SPG601-associated modulation of resting-state EEG and improvement in executive function in a fragile X syndrome randomized controlled crossover study.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. Despite extensive research, no targeted treatments exist for the core symptoms of FXS. SPG601 represents the first BK channel activator to enter clinical testing for FXS, designed to restore synaptic function by correcting specific ion channel dysfunction downstream of fragile X messenger ribonucleoprotein protein (FMRP) loss. We conducted a randomized, double-blind, placebo-controlled, 2-period balanced crossover study in 10 adult men with genetically confirmed full-mutation fragile X syndrome. Participants received single doses of SPG601 800 mg and placebo separated by a 1-week washout period. Given the first in FXS nature of the study, the safety and tolerability of SPG601 were evaluated as a primary outcome. Additional endpoints included resting-state EEG power spectral density analysis across predefined frequency bands and auditory-evoked gamma oscillations combined with cognitive assessments using validated instruments and clinical global impressions scales. Among EEG measurements, excessive high frequency gamma band activity has been most extensively validated as a biomarker across species in FXS and has demonstrated correlation with severity of the human FXS phenotype and therefore served as the primary neurophysiologic endpoint. SPG601 was well tolerated with a favorable safety profile. SPG601 demonstrated significant modulation of resting-state EEG power spectral density compared to placebo. Significant treatment effects were observed for gamma power (F = 5.20, p = 0.023), alpha2 power (F = 17.43, p < 0.001), and theta power (F = 7.06, p = 0.008). SPG601 also significantly modulated aperiodic EEG slope (F = 5.28, p = 0.022), indicating alterations in the broadband 1/f component reflecting excitation-inhibition balance. Cognitive improvement was observed in the NIH Toolbox Flanker Inhibitory Control and Attention Test across multiple scoring metrics (p = 0.027). No significant effects were observed on auditory-evoked gamma measures. This study provides the first clinical evidence that SPG601 produces significant neurophysiological changes in FXS, accompanied by a cognitive enhancement in executive function.