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Effects of AFQ056 on language learning in fragile X syndrome
Journal article   Open access   Peer reviewed

Effects of AFQ056 on language learning in fragile X syndrome

Elizabeth Berry-Kravis, Leonard Abbeduto, Randi Hagerman, Christopher S Coffey, Merit Cudkowicz, Craig A Erickson, Andrea McDuffie, David Hessl, Lauren E Ethridge, Flora Tassone, …
The Journal of clinical investigation, Vol.134(5), e171723
03/01/2024
DOI: 10.1172/JCI171723
PMCID: PMC10904045
PMID: 37651202
url
https://doi.org/10.1172/JCI171723View
Published (Version of record) Open Access

Abstract

BACKGROUND. FXLEARN, the first-ever large multi-site trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a new paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of mGluR5 negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3-6 year-old children with FXS, expected to have more learning plasticity than adults, where prior trials of mGluR5 NAMs have failed. METHODS. After a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-report cognitive and language measures. RESULTS. FXLEARN enrolled 110 participants, randomized 99, and 91 completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures. CONCLUSION. Despite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from pre-clinical models to humans in genetic neurodevelopmental disorders.

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