BACKGROUND: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose dependent SOD1 reduction in cell culture systems. A previous phase-1 trial showed pyrimethamine lowers SOD1 levels in leucocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to ALS (fALS/SOD1).
METHODS AND STUDY DESIGN: Multicenter (5 sites), open-label, 9-month duration, dose-ranging, to determine safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF of FALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effects assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS, ALSFRS-R and single item McGill Quality of Life (SIS-MQoL) were measured at screening, visit 6 and 9.
RESULTS: We enrolled 32 patients; 24 completed 6 visits (18 weeks) and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p<0.001) with a mean reduction of 13.5% (95% CI: 8.4, 18.5) and at visit 9 (p<0.001) with a mean reduction of 10.5% (95% CI: 5.2, 15.8).
INTERPRETATION: Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy. This article is protected by copyright. All rights reserved.
- Journal Article