Effect of the mGluR5-NAM Basimglurant on Behavior in Adolescents and Adults with Fragile X Syndrome in a Randomized, Double-Blind, Placebo-Controlled Trial: FragXis Phase 2 Results
Open accessAbstract
Preclinical data suggest that inhibition of the metabotropic glutamate receptor 5 (mGluR5) receptor might hold therapeutic benefits in Fragile X syndrome (FXS). Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS. The early short-term clinical trials with mGluR5 NAMs, including basimglurant, assessing the effects in individuals with FXS, were supportive of further exploration in larger, well-controlled trials. We evaluated basimglurant, a potent and selective mGluR5 NAM, in a 12-week, double-blind, parallel-group study of 183 adults and adolescents (aged 14-50, mean 23.4 years) with FXS. Individuals with an FMR1 full mutation were randomized to placebo or one of two doses of basimglurant. The primary efficacy endpoint was the change from baseline in behavioral symptoms using the Anxiety Depression and Mood Scale (ADAMS) total score. All treatment arms showed marked behavioral improvements from baseline to week 12 with less improvement in the basimglurant 1.5 mg arm than placebo; however, basimglurant 0.5 mg was inferior to placebo in the ADAMs total score. Treatment with basimglurant was overall well-tolerated. A higher incidence of adverse events classified as psychiatric disorders were reported in patients treated with basimglurant, including three patients with hallucinations or psychosis. In this phase 2 clinical trial, basimglurant did not demonstrate improvement over placebo. Evaluation of the overall risk-benefit in younger patient populations is an important consideration for the design of potential further investigations of efficacy with this class of medications.
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In the adult and adolescent FragXis study, patients were randomly assigned to basimglurant or placebo with stratification by gender and age group.
“Patients were randomly assigned to receive basimglurant (0.5 or 1.5 mg once a day (q.d.)) or placebo, with stratification by gender and age group (14–17 and 18–50 years) to ensure that about one-third of participants were adolescents.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [73]
A large randomized, double-blind, placebo-controlled phase II trial with the mGluR5 antagonist basimglurant was conducted in adult and adolescent patients with FXS.
“This reference reports the large randomized, double-blind, placebo-controlled phase II trial with the mGluR5 antagonist basimglurant in adult and adolescent patients with FXS.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [73]
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Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome
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- Authors
- FragXis Study Group, Youssef, E. A., Berry-Kravis, E., Czech, C., Hagerman, R. J., Hessl, D., Wong, C. Y., Rabbia, M., Deptula, D., John, A., Kinch, R., Drewitt, P., Lindemann, L., Marcinowski, M., Langland, R., Horn, C., Fontoura, P., Santarelli, L., & Quiroz, J. A.
- Affiliations
- Rush University Medical Center (US)
- F. Hoffmann-La Roche AG (CH)
- University of California Davis Medical Center (US)
- Genentech (US)
- Gilead Sciences (United States) (US)
- Roche (United Kingdom) (GB)
- Corresponding author
- Youssef, Eriene A
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2017-08-17
- Volume
- 43
- Issue
- 3
- Pages
- 503-512
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC5770759
- OpenAlex
- W2750406832
- Cited by
- 133
- References
- 31
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 12 · 2023: 11 · 2022: 13 · 2021: 21 · 2020: 17 · 2019: 25 · 2018: 8 · 2017: 3
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuropsychopharmacology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- fragile X syndrome, metabotropic glutamate receptor 5, negative allosteric modulators, FMR1 full mutation, behavioral symptoms, anxiety, depression, psychosis, hallucinations, adverse events, adolescents, adults, risk-benefit assessment
- MeSH terms
- Adolescent, Adult, Double-Blind Method, Female, Fragile X Syndrome, Humans, Imidazoles, Male, Middle Aged, Psychotropic Drugs, Pyridines, RNA, Messenger, Treatment Failure, Excitatory Amino Acid Antagonists, DNA Methylation, Fragile X Messenger Ribonucleoprotein 1, Young Adult, Receptor, Metabotropic Glutamate 5
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