| Reference | [1]. Expert Opin Investig Drugs. 2014 Aug;23(8):1165-79. doi: 10.1517/13543784.2014.931370. Epub 2014 Jun 24.<br />
Mavoglurant as a treatment for Parkinson's disease.<br />
Petrov D(1), Pedros I, de Lemos ML, Pallàs M, Canudas AM, Lazarowski A, Beas-Zarate C, Auladell C, Folch J, Camins A.<br />
Author information: (1)Universitat de Barcelona, Institut de Biomedicina (IBUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Unitat de Farmacologia I Farmacognòsia, Facultat de Farmàcia , Barcelona, Avda/Joan XXIII , Spain [email protected].<br />
INTRODUCTION: A major unresolved issue in the Parkinson's disease (PD) treatment is the development of l-DOPA-induced dyskinesias (LIDs) as a side effect of chronic L-DOPA administration. Currently, LIDs are managed in part by reducing the L-DOPA dose or by the administration of amantadine. However, this treatment is only partially effective. A potential strategy, currently under investigation, is the coadministration of metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) and L-DOPA; a treatment that results in the improvement of dyskinesia symptoms and that permits reductions in l-DOPA dosage frequency. AREAS COVERED: The authors examine the role of mGluR5 in the pathophysiology of PD and the potential use of mGluR5 NAM as an adjuvant therapy together with a primary treatment with L-DOPA. Specifically, the authors look at the mavoglurant therapy and the evidence presented through preclinical and clinical trials. EXPERT OPINION: Interaction between mGluR5 NAM and L-DOPA is an area of interest in PD research as concomitant treatment results in the improvement of LID symptoms in humans, thus enhancing the patient's quality of life. However, few months ago, Novartis decided to discontinue clinical trials of mavoglurant for the treatment of LID, due to the lack of efficacy demonstrated in trials NCT01385592 and NCT01491529, although no safety concerns were involved in this decision. Nevertheless, the potential application of mGluR5 antagonists as neuroprotective agents must be considered and further studies are warranted to better investigate their potential.<br />
DOI: 10.1517/13543784.2014.931370 PMID: 24960254 [Indexed for MEDLINE]<br />
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[2]. Sci Rep. 2018 Nov 19;8(1):16970. doi: 10.1038/s41598-018-34978-4.<br />
Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents.<br />
Hagerman R(1), Jacquemont S(2)(3), Berry-Kravis E(4), Des Portes V(5), Stanfield A(6), Koumaras B(7), Rosenkranz G(8), Murgia A(9), Wolf C(10), Apostol G(8), von Raison F(11).<br />
Author information: (1)MIND Institute and Department of Pediatrics, UC Davis Medical Center, Sacramento, CA, USA. (2)Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. (3)CHU Sainte-Justine Research Centre, Montreal, Canada. (4)Rush University Medical Centre, Department of Pediatrics, Neurological Sciences, and Biochemistry, Chicago, IL, USA. (5)National Reference Center for Fragile X and Other XLID, CIC 1407 INSERM – Hospices Civils de Lyon, Université de Lyon and CNRS UMR 5304 (L2C2), Bron, France. (6)Patrick Wild Centre, Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK. (7)Neurodegeneration Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. (8)Neuroscience Development, Novartis Pharma AG, Basel, Switzerland. (9)Laboratory of Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padova, Padova, Italy. (10)Lycalis sprl, Brussels, Belgium. (11)Neuroscience Development, Novartis Pharma AG, Basel, Switzerland. [email protected].<br />
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.<br />
DOI: 10.1038/s41598-018-34978-4 PMCID: PMC6242849 PMID: 30451888 [Indexed for MEDLINE]<br />
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[3]. Neurol Sci. 2021 Aug;42(8):3135-3143. doi: 10.1007/s10072-021-05319-7. Epub 2021 May 20.<br />
Mavoglurant (AFQ056) for the treatment of levodopa-induced dyskinesia in patients with Parkinson's disease: a meta-analysis.<br />
Negida A(1)(2)(3), Ghaith HS(4)(5), Fala SY(4)(6), Ahmed H(4)(7), Bahbah EI(4)(8), Ebada MA(4)(7), Aziz MAE(4)(9).<br />
Author information: (1)Medical Research Group of Egypt, Cairo, Egypt. [email protected]. (2)Faculty of Medicine, School of Medicine, Zagazig University, Sharkia, Zagazig, 44523, Egypt. [email protected]. (3)School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK. [email protected]. (4)Medical Research Group of Egypt, Cairo, Egypt. (5)Faculty of Medicine, Al-Azhar University, Cairo, Egypt. (6)Faculty of Medicine, Suez Canal University, Ismailia, Egypt. (7)Faculty of Medicine, School of Medicine, Zagazig University, Sharkia, Zagazig, 44523, Egypt. (8)Faculty of Medicine, Al-Azhar University of Damietta, Damietta, Egypt. (9)Neuropsychiatry Department, Omr Shahin Mental Hospital, Cairo, Egypt.<br />
BACKGROUND: Mavoglurant (AFQ056), a selective metabotropic glutamate receptor 5 (mGluR5) inhibitor, was tested for t levodopa-induced dyskinesia (LID) in patients with Parkinson's Disease (PD). However, clinical trials showed inconsistent results regarding the efficacy of mavoglurant in treating LID in patients with Parkinson's disease (PD). METHODS: A computer literature search of PubMed, Scopus, Web of science, and Cochrane CENTRAL was conducted until March 2021. We selected relevant randomized controlled trials comparing mavoglurant to placebo. Study data were extracted and pooled as mean difference (MD) in the meta-analysis model. RESULTS: Six RCTs were included in this meta-analysis with a total of 485 patients. Mavoglurant was not significantly superior to placebo in terms of the "off-time" (MD -0.27 h, 95% CI -0.65 to 0.11), "on time" (MD 0.29 h, 95% CI -0.09 to 0.66), Lang-Fahn activities of daily living dyskinesia scale (MD -0.95, 95% CI -1.98 to 0.07), UPDRS-III (MD -0.51, 95% CI -1.66 to 0.65), or UPDRS-IV (MD -0.41, 95% CI -0.85 to 0.03). However, the pooled modified abnormal involuntary movement scale favored the mavoglurant group than the placebo group (MD -2.53, 95% CI -4.23 to -0.82). CONCLUSIONS: This meta-analysis provides level one evidence that mavoglurant is not effective in treating the LID in patients with PD.<br />
DOI: 10.1007/s10072-021-05319-7 PMID: 34014397 [Indexed for MEDLINE]<br />
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[4]. Expert Opin Investig Drugs. 2014 Jan;23(1):125-34. doi: 10.1517/13543784.2014.857400. Epub 2013 Nov 20.<br />
Development of mavoglurant and its potential for the treatment of fragile X syndrome.<br />
Gomez-Mancilla B(1), Berry-Kravis E, Hagerman R, von Raison F, Apostol G, Ufer M, Gasparini F, Jacquemont S.<br />
Author information: (1)Novartis Institutes for BioMedical Research Basel, Forum 1 , Novartis Campus, CH-4056 Basel , Switzerland +41 61 324 0164 ; +41 61 324 8913 ; [email protected].<br />
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.<br />
DOI: 10.1517/13543784.2014.857400 PMID: 24251408 [Indexed for MEDLINE]<br />
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[5]. Sci Transl Med. 2016 Jan 13;8(321):321ra5. doi: 10.1126/scitranslmed.aab4109.<br />
Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials.<br />
Berry-Kravis E(1), Des Portes V(2), Hagerman R(3), Jacquemont S(4), Charles P(5), Visootsak J(6), Brinkman M(7), Rerat K(8), Koumaras B(9), Zhu L(10), Barth GM(11), Jaecklin T(12), Apostol G(12), von Raison F(13).<br />
Author information: (1)Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA. (2)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. (3)Medical Investigation of Neurodevelopmental Disorders Institute and Department of Pediatrics, UC Davis Medical Center, Sacramento, CA 95817, USA. (4)Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland. CHU Sainte-Justine Research Centre, Montreal, Quebec H3T 1C5, Canada. (5)Département de Génétique et Cytogénétique, Unité Fonctionnelle de Génétique Médicale, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France. (6)Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. (7)Novartis Pharma GmbH, 90429 Nürnberg, Germany. (8)Novartis Pharmaceuticals SAS, 92500 Rueil-Malmaison, France. (9)Neurodegeneration Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936-1080, USA. (10)Integrated Quantitative Science, Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936-1080, USA. (11)Department of Child and Adolescent Psychiatry, University Hospital of Tübingen, 72076 Tübingen, Baden-Württemberg, Germany. (12)Neuroscience Development, Novartis Pharma AG, CH-4056 Basel, Switzerland. (13)Neuroscience Development, Novartis Pharma AG, CH-4056 Basel, Switzerland. [email protected].<br />
Comment in Sci Transl Med. 2016 Jan 13;8(321):321fs1.<br />
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.<br />
DOI: 10.1126/scitranslmed.aab4109 PMID: 26764156 [Indexed for MEDLINE]
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