United States. There is no effective treatment for these diseases.
Substantial evidence supports a disease model for TSD and SD which attributes pathology to decreased or absent Hex A levels in neuronal lysosomes of the brain. The problem in GM2 - gangliosidosis is the inability of the cell to metabolize GM2 gangliosides. When the residual activity of Hex A falls below a critical threshold level, GM2 ganglioside influx into the lysosome (the site of Hex A activity) exceeds the degradation rate and excess substrate continuously accumulates. Consequently, the lysosomes increase in size and number, giving rise to a storage disease.
The majority of the mutations in Hex A affect the ability of the enzyme to obtain and/or retain its native 3-dimensional fold in the endoplasmic reticulum (ER) where intracellular quality control is performed to retain and degrade defective enzymes. Pharmacological chaperones (PC)s are small molecules that can stabilize the native conformation of a mutant enzyme in the ER and allow it to escape the ER's quality control system and its associated degradation pathway (ERAD). PCs have the potential to act as drugs when they can stabilize the native conformation of a mutant enzyme.
In 2006 ExSAR applied for orphan drug designation from the FDA for Pyrimethamine (Pyrimethamine) for the treatment of patients affected with late-onset GM2-gangliosidosis. The application is pending the positive outcome of clinical trials. Pyrimethamine is an FDA-approved drug which readily passes the bloodbrain barrier (BBB). It is currently used to treat malaria and toxoplasmosis. Our in vitro cell-based studies with fibroblasts from these patients show that Pyrimethamine can function as a PC for Hex A and raise intracellular Hex A levels. Our hypothesis is that Pyrimethamine administered to adult TSD and SD patients can improve neurological function and health.
The over objective of the project is to assess the safety and tolerability of the drug. We first conduct a Phase I trial, which is the current study, using Pyrimethamine to treat patients affected with GM2-gangliosidosis. Hex A and B (αβ) activities in plasma and peripheral blood leukocytes will also be measured. The working hypotheses of the Phase I trial are that Pyrimethamine administered according to the regimen of the trial will be tolerated and safe and result in increased Hex A levels in blood and brain.
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
United States, New York | |
New York University, School of Medicine, Department of Neurology | |
New York, New York, United States, 10016 | |
United States, Ohio | |
University Hospitals of Cleveland | |
Cleveland, Ohio, United States, 44106 | |
Canada, Ontario | |
Division of Clinical & Metabolic Genetics, Hospital for Sick Children | |
Toronto, Ontario, Canada, M5G 1X8 |
Study Chair: | Bijan Almassian, Ph.D. | ExSAR Corporation |
Responsible Party: | ExSAR Corporation ( Dr. Bijan Almassian ) |
Study ID Numbers: | 3448, CL-Pyrimethamine-001, FDA OPD Grant: FD-R-03448-01 |
Study First Received: | May 15, 2008 |
Last Updated: | October 1, 2008 |
ClinicalTrials.gov Identifier: | NCT00679744 |
Health Authority: | United States: Food and Drug Administration |
Tay-Sachs disease. Sandhoff disease. GM2 Gangliosidosis. |
β-hexosaminidase deficiency. Hexosaminidase Phase I clinical trial. |
Pyrimethamine Lipid Metabolism, Inborn Errors Gangliosidosis (GM2) Type1 Sphingolipidoses Metabolic Diseases Lysosomal Storage Diseases Sphingolipidosis Central Nervous System Diseases Tay-Sachs disease Brain Diseases Folic Acid Metabolism, Inborn Errors |
Genetic Diseases, Inborn Gangliosidoses, GM2 Brain Diseases, Metabolic, Inborn Lipidoses Metabolic disorder Tay-Sachs Disease Sandhoff disease Gangliosidoses Sandhoff Disease Lipid Metabolism Disorders Brain Diseases, Metabolic |
Anti-Infective Agents Antimalarials Antiparasitic Agents Antiprotozoal Agents Molecular Mechanisms of Pharmacological Action Lysosomal Storage Diseases, Nervous System |
Therapeutic Uses Nervous System Diseases Enzyme Inhibitors Folic Acid Antagonists Pharmacologic Actions |