Metabotropic glutamate receptor 5 (mGluR5) is involved in cocaine reward processing and addiction. Preclinical studies suggest that blocking this receptor inhibits cocaine self-administration and seeking behavior in rodents. We assessed a selective noncompetitive antagonist of mGluR5 called mavoglurant in a phase 2 randomized, placebo-controlled clinical trial of 68 adults with cocaine use disorder. Study participants were randomly assigned in a 1:1 ratio to an up-titrating schedule of oral mavoglurant twice daily up to 200 mg for 98 days or placebo. The primary end point was the proportion of cocaine use days over the treatment period assessed by a retrospective self-report using Timeline Followback. Secondary end points were urine analysis of the cocaine metabolite benzoylecgonine and alcohol use measured by Timeline Followback assessment. Exploratory end points included testing for cocaine and alcohol metabolites in hair samples. The posterior probability of mavoglurant reducing cocaine use at the end of treatment was ≥99.0% for a treatment difference <0 and ≥36.6% for a treatment difference <-10%. The difference between mavoglurant and placebo was also assessed using analysis of covariance (P = 0.021). Urine benzoylecgonine concentration was lower in the mavoglurant-treated group versus placebo (P = 0.025); there was reduced alcohol consumption in the treatment group (P = 0.072). Seventy-six percent (randomized set) and 79% (safety analysis set) of patients completed the final treatment visit. Adverse events in the treatment group were headache, dizziness, and nausea. In this small and short trial, mavoglurant reduced cocaine and alcohol use in patients with chronic cocaine use disorder.

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a clinically and biologically defined subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1’s mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest.

Keywords: ASD-Phen1; STP1; ibudilast; bumetanide; phase 1b; EGG; NIH-TCB; SRS-2; ABC-C

Copy-number variants (CNVs) are genome-wide structural variations involving the duplication or deletion of large nucleotide sequences. While these types of variations can be commonly found in humans, large and rare CNVs are known to contribute to the development of various neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). Nevertheless, given that these NDD-risk CNVs cover broad regions of the genome, it is particularly challenging to pinpoint the critical gene(s) responsible for the manifestation of the phenotype. In this study, we performed a meta-analysis of CNV data from 11,614 affected individuals with NDDs and 4,031 control individuals from SFARI database to identify 41 NDD-risk CNV loci, including 24 novel regions. We also found evidence for dosage-sensitive genes within these regions being significantly enriched for known NDD-risk genes and pathways. In addition, a significant proportion of these genes was found to (1) converge in protein-protein interaction networks, (2) be among most expressed genes in the brain across all developmental stages, and (3) be hit by deletions that are significantly over-transmitted to individuals with ASD within multiplex ASD families from the iHART cohort. Finally, we conducted a burden analysis using 4,281 NDD cases from Decipher and iHART cohorts, and 2,504 neurotypical control individuals from 1000 Genomes and iHART, which resulted in the validation of the association of 162 dosage-sensitive genes driving risk for NDDs, including 22 novel NDD-risk genes. Importantly, most NDD-risk CNV loci entail multiple NDD-risk genes in agreement with a polygenic model associated with the majority of NDD cases.