Adolescents and adults diagnosed with fragile X syndrome (FXS) showed improvement in social gaze behavior — measured by their ability to maintain visual contact and the eye’s pupil reactivity — when treated with Novartis’ mavoglurant.
FXS is a neurodevelopment disorder characterized by disturbances in behavior and cognitive defects due to an error on the FMR1 gene, located in the X chromosome.
The absence of the FMRP protein results in brain underdevelopment and gives rise to problems such as intellectual disability, comorbid autism or autistic behaviors and high rates of anxiety and social withdrawal, accompanied by lack of attention and distraction.
FMRP regulates protein production at the synapse — the site where neurons communicate — via metabotropic glutamate receptors (mGluRs), among other targets. Glutamate is the main excitatory neurotransmitter in the central nervous system, which includes the brain and the spinal cord, participating in a wide range of neural functions such as learning and memory.
Numerous studies have shown that targeting a metabotropic glutamate receptor called mGluR5 can revert many of the symptoms observed in animal models of FXS.
Mavoglurant (AFQ056) is a mGluR5 negative regulator developed by Novartis, shown to be safe and well tolerated in the long-term to treat adolescents and adults with FXS. However, two Phase 2b clinical trials failed to show a significant benefit in mavoglurant treatment, namely when the primary measures were behavioral ratings, leading to its discontinuation in 2014.
Now, researchers hypothesized that the outcome measures of these trials were not fully adequate to measure the core features of FXS phenotype.
“[T]he outcome measures used in targeted treatment trials may need to be more syndrome-specific and closer to the underlying neurobiology of the condition, at least at the stage of determining whether there is target engagement,” researchers said.
“Gaze avoidance is a hallmark phenotypic feature of FXS that reflects social anxiety and hyperarousal, and interferes with and alters social reciprocity, engagement and social-emotional development,” they stated.
People with fragile X are sensitive to gaze initiation and dislike eye contact. Moreover, FXS patients also show increased pupil reactivity — relaxation and contraction of the pupil in response to a stimulus — to emotional faces than normal developing controls.
Using infrared eye tracking that reliably evaluates gaze avoidance, researchers examined social gaze behavior and pupil reactivity in fragile X patients who had enrolled in two Phase 2 trials of mavoglurant. One of the trials (NCT01253629) recruited fragile X patients ages 12-17; another (NCT01357239) recruited people ages 18-45.
The participants were randomized to either placebo (control group, 18 participants) or to treatment with mavoglurant, delivered at three different doses — 25 milligrams (11 participants), 50 milligrams (12 participants) or 100 milligrams (16 participants).
Gaze behavior was evaluated at the beginning of the study (baseline) and 12 weeks following treatment. The eye tracker consisted of an infrared video-based tracking system that monitors eye movements “employing a cornea reflection technique with a sampling rate of 120 Hz,” researchers stated. “The tracker is embedded in the computer monitor and is considered less invasive than head- mounted units, promoting more natural user behavior.”
Eye tracking data was collected during passive viewing of 60 color photographs of adult faces and 60 scrambled versions of each facial image. Faces demonstrated a calm, happy, or fearful expression. Each trial consisted of the presentation of a scrambled face for one second, followed by its matching face for three seconds (20 trials of each). Eye gaze behavior and pupil size were recorded.
There were no significant differences between changes in total time looking at faces overall among groups. However, there was a significant difference in total absolute looking time to the eye region between patients treated with 25 mg of mavoglurant and those on placebo. “There was no significant difference in amount of change for individuals in the 50 mg or 100 mg groups relative to the placebo group,” researchers said.
Regarding fixations to the eye region, those treated with 25 mg and 100 mg mavoglurant showed a significant difference (increase) in the amount of change relative to controls. No significant differences were observed in the 50 mg group.
“[E]motion had a significant effect on pupil reactivity over time, such that, relative to calm, both fearful … and happy faces … elicited … more pupil dilation in the placebo condition, compared to baseline,” researchers said.
After 12 weeks of treatment, mavoglurant-treated patients showed greater pupil dilation in the calm condition compared to the placebo group. However, the 25 mg dose of mavoglurant resulted in significantly less change in pupil reactivity compared with placebo-treated patients in the happy condition.
Because there was not a clear correlation between benefits of mavoglurant at increasing doses, researchers looked at the influence of concomitant psychoactive medications.
They found that the differences in total absolute looking time to the eye region and number of fixations varied according to psychoactive medications, but the same was not true for pupil reaction to faces.
Overall, these findings suggest that “mavoglurant … significantly improves visual attention to the eyes in adults and adolescents with FXS relative to placebo in the context of a controlled trial,” researchers said, adding that “[t]he improvement in eye gaze as a result of mavoglurant treatment in FXS may be driven by decreases in levels of social anxiety.”
“It is our hope that these findings will help to guide future clinical trials by showing the potential for mGluR5 negative modulators to modify human behaviour,” researchers concluded.