Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials

Abstract

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.

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

“…While preliminary molecular characterization of epigenetic (full-methylation) patterns of ASD in FXS in the Phase II trials [82] has suggested that methylation status may constitute a treatment-sensitive biomarker for predicting response to a mGluR5 inhibitor [83,84], this finding was not replicated in two large phase III trials of mavoglurant [85]. Neither of these studies, as reported by Berry-Kravis and colleagues [85], reached the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community edition using the FXS-specific algorithm (ABC-CFX) after 12 weeks of treatment with mavoglurant. These studies with mavoglurant also indicated that the methylation state of the FMR1 promoter was also not able to predict drug efficacy.…”

“…For example, phase IIb/III clinical trials studying social and other behaviors in individuals with ASD in FXS using a subtype-selective mGluR5 inhibitors (basimglurant and mavoglurant) have shown no therapeutic benefits in FXS patients for unknown reasons [81]. While preliminary molecular characterization of epigenetic (full-methylation) patterns of ASD in FXS in the Phase II trials [82] has suggested that methylation status may constitute a treatment-sensitive biomarker for predicting response to a mGluR5 inhibitor [83,84], this finding was not replicated in two large phase III trials of mavoglurant [85]. Neither of these studies, as reported by Berry-Kravis and colleagues [85], reached the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community edition using the FXS-specific algorithm (ABC-CFX) after 12 weeks of treatment with mavoglurant.…”

“…These studies with mavoglurant also indicated that the methylation state of the FMR1 promoter was also not able to predict drug efficacy. The authors [85] concluded that the preclinical results suggest that future clinical trials might beneficially 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. Data from basimglurant IIa/b studies of adult, adolescents and children (Roche) are not in public domain.…”

Review of targeted treatments in fragile X syndrome

“…However, a small subgroup of participants with fully methylated FMR1 promoter regions showed significant improvements in stereotypic behavior, hyperactivity, and inappropriate speech as measured by the Aberrant Behavior Checklist-Community Edition (ABC-C) as well as in the overall ABC-C total score. These results encouraged two larger, multinational double-blind, placebo-controlled and parallel group trials of mavoglurant: one in adolescents (Phase III trial) and one in adults (Phase II trial) (23). In each study, participants were stratified into partial or full FMR1 methylation groups and then randomized to placebo or one of three doses of mavoglurant: 25 mg BID, 50 mg BID, or 100 mg BID.…”

Clinical trials for neurodevelopmental disorders: At a therapeutic frontier

“…We often are quick to conclude that "negative" findings in a trial prove that a treatment is ineffective under all conditions or that the presumed underlying pathophysiological mechanisms are not valid. However, as reinforced by the well-designed, properly powered study in this issue by Berry-Kravis et al (1), negative findings can provide an opportunity opportunity to reflect on clinical trial design and implementation, as well as the underlying mechanistic motivations, and provide lessons for treatment studies of neurodevelopmental disorders in general. Berry-Kravis et al highlight key themes to consider in clinical trials: choice of treatment group, target engagement, selection of outcome measures, and the impact of the placebo effect.…”