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

Peter A. Ljubenkov; Lauren Edwards; Leonardo Iaccarino; Renaud La Joie; Julio C. Rojas; Mary Koestler; Baruch Harris; Bradley F. Boeve; Barbara Borroni; John C. Van Swieten; Murray Grossman; Florence Pasquier; Giovanni B. Frisoni; Catherine J. Mummery; Rik Vandenberghe; Isabelle Le Ber; Didier Hannequin; Scott M. McGinnis; Sophie Auriacombe; Marco Onofrj; Ira J. Goodman; Henry J. Riordan; Gary Wisniewski; Jacob Hesterman; Ken Marek; Beth Ann Haynes; Holger Patzke; Gerhard Koenig; Dana Hilt; Hans Moebius; Adam L. Boxer

doi:10.1001/jamanetworkopen.2021.25584

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

Peter A. Ljubenkov^*, Lauren Edwards, Leonardo Iaccarino, Renaud La Joie, Julio C. Rojas, Mary Koestler, Baruch Harris, Bradley F. Boeve, Barbara Borroni, John C. Van Swieten, Murray Grossman, Florence Pasquier, Giovanni B. Frisoni, Catherine J. Mummery, Rik Vandenberghe, Isabelle Le Ber, Didier Hannequin, Scott M. McGinnis, Sophie Auriacombe, Marco OnofrjIra J. Goodman, Henry J. Riordan, Gary Wisniewski, Jacob Hesterman, Ken Marek, Beth Ann Haynes, Holger Patzke, Gerhard Koenig, Dana Hilt, Hans Moebius, Adam L. Boxer

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › Academic › peer-review

5 Citations (Scopus)

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Abstract

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.

Original language	English
Article number	25584
Journal	JAMA network open
Volume	4
Issue number	9
DOIs	https://doi.org/10.1001/jamanetworkopen.2021.25584
Publication status	Published - 24 Sept 2021

Bibliographical note

Funding 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 Information:
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.

Publisher Copyright:
© 2021 BMJ Publishing Group. All rights reserved.

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Ljubenkov, P. A., Edwards, L., Iaccarino, L., La Joie, R., Rojas, J. C., Koestler, M., Harris, B., Boeve, B. F., Borroni, B., Van Swieten, J. C., Grossman, M., Pasquier, F., Frisoni, G. B., Mummery, C. J., Vandenberghe, R., Le Ber, I., Hannequin, D., McGinnis, S. M., Auriacombe, S., ... Boxer, A. L. (2021). Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients with Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial. JAMA network open, 4(9), [25584]. https://doi.org/10.1001/jamanetworkopen.2021.25584

@article{938746d2b38c47ebae99141fe61b918c,

title = "Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients with Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial",

abstract = "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.",

author = "Ljubenkov, {Peter A.} and Lauren Edwards and Leonardo Iaccarino and {La Joie}, Renaud and Rojas, {Julio C.} and Mary Koestler and Baruch Harris and Boeve, {Bradley F.} and Barbara Borroni and {Van Swieten}, {John C.} and Murray Grossman and Florence Pasquier and Frisoni, {Giovanni B.} and Mummery, {Catherine J.} and Rik Vandenberghe and {Le Ber}, Isabelle and Didier Hannequin and McGinnis, {Scott M.} and Sophie Auriacombe and Marco Onofrj and Goodman, {Ira J.} and Riordan, {Henry J.} and Gary Wisniewski and Jacob Hesterman and Ken Marek and Haynes, {Beth Ann} and Holger Patzke and Gerhard Koenig and Dana Hilt and Hans Moebius and Boxer, {Adam L.}",

note = "Funding 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{\textquoteright}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 Information: 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. Publisher Copyright: {\textcopyright} 2021 BMJ Publishing Group. All rights reserved.",

year = "2021",

month = sep,

day = "24",

doi = "10.1001/jamanetworkopen.2021.25584",

language = "English",

volume = "4",

journal = "JAMA network open",

issn = "2574-3805",

publisher = "American Medical Association",

number = "9",

}

Ljubenkov, PA, Edwards, L, Iaccarino, L, La Joie, R, Rojas, JC, Koestler, M, Harris, B, Boeve, BF, Borroni, B, Van Swieten, JC, Grossman, M, Pasquier, F, Frisoni, GB, Mummery, CJ, Vandenberghe, R, Le Ber, I, Hannequin, D, McGinnis, SM, Auriacombe, S, Onofrj, M, Goodman, IJ, Riordan, HJ, Wisniewski, G, Hesterman, J, Marek, K, Haynes, BA, Patzke, H, Koenig, G, Hilt, D, Moebius, H & Boxer, AL 2021, 'Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients with Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial', JAMA network open, vol. 4, no. 9, 25584. https://doi.org/10.1001/jamanetworkopen.2021.25584

TY - JOUR

T1 - Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients with Progranulin Gene Haploinsufficiency

T2 - A Randomized Clinical Trial

AU - Ljubenkov, Peter A.

AU - Edwards, Lauren

AU - Iaccarino, Leonardo

AU - La Joie, Renaud

AU - Rojas, Julio C.

AU - Koestler, Mary

AU - Harris, Baruch

AU - Boeve, Bradley F.

AU - Borroni, Barbara

AU - Van Swieten, John C.

AU - Grossman, Murray

AU - Pasquier, Florence

AU - Frisoni, Giovanni B.

AU - Mummery, Catherine J.

AU - Vandenberghe, Rik

AU - Le Ber, Isabelle

AU - Hannequin, Didier

AU - McGinnis, Scott M.

AU - Auriacombe, Sophie

AU - Onofrj, Marco

AU - Goodman, Ira J.

AU - Riordan, Henry J.

AU - Wisniewski, Gary

AU - Hesterman, Jacob

AU - Marek, Ken

AU - Haynes, Beth Ann

AU - Patzke, Holger

AU - Koenig, Gerhard

AU - Hilt, Dana

AU - Moebius, Hans

AU - Boxer, Adam L.

N1 - Funding 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 Information: 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. Publisher Copyright: © 2021 BMJ Publishing Group. All rights reserved.

PY - 2021/9/24

Y1 - 2021/9/24

N2 - 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.

AB - 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.

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U2 - 10.1001/jamanetworkopen.2021.25584

DO - 10.1001/jamanetworkopen.2021.25584

M3 - Article

AN - SCOPUS:85115908987

SN - 2574-3805

VL - 4

JO - JAMA network open

JF - JAMA network open

IS - 9

M1 - 25584

ER -

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

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