Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial
Open accessAbstract
Research on animal models of fragile X syndrome suggests that STX209, a γ-aminobutyric acid type B (GABA(B)) agonist, might improve neurobehavioral function in affected patients. We evaluated whether STX209 improves behavioral symptoms of fragile X syndrome in a randomized, double-blind, placebo-controlled crossover study in 63 subjects (55 male), ages 6 to 39 years, with a full mutation in the FMR1 gene (>200 CGG triplet repeats). We found no difference from placebo on the primary endpoint, the Aberrant Behavior Checklist-Irritability (ABC-I) subscale. In the other analyses specified in the protocol, improvement was seen on the visual analog scale ratings of parent-nominated problem behaviors, with positive trends on multiple global measures. Post hoc analysis with the ABC-Social Avoidance scale, a newly validated scale for the assessment of fragile X syndrome, showed a significant beneficial treatment effect in the full study population. A post hoc subgroup of 27 subjects with more severe social impairment showed improvements on the Vineland II-Socialization raw score, on the ABC-Social Avoidance scale, and on all global measures. STX209 was well tolerated, with 8% incidences of sedation and of headache as the most frequent side effects. In this exploratory study, STX209 did not show a benefit on irritability in fragile X syndrome. Nonetheless, our results suggest that GABA(B) agonists have potential to improve social function and behavior in patients with fragile X syndrom…
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Treatment with GABAA and GABAB receptor modulators seems to control hyperexcitability in Fmr1 mutant mice, but similar approaches in human patients have failed to yield positive outcomes.
“Similarly, treatment with GABAA and GABAB receptor modulators seems to control hyperexcitability in Fmr1 mutant mice, but similar approaches in human patients have failed to yield positive outcomes 107,116 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [116]
Between 2008 and 2014, large clinical trials tested two mGluR5 antagonists, basimglurant and mavoglurant, and the GABAB agonist arbaclofen.
“Large clinical trials were conducted between 2008 and 2014 (FIG. 2) for two mGluR5 antagonists (basimglurant66 and mavoglurant67) as well as a GABAB agonist (arbaclofen68) (BOX 2).”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [68]
A broad range of secondary outcome measures were tested to search for a sensitive measure or subgroup of responders to inform the design of subsequent phase IIb and III trials.
“As a result, a broad range of secondary outcome measures were tested to search for a sensitive measure or subgroup of responders to inform the design of subsequent phase IIb and III trials68,71.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [68]
The promising mouse studies led to human trials in FXS that initially showed improvements in those with ASD plus FXS leading to phase 3 trials in FXS.
“The promising mouse studies led to human trials in FXS [131] that initially showed improvements in those with ASD plus FXS leading to phase 3 trials in FXS [132].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [131]
Cites
Verkerk, A. J. M. H., Pieretti, M., Sutcliffe, J. S., Fu, Y.-H., Kuhl, D. P. A., Pizzuti, A., Reiner, O., Richards, S., Victoria, M. F., Zhang, F., et al. (1991) · Cell · doi:10.1016/0092-8674(91)90397-h · Cited by 3,481 · see citing works
The mGluR theory of fragile X mental retardation
Bear, M. F., Huber, K. M., & Warren, S. T. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.04.009 · Cited by 1,580 · see citing works
Self-citationRisperidone in Children with Autism and Serious Behavioral Problems
McCracken, J. T., McGough, J., Shah, B., Cronin, P., Hong, D., Aman, M. G., Arnold, L. E., Lindsay, R., Nash, P., Hollway, J., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa013171 · Cited by 1,574 · see citing works
THE BEHAVIOR OF CHILDREN RECEIVING BENZEDRINE
Bradley, C. (1937) · American Journal of Psychiatry · doi:10.1176/ajp.94.3.577 · Cited by 1,035 · see citing works
Jacquemont, S., Curie, A., des Portes, V., Torrioli, M. G., Berry-Kravis, E., Hagerman, R. J., Ramos, F. J., Cornish, K., He, Y., Paulding, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3001708 · Cited by 609 · see citing works
Self-citationSuppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP
Yan, Q. J., Rammal, M., Tranfaglia, M., & Bauchwitz, R. P. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2005.06.004 · Cited by 521 · see citing works
Henderson, C., Wijetunge, L., Kinoshita, M. N., Shumway, M., Hammond, R. S., Postma, F. R., Brynczka, C., Rush, R., Thomas, A., Paylor, R., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004218 · Cited by 249 · see citing works
Self-citationPsychopharmacology in fragile X syndrome—Present and future
Berry‐Kravis, E., & Potanos, K. (2004) · Mental Retardation and Developmental Disabilities Research Reviews · doi:10.1002/mrdd.20007 · Cited by 151 · see citing works
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Hagerman, R. J., Berry-Kravis, E., Hazlett, H. C., Bailey, D. B., Moine, H., Kooy, R. F., Tassone, F., Gantois, I., Sonenberg, N., Mandel, J. L., et al. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.65 · Cited by 838 · see citing works
Self-citationDisentangling the heterogeneity of autism spectrum disorder through genetic findings
Jeste, S. S., & Geschwind, D. H. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.278 · Cited by 644 · see citing works
Altering the course of schizophrenia: progress and perspectives
Millan, M. J., Andrieux, A., Bartzokis, G., Cadenhead, K., Dazzan, P., Fusar-Poli, P., Gallinat, J., Giedd, J., Grayson, D. R., Heinrichs, M., et al. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.28 · Cited by 516 · see citing works
The translation of translational control by FMRP: therapeutic targets for FXS
Darnell, J. C., & Klann, E. (2013) · Nature Neuroscience · doi:10.1038/nn.3379 · Cited by 491 · see citing works
Developmental timing and critical windows for the treatment of psychiatric disorders
Marín, O. (2016) · Nature Medicine · doi:10.1038/nm.4225 · Cited by 374 · see citing works
Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome
Berry-Kravis, E. M., Lindemann, L., Jønch, A. E., Apostol, G., Bear, M. F., Carpenter, R. L., Crawley, J. N., Curie, A., Des Portes, V., Hossain, F., et al. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.221 · Cited by 336 · see citing works
Self-citationFragile X syndrome: causes, diagnosis, mechanisms, and therapeutics
Bagni, C., Tassone, F., Neri, G., & Hagerman, R. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63141 · Cited by 321 · see citing works
Self-citationLeigh, M. J. S., Nguyen, D. V., Mu, Y., Winarni, T. I., Schneider, A., Chechi, T., Polussa, J., Doucet, P., Tassone, F., Rivera, S. M., et al. (2013) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/dbp.0b013e318287cd17 · Cited by 298 · see citing works
Self-citationDysregulation and restoration of translational homeostasis in fragile X syndrome
Richter, J. D., Bassell, G. J., & Klann, E. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn4001 · Cited by 275 · see citing works
Henderson, C., Wijetunge, L., Kinoshita, M. N., Shumway, M., Hammond, R. S., Postma, F. R., Brynczka, C., Rush, R., Thomas, A., Paylor, R., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004218 · Cited by 249 · see citing works
Self-citationProgress toward treatments for synaptic defects in autism
Delorme, R., Ey, E., Toro, R., Leboyer, M., Gillberg, C., & Bourgeron, T. (2013) · Nature Medicine · doi:10.1038/nm.3193 · Cited by 218 · see citing works
Han, S., Tai, C., Jones, C. J., Scheuer, T., & Catterall, W. A. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.016 · Cited by 231 · see citing works
An Update on Psychopharmacological Treatment of Autism Spectrum Disorder
Aishworiya, R., Valica, T., Hagerman, R., & Restrepo, B. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01183-1 · Cited by 233 · see citing works
Self-citationLemonnier, E., Villeneuve, N., Sonie, S., Serret, S., Rosier, A., Roue, M., Brosset, P., Viellard, M., Bernoux, D., Rondeau, S., et al. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.10 · Cited by 218 · see citing works
Silverman, J. L., Pride, M. C., Hayes, J. E., Puhger, K. R., Butler-Struben, H. M., Baker, S., & Crawley, J. N. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.66 · Cited by 215 · see citing works
Preclinical research in Rett syndrome: setting the foundation for translational success
Katz, D. M., Berger-Sweeney, J. E., Eubanks, J. H., Justice, M. J., Neul, J. L., Pozzo-Miller, L., Blue, M. E., Christian, D., Crawley, J. N., Giustetto, M., et al. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.011007 · Cited by 206 · see citing works
Arbaclofen in fragile X syndrome: results of phase 3 trials
Berry-Kravis, E., Hagerman, R., Visootsak, J., Budimirovic, D., Kaufmann, W. E., Cherubini, M., Zarevics, P., Walton-Bowen, K., Wang, P., Bear, M. F., et al. (2017) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-016-9181-6 · Cited by 183 · see citing works
Self-citationVeenstra-VanderWeele, J., Cook, E. H., King, B. H., Zarevics, P., Cherubini, M., Walton-Bowen, K., Bear, M. F., Wang, P. P., & Carpenter, R. L. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.237 · Cited by 168 · see citing works
Self-citationHessl, D., Sansone, S. M., Berry-Kravis, E., Riley, K., Widaman, K. F., Abbeduto, L., Schneider, A., Coleman, J., Oaklander, D., Rhodes, K. C., et al. (2016) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-016-9167-4 · Cited by 126 · see citing works
Self-citationBerry-Kravis, E. M., Harnett, M. D., Reines, S. A., Reese, M. A., Ethridge, L. E., Outterson, A. H., Michalak, C., Furman, J., & Gurney, M. E. (2021) · Nature Medicine · doi:10.1038/s41591-021-01321-w · Cited by 131 · see citing works
Self-citationDrug discovery for autism spectrum disorder: challenges and opportunities
Ghosh, A., Michalon, A., Lindemann, L., Fontoura, P., & Santarelli, L. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4102 · Cited by 108 · see citing works
Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back
Gross, C., Hoffmann, A., Bassell, G. J., & Berry-Kravis, E. M. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0355-9 · Cited by 105 · see citing works
Self-citationStoppel, L. J., Kazdoba, T. M., Schaffler, M. D., Preza, A. R., Heynen, A., Crawley, J. N., & Bear, M. F. (2018) · Neuropsychopharmacology · doi:10.1038/npp.2017.236 · Cited by 92 · see citing works
Self-citationPrenatal stress and inhibitory neuron systems: implications for neuropsychiatric disorders
Fine, R., Zhang, J., & Stevens, H. E. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.35 · Cited by 96 · see citing works
Port, R. G., Gaetz, W., Bloy, L., Wang, D., Blaskey, L., Kuschner, E. S., Levy, S. E., Brodkin, E. S., & Roberts, T. P. L. (2017) · Autism Research · doi:10.1002/aur.1686 · Cited by 94 · see citing works
Thurman, A. J., McDuffie, A., Hagerman, R., & Abbeduto, L. (2014) · Research in Developmental Disabilities · doi:10.1016/j.ridd.2014.01.032 · Cited by 70 · see citing works
Self-citationGurney, M. E., Cogram, P., Deacon, R. M., Rex, C., & Tranfaglia, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-15028-x · Cited by 69 · see citing works
Radwan, B., Dvorak, D., & Fenton, A. A. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.01.003 · Cited by 63 · see citing works
Qin, M., Huang, T., Kader, M., Krych, L., Xia, Z., Burlin, T., Zeidler, Z., Zhao, T., & Smith, C. B. (2015) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyv034 · Cited by 62 · see citing works
Hyperexcitability and homeostasis in fragile X Syndrome.
Liu, X., Kumar, V., Tsai, N.-P., & Auerbach, B. D. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.805929 · Cited by 53 · see citing works
Bennett (2023) · doi:10.1097/yco.0000000000000775 · Cited by 51 · see citing works
Placebo Responses in Genetically Determined Intellectual Disability: A Meta-Analysis
Curie, A., Yang, K., Kirsch, I., Gollub, R. L., des Portes, V., Kaptchuk, T. J., & Jensen, K. B. (2015) · PLOS ONE · doi:10.1371/journal.pone.0133316 · Cited by 43 · see citing works
New therapeutic options for autism spectrum disorder: experimental evidences
Peñagarikano, O. (2015) · Experimental Neurobiology · doi:10.5607/en.2015.24.4.301 · Cited by 24 · see citing works
van der Vaart, T., Overwater, I. E., Oostenbrink, R., Moll, H. A., & Elgersma, Y. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2015.0443 · Cited by 17 · see citing works
Placebo effects in children with autism spectrum disorder
Curie, A., Oberlander, T. F., & Jensen, K. B. (2023) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.15574 · Cited by 16 · see citing works
- Authors
- Berry-Kravis, E. M., Hessl, D., Rathmell, B., Zarevics, P., Cherubini, M., Walton-Bowen, K., Mu, Y., Nguyen, D. V., Gonzalez-Heydrich, J., Wang, P. P., Carpenter, R. L., Bear, M. F., & Hagerman, R. J.
- Affiliations
- Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA.
- University of California Davis Medical Center (US)
- Seaside Therapeutics (United States) (US)
- University of California, Davis (US)
- Department of Psychiatry, Children’s Hospital Boston, Boston, MA 02115, USA.
- Massachusetts Institute of Technology (US)
- Corresponding author
- Wang, Paul P.
- Venue
- Science Translational Medicine
- Published
- 2012-09-19
- Volume
- 4
- Issue
- 152
- Pages
- 152ra127-152ra127
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W2101716121
- Cited by
- 328
- References
- 8
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 19 · 2023: 13 · 2022: 20 · 2021: 12 · 2020: 15 · 2019: 19 · 2018: 13 · 2017: 44 · 2016: 30 · 2015: 36 · 2014: 39 · 2013: 40 · 2012: 18
- FWCI
- 25.55
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by-nc-sa
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- fragile X syndrome, GABA-B receptor agonist, FMR1 full mutation, irritability, social avoidance, social function, neurobehavioral function, Aberrant Behavior Checklist, sedation, headache
- MeSH terms
- Adolescent, Adult, Baclofen, Behavior, Child, Female, Fragile X Syndrome, Humans, Male, Nervous System, Neuropsychological Tests, Reproducibility of Results, Treatment Outcome, Young Adult
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