Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials

Science Translational Medicine

Volumn 8, Issue 321, 2016, Pages

  Berry Kravis, Elizabeth ^a   Des Portes, Vincent ^b,c   Hagerman, Randi ^d   Jacquemont, Sébastien ^e,f   Charles, Perrine ^g   Visootsak, Jeannie ^h   Brinkman, Marc ⁱ   Rerat, Karin ^j   Koumaras, Barbara ^k   Zhu, Liansheng ^k   Barth, Gottfried Maria ^l   Jaecklin, Thomas ^k   Apostol, George ^k   Von Raison, Florian ^k  

^a RUSH UNIVERSITY MEDICAL CENTER   (United States)

^b UNIVERSITÉ DE LYON   (France)

^c INSTITUT DES SCIENCES COGNITIVES   (France)

^d UNIVERSITY OF CALIFORNIA   (United States)

^e LAUSANNE UNIVERSITY HOSPITAL   (Switzerland)

^f UNIVERSITY OF MONTREAL   (Canada)

^g PITIÉ SALPÊTRIÈRE HOSPITAL   (France)

^h EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

ⁱ Novartis Pharma GmbH   (Germany)

^j NOVARTIS PHARMA K K   (Japan)

^k NOVARTIS PHARMA AG   (Switzerland)

^l UNIVERSITY HOSPITAL TÜBINGEN   (Germany)

more..

Author keywords

[No Author keywords available]

Indexed keywords

MAVOGLURANT; PLACEBO; INDOLE DERIVATIVE;

ABERRANT BEHAVIOR CHECKLIST COMMUNITY EDITION; ADOLESCENT; ADULT; AFFECT; AGITATION; APPENDICITIS; ARTICLE; CHILD; CONTROLLED STUDY; DECREASED APPETITE; DIZZINESS; DNA METHYLATION; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG DOSE COMPARISON; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FEMALE; FRAGILE X SYNDROME; HEADACHE; HUMAN; HYPERACTIVITY; HYPERHIDROSIS; INSOMNIA; MAJOR CLINICAL STUDY; MALE; MENTAL DISEASE; MULTICENTER STUDY; PARALLEL DESIGN; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RHINOPHARYNGITIS; SCORING SYSTEM; SIDE EFFECT; SINGLE BLIND PROCEDURE; TACHYCARDIA; UNSPECIFIED SIDE EFFECT; UPPER RESPIRATORY TRACT INFECTION; VISUAL HALLUCINATION; VOMITING; AGE; BEHAVIOR; COGNITION; DEMOGRAPHY; DRUG EFFECTS; GENETICS; LEAST SQUARE ANALYSIS; TREATMENT OUTCOME;

ADOLESCENT; ADULT; AGE FACTORS; BEHAVIOR; COGNITION; DEMOGRAPHY; DNA METHYLATION; DOUBLE-BLIND METHOD; FEMALE; FRAGILE X SYNDROME; HUMANS; INDOLES; LEAST-SQUARES ANALYSIS; MALE; PLACEBOS; TREATMENT OUTCOME;

EID: 84954289367     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aab4109     Document Type: Article

References (33)

1. R. J. Hagerman, P. J. Hagerman, Eds., Fragile X Syndrome: Diagnosis, Treatment, and Research (The Johns Hopkins University Press, Baltimore, 2002).
2. F. J. Song, P. Barton, V. Sleightholme, G. L. Yao, A. Fry-Smith, Screening for fragile X syndrome: A literature review and modelling study. Health Technol. Assess. 7, 1-106 (2003).
3. D. I. Zafeiriou, A. Ververi, V. Dafoulis, E. Kalyva, E. Vargiami, Autism spectrum disorders: The quest for genetic syndromes. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B, 327-366 (2013).
4. J. Hunter, O. Rivero-Arias, A. Angelov, E. Kim, I. Fotheringham, J. Leal, Epidemiology of fragile X syndrome: A systematic review and meta-analysis. Am. J. Med. Genet. A 164A, 1648-1658 (2014).
5. S. L. Hartley, M. M. Seltzer, M. Raspa, M. Olmstead, E. Bishop, D. B. Bailey Jr., Exploring the adult life of men and women with fragile X syndrome: Results from a national survey. Am. J. Intellect. Dev. Disabil. 116, 16-35 (2011).
6. A. J. M. H. Verkerk, M. Pieretti, J. S. Sutcliffe, Y.-H. Fu, D. P. A. Kuhl, A. Pizzuti, O. Reiner, S. Richards, M. F. Victoria, F. Zhang, B. E. Eussen, G.-J. B. van Ommen, L. A. J. Blonden, G. J. Riggins, J. L. Chastain, C. B. Kunst, H. Galjaard, C. T. Caskey, D. L. Nelson, B. A. Oostra, S. T. Warren, Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905-914 (1991).
7. D. Devys, Y. Lutz, N. Rouyer, J.-P. Bellocq, J.-L. Mandel, The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nat. Genet. 4, 335-340 (1993).
8. E. Fernández, N. Rajan, C. Bagni, The FMRP regulon: From targets to disease convergence. Front. Neurosci. 7, 191 (2013).
9. F. Zalfa, M. Giorgi, B. Primerano, A. Moro, A. Di Penta, S. Reis, B. Oostra, C. Bagni, The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 112, 317-327 (2003).
10. K. M. Huber, S. M. Gallagher, S. T. Warren, M. F. Bear, Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl. Acad. Sci. U.S.A. 99, 7746-7750 (2002).
11. C. X. He, C. Portera-Cailliau, The trouble with spines in fragile X syndrome: Density, maturity and plasticity. Neuroscience 251, 120-128 (2013).
12. M. F. Bear, K. M. Huber, S. T. Warren, The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370-377 (2004).
13. J. Levenga, S. Hayashi, F. M. de Vrij, S. K. Koekkoek, H. C. van der Linde, I. Nieuwenhuizen, C. Song, R. A. M. Buijsen, A. S. Pop, B. Gomezmancilla, D. L. Nelson, R. Willemsen, F. Gasparini, B. A. Oostra, AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome. Neurobiol. Dis. 42, 311-317 (2011).
14. I. Gantois, A. S. Pop, C. E. de Esch, R. A. Buijsen, T. Pooters, B. Gomez-Mancilla, F. Gasparini, B. A. Oostra, R. D'Hooge, R. Willemsen, Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice. Behav. Brain Res. 239, 72-79 (2013).
15. A. S. Pop, J. Levenga, C. E. F. de Esch, R. A. M. Buijsen, I. M. Nieuwenhuizen, T. Li, A. Isaacs, F. Gasparini, B. A. Oostra, R. Willemsen, Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant. Psychopharmacology 231, 1227-1235 (2014).
16. S. Jacquemont, A. Curie, V. des Portes, M. G. Torrioli, E. Berry-Kravis, R. J. Hagerman, F. J. Ramos, K. Cornish, Y. He, C. Paulding, G. Neri, F. Chen, N. Hadjikhani, D. Martinet, J. Meyer, J. S. Beckmann, K. Delange, A. Brun, G. Bussy, F. Gasparini, T. Hilse, A. Floesser, J. Branson, G. Bilbe, D. Johns, B. Gomez-Mancilla, Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci. Transl. Med. 3, 64ra1 (2011).
17. S. Hines, F. Bennett, Effectiveness of early intervention for children with Down syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 2, 96-101 (1996).
18. A. Michalon, M. Sidorov, T. M. Ballard, L. Ozmen, W. Spooren, J. G. Wettstein, G. Jaeschke, M. F. Bear, L. Lindemann, Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74, 49-56 (2012).
19. J. C. Darnell, E. Klann, The translation of translational control by FMRP: Therapeutic targets for FXS. Nat. Neurosci. 16, 1530-1536 (2013).
20. T. Su, H. X. Fan, T. Jiang, W. W. Sun, W. Y. Den, M. M. Gao, S. Q. Chen, Q. H. Zhao, Y. H. Yi, Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome. Psychopharmacology 215, 291-300 (2011).
21. C. A. Hoeffer, E. Sanchez, R. J. Hagerman, Y. Mu, D. V. Nguyen, H. Wong, A. M. Whelan, R. S. Zukin, E. Klann, F. Tassone, Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav. 11, 332-341 (2012).
22. C. G. Gkogkas, A. Khoutorsky, R. Cao, S. M. Jafarnejad, M. Prager-Khoutorsky, N. Giannakas, A. Kaminari, A. Fragkouli, K. Nader, T. J. Price, B. W. Konicek, J. R. Graff, A. K. Tzinia, J. C. Lacaille, N. Sonenberg, Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep. 9, 1742-1755 (2014).
23. M. Dziembowska, D. I. Pretto, A. Janusz, L. Kaczmarek, M. J. Leigh, N. Gabriel, B. Durbin-Johnson, R. J. Hagerman, F. Tassone, High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Am. J. Med. Genet. A 161A, 1897-1903 (2013).
24. A Schneider, MJ Leigh, P Adams, R Nanakul, T Chechi, J Olichney, R Hagerman, D Hessl, Electrocortical changes associated with minocycline treatment in fragile X syndrome. J. Psychopharmacol. 27, 956-963 (2013).
25. M. G. Aman, W. H. Burrow, P. L. Wolford, The Aberrant Behavior Checklist-Community: Factor validity and effect of subject variables for adults in group homes. Am. J. Ment. Retard. 100, 283-292 (1995).
26. M. G. Aman, N. N. Singh, A. W. Stewart, C. J. Field, The aberrant behavior checklist: A behavior rating scale for the assessment of treatment effects. Am. J. Ment. Defic. 89, 485-491 (1985).
27. S. M. Sansone, K. F. Widaman, S. S. Hall, A. L. Reiss, A. Lightbody, W. E. Kaufmann, E. Berry-Kravis, A. Lachiewicz, E. C. Brown, D. Hessl, Psychometric study of the Aberrant Behavior Checklist in Fragile X Syndrome and implications for targeted treatment. J. Autism Dev. Disord. 42, 1377 (2012).
28. W. Guy, in ECDEU Assessment Manual for Psychopharmacology (National Institute of Mental Health Psychopharmacology Research Branch Mental Health Administration, Rockville, MD, 1976), pp. 217-222.
29. K. S. L. Lam, M. G. Aman, The Repetitive Behavior Scale-Revised: Independent validation in individuals with autism spectrum disorders. J. Autism Dev. Disord. 37, 855-866 (2007).
30. J. N. Constantino, S. A. Davis, R. D. Todd, M. K. Schindler, M. M. Gross, S. L. Brophy, L. M. Metzger, C. S. Shoushtari, R. Splinter, W. Reich, Validation of a brief quantitative measure of autistic traits: Comparison of the social responsiveness scale with the autism diagnostic interview-revised. J. Autism Dev. Disord. 33, 427-433 (2003).
31. C. T. Gualtieri, L. G. Johnson, Reliability and validity of a computerized neurocognitive test battery, CNS Vital Signs. Arch. Clin. Neuropsychol. 21, 623-643 (2006).
32. T. Manly, V. Anderson, I. Nimmo-Smith, A. Turner, P. Watson, I. H. Robertson, The differential assessment of children's attention: The Test of Everyday Attention for Children (TEA-Ch), normative sample and ADHD performance. J. Child Psychol. Psychiatry 42, 1065-1081 (2001).
33. D. I. Kaufer, J. L. Cummings, P. Ketchel, V. Smith, A. MacMillan, T. Shelley, O. L. Lopez, S. T. DeKosky, Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J. Neuropsychiatry Clin. Neurosci. 12, 233-239 (2000).