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ZYN002 Gel Shows Long-Term Safety and Behavioral Improvements in Fragile X Syndrome
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Key Takeaways
- ZYN002 demonstrated a favorable safety profile in patients with Fragile X syndrome, with application site pain as the most common adverse event.
- Clinically meaningful improvements in irritability-related behaviors were observed, supporting further investigation of ZYN002.
Newly presented open-label extension results at AAN 2025 suggest that investigational ZYN002, a cannabidiol gel, may help improve irritability in children and adolescents living with Fragile X syndrome.
Kristen Bzdek, MD
(Credit: LinkedIn)
Recently reported long-term data from an open-label extension study (NCT03802799) showed that ZYN002 (Harmony Biosciences), an investigational transdermal cannabidiol gel, was generally well tolerated among patients with Fragile X syndrome (FXS). Presented at the 2025 American Academy of Neurology (AAN) Annual Meeting, held April 5-9, in San Diego, California, secondary analyses also suggested potential benefit in addressing irritability-related behaviors, supporting further investigation.1
The results came from the ongoing ZYN2-CL-017 study, a long-term open-label safety extension trial evaluating the safety and efficacy of ZYN002 in patients with FXS. The gel, a pharmaceutically produced—not plant-derived—form of cannabidiol, is being developed to treat behavioral symptoms in FXS. In the trial, ZYN002 demonstrated a favorable safety profile, with the most common treatment-related adverse event (AE) reported as application site pain (6.7%).
A total of 240 patients, aged 3 to 17 years at the time of entry, were included in the analysis. All participants had previously enrolled in either the CONNECT-FX (ZYN2-CL-016, NCT03614663), a phase 3 double-blind placebo-controlled trial, or FAB-C (ZYN2-CL-009), a phase 1/2 open-label trial.2,3 Presented by lead author Kristen Bzdek, MD, senior medical director of clinical development and strategy at Harmony Biosciences, safety assessments in the open-label extension included AEs, vital signs, laboratory evaluations, and electrocardiograms.
Among 197 patients in the secondary analysis cohort—those who had completed CONNECT-FX—clinically meaningful improvements were observed in scores on the Irritability subscale of the Aberrant Behavior Checklist–Community FXS (ABC-CFXS) version from their original baseline values. At month 36 of the open-label extension, caregiver-reported global impression of change scores reflected clinically meaningful improvements in 73.3% of patients who continued ZYN002 and in 72.0% of patients who transitioned from placebo to ZYN002.
Prior results from the CONNECT-FX study reported that the investigational cannabidiol gel showed promising effects in patients with higher levels of FMR1 gene methylation, a group often more severely affected by FXS. In the trial, the gel was administered daily over 12 weeks, in doses of 250 mg or 500 mg based on weight, as an add-on to standard care. Despite the trial’s primary end point not being met in the full cohort, post hoc analyses showed significant improvements in patients with at least 90% FMR1 gene methylation.2
The trial enrolled 212 patients with a mean age of 9.7 years; 75% were boys. Of these, 169 participants (79.7%) had at least 90% methylation of the FMR1 promoter region in addition to a full mutation. Among this subgroup, treatment with ZYN002 led to statistically significant improvement in the primary outcome: change in social avoidance (SA) scores on the ABC-CFXS SA subscale (nominal P = .020).
Published in the Journal of Neurodevelopmental Disorders, researchers noted that additional benefits were observed in caregiver-reported measures. Statistically significant improvements were observed in SA and isolation (P = .038), irritable and disruptive behaviors (P = .028), and social interactions (P = .002). Similar results were also seen in patients with 100% methylation of the FMR1 gene.
Overall, ZYN002 was well tolerated throughout the trial. All treatment-emergent adverse events were mild or moderate, with the most common treatment-related event being application site pain (ZYN002 group, 6.4% vs placebo, 1.0%). Authors noted that the CONNECT-FX data suggest that ZYN002 may offer benefit for patients with high levels of FMR1 methylation, those most likely to experience gene silencing and severe behavioral symptoms.
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