Can Pyrimethamine Lower CSF SOD1 Levels in Familial ALS? Results from a Multicenter Phase Ib Trial (S43.007)

Objective: To determine if pyrimethamine can lower CSF SOD1 levels in familial Background: Reduction of superoxide dismutase 1 (Cu/Zn-SOD1) levels prolongs survival in SOD1 transgenic mouse models of FALS. 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 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 (pu003c0.001) with a mean CSF Cu/Zn-SOD1 level reduction of 13.5[percnt] (95[percnt] CI(-18.5, -8.4)) and at visit 9 (pu003c0.001) 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 Disclosure: Dr. Lange has received personal compensation for activities with Genzyme as a consultant. Dr. Remanan has nothing to disclose. Dr. Shahbazi has nothing to disclose. Dr. Silani has nothing to disclose. Dr. Ludolph has nothing to disclose. Dr. Ajroud-Driss has nothing to disclose. Dr. Appel has received research support from Neuraltus, Inc., and GlaxoSmithKline. Dr. Kaplan has nothing to disclose. Dr. Fields has nothing to disclose. Dr. Marklund has nothing to disclose. Dr. Andersen has nothing to disclose.