Scientific article
Open access

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial

Published inJAMA network open, vol. 4, no. 9, e2125584
Publication date2021-09
First online date2021-09-24

Importance: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations.

Objective: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency.

Design, setting, and participants: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021.

Interventions: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days.

Main outcomes and measures: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]).

Conclusions and relevance: In this randomized clinical trial, the current formulation of FRM-0334 did not elevate PRGN levels, which could reflect a lack of efficacy at attained exposures, low bioavailability, or some combination of the 2 factors. Bifrontal FDG-PET is a sensitive measure of symptomatic GRN haploinsufficiency. International multicenter clinical trials of FTD-GRN are feasible.

Trial registration: ClinicalTrials.gov Identifier: NCT02149160.

  • Adult
  • Aged
  • Biological Availability
  • Female
  • Frontotemporal Dementia / drug therapy
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism
  • Haploinsufficiency / drug effects
  • Histone Deacetylase Inhibitors / adverse effects
  • Histone Deacetylase Inhibitors / pharmacokinetics
  • Histone Deacetylase Inhibitors / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • Organic Chemicals / adverse effects
  • Organic Chemicals / pharmacokinetics
  • Organic Chemicals / therapeutic use
  • Progranulins / genetics
  • Progranulins / metabolism
  • NIA NIH HHS - [P01 AG066597]
Citation (ISO format)
LJUBENKOV, Peter A et al. Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial. In: JAMA network open, 2021, vol. 4, n° 9, p. e2125584. doi: 10.1001/jamanetworkopen.2021.25584
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Article (Published version)
Secondary files (3)
ISSN of the journal2574-3805

Technical informations

Creation11/16/2022 11:49:09 AM
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