SOD1 Inhibition by Pyrimethamine in Familial Amyotrophic Lateral Sclerosis (ALS)

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

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 Overview

• Status: Completed
• Conditions: Familial Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Pyrimethamine

Detailed Description

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 Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Ulm, Germany
    • Universitäts- und Rehabilitationskliniken Ulm
• Italy
  • Milan, Italy
    • Milano Neurological Institute
• Sweden
  • Umea, Sweden
    • Umea University
• United States
  • New York
    • New York, New York, United States, 10021
      • Weill Cornell Medical Center/New York Presbyterian Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Methodist Neurological Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pyrimethamine; Open label. Only one arm will receive the intervention.	Drug: Pyrimethamine; Open Label, dose escalating,; Other Names: Daraprim

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in SOD1 CSF	Reported change in mean SOD1 CSf from baseline to visit 6 (week 18) and end of study for all subjects who completed the measure	baseline, Visit 6 week 18, end of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Appel ALS Score	an objective and timed measurement of strength and function of subjects including muscle testing, respiratory function and fine motor function, all summed together for a total value, and is measured at baseline, visit 2, visit 6 and end of study. The scale ranges from 30 in a healthy person to to 164 in a maximally impaired person; an increase in score indicates progression and is expected in disease progression.	Week 0, 6, 18, and end of study

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: Muscular Dystrophy Association
• Investigators: Principal Investigator: Dale J. Lange, M.D., Hospital for Special Surgery/Weill Cornell Medical Center

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): May 1, 2016

Study Registration Dates

• First Submitted: December 17, 2009
• First Submitted That Met QC Criteria: March 8, 2010
• First Posted (Estimate): March 10, 2010

Study Record Updates

• Last Update Posted (Actual): June 19, 2017
• Last Update Submitted That Met QC Criteria: May 19, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: ALS; Familial ALS; SOD1 Gene Mutation
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Pyrimethamine
• Other Study ID Numbers: 0903010259

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided