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
Elizabeth Berry-Kravis 1, Randi Hagerman 2 3, Jonathan Cohen 4 5, Dejan Budimirovic 6 7, Caroline B Buchanan 8, Natalie Silove 9, Nancy Tich 10, Anthony Thibodeau 10, Thomas Dobbins 11, Terri Sebree 12, Stephen O'Quinn 13, David S Albers 10, Kristen G Bzdek 14, George Nomikos 10, Kumar Budur 10
- 1Departments of Pediatrics and Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
- 2Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, CA, USA.
- 3Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA, USA.
- 4Fragile X Alliance Inc, North Caulfield, Melbourne, VIC, Australia.
- 5Honorary Research Associate, Diagnosis and Development, Victorian Clinical Genetic Services and Murdoch Childrens Research Institute, Melbourne, VIC, Australia.
- 6Departments of Psychiatry and Child Psychiatry, Fragile X Clinic, Kennedy Krieger Institute/the Johns Hopkins Medical Institutions, Baltimore, MD, USA.
- 7Department of Psychiatry & Behavioral Sciences-Child Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA.
- 8Greenwood Genetic Center, Greenville, SC, USA.
- 9The Children’s Hospital at Westmead, Sydney, Australia.
- 10Harmony Biosciences, Plymouth Meeting, PA, USA.
- 11The Griesser Group, Conshohocken, PA, USA.
- 12Pharmaceutical Consulting, LLC, Johnson City, TX, USA.
- 13Perissos Inc, Wake Forest, NC, USA.
- 14Harmony Biosciences, Plymouth Meeting, PA, USA. Publications@harmonybiosciences.com.
Affiliationer
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 scores.
Conclusions: Interim analysis results of the ongoing OLE in children, adolescents, and young adults with FXS demonstrated that ZYN002 has a favorable long-term safety profile and is generally well tolerated. Clinically meaningful changes in behaviors from baseline continued to be observed during the OLE. These findings support further study of ZYN002 in patients with FXS.
Trial registration: ZYN2-CL-017 is registered on Clinicaltrials.gov (NCT03802799) on December 26, 2018.
Keywords: Endocannabinoid system; Fragile x syndrome; Irritability; Social avoidance; Transdermal cannabidiol.
