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Arbaclofen in fragile X syndrome: results of phase 3 trials
Open accessAbstract
Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS. Two phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12–50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5–11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-C FX ). Secondary outcomes included other ABC-C FX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score. A total 119 of 125 randomized subjects completed the adolescent/adult study ( n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations ( n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-C FX Irritability subscale ( p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-C FX Social Avoidance and Hyperactivity subscales (both p < 0.1) and CGI-I ( p = 0.119). Effect size in the highest dose group was similar to effect sizes for FDA-approved serotonin reuptake inhibitors (SSRIs). Arbaclofen did not meet the primary outcome of improved social avoidance in FXS in either study. Data from secondary measures in the child study suggests younger patients may derive benefit, but additional studies with a larger cohort on higher doses would be required to confirm this finding. The reported studies illustrate the challenges but represent a significant step forward in translating targeted treatments from preclinical models to clinical trials in humans with FXS.
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“In the phase III study, children receiving the highest dose of arbaclofen also showed improvement over placebo on the secondary end points of the ABC-CFX Irritability subscale (P = 0.03) and the Parenting Stress Index (P = 0.03).”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [72]
In the citing paper
“In the phase III study carried out in children, the primary end point (ABC-CFX Social Avoidance subscale) narrowly missed significant improvement (P = 0.08)72.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [72]
In the citing paper
“This trial was limited by a lack of full enrolment due to financial issues for the sponsor, the use of fixed rather than flexible dosing and possible inflation of symptoms by families in order to meet inclusion criteria72.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [72]
In the citing paper
“However, the adult studies of FXS did not demonstrate efficacy and the pediatric trials did not reach significance for the primary outcome measure, but did show limited improvements in secondary measures including the Parenting Stress Index because of lowered irritability in the children [132].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [132]
In the citing paper
“However, the adult studies of FXS did not demonstrate efficacy and the pediatric trials did not reach significance for the primary outcome measure, but did show limited improvements in secondary measures including the Parenting Stress Index because of lowered irritability in the children [132].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [132]
In the citing paper
“However, the adult studies of FXS did not demonstrate efficacy and the pediatric trials did not reach significance for the primary outcome measure, but did show limited improvements in secondary measures including the Parenting Stress Index because of lowered irritability in the children [132].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [132]
In the citing paper
“The promising mouse studies led to human trials in FXS [131] that initially showed improvements in those with ASD plus FXS leading to phase 3 trials in FXS [132].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [132]
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Metadata
- Authors
- Berry-Kravis, E., Hagerman, R., Visootsak, J., Budimirovic, D., Kaufmann, W. E., Cherubini, M., Zarevics, P., Walton-Bowen, K., Wang, P., Bear, M. F., & Carpenter, R. L.
- Affiliations
- University of California Davis Medical Center (US)
- Emory University (US)
- Kennedy Krieger Institute (US)
- Boston Children's Hospital (US)
- Seaside Therapeutics (United States) (US)
- Simons Foundation (US)
- Autism Speaks (US)
- Massachusetts Institute of Technology (US)
- Rett Syndrome Research Trust (US)
- Venue
- Journal of Neurodevelopmental Disorders
- Published
- 2017-06-12
- Volume
- 9
- Issue
- 1
- Pages
- 3-3
- ISSN
- 1866-1947 (ISSN-L)
- 1866-1955
- PMC
- PMC5467054
- OpenAlex
- W2576165191
- Cited by
- 183
- References
- 39
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 16 · 2023: 13 · 2022: 22 · 2021: 21 · 2020: 24 · 2019: 23 · 2018: 17 · 2017: 11
- FWCI
- 13.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Neurodevelopmental Disorders (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Seaside Therapeutics, Inc.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Keywords
- fragile X syndrome, social avoidance, irritability, hyperactivity, parental stress, adaptive behavior, adverse events, dose-response relationship, children and adolescents, serotonin reuptake inhibitors, NMDA receptor antagonists, behavioral phenotypes, drug safety and efficacy
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