Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial
- PMID: 33927413
- DOI: 10.1038/s41591-021-01321-w
Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial
Abstract
The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18-41 years) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631 ). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342) and Cognition Crystallized Composite score (+5.31, P = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.
Similar articles
-
Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D).Sci Rep. 2017 Nov 7;7(1):14653. doi: 10.1038/s41598-017-15028-x. Sci Rep. 2017. PMID: 29116166 Free PMC article.
-
Effects of chronic inhibition of phosphodiesterase-4D on behavior and regional rates of cerebral protein synthesis in a mouse model of fragile X syndrome.Neurobiol Dis. 2021 Nov;159:105485. doi: 10.1016/j.nbd.2021.105485. Epub 2021 Aug 16. Neurobiol Dis. 2021. PMID: 34411704
-
Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders.J Med Chem. 2019 May 23;62(10):4884-4901. doi: 10.1021/acs.jmedchem.9b00193. Epub 2019 Apr 23. J Med Chem. 2019. PMID: 31013090 Free PMC article.
-
Phosphodiesterase-4B as a Therapeutic Target for Cognitive Impairment and Obesity-Related Metabolic Diseases.Adv Neurobiol. 2017;17:103-131. doi: 10.1007/978-3-319-58811-7_5. Adv Neurobiol. 2017. PMID: 28956331 Review.
-
Increasing our understanding of human cognition through the study of Fragile X Syndrome.Dev Neurobiol. 2014 Feb;74(2):147-77. doi: 10.1002/dneu.22096. Epub 2013 Jul 30. Dev Neurobiol. 2014. PMID: 23723176 Free PMC article. Review.
Cited by
-
Characterization of a Clinically and Biologically Defined Subgroup of Patients with Autism Spectrum Disorder and Identification of a Tailored Combination Treatment.Biomedicines. 2024 Apr 30;12(5):991. doi: 10.3390/biomedicines12050991. Biomedicines. 2024. PMID: 38790952 Free PMC article.
-
A Molecular Framework for Delirium.Neurohospitalist. 2024 Apr;14(2):147-156. doi: 10.1177/19418744231207925. Epub 2023 Nov 10. Neurohospitalist. 2024. PMID: 38666272 Review.
-
Beyond traditional pharmacology: evaluating phosphodiesterase inhibitors in autism spectrum disorder.Neuropsychopharmacology. 2024 Aug;49(9):1359-1360. doi: 10.1038/s41386-024-01860-z. Epub 2024 Apr 11. Neuropsychopharmacology. 2024. PMID: 38605185 No abstract available.
-
State-of-the-art therapies for fragile X syndrome.Dev Med Child Neurol. 2024 Jul;66(7):863-871. doi: 10.1111/dmcn.15885. Epub 2024 Feb 22. Dev Med Child Neurol. 2024. PMID: 38385885 Review.
-
mGluR7 allosteric modulator AMN082 corrects protein synthesis and pathological phenotypes in FXS.EMBO Mol Med. 2024 Mar;16(3):506-522. doi: 10.1038/s44321-024-00038-w. Epub 2024 Feb 19. EMBO Mol Med. 2024. PMID: 38374465 Free PMC article.
References
Publication types
MeSH terms
Substances
Associated data
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous