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.
People with the genetic disorder fragile X syndrome exhibit a variable constellation of debilitating physical and cognitive problems. 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. Promising evidence from mouse models had raised hopes that an overactive glutamate signaling pathway (mGluR) was a smoking gun at the heart of the disease and that it could be successfully repaired.
A pilot study in patients supported the mouse work: Down-regulation of mGluR improved behavioral problems, at least in patients carrying a certain genetic methylation marker.
In a larger, well-powered clinical trial, published in the journal Science Translational Medicine these results are put to the test and come up short. In adolescent or adult fragile X patients, whether they have the methylation marker or not, the glutamate antagonist mavoglurant had no effect on patient behavior.
The authors discuss what further trials will be required, however, before permanently putting the mGluR theory of fragile X syndrome out to pasture. Cross over phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes.
In the two phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of mavoglurant in FXS, designed to confirm this result in adults and adolescents 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 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, authors 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.