Challenges in Conducting Clinical Trials for Pharmacotherapies in Fragile X Syndrome: Lessons Learned
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REVIEW ARTICLE
Challenges in Conducting Clinical Trials for Pharmacotherapies in Fragile X Syndrome: Lessons Learned Christina M. Harkins1 • Kelli C. Dominick1,2 • Logan K. Wink1,2 • Ernest V. Pedapati1,2 • Rebecca C. Shaffer1 • Sarah E. Fitzpatrick1 • Matthew H. Davenport1 • John A. Sweeney2 • Craig A. Erickson1,2
Published online: 27 July 2017 Springer International Publishing AG 2017
Abstract Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and most common single gene cause of autism spectrum disorder (ASD). Even in the context of a single gene disorder like FXS, characteristic cognitive and behavioral heterogeneity creates challenges in conducting targeted pharmacotherapy trials. Neuroscientific advances have elucidated aspects of the underlying neurobiology in FXS and have guided targeted treatment development in the last decade. However, despite significant preclinical progress, recent clinical trials have failed to consistently demonstrate therapeutic efficacy based on behavioral outcome measures in patients with FXS. One potential explanation for these failures is that many behavioral measures are not capable of quantitively capturing clinically significant change in such short-term trials. Further, the use of parent and clinician report instruments as primary outcome measures creates additional challenges in clinical trials. Future trials may employ more quantitative measures of evaluating the pathophysiology of FXS to avoid placebo-response resulting from rater bias. Quantitative measures of language, eye gaze, molecular dysregulation, and brain function may be used to identify which individuals may best respond to a particular treatment and to capture potential treatment-associated change. Here, we present a thorough review and reconsideration of the challenges encountered in conducting clinical trials in FXS to allow for lessons learned to drive future success in this field.
& Craig A. Erickson [email protected] 1
Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue MLC 4002, Cincinnati, OH 45229, USA
2
University of Cincinnati College of Medicine, 3235 Eden Avenue, CARE/Crawley Building Suite E-870, Cincinnati, OH 45267, USA
Key Points Introducing pharmacodynamic approaches earlier in FXS trials may enhance future trial success through incorporation of quantitative biomarker measures designed to demonstrate target engagement using early pharmacokinetic-pharmacodynamic (pK:pD) relationships to enrich sample and outcome measure selection. Defining the natural history of more objective, quantitative measures of pathophysiology in FXS will become increasingly important as FXS trials move from short-term to longer-term treatment periods. Preclinical assays such as induced pluripotent stem cell (iPSC)-derived neuronal species may serve as tools in the translational treatment pipeline as potential findings are put into a developmental context impacting preclinical and clinical study.
1 Introduction Fragile X syndrome (FXS) is the leading inher
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