The challenges of clinical trials in fragile X syndrome

Abstract

RationaleAdvances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement.ObjectivesWe review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders.ResultsResidual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains.ConclusionAppropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders.

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

“…For example, phase IIb/III clinical trials studying social and other behaviors in individuals with ASD in FXS using a subtype-selective mGluR5 inhibitors (basimglurant and mavoglurant) have shown no therapeutic benefits in FXS patients for unknown reasons [81]. While preliminary molecular characterization of epigenetic (full-methylation) patterns of ASD in FXS in the Phase II trials [82] has suggested that methylation status may constitute a treatment-sensitive biomarker for predicting response to a mGluR5 inhibitor [83,84], this finding was not replicated in two large phase III trials of mavoglurant [85]. Neither of these studies, as reported by Berry-Kravis and colleagues [85], reached the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community edition using the FXS-specific algorithm (ABC-CFX) after 12 weeks of treatment with mavoglurant.…”

“…As noted earlier, this work is important to delineate neurobiological phenotypes within FXS but can be only demonstrated through double-blind, randomized, placebo-controlled studies. Yet, these clinical trials have also highlighted challenges such as the populations heterogeneity, the lack of specific and sensitive outcome measures capturing the full range of improvements of patients with FXS, and a lack of reliable biomarkers that can track whether a specific mechanism is responsive to a new drug within relatively short period of time, and whether the biomarker response correlates with clinical improvement [87,83].…”

“…On the other hand, individuals with the PM present with a spectrum of unfolding genetic and clinical phenotypes [11], the best defined are early menopause due to ovarian failure (FX-POI) [7] (Sherman et al, 2014), and intention tremor, cerebellar ataxia, neuropathy and cognitive decline (FX-TAS) [8]. Clinically, FX-TAS occurs at ages 50−60 years in approximately 40−50% of male carriers and 16% of female carriers with an average age of onset at 62 years [8,12]. Around 20% of females may develop FXPOI that manifest with early signs of menopause in the 30s.…”

The complex genetics in autism spectrum disorders

“…2-methyl-6-(phenylethynyl)-pyridine (MPEP), a potent negative modulator of mGluR5 [60], consistently rescues many FXSrelated deficits in KO mice [50,55,56,[61][62][63], fly [64][65][66] and zebrafish [67], implying the therapeutic potential of FXS using mGluR5 inhibitors. Indeed, multiple human clinical trials with chemicals targeting mGluR5, or mGluRs-related signaling pathways, or presynaptic release of glutamate, such as gamma-aminobutyric acid (GABA) B receptor agonists, are being conducted, and are showing promising, but as yet inconclusive, results with regard to treating FXS [68][69][70][71].…”

Autism spectrum disorders - an emerging area in psychopharmacology

“…Nonetheless, recent advances in Fragile X syndrome suggest that this strategy is indeed viable (Pop et al 2013;Jacquemont et al 2013;Pop et al 2014).…”