Background <p>22q11.2 deletion syndrome (22qDS) is a genetic disorder affecting various body systems and associated with behavioral and psychiatric conditions, with no currently approved pharmacological treatments. </p> <p>ZYN002, a transdermal gel containing synthetic cannabidiol, has been demonstrated to be well tolerated, showing potential benefit in related neurodevelopmental disorders. The INSPIRE study evaluated the safety, tolerability, and effectiveness of ZYN002 in children and adolescents with 22qDS.</p> Methods <p>INSPIRE was a phase 2, open-label, multicenter trial comprising a 14-week treatment period (Period 1) followed by an optional 24-week, open-label extension (Period 2) for participants with ≥35% improvement on the Aberrant Behavior Checklist-Community (ABC-C) irritability subscale upon Period 1 completion. </p> <p>Participants aged 4 to &lt;18 years with genetically confirmed 22qDS, Clinical Global Impression-Severity score ≥4, and Pediatric Anxiety Rating Scale-Revised (PARS-R) score ≥10, both at Screening and Visit 2 (Day 1), were enrolled. Weight-based, transdermal ZYN002 administration occurred twice daily. Primary outcomes were safety and tolerability, including the incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included the PARS-R; Anxiety, Depression, and Mood Scale (ADAMS); ABC-C; Clinical Global Impression-Improvement (CGI-I), and Qualitative Caregiver-Reported Behavioral Problems survey.</p> Results <p>Twenty participants initiated treatment; 17 completed Period 1, and 13 continued into Period 2. ZYN002 was well tolerated; only mild TEAEs were experienced in 35% of participants, and 15% reported treatment-related AEs. Upon Period 1 completion, significant changes from Baseline were observed across all measures: 40.6% PARS-R reduction (<i>P</i>=0.0005); 45.3% ADAMS total score reduction (<i>P</i>=0.0005) with clinically meaningful improvements in all subscales; and significant improvements in all ABC-C subscales, including irritability (36.3%, <i>P</i>=0.0055). On the CGI-I, 75% of participants were rated as “improved” or better relative to Baseline. For the behavioral problems survey, &gt;80% of caregivers reported improvement in ≥1 problem during each period. Anxiety and irritability scores from Baseline through Period 2 maintained a similar reduction to Period 1.</p> Conclusions <p>In this interventional, open-label trial of pediatric participants with 22qDS, ZYN002 was considered safe and well tolerated, and was associated with reductions in anxiety-related and behavioral symptoms, supporting further investigation of ZYN002 in a phase 3 randomized controlled trial.</p> Trial registration <p>Clinicaltrials.gov (NCT05149898) registered on October 5, 2021.</p>