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

Nature Medicine volume 27, pages 862–870 (2021)Cite this article

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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.

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Fig. 1: Forest plots of clinical outcomes.
Fig. 2: LS mean change from baseline values through week 24 for the NIH-TCB and VAS caregiver rating scales.
Fig. 3: Exploratory biomarkers showing the numerical superiority of BPN14770 over placebo.

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Data availability

All requests for raw and analyzed data will be promptly reviewed by the study sponsor, Tetra Therapeutics, and by the clinical site, Rush University Medical Center, to verify if the request is subject to any intellectual property or confidentiality obligations. Patient-related data not included in the paper were generated as part of a clinical trial and may be subject to patient confidentiality as required by the Health Insurance Portability and Accountability Act. Any data that can be shared will be released via a material transfer agreement. Requests for data may be made to Elizabeth_Berry-Kravis@rush.edu or to info@tetratherapeutics.com.

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Acknowledgements

We thank the patients and their families for participating in the clinical trial. Direct clinical costs were funded by the FRAXA Research Foundation. Access to and training on the NIH-TCB was obtained in association with work on HD076189 (E.M.B.K.). Tetra Therapeutics provided drug product and funded trial administration and independent data analysis.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL, USA

    Elizabeth M. Berry-Kravis, Abigail H. Outterson, Claire Michalak & Jeremiah Furman

  2. Tetra Therapeutics, Grand Rapids, MI, USA

    Mark D. Harnett, Scott A. Reines & Mark E. Gurney

  3. Department of Psychology, University of Oklahoma, Norman, OK, USA

    Melody A. Reese & Lauren E. Ethridge

  4. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Lauren E. Ethridge

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  1. Elizabeth M. Berry-Kravis
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Contributions

E.M.B.-K. designed and conducted the clinical study. M.D.H. led the biostatistical analysis. S.A.R. designed the clinical study and served as medical monitor. L.E.E. and M.A.R. analyzed the EEG data. A.H.O., C.M. and J.F. conducted the clinical study. M.E.G. contributed to the clinical protocol and drafted the manuscript.

Corresponding authors

Correspondence to Elizabeth M. Berry-Kravis or Mark E. Gurney.

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Competing interests

E.M.B.-K., L.E.E., M.A.R., A.O., C.M. and J.F. declare no competing interests. M.D.H. and S.D.R. are paid consultants to Tetra Therapeutics. M.E.G. is an employee of Tetra Therapeutics, which is a wholly owned subsidiary of Shionogi & Company that has a financial interest in BPN14770.

Additional information

Peer reviewer information Nature Medicine thanks Allan Reiss, Dejan Budimirovic and Blythe Durbin-Johnson for their contribution to the peer review of this work. Jerome Staal was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 CONSORT flow diagram for the Phase 2 trial.

A total of 30 subjects were screened, all met criteria for entry, 15 were randomized to the A-B (drug-placebo) treatment sequence and 15 were randomized to the B-A (placebo-drug) treatment sequence. There were no discontinuations so the Safety, ITT and Completer populations were identical (n = 30 subjects).

Extended Data Fig. 2 Subject demographics and baseline characteristics for the treatment Sequence A-B (BPN14770 to Placebo) and treatment Sequence B-A (Placebo to BPN14770).

Abbreviations: max=maximum; min=minimum; SD=standard deviation.

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Supplementary Information

Clinical Protocol and Statistical Analysis Plan.

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Berry-Kravis, E.M., Harnett, M.D., Reines, S.A. et al. Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial. Nat Med 27, 862–870 (2021). https://doi.org/10.1038/s41591-021-01321-w

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