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PDE4D变构抑制剂可改善FXS认知和预后
作者:小柯机器人 发布时间:2021/4/30 18:17:46

美国利乐治疗Mark E. Gurney、美国拉什大学医学中心Elizabeth M. Berry-Kravis合作取得最新进展。他们研究了患有脆性X综合征(FXS)的成年人对磷酸二酯酶4D(PDE4D)的抑制作用,这是一项随机、安慰剂对照的2期临床试验。 2021年4月29日出版的《自然-医学》杂志发表了这项成果。

这项研究的目的是确定PDE4D变构抑制剂(BPN14770)是否会改善FXS患者的认知功能和行为预后。这项2期试验是针对30名FXS成年男性患者(年龄在18-41岁之间)进行的一项为期24周的随机、安慰剂对照、双向交叉研究。参与者每天两次口服BPN14770 或安慰剂25毫克。预先确定安全性和耐受性的主要预后,其次为认知表现,护理者评定量表和医师评定量表的疗效(ClinicalTrials.gov标识符:NCT03569631)。该研究符合主要预后指标,因为BPN14770具有良好的耐受性、活性和安慰剂治疗组之间无有意义的差异。

该研究还满足了认知和日常功能的关键次要疗效指标。使用美国国立卫生研究院工具箱的认知电池评估对口头阅读能力(最小二乘均差+ 2.81,P = 0.0157)、图片词汇量(+ 5.81,P = 0.0342)和认知结晶综合评分(+5.31, P = 0.0018)进行评估,表明了认知获益。通过视觉模拟看护者评定量表评估获益被判断为对语言(+14.04,P = 0.0051)和日常功能(+14.53,P = 0.0017)具有临床意义。对FXS的成年男性对认知能力的直接计算机评估进行的这项研究的结果表明,与语言相关的领域中的认知能力得到了显著改善,而语言和日常功能的评估也得到了相应的改善。

附:英文原文

Title: Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial

Author: Elizabeth M. Berry-Kravis, Mark D. Harnett, Scott A. Reines, Melody A. Reese, Lauren E. Ethridge, Abigail H. Outterson, Claire Michalak, Jeremiah Furman, Mark E. Gurney

Issue&Volume: 2021-04-29

Abstract: The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18–41 years) with FXS. Participants received oral doses of BPN14770 25mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P=0.0157), Picture Vocabulary (+5.81, P=0.0342) and Cognition Crystallized Composite score (+5.31, P=0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P=0.0051) and daily functioning (+14.53, P=0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.

DOI: 10.1038/s41591-021-01321-w

Source: https://www.nature.com/articles/s41591-021-01321-w

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex