Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial

Nat Med. 2021 May;27(5):862-870. doi: 10.1038/s41591-021-01321-w. Epub 2021 Apr 29.


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 ( 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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cognition / drug effects*
  • Cross-Over Studies
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / pathology
  • Humans
  • Language Tests
  • Male
  • Phosphodiesterase 4 Inhibitors / therapeutic use*
  • Placebos / administration & dosage
  • Psychometrics / statistics & numerical data
  • Treatment Outcome
  • Young Adult


  • FMR1 protein, human
  • Phosphodiesterase 4 Inhibitors
  • Placebos
  • Fragile X Mental Retardation Protein
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4D protein, human

Associated data