Safety and tolerability of STP1 (PDE 3,4 inhibitor and NKCC1 inhibitor), in a subgroup of ASD patients (ASD-Phen1)

Abstract

Abstract Background Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with considerable clinical heterogeneity. This study aimed to explore the safety and tolerability of STP1, a combination of ibudilast and bumetanide, in a specific subgroup of ASD patients. Methods We conducted a randomized, double-blind, placebo-controlled, parallel-group, 2-dose ascending study. Each dose was given for 14 days treatment in a specific subgroup of adults ASD patients, ASD-Phenotype 1 (ASD-Phen1). Nine patients were assigned to STP1 and 3 received placebo (PL). Safety and tolerability of STP1 were measured as well as electrophysiological markers (EEG, Auditory habituation, and Auditory chirp synchronization) to elucidate the mechanism of action of STP1, in addition to clinical scales (NIH-CTB-Crystalized composite, ABC-C and SRS-2). Results STP1 was safe and well tolerated. Electrophysiological markers showed a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function (frontal left and right poles) and memory (left and right entorhinal regions). Treatment with STP1 showed a significant increase of alpha 2 power in frontal and occipital regions and in brain areas associated with memory function (left superior right isthmus cingulate ) and sensory function (right paracentral regions), an improvement in habituation function (quantified by decreased N1 amplitudes for repeated sounds), as well as an increase of the neural synchronization to the auditory chirp. Numerical improvements were observed in the SRS-2 and ABC-C and NIH-CTB Crystalized composite scores, although not reaching statistical significance. Limitations The sample size was limited to twelve adult patients. Conclusions STP1 was safe and well tolerated in ASD-Phen1 patients. STP1 showed an indirect target engagement as evidenced using EEG, and ERPs in ASD brain regions of interest (Frontal, Temporal and Parietal Cortex). Trial registration This study was prospectively registered at clinicaltrials.gov (NCT04644003)