A Phase 1 interventional study of Pyrimethamine in G(M2) Ganglioside, Tay-Sachs Disease Ganglioside and Sandhoff Disease Ganglioside, sponsored by Exsar Corporation. Withdrawn at 3 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2013-02-25.
Sponsored by Exsar Corporation · Phase 1 and Interventional
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.
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.
24 studies on the registry are indexed under Tay-Sachs Disease; 4 are open to participants now.
Browse Tay-Sachs Disease studies →Exsar Corporation is the lead sponsor of 2 studies on the registry; none are open to participants now.
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Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
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The human immunodeficiency virus, which weakens the immune system.
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Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
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After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
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It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis B tests
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis C tests
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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.
Drug: Pyrimethamine
Pyrimethamine will be given PO once daily for 8 consecutive weeks.
The primary outcome measure is safety and tolerability, based on conventional laboratory and clinical assessments.
Time frame: The primary outcome measure, which is safety and tolerability, will be assessed weekly during the 8-week treatment period and biweekly during the 4-week post-treatment period.
The secondary outcome measure is to assess changes in β-hexosaminidase A and B activities in plasma and peripheral blood leukocytes.
Time frame: The secondary outcome measure will be assessed weekly during the 4-week treatment period and at the end of the 4-week post-treatment period.
This study is withdrawn, as verified in Feb 2013. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Pyrimethamine
Exsar Corporation