The objective of this study will be to evaluate the safety, tolerability and effect on SOD1 levels by pyrimethamine in patients with familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing relentlessly progressive weakness of the arms, legs and respiratory muscles that is uniformly fatal. There are approximately 30,000 patients living with ALS in the United States. There is no treatment. The cause is uncertain in most patients. However, 3% of patients (< 1000 in number) have a familial form of ALS (FALS), phenotypically identical to the sporadic illness, that is caused by a mutation in the gene coding for the free radical scavenging enzyme copper/zinc superoxide dismutase (SOD1). Inserting the SOD1 mutant gene into mice causes them to develop a disease closely resembling ALS.

Inhibiting expression of the SOD1 gene prevents animals from developing the disease. Increasing or decreasing the number of mutated genes proportionately speeds or slows the progression of the disease. Therefore, reducing SOD1 levels in patients with SOD1 associated FALS may be a promising therapeutic approach. Through an extensive in vitro screening program for medications having the ability to reduce SOD1 levels, several molecules that reduce SOD1 protein levels are known. One of the most potent molecules is pyrimethamine, an FDA approved medication used for the treatment of malaria and toxoplasmosis. Pyrimethamine dramatically reduces SOD1 levels in mice and our preliminary studies show similar findings in humans. Our study's primary objective is to determine if familial ALS patients taking pyrimethamine will show a decline in SOD1 levels in the CSF by 15% or more. We will also determine if SOD1 and pyrimethamine are present in the blood and if the SOD-1 levels decline over the course of the study. We will also evaluate the safety and tolerability of pyrimethamine in patients with FALS. Secondary objectives will be to determine dose optimization for maximal SOD1 level reduction and tolerability of medication. We will also assess the feasibility of proceeding to phase II/III studies using pyrimethamine. Change in ALS-FRS, Appel ALS score and quality of life will also be measured. A clinical effect realized in patients with FALS associated with an SOD1 mutation may serve as an important foundation toward finding a treatment for sporadic ALS.

Inclusion Criteria:

• Subjects with definite, probable, or laboratory supported probable ALS will be eligible.

  1. ALS diagnosed as probable, laboratory supported probable or definite according to the World Federation of Neurology El Escorial criteria [Brooks et al. 2000]
  2. Age 18 or older
  3. Capable of providing informed consent and complying with trial procedures
  4. SOD1 mutation confirmation by study team
  5. Not taking Riluzole (Rilutek) or on a stable dose for 30 days
  6. Not taking Coenzyme QR10R or on a stable dose and brand for 30 days
  7. Absence of exclusion criteria

Exclusion Criteria:

1. History or evidence of malabsorption syndromes
2. Exposure to any experimental agent within 30 days of onset of this protocol
3. Women who are pregnant or planning to become pregnant
4. Women of childbearing potential not practicing contraception
5. Women who are breastfeeding
6. Enrollment in another research study within 30 days of or during this trial
7. Alcoholism
8. Patients taking phenytoin (Dilantin) or other therapy affecting folate levels
9. Dementia (MMSE <22)
10. Seizure disorder
11. Folate deficiency
12. Megaloblastic anemia
13. Cardiovascular disorder/arrhythmia
14. Impaired kidney function, defined as creatinine levels of 2.5 x ULN
15. Impaired liver function, defined as AST or ALT of 3 X ULN
16. Advanced ALS patients, defined as those with any of the following: forced vital capacity <60% (use of BIPAP is allowed); tracheostomy; or mechanical ventilation
17. Use of any of the following medications: cytosine, arabinoside, methotrexate, daunorubicin, sulfonamides, zidovudine, lorazepam, coumadin, sulfamethoxazole, and trimethoprim
18. Patients taking Lithium within 30 days of or during this trial
19. Incapable of providing informed consent and complying with trial procedures

AE's were collected over the course of the study and up to 30 days following the last dose taken.

CTCAE version 4.0 was used to assess the severity of AE's experienced during the study. This uses a grading system (referring to the severity) to assess the AEs. The CTCAE v4.0 displays Grades 1-5 with unique clinical descriptions of severity for each AE based on this general guideline: G1 Mild AE, G2 Moderate AE, G3 Severe or medically significant but not immediately life-threatening, G4 Life-threatening, G5 Death related to AE.

SAE reporting per criteria od clinicaltrials.gov