Can Pyrimethamine Lower CSF SOD1 Levels in Familial ALS? Results from a Multicenter Phase Ib Trial (S43.007)
Bibliographic record
Abstract
Objective: To determine if pyrimethamine can lower CSF SOD1 levels in familial ALS. Background: Reduction of superoxide dismutase 1 (Cu/Zn-SOD1) levels prolongs survival in SOD1 transgenic mouse models of FALS. Pyrimethamine causes a dose dependent reduction of Cu/Zn-SOD1 levels in cell culture systems. Previously, we showed pyrimethamine lowers SOD1 levels in lymphocytes in patients with Cu/Zn-SOD1 mutations. This study investigated whether pyrimethamine lowers cerebrospinal fluid (CSF) Cu/Zn-SOD1 levels in patients with ALS associated with SOD1 mutations. Methods: The study was a multicenter (5 sites), open-label, 9 months duration, dose-ranging clinical study to determine the ability of pyrimethamine to reduce Cu/Zn-SOD1 levels in the CSF of patients with documented Cu/Zn-SOD1 mutation. All participants were to have 3 separate lumbar punctures, blood draws, clinical assessment of strength, motor function, quality of life, and adverse effects assessments. Both Cu/Zn-SOD1 and pyrimethamine levels were measured in the CSF. Blood was analyzed for pyrimethamine levels and Cu/Zn-SOD1 levels in red blood cells. Appel ALS, ALSFRS-R and single item McGill Quality of Life (SiS-MQoL) measures were performed at screening, visit 6 (18 weeks) and 9 (36 weeks). Results: Following approval from Institutional review boards (IRB) at all participating sites, 32 patients (with 23 unique SOD1 mutations) were enrolled in the study; 23 remained in the study for 9 months; 9 did not. A generalized estimating equations (GEE) model was used to analyze CSF SOD1 levels. This model showed a significant reduction in Cu/Zn-SOD1 levels at visit 6 (p<0.001) with a mean CSF Cu/Zn-SOD1 level reduction of 13.5[percnt] (95[percnt] CI(-18.5, -8.4)) and at visit 9 (p<0.001) with a mean reduction of -10.5[percnt] (95[percnt] CI(-15.8, -5.2)). Conclusions: Pyrimethamine is a small molecule that is safe and well tolerated in ALS. This molecule is capable of producing a significant reduction in Cu/Zn-SOD1 levels in FALS patients with Cu/Zn-SOD1 mutations.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".