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]). Results: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334 was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P =.56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P =.13), or exploratory pharmacodynamic measures. Plasma FRM-0334 exposure did not increase proportionally with dose. Brain FDG-PET data were available in 26 of 27 randomized participants. In a cross-sectional analysis of 26 individuals, bifrontal cortical FDG hypometabolism was associated with worse Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 × 10-2standardized uptake value ratio [SUVR] units/CDR units; 95% CI, -4.9 × 10-2to -2.2 × 10-2; P <.001), high cerebrospinal fluid NfL (b = -9.2 × 10-5SUVR units/pg NfL/mL; 95% CI, -1.3 × 10-4to -5.6 × 10-5; P <.001), and high CSF t-tau (-7.2 × 10-4SUVR units/pg t-tau/mL; 95% CI, -1.4 × 10-3to -9.5 × 10-5; P =.03). 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.
|Journal||JAMA network open|
|Publication status||Published - 24 Sept 2021|
Bibliographical noteFunding Information:
Conflict of Interest Disclosures: Dr La Joie reported receiving grants from the National Institute on Aging during the conduct of the study. Dr Rojas reported serving as site principal investigator for Eli Lilly clinical trials during the conduct of the study. Dr Harris reported being a salaried employee for FORUM Pharmaceuticals during the conduct of the study and receiving personal fees from F Prime Capital outside the submitted work. Dr Boeve reported receiving grants from FORUM Pharmaceuticals, Biogen, Alector, and EIP Pharma outside the submitted work; and being an SAB member, Tau Consortium. Dr Grossman reported receiving site reimbursement for treatment trial participation from FORUM Pharmaceuticals during the conduct of the study. Dr Vandenberghe reported having a trial agreement with FORUM Pharmaceuticals, Merck, Biogen, AbbVie, Roche, and AC Immune outside the submitted work. Dr Le Ber reported receiving an ANR public grant and grants from PHRC, personal fees from Alector, and personal fees from Prevail Therapeutic outside the submitted work. Dr McGinnis reported receiving reimbursement for conducting a clinical therapeutic trial from FORUM Pharmaceuticals during the conduct of the study. Dr Riordan reported receiving trial related services from Worldwide Clinical Trials during the conduct of the study. Dr Marek reported receiving personal fees from Invicro, The Michael J. Fox Foundation, Roche, Takeda, GEHC, Sanofi, Neuron23, Denali, UCB, and Biohaven outside the submitted work. Dr. Haynes reported being an employee of FORUM Pharmaceuticals during the conduct of this study. Dr Koenig reported being an employee of FORUM Pharmaceuticals until May 1, 2016. Dr Hilt reported being a full-time employee of FORUM Pharmaceuticals during the conduct of the study. Dr Boxer reported receiving grants from FORUM Pharmaceuticals, the National Institutes of Health, Bluefield Project, Association for Frontotemporal Dementia, and the Alzheimer’s Association; personal fees from Alector, Arkuda, GlaxoSmithKline, and Passage Bio; and nonfinancial support from Eli Lilly in the form of a research collaboration and nonfinancial support from Novartis in the form of a research collaboration outside the submitted work. No other disclosures were reported.
Funding/Support: This study was supported by FORUM Pharmaceuticals (owner and supplier of FRM-0334 during the duration of this study), and Bluefield Project to Cure Frontotemporal Dementia.
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