O4‐02‐01: PHASE 2A RANDOMIZED, DOUBLE‐BLIND, PLACEBO‐CONTROLLED TRIAL OF THE HISTONE DEACETYLASE INHIBITOR (HDACI), FRM‐0334, IN ASYMPTOMATIC CARRIERS OF, OR PATIENTS WITH FRONTOTEMPORAL LOBAR DEGENERATION (FTLD) DUE TO, PROGRANULIN GENE MUTATIONS

FTLD is a common cause of dementia in individuals whose symptoms begin prior to age 65. Autosomal dominant mutations in the progranulin gene (GRN) cause up to 3-5% of FTLD by reducing progranulin protein (PGRN) production, leading to lysosomal dysfunction, neurodegeneration, inflammation and death. In preclinical models, HDACi have been found to increase GRN expression. FRM-0334 is a brain penetrant HDACi that elevated PGRN mRNA levels in human FTLD-GRN patient fibroblasts and PGRN protein in mouse brains. 28 individuals with FTLD- causing GRN mutations were randomized to either 300 or 500mg of FRM-0334 or placebo (12 drug : 3 placebo) taken orally daily for 28 days in two sequential dose cohorts. Primary objectives were to assess safety and tolerability, and the ability of FRM-0334 to increase plasma PGRN concentration. Secondary objectives were to assess FRM-0334 effects on CSF PGRN, as well as FRM-0334 pharmacokinetics. Exploratory objectives were to examine FRM-0334 effects on clinical measures, CSF biomarkers of neurodegeneration and FDG-PET scans. FRM-0334 was safe and well tolerated in asymptomatic and symptomatic GRN mutation carriers. There were no treatment related changes in blood or CSF PGRN levels, which remained stable in each individual over 28 days. Systemic and CSF FRM-0334 levels were not proportional to the administered dose and did not reach exposures which would be necessary based on preclinical experimentation to increase GRN mRNA & PGRN. No changes in exploratory outcomes were observed. There was considerable heterogeneity in clinical and imaging findings between participants at baseline. FRM-0334 was safe and well tolerated in GRN mutation carriers but had no effect at doses tested on PGRN levels. Systemic and CSF FRM-0334 levels were lower than expected suggesting insufficient FRM-0334 exposure. Therefore the hypothesis that HDAC inhibition can increase PGRN expression in humans was not fully tested. Additional studies with brain permeant HDACi should be pursued. Improved methods to measure treatment effects in heterogeneous FTLD-GRN populations are needed.