Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial.
Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial.
复制标题
组蛋白去乙酰化酶抑制剂FRM-0334对颗粒蛋白前体基因单倍不足患者颗粒蛋白前体水平的影响：一项随机临床试验。
DOI：
10.1001/jamanetworkopen.2021.25584
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发表时间：
2021-09-01
影响因子：
13.8
通讯作者：
Boxer AL
中科院分区：
文献类型：
--
作者：
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
组蛋白去乙酰化酶抑制剂FRM-0334在前颗粒蛋白基因（GRN）单倍功能不全患者中的安全性、耐受性、药效学和药代动力学特征是什么？在这项随机安慰剂对照临床试验中，有27名受试者患有GRN单倍功能不全，FRM-0334是安全且耐受性良好的；然而，它不能增加血浆前颗粒蛋白和脑脊液前颗粒蛋白，也不能证明其剂量依赖性的口服生物利用度。研究的FRM-0334配方不应在未来的临床试验中进行研究，纳入GRN单倍功能不全的受试者；这项研究没有完全解决组蛋白去乙酰化酶抑制改变GRN表达的潜力。这项随机临床试验研究了组蛋白去乙酰化酶抑制剂FRM-0334在前颗粒蛋白基因单倍不全患者中的药代动力学和药效学特征、耐受性和安全性。在临床前模型中，组蛋白去乙酰化酶抑制剂多次显示可提高颗粒蛋白前水平。本报告描述了一种组蛋白去乙酰化酶抑制剂治疗由前颗粒蛋白（GRN）基因变异引起的额颞叶痴呆（FTD）的首个随机临床试验。目的：研究口服FRM-0334对GRN单倍不全患者血浆前颗粒蛋白和其他探索性生物标志物(包括氟脱氧葡萄糖（FDG) -正电子发射断层扫描（PET））的安全性、耐受性、血浆药代动力学和药效学影响。在这项随机、双盲、安慰剂对照、剂量递增、2a期安全性、耐受性和药效学临床研究中，对伴有颗粒蛋白变化的前驱至中度FTD患者给予2剂组蛋白去乙酰化酶抑制剂（FRM-0334）。参与者的招募时间为2015年1月13日至2016年4月13日。该研究包括27名患有FTD前体症状（n = 8）或轻中度症状（n = 19）和GRN杂合致病性变异的参与者，并在北美、英国和欧盟的多个中心进行。数据分析时间为2019年6月9日至2021年5月13日。每天口服安慰剂（n = 5）， 300 mg FRM-0334 （n = 11）或500 mg FRM-0334 (n = 11)，持续28天。主要结果是FRM-0334的安全性和耐受性及其对血浆前颗粒蛋白的外周药效学影响。次要观察结果为FRM-0334的血浆药动学特征及其对脑脊液前颗粒蛋白的药效学影响。探索性结果包括FDG-PET、FTD临床严重程度和脑脊液生物标志物（神经丝轻链[NfL]、β淀粉样蛋白1-42、磷酸化tau 181和总tau [t-tau]）。共有27名GRN变异患者（平均[SD]年龄56.6[10.5]岁，16名女性[59.3%]，26名白人[96.3%]）被随机分配并完成治疗。FRM-0334安全且耐受性良好，但不影响血浆前颗粒蛋白（治疗后每日变化4.3 pg/mL）； 95% CI, -10.1 ~ 18.8 pg/mL；56)，脑脊液前颗粒蛋白(0.42 pg/mL /天；95% CI, -0.12至0.95 pg/mL; P =。13)，或探索性药效学测量。血浆FRM-0334暴露不随剂量成比例增加。27名随机受试者中有26名的脑FDG-PET数据可用。在26个个体的横断面分析中，双额皮质FDG低代谢与较差的临床痴呆评分（CDR）和国家阿尔茨海默病协调中心额颞叶变性相关(b = - 3.6 × 10−2标准化摄取值比[SUVR]单位/CDR单位；95% CI, - 4.9 × 10−2至- 2.2 × 10−2;P <。0.001)，脑脊液NfL高（b =−9.2 × 10−5 SUVR单位/pg NfL/mL； 95% CI,−1.3 × 10−4至−5.6 × 10−5;P < 0.001）。001),和高CSF t-tau(−7.2×10−4 SUVR单位/ pg t-tau /毫升;95%可信区间,1.4×10−−3−9.5×10−5;P = 03)。在这项随机临床试验中，目前的FRM-0334配方并没有提高PRGN水平，这可能反映了在达到的暴露下缺乏疗效，低生物利用度，或者是两种因素的某种组合。双额位FDG-PET是症状性GRN单倍体功能不全的敏感指标。FTD-GRN的国际多中心临床试验是可行的。ClinicalTrials.gov标识符：NCT02149160
What is the safety, tolerability, pharmacodynamic, and pharmacokinetic profile of the histone deacetylase inhibitor FRM-0334 in participants with progranulin gene (GRN) haploinsufficiency? In this randomized placebo-controlled clinical trial including 27 participants with GRN haploinsufficiency, FRM-0334 was safe and well tolerated; however, it failed to increase plasma progranulin and cerebrospinal fluid progranulin and failed to demonstrate dose-dependent oral bioavailability. The studied formulation of FRM-0334 should not be investigated in future clinical trials enrolling participants with GRN haploinsufficiency; this study did not fully address the potential of histone deacetylase inhibition to alter GRN expression. This randomized clinical trial investigates the pharmacokinetic and pharmacodynamic profile, tolerability, and safety of the histone deacetylase inhibitor FRM-0334 in people with progranulin gene haploinsufficiency. 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. 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. 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. 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. 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]). 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 × 10−2 standardized uptake value ratio [SUVR] units/CDR units; 95% CI, −4.9 × 10−2 to −2.2 × 10−2; P < .001), high cerebrospinal fluid NfL (b = −9.2 × 10−5 SUVR units/pg NfL/mL; 95% CI, −1.3 × 10−4 to −5.6 × 10−5; P < .001), and high CSF t-tau (−7.2 × 10−4 SUVR units/pg t-tau/mL; 95% CI, −1.4 × 10−3 to −9.5 × 10−5; P = .03). 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. ClinicalTrials.gov Identifier: NCT02149160
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影响因子：
3.7
作者：
Hanson JE;La H;Plise E;Chen YH;Ding X;Hanania T;Sabath EV;Alexandrov V;Brunner D;Leahy E;Steiner P;Liu L;Scearce-Levie K;Zhou Q
通讯作者：
Zhou Q
影响因子：
5.6
作者：
Alquezar, Carolina;Esteras, Noemi;Martin-Requero, Angeles
通讯作者：
Martin-Requero, Angeles
影响因子：
4.8
作者：
BHANDARI, V;GIAID, A;BATEMAN, A
通讯作者：
BATEMAN, A
影响因子：
2.3
作者：
Meeter LH;Patzke H;Loewen G;Dopper EG;Pijnenburg YA;van Minkelen R;van Swieten JC
通讯作者：
van Swieten JC
DOI：
10.1038/nrn.2017.36
发表时间：
2017-06
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Kao AW;McKay A;Singh PP;Brunet A;Huang EJ
通讯作者：
Huang EJ