Zynerba‘s Zygel (ZYN002), a cannabidiol gel placed on the skin, was well-tolerated and led to a “clinically meaningful” easing of anxiety and other behavioral symptoms in children and teenagers with fragile X syndrome, according to results of a clinical trial in Australia.
The findings, “A phase 1/2, open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol (ZYN002) for the treatment of pediatric fragile X syndrome,” were published in the Journal of Developmental Disorders.
Recent studies suggest that behavioral abnormalities in people with fragile X and other neurological conditions are linked to problems in the endocannabinoid system, which is thought to be modulated by cannabidiol (CBD) — a naturally occurring chemical found in cannabis that does not get users “high.”
Zygel is a CBD formulated clear gel that is manufactured pharmaceutically to deliver controlled amounts of CBD into the bloodstream through the skin.
The open-label Phase 1/2 trial (ACTRN12617000150347) FAB-C — which stands for Treatment of Fragile X Syndrome Anxiety and Behavioral Challenges with CBD — enrolled 20 fragile X patients between ages 6 and 17 at multiple sites in Australia. Half of the patients had anxiety, one-third had attention deficit hyperactivity disorder, and three had sleep disorders. Three other patients had epilepsy.
Zygel was administered twice daily for 12 weeks as an add-on therapy. During the study’s first six weeks, researchers tested increasing doses of the gel, ranging from 50 mg up to 250 mg daily. Weeks seven through 12 were considered a maintenance period, during which patients received Zygel at a stable dose (the highest tolerated dose given during the titration period).
To determine Zygel’s effect on behavioral symptoms, several instruments were used to measure mood, behavior, and health-related quality of life, based either on parents and caregivers or clinician ratings. Scales included the Anxiety, Depression, and Mood Scale (ADAMS), the Aberrant Behavior Checklist – Community for FXS (ABC-CFXS), the Pediatric Anxiety Rating Scale (PARS-R) and the Pediatric Quality of Life Inventory (PedsQL).
A total of 18 patients completed all 12 weeks of the study and were included in efficacy analyses — 16 given a Zygel daily maintenance dose of 250 mg, and two who received a 100 mg maintenance dose. Of these, 13 continued in a 24-month extension study phase.
Effectiveness data were consistent and showed that Zygel led to clinical improvements in a range of key emotional and behavioral symptoms associated with fragile X.
The trial reached most of its efficacy goals, showing that patients experienced a 48.9% reduction in the total score of ADAMS (a validated scale for assessing anxiety and mood) at the end of the 12-week treatment period compared to scores at the study’s start.
This reduction translated into lesser manic/hyperactive, social avoidance, general anxiety, and compulsive behaviors.
Improvements were also noted in the ABC-CFXS scale relative to social avoidance, stereotypy (repetitive actions), social unresponsiveness, irritability, hyperactivity, and inappropriate speech.
Likewise, health-related quality of life improved, in particular psychosocial and emotional health.
The greatest benefits in terms of emotional symptoms were in anxiety, while lower social avoidance and stereotypy were the largest gains in terms of behavior.
Zynerba noted that data were consistent in showing improvements in both internalized (e.g., anxiety, social avoidance) and externalized symptoms (e.g., irritability).
In this study, no placebo or control group was used. But Zynerba said that benefits seen with Zygel were generally greater than those reported for placebo in earlier controlled clinical trials in fragile X.
Treatment was well-tolerated, with most treatment-emergent adverse events (reported by 85% of participants) being mild in severity (70%) and resolved by the end of the 12-week treatment period with no dose adjustment. No serious adverse events were reported, and there were no significant alterations in liver function or other laboratory values.
“ZYN002 [Zygel] was well tolerated and produced clinically meaningful reductions in anxiety and behavioral symptoms in children and adolescents with [fragile X],” the researchers wrote.
A placebo-controlled Phase 2/3 study, CONNECT-FX (NCT03614663), is underway to confirm Zygel’s benefits in easing behavioral symptoms in young people with fragile X. The study is taking place at multiple sites in the U.S., Australia and New Zealand, and currently recruiting patients. For more information about this trial, please visit here.
“Children with Fragile X syndrome exhibit a number of developmental and behavioral symptoms … that significantly impact the family, and the child’s capacity to interact with them, their peers, and care providers. My hope is that if we can successfully treat these symptoms, we can enhance the child’s ability to engage and interact. In that regard, these open label data are promising, and are an important step in the development of ZYN002,” the study’s lead investigator Honey Heussler, MBBS, a pediatrician and medical director at Children’s Health Queensland and a professor at the University of Queensland, said in a press release.
Zygel was place on fast track by the U.S. Food and Drug Administration (FDA) in March to treat behavioral symptoms in patients with fragile X. A fast track designation allows a more expedited review of an investigative therapy to potentially speed its availability to patients.