Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents

Scientific Reports

Sebastien Jacquemont¹  Alessandra Murgia²  Christian Wolf³  Randi Hagerman⁴  Vincent Des Portes⁵  Barbara Koumaras⁶  George Apostol⁷  Florian von Raison⁷  Gerd Rosenkranz⁷  Andrew Stanfield⁸  Elizabeth Berry-Kravis⁹ 

[1] Centre Hospitalier Universitaire Vaudois;Laboratory of Molecular Genetics of Neurodevelopment, Department of Women’s and Children’s Health, University of Padova;Lycalis sprl;MIND Institute and Department of Pediatrics, UC Davis Medical Center;National Reference Center for Fragile X and Other XLID, CIC 1407 INSERM - Hospices Civils de Lyon, Université de Lyon and CNRS UMR 5304 (L2C2);Neurodegeneration Global Development, Novartis Pharmaceuticals Corporation;Neuroscience Development, Novartis Pharma AG;Patrick Wild Centre, Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital;Rush University Medical Centre, Department of Pediatrics, Neurological Sciences, and Biochemistry;

关键词: Mavoglurant;    Core Studies;    Fragile X Mental Retardation Protein (FMRP);    Repetitive Behavior Scale-Revised (RBS-R);    Extension Study Baseline;   

DOI  :  10.1038/s41598-018-34978-4

来源: DOAJ

【 摘 要 】

Abstract Fragile X syndrome (FXS) is the most common monogenic cause of inherited intellectual and developmental disabilities. Mavoglurant, a selective metabotropic glutamate receptor subtype-5 antagonist, has shown positive neuronal and behavioral effects in preclinical studies, but failed to demonstrate any behavioral benefits in two 12-week, randomized, placebo-controlled, double-blind, phase IIb studies in adults and adolescents with FXS. Here we report the long-term safety (primary endpoint) and efficacy (secondary endpoint) results of the open-label extensions. Adolescent (n = 119, aged 12–19 years) and adult (n = 148, aged 18–45 years) participants received up to 100 mg bid mavoglurant for up to 34 months. Both extension studies were terminated prematurely due to lack of proven efficacy in the core studies. Mavoglurant was well tolerated with no new safety signal. Five percent of adults and 16.9 percent of adolescents discontinued treatment due to adverse events. Gradual and consistent behavioral improvements as measured by the ABC-CFX scale were observed, which were numerically superior to those seen in the placebo arm of the core studies. These two extension studies confirm the long-term safety of mavoglurant in FXS, but further investigations are required to determine whether and under which conditions the significant preclinical results obtained with mGluR5 inhibition can translate to humans.

【 授权许可】

Unknown