Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2023 Aug 31;134(5):e171723.
doi: 10.1172/JCI171723.

Effects of AFQ056 on language learning in fragile X syndrome

Elizabeth Berry-Kravis  1 , Leonard Abbeduto  2 , Randi Hagerman  3 , Christopher S Coffey  4 , Merit Cudkowicz  5 , Craig A Erickson  6 , Andrea McDuffie  2 , David Hessl  2 , Lauren Ethridge  7 , Flora Tassone  8 , Walter E Kaufmann  9 , Katherine Friedmann  10 , Lauren Bullard  2 , Anne Hoffmann  11 , Jeremy Veenstra-VanderWeele  12 , Kevin Staley  5 , David Klements  5 , Michael Moshinsky  5 , Brittney Harkey  5 , Jeff Long  4 , Janel Fedler  4 , Elizabeth Klingner  4 , Dixie Ecklund  4 , Michele Costigan  4 , Trevis Huff  4 , Brenda Pearson  4 ; NeuroNEXT FXLEARN Investigators
Affiliations
Randomized Controlled Trial

Effects of AFQ056 on language learning in fragile X syndrome

Elizabeth Berry-Kravis et al. J Clin Invest. .

Abstract

BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter 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-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who 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.CONCLUSIONDespite 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 preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.

Keywords: Clinical trials; Neurodevelopment; Neuroscience; Translation.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: EBK has received funding from Acadia, Biogen, BioMarin, Erydel, GeneTx/Ultragenyx, Ionis, Jaguar, Kisbee, Neuren, Neurogene, Orphazyme/Kempharm/Zevra, PTC Therapeutics, Roche, Taysha, Tetra/Shionogi, Yamo, Zynerba, and Mallinckrodt Pharmaceuticals for consulting or for clinical trials in genetic neurological disorders. LA has received funding from F. Hoffmann–La Roche Ltd., Roche TCRC Inc., and Neuren Pharmaceuticals Ltd. for consulting or work on NDDs. RH has received funding from Zynerba Pharmaceuticals and the Azrieli Foundation for clinical trials in FXS. CAE is a current consultant to Forge, Stalicla, Impel, and Scioto Bioscience. DH has received funding from Autifony, Ovid, Tetra, Healx, Roche, Novartis, and Zynerba to consult on FXS trial design. WEK is chief scientific officer of Anavex Life Sciences Corp. and serves on the Data and Safety Monitoring Board for a phase 3 trial of BPN14770 in FXS for the Tetra Therapeutics/Shionogi Group. LE has consulted for Healx, Autifony, Tetra Therapeutics, Ultragenyx, and Ovid about ERP and EEG in NDDs. JVV has served on advisory boards for Roche, Novartis, SynapDx, the Simons Foundation, Autism Speaks, and the Brain Behavior Research Foundation. JVV has received research funding from Roche, Novartis, SynapDx, Janssen, Forest, Acadia, Yamo, Seaside Therapeutics, and MapLight. He has received stipends for editorial work from Wiley and Springer.

Figures

Figure 1
Figure 1. FXLEARN protocol design.
v1, visit 1.
Figure 2
Figure 2. CONSORT diagram.
FXLEARN consented 110 participants and randomized 99 to AFQ056 (n = 50) or placebo (n = 49). There were 8 early terminations during the randomized period and 15 during the open-label period. The red box shows the groups at the end of the randomized period, on which primary outcomes were based.
Figure 3
Figure 3. WCS score change over time.
Shown for ITT (upper left), per protocol (PP) (upper right), ITT low functioning (<50 WCS, lower right) and high functioning (≥50 WCS) (lower left) groups. BL, baseline.
See this image and copyright information in PMC

Comment in

  • Challenges in developing therapies in Fragile X syndrome: how the FXLEARN trial can guide research

Similar articles

See all similar articles

Cited by

References

    1. Coffee B, et al. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet. 2009;85(4):503–514. doi: 10.1016/j.ajhg.2009.09.007. - DOI - PMC - PubMed
    1. Willemsen R, et al. CGG repeat in the FMR1 gene: size matters. Clin Genet. 2011;80(3):214–225. doi: 10.1111/j.1399-0004.2011.01723.x. - DOI - PMC - PubMed
    1. Huber KM, et al. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A. 2002;99(11):7746–7750. doi: 10.1073/pnas.122205699. - DOI - PMC - PubMed
    1. Hagerman RJ, et al. Fragile X syndrome: clinical presentation, pathology and treatment. Gac Med Mex. 2017;3(1):1–66. doi: 10.24875/GMM.19005275. - DOI - PubMed
    1. de Vries B, et al. Mental status of females with an FMR1 gene full mutation. Am J Hum Genet. 1996;58(5):1025. - PMC - PubMed

Publication types

Supplementary concepts