Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials
Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials
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DOI：
10.1126/scitranslmed.aab4109
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发表时间：
2016-01-13
影响因子：
17.1
通讯作者：
von Raison, Florian
中科院分区：
文献类型：
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作者：
Berry-Kravis, Elizabeth;Portes, Vincent Des;von Raison, Florian
脆性X综合征（FXS）是遗传性智力障碍和自闭症谱系障碍最常见的病因，通常是由X连锁的FMR1基因转录沉默引起的。在动物模型中的研究表明，代谢型谷氨酸受体5（mGluR5）介导的信号通路上调所导致的突触可塑性改变是一种假定的下游效应。一项随机、安慰剂对照、交叉的2期试验的事后分析表明，选择性mGluR5拮抗剂马沃格鲁坦改善了FMR1基因完全甲基化的FXS患者的行为症状。我们展示了两项关于马沃格鲁坦治疗FXS的2b期、多中心、随机、双盲、安慰剂对照、平行组研究的结果，这些研究旨在成人（n = 175，年龄18 - 45岁）和青少年（n = 139，年龄12 - 17岁）中证实这一结果。在两项试验中，参与者根据甲基化状态分层，并随机接受马沃格鲁坦（每日两次，每次25、50或100mg）或安慰剂治疗12周。在使用马沃格鲁坦治疗12周后，两项研究均未达到通过使用FXS特定算法的异常行为检查表 - 社区版（ABC - C - FX）测量的行为症状改善这一主要疗效终点。马沃格鲁坦的安全性和耐受性情况与先前描述的一致，不良事件较少。因此，在我们的研究条件下，我们无法证实FXS的mGluR理论，也无法证实FMR1启动子的甲基化状态预测马沃格鲁坦疗效的能力。临床前结果表明，未来的临床试验可能有益地探索在更年轻的人群中开始治疗，治疗持续时间更长，安慰剂导入期更长，并确定新的标志物以更好地评估行为和认知益处。
Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling, as a putative downstream effect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of mavoglurant in FXS, designed to confirm this result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community Edition using the FXS-specific algorithm (ABC-C-FX) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with few adverse events. Therefore, under the conditions of our study, we could not confirm the mGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predict mavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits.