Development of mavoglurant and its potential for the treatment of fragile X syndrome

Gomez‐Mancilla, Baltazar; Berry‐Kravis, Elizabeth; Hagerman, Randi J.; Raison, Florian von; Apostol, George; Ufer, Mike; Gasparini, F.; Jacquemont, Sébastien

doi:10.1517/13543784.2014.857400

Cited by 26 publications

(12 citation statements)

References 53 publications

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“…It is a sensitive instrument for rating maladaptive and inappropriate behaviors in patients with intellectual disabilities. In patients with FXS, it has also been used as an endpoint in clinical studies (in the original or a modified version) [41–43]. For example, in the mavoglurant studies, mean total scores at first documentation were, across the placebo and treatment groups, between 40.0 and 50.6 points in adults, and between 48.3 and 58.5 points in adolescents.…”

Section: Discussionmentioning

confidence: 99%

Characterization, treatment patterns, and patient-related outcomes of patients with Fragile X syndrome in Germany: final results of the observational EXPLAIN-FXS study

et al. 2016

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BackgroundAs data on the phenotype, characteristics and management of patients with Fragile X Syndrome (FXS) are limited, we aimed to collect such data in Germany in experienced centres involved in the treatment of such patients.MethodsEXPLAIN-FXS is a prospective observational (non-interventional) study (registry) performed between April 2013 and January 2016 at 18 sites in Germany. Requirements for patient participation included confirmed diagnosis of FXS by genetic testing (>200 CGG repeats) and written informed consent. Patients were followed for up to 2 years.ResultsSeventy-five patients (84.0 % males, mean age 16.7 ± 14.5 years, ranging from 2 - 82 years) were analysed. The mean 6-item score, determined according to Giangreco (J Pediatr 129:611-614, 1996), was 6.9 ± 2.5 points. At least one neurological finding each was noted in 53 patients (69.7 %). Specifically, ataxia was noted in 5 patients (6.6 %), lack of fine motor skills in 40 patients, (52.6 %), muscle tonus disorder in 4 patients (5.3 %), and other neurological disorders in 39 patients (51.3 %). Spasticity was not noted in any patient.Seizures were reported in 6 patients (8.1 %), anxiety disorders in 22 patients (30.1 %), depression in 7 patients (9.6 %), ADHD/ADD in 36 patients (49.3 %), impairment of social behavior in 39 patients (53.4 %), and other comorbidities in 23 patients (31.5 %). The mean Aberrant Behaviour Checklist Community Edition (ABC-C) score on behavioral symptoms, obtained in 71 patients at first documentation, was 48.4 ± 27.8 (median 45.0, range 5-115). The mean visual analogue scale (VAS) score, obtained in 59 patients at first documentation, was 84.9 ± 14.6 points (median 90; range 50 – 100).ConclusionsThis report describes the largest cohort of patients with FXS in Europe. The reported observations indicate a substantial burden of disease for patients and their caregivers. Based on these observations, an early expert psychiatric diagnosis is recommended for suspected FXS patients. Further recommendations include multimodal and multi-professional management that is tailored to the individual patient’s needs.Trial registrationThe ClinTrials.gov identifier is NCT01711606. Registered on 18 October 2012.

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Section: Discussionmentioning

confidence: 99%

Characterization, treatment patterns, and patient-related outcomes of patients with Fragile X syndrome in Germany: final results of the observational EXPLAIN-FXS study

et al. 2016

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“…RO4917523 (Roche Pharmaceuticals) and STX107 (Seaside Therapeutics) are in Phase 2 trials. The outcome of a clinical trial with Fenobam showed an improvement of 20% in the PPI (Berry-Kravis et al 2009), although the mGluR5 antagonist AFQ056 (Novartis) was very recently discontinued due to the lack of positive outcome measurements (Busquets-Garcia et al 2014;Gomez-Mancilla et al 2014).…”

Section: Behavioral Phenotypes Of Fxs Wwwlearnmemorgmentioning

confidence: 99%

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

2014

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The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the FMR1 gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain and nonneuronal cells. During brain development, FMRP controls the expression of key molecules involved in receptor signaling, cytoskeleton remodeling, protein synthesis and, ultimately, spine morphology. Symptoms associated with FXS include neurodevelopmental delay, cognitive impairment, anxiety, hyperactivity, and autistic-like behavior. Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome. Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities.

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“…To date, the mGluR5 antagonists, proposed as targeted treatments, have not demonstrated efficacy in FXS in trials 21 , although they have not been studied in children under 5 years old 22 . There is emerging evidence that treatment in young children with neurodevelopmental problems may have the best effects because the brain is still rapidly developing and thus most susceptible to intervention 23–27 .…”

Section: Introductionmentioning

confidence: 99%

A Randomized, Double-Blind, Placebo-Controlled Trial of Low-Dose Sertraline in Young Children With Fragile X Syndrome

Hess

Fitzpatrick

Nguyen

et al. 2016

J Dev Behav Pediatr

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Objective Observational studies and anecdotal reports suggest sertraline, a selective serotonin reuptake inhibitor (SSRI), may improve language development in young children with fragile X syndrome (FXS). We evaluated the efficacy of six months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 52 children with FXS ages 2–6 years. Results Eighty-one subjects were screened for eligibility and 57 were randomized to sertraline (27) or placebo (30). Two subjects from the sertraline arm and three from the placebo arm discontinued. Intent-to-treat analysis showed no difference from placebo on the primary outcomes: the Mullen Scales of Early Learning (MSEL) expressive language age equivalent and Clinical Global Impression-Improvement (CGI-I). However, analyses of secondary measures showed significant improvements, particularly in motor and visual perceptual abilities and social participation. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events occurred. Conclusion This randomized controlled trial of six-months of sertraline treatment showed no primary benefit with respect to early expressive language development and global clinical improvement. However, in secondary, exploratory analyses there were significant improvements seen on motor and visual perceptual subtests, the Cognitive T score sum on the MSEL, and on one measure of Social Participation on the Sensory Processing Measure–Preschool. Further, post hoc analysis found significant improvement in early expressive language development as measured by the MSEL among children with ASD on sertraline. Treatment appears safe for this 6-month period in young children with FXS, but we do not know the long-term side effects of this treatment. These results warrant further studies of sertraline in young children with FXS using refined outcome measures, as well as longer term follow-up studies to address long-term side effects of low-dose sertraline in early childhood.

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Development of mavoglurant and its potential for the treatment of fragile X syndrome

Cited by 26 publications

References 53 publications

Characterization, treatment patterns, and patient-related outcomes of patients with Fragile X syndrome in Germany: final results of the observational EXPLAIN-FXS study

Characterization, treatment patterns, and patient-related outcomes of patients with Fragile X syndrome in Germany: final results of the observational EXPLAIN-FXS study

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

A Randomized, Double-Blind, Placebo-Controlled Trial of Low-Dose Sertraline in Young Children With Fragile X Syndrome

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