Abstract
BackgroundNumerous preclinical studies have supported the theory that enhanced activation of mGluR5 signaling, due to the absence or reduction of the FMR1 protein, contributes to cognitive and behavioral deficits in patients with fragile X syndrome (FXS). However multiple phase 2 controlled trials in patients with FXS have failed to demonstrate efficacy of compounds that negatively modulate mGluR5, including two phase 2b randomized controlled trials (RCT) of mavoglurant (AFQ056, Novartis Pharma AG), when the primary measures of interest were behavioral ratings. This has cast some doubt onto the translation of the mGluR5 theory from animal models to humans with the disorder.MethodsWe evaluated social gaze behavior–a key phenotypic feature of the disorder—and sympathetic nervous system influence on pupil size using a previously-validated eye tracking paradigm as a biobehavioral probe, in 57 adolescent or adult patients with FXS at baseline and following three months of blinded treatment with one of three doses of mavoglurant or placebo, within the context of the AFQ056 RCTs.ResultsPatients with FXS treated with mavoglurant demonstrated increased total absolute looking time and number of fixations to the eye region while viewing human faces relative to baseline, and compared to those treated with placebo. In addition, patients had greater pupil reactivity to faces relative to baseline following mavoglurant treatment compared to placebo.DiscussionThe study shows that negative modulation of mGluR5 activity improves eye gaze behavior and alters sympathetically-driven reactivity to faces in patients with FXS, providing preliminary evidence of this drug’s impact on behavior in humans with the disorder.
Highlights
Fragile X syndrome (FXS) has been at the forefront of translational efforts in neurodevelopmental disorders to bring targeted treatments from basic laboratory studies and animal models to patients and their families, with the goal of normalizing the neurobiology, behavioral disturbances and cognitive deficits associated with the Fragile X Mental Retardation 1 (FMR1) gene mutation
The Fragile X Mental Retardation Protein (FMRP) is an mRNA binding protein that aids in regulating the translation of many neuronal mRNA [8]
Participants in this study were diagnosed with fragile X syndrome (FXS) with molecular confirmation, and enrolled in one of two identically designed randomized, double-blind, randomized controlled trials (RCT) of mavoglurant, with the only difference between the trials being that one trial enrolled adolescents age 12–17, and the other enrolled adults age 18–45
Summary
Numerous preclinical studies have supported the theory that enhanced activation of mGluR5 signaling, due to the absence or reduction of the FMR1 protein, contributes to cognitive and behavioral deficits in patients with fragile X syndrome (FXS). Multiple phase 2 controlled trials in patients with FXS have failed to demonstrate efficacy of compounds that negatively modulate mGluR5, including two phase 2b randomized controlled trials (RCT) of mavoglurant (AFQ056, Novartis Pharma AG), when the primary measures of interest were behavioral ratings. This has cast some doubt onto the translation of the mGluR5 theory from animal models to humans with the disorder. All other relevant data is legally owned by Norvatis and available upon request https://www.novartis.com/our-focus/navigatenovartis/healthcare-professionals/managedaccess-programs/managed-access-request-form The authors confirm they had no special access or privileges, and other interested researchers may access the data in the same way as the author
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