Effects of mavoglurant on visual attention and pupil reactivity while viewing photographs of faces in Fragile X Syndrome

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.

Atypical Social Attention and Emotional Face Processing in Autism Spectrum Disorder: Insights From Face Scanning and Pupillometry

“…The utility of the emotional faces eye-tracking paradigm assessed in the present study should continue to be evaluated given the wide range of test-retest reliability coefficients reported, in addition to other eye-tracking paradigms that are widely used in the literature that have been shown to consistently distinguish between clinical groups. More recently, a clinical trial utilizing an extended version of the emotional faces paradigm suggested the paradigm was sensitive enough to detect increases in overall looking time, fixations, and pupil reactivity in adolescents and adults with FXS (Hessl et al, 2019). Since many individuals with FXS also receive a co-occurring diagnosis of ASD (Klusek et al, 2014;Talisa et al, 2014;Thurman et al, 2014), the emotional faces paradigm may be sensitive enough to detect a change in treatment trials targeting social and emotional impairments in idiopathic ASD.…”

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

“…In 2002, it was found that mGluR-LTD at hippocampal CA3:CA1 synapses is exaggerated in Fmr1 KO mice 75 and it was later discovered that in the absence of FMRP, mGluR-LTD no longer requires new protein synthesis 129 . The mGluR-LTD pathway has been targeted in multiple pharmacological studies aimed at developing treatments for FXS 19,[130][131][132][133][134][135][136] , yet we still have a limited understanding of which mRNAs regulated by FMRP are the most important for altered mGluR-LTD phenotypes 19 . mGluR-LTD is central to motor learning tasks mediated by Purkinje cells, evidenced by impairment of conditioned eyeblink responses in global mGluR1 KO mice that can be rescued by Purkinje cell-specific mGluR1 expression 137,138 .…”

mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence

“…It is entirely possible that the failure of these trials to demonstrate benefit in their primary endpoint was due to acquired treatment resistance. It is also possible that not all efficacy measures are equally affected by treatment resistance ( Figure 7B ), perhaps explaining why significant improvements could still be observed using other functional measures, notably in subjects receiving the lower drug doses ( 56 ). Regardless, our findings make the case for limiting the duration of continuous treatment, perhaps by providing rest periods, to prevent development of drug resistance that may have masked some benefits of mGluR5 NAMs in previous clinical trials.…”