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

Abstract

Introduction: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. With no curative treatment available, current therapeutic approaches are aimed at symptom management. FXS is caused by silencing the FMR1 gene, which encodes FMRP; as loss of FMRP leads to the development of symptoms associated with FXS.

Areas covered: In this evaluation, the authors examine the role of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of FXS, and its suitability as a target for rescuing the disease state. Furthermore, the authors review the evidence from preclinical studies of pharmacological interventions targeting mGluR5 in FXS. Lastly, the authors assess the findings from clinical studies in FXS, in particular the use of the Aberrant Behavior Checklist-Community Edition (ABC-C) and the recently developed ABC-C for FXS scale, as clinical endpoints to assess disease modification in this patient population.

Expert opinion: There is cautious optimism for the successful treatment of the core behavioral and cognitive symptoms of FXS based on preclinical data in animal models and early studies in humans. However, the association between mGluR5-heightened responsiveness and the clinical phenotype in humans remains to be demonstrated. Many questions regarding the optimal treatment and outcome measures of FXS remain unanswered.

Keywords::

• Aberrant Behavior Checklist
• FMRP
• fragile X syndrome
• FXS
• mavoglurant
• mGluR5

Acknowledgements

The authors thank K O'Rourke, PhD, of iMed Comms, who provided medical writing assistance with this review.

Declaration of interest

Financial support for medical editorial assistance was provided by Novartis Pharma AG. B Gomez-Mancilla is an employee of, holds shares in, and has received cover/reimbursement of travel/accommodation expenses from Novartis Pharma AG. E Berry-Kravis' institution has received consultancy fees from Novartis Pharma AG and Roche, grants from Novartis, Roche and Seaside Therapeutics for running clinical trials as a site for arbaclofen, RO4917523, and mavoglurant trials. E Berry Kravis has also received honoraria from Novartis Pharma AG to do a preceptorship for personnel working on the mavoglurant project at Novartis and cover/reimbursement of travel/accommodation expenses from Novartis Pharma AG. F Gasparini is an employee of, holds shares in, and has received cover/reimbursement of travel/accommodation expenses from Novartis Pharma AG. F von Raison is an employee of, and holds shares in, Novartis Pharma AG. G Apostol is an employee of, and holds shares in, Novartis Pharma AG; G Apostol's spouse is an employee of Novartis International AG. M Ufer is an employee of, and holds shares in, Novartis Pharma AG. R Hagerman's institution has received grants from Curemark, Novartis Pharma AG, Roche and Seaside Therapeutics, and money from NICHD HD 036071; R Hagerman is an employee of the University of California at Davis, and has received consultancy fees and honoraria from Novartis, honoraria from Genentech, book royalties from Oxford University Press and Johns Hopkins University Press, and cover/reimbursement of travel/accommodation expenses from Novartis Pharma AG. No author has received payment in preparation of this manuscript.

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