Challenges in Conducting Clinical Trials for Pharmacotherapies in Fragile X Syndrome: Lessons Learned

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.