Phase I/II Study of SOD1 Inhibition by Pyrimethamine in Familial ALS

Study Purpose:

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.

Study Status:

Not recruiting


Familial Amyotrophic Lateral Sclerosis

Study Type:


Type of Intervention:


Intervention Name:




Phase 1/Phase 2

Study Chair(s)/Principal Investigator(s):

Dale J. Lange, M.D., Hospital for Special Surgery/Weill Cornell Medical Center ID:


Neals Affiliated?


Coordinating Center Contact Information

Weill Medical College of Cornell University

1305 York Avenue
New York, New York, 10021 United States

Full Study Summary:

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.

Study Sponsor:

Weill Medical College of Cornell University

Participant Duration:

9 months

Estimated Enrollment:


Estimated Study Start Date:

10 / 31 / 2009

Estimated Study Completion Date:

05 / 01 / 2016

Posting Last Modified Date:

06 / 19 / 2017

Date Study Added to

03 / 10 / 2010

Minimum Age:

18 Years

Maximum Age:


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

Weill Cornell Medical Center/New York Presbyterian Hospital

New York, New York 10021
United States

Methodist Neurological Institute

Houston, Texas 77030
United States

Universit├Ąts- und Rehabilitationskliniken Ulm


Milano Neurological Institute


Umea University