Clinical Takeaway
Transdermal cannabidiol gel (ZYN002) has demonstrated an acceptable long-term safety and tolerability profile in children and adolescents with Fragile X syndrome across an ongoing open-label extension study. The treatment targets dysregulated endocannabinoid signaling, which is a recognized feature of Fragile X syndrome pathophysiology. These interim findings support continued investigation of transdermal CBD as a potential option for managing behavioral symptoms in this population.
#19 Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study.
Citation: Berry-Kravis Elizabeth et al.. Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study.. Journal of neurodevelopmental disorders. 2025. PMID: 41254489.
Design: 5 Journal: 0 N: 2 Recency: 2 Pop: 2 Human: 1 Risk: -2
This interim analysis provides critical long-term safety and tolerability data for transdermal cannabidiol in the pediatric and adolescent FXS population, addressing a significant evidence gap given the limited chronic dosing experience with cannabinoid therapeutics in this vulnerable age group. The findings directly inform clinical decision-making regarding sustained cannabidiol therapy as an adjunctive treatment for behavioral dysregulation in FXS, a condition with limited pharmacological options and substantial morbidity. Establishing a favorable safety profile through systematic monitoring of this novel transdermal formulation is essential for advancing cannabidiol toward potential regulatory approval and clinical integration in FXS management.
Quality Gate Alerts:
- Preclinical only
Methodological Considerations:
- Open-label design — placebo effect not excluded
Abstract: BACKGROUND: Dysregulated endocannabinoid signaling is involved in Fragile X syndrome (FXS), suggesting a potential role for the endocannabinoid signaling modulator, cannabidiol, in treatment. ZYN002 is a synthetic cannabidiol that has been uniquely formulated as a gel for transdermal delivery and is currently under investigation for the treatment of behavioral symptoms associated with FXS. DESIGN: ZYN2-CL-017 is an ongoing, long-term, open-label extension (OLE) safety trial of ZYN002 in patients with FXS. We are enrolling patients from past and current ZYN002 clinical trials to evaluate the safety and tolerability of ZYN002 in patients with FXS. METHODS: Primary safety assessments were conducted in patients who enrolled into the OLE from 2 completed ZYN002 trials. Secondary analyses, conducted in a subgroup enrolled from a completed placebo-controlled trial of ZYN002, included the FXS-specific Aberrant Behavior Checklist-Community Social Avoidance and Irritability subscales (ABC-CFXS SA and ABC-CFXS Irr, examined change from baseline of the randomized study) and the Caregiver Global Impression of Change (CaGI-C, examined change from baseline of the OLE), in which caregivers were asked to rate the change in their child’s overall behavior. RESULTS: At the time of this interim analysis data cut (January 31, 2024), 240 patients had been enrolled from 2 completed ZYN002 trials. Mean age at entry to the OLE was 9.7 years (range 3-17 years), and the majority were male (76.3%) and White (80.4%). Mean exposure to ZYN002 during the initial trials and OLE was 28 months. Treatment-related adverse events (AEs) were reported in 12.9% of patients; the most common (6.7% of patients) was short-term application site pain. The highest degree of skin irritation reported by investigators was moderate erythema in 7 patients (2.9%). In the secondary analysis cohort (n=196 evaluable patients), patients demonstrated clinically meaningful changes in ABC-CFXS SA, ABC-CFXS Irr, and CaGI-C scor