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

• Published in: Nature medicine Vol. 27; no. 5; pp. 862 - 870
• Main Authors: Berry-Kravis, Elizabeth M., Harnett, Mark D., Reines, Scott A., Reese, Melody A., Ethridge, Lauren E., Outterson, Abigail H., Michalak, Claire, Furman, Jeremiah, Gurney, Mark E.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2021; Nature Publishing Group
• Subjects: 692/308; 692/699/476; Allosteric properties; Biomedical and Life Sciences; Biomedicine; Cancer Research; Caregivers; Clinical trials; Cognition; Cognition & reasoning; Cognition disorders; Cognitive ability; Crystallization; Domains; Drug therapy; Enzyme inhibitors; Fragile X syndrome; Infectious Diseases; Intellectual disabilities; Language; Males; Metabolic Diseases; Molecular Medicine; Neurosciences; Patients; Phosphodiesterase; Placebos; Testing; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-021-01321-w

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.
A randomized crossover study of BPN14770 in adult males with fragile X syndrome shows significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.