title: Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials.
abstract: Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling, as a putative downstream effect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of mavoglurant in FXS, designed to confirm this result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community Edition using the FXS-specific algorithm (ABC-C(FX)) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with few adverse events. Therefore, under the conditions of our study, we could not confirm the mGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predict mavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits.
authors.affiliation: Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Berry-Kravis
authors.affiliation: National Reference Center for Fragile X and Other X-Linked Intellectual Disabilities, CIC 1407 INSERM, Hospices Civils de Lyon, Université de Lyon, 69002 Lyon, France. CNRS UMR 5304 (Laboratoire sur le Langage, le Cerveau et la Cognition), 69500 Bron, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Des Portes
authors.affiliation: Medical Investigation of Neurodevelopmental Disorders Institute and Department of Pediatrics, UC Davis Medical Center, Sacramento, CA 95817, USA.
authors.forename: Randi
authors.initials: R
authors.lastname: Hagerman
authors.affiliation: Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland. CHU Sainte-Justine Research Centre, Montreal, Quebec H3T 1C5, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacquemont
authors.affiliation: Département de Génétique et Cytogénétique, Unité Fonctionnelle de Génétique Médicale, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Visootsak
authors.affiliation: Novartis Pharma GmbH, 90429 Nürnberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Brinkman
authors.affiliation: Novartis Pharmaceuticals SAS, 92500 Rueil-Malmaison, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Rerat
authors.affiliation: Neurodegeneration Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936-1080, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Koumaras
authors.affiliation: Integrated Quantitative Science, Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936-1080, USA.
authors.forename: Liansheng
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany.
authors.forename: Gottfried Maria
authors.initials: GM
authors.lastname: Barth
authors.affiliation: Neuroscience Development, Novartis Pharma AG, CH-4056 Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jaecklin
authors.affiliation: Neuroscience Development, Novartis Pharma AG, CH-4056 Basel, Switzerland.
authors.forename: George
authors.initials: G
authors.lastname: Apostol
authors.affiliation: Neuroscience Development, Novartis Pharma AG, CH-4056 Basel, Switzerland. florian.von_raison@novartis.com.
authors.forename: Florian
authors.initials: F
authors.lastname: von Raison
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001519:Behavior; D003071:Cognition; D019175:DNA Methylation / Q000187:drug effects; D003710:Demography; D004311:Double-Blind Method; D005260:Female; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D016018:Least-Squares Analysis; D008297:Male; D010919:Placebos; D016896:Treatment Outcome
chemical_list: D007211:Indoles; D010919:Placebos; C581397:mavoglurant