Cannabidiol gel ZYN002 for fragile X fails to meet goal in clinical trial
No greater effects seen vs. placebo in social avoidance behavior
A large clinical trial investigating the effects of Harmony Biosciences’ cannabidiol (CBD) gel ZYN002 on behavioral symptoms in children and young adults with fragile X syndrome has failed to meet its primary goal, the developer announced.
Data from the Phase 3 trial, called RECONNECT (NCT04977986), showed no significantly greater effect with ZYN002 on social avoidance behavior — avoiding social situations because of fear or discomfort — relative to a placebo.
According to the company, this was mainly due to a higher-than-expected response in the placebo group.
“Although the [trial] did not achieve its primary endpoint, the findings from this study provide valuable insights into fragile X syndrome, a rare neurobehavioral condition with significant unmet medical need and no [U.S.-approved] therapies,” Kumar Budur, MD, chief medical and scientific officer at Harmony, said in a company press release. “We will conduct a comprehensive analysis of the full dataset to better understand the results as part of our continued commitment to the fragile X community.”
ZYN002 does not contain THC, the compound that causes the euphoric effect of cannabis. As such, the developer noted that it “has the potential to be a nonscheduled product,” meaning it would not be classified as a controlled substance if used as a treatment.
A neurodevelopmental disorder, fragile X is caused by mutations in the FMR1 gene, which resulting in low or no production of the FMRP protein vital for nerve cell function.
The amount of FMRP produced depends on the specific FMR1 mutation and the associated level of methylation — a chemical tag that suppresses protein production without changing the DNA sequence. Usually, if a mutation causes complete methylation, no FMRP will be produced, and the disease will be more severe.
Lab-made CBD version ZYN002 has no psychoactive, intoxicating effects
The neurological changes related to fragile X can result in symptoms such as intellectual disability and delayed development. Behavioral problems, which may include hyperactivity, anxiety, irritability, and social avoidance, are also common.
Researchers believe some of these behavioral symptoms may be related to problems in the endocannabinoid system, a natural system in the body that’s important for brain function. ZYN002 aims to restore endocannabinoid signaling, which Harmony had expected to ease behavioral symptoms among the fragile X patients in trial.
ZYN002 contains a lab-made version of CBD, a component of the cannabis plant that doesn’t have psychoactive or intoxicating effects and that modulates the body’s endocannabinoid system. The gel formulation of this compound allows the active ingredient to be absorbed through the skin into the bloodstream, making for a product expected to be easy to use.
Harmony and the medication’s original developer, Zynerba Pharmaceuticals, have run several clinical trials testing the gel in children and adolescents with fragile X.
An open-label extension Phase 2/3 clinical study (NCT03802799) allowed participants in earlier trials to continue receiving ZYN002 for a longer period. Up to four years of data from this study demonstrated reduced social avoidance behavior. These effects were particularly pronounced for individuals with complete FMR1 methylation.
Long-term treatment was also associated with reduced irritability, with more than 60% of participants experiencing a clinically meaningful decrease in this symptom as measured using caregiver assessments.
ZYN002 was generally safe and well tolerated across trials.
Similar behavior changes seen for children, young adults in trial
The Phase 3 RECONNECT study was designed to be a confirmatory trial to support submissions for potential regulatory approval of ZYN002. A total of 215 children and young adults with fragile X, ages 3 to 29, were randomly assigned to receive, twice daily, either a weight-based dose of ZYN002 or a placebo for 18 months, or 1.5 years.
The trial’s primary goal was to evaluate whether ZYN002 was superior to the placebo at reducing social avoidance behaviors in participants with complete FMR1 methylation. This was assessed with the social avoidance subscale of the caregiver-completed Aberrant Behavior Checklist-Community Fragile X Factor Structure (ABC-C FXS), which was completed by caregivers.
However, the results showed that the ZYN002 and placebo groups had statistically similar changes in the ABC-C FXS social avoidance subscore between the beginning and end of the trial. That means that the study failed to meet its main goal.
While these results are not what we anticipated, we remain confident in our ability to bring innovative therapies to patients.
Harmony stated that high response rates in the placebo group contributed to this lack of statistical significance between groups, but did not provide any further details, with the company noting it planned a full analysis.
“While these results are not what we anticipated, we remain confident in our ability to bring innovative therapies to patients,” said Jeffrey M. Dayno, MD, Harmony’s president and CEO.
For his part, Budur voiced appreciation for all those involved in the study.
“We are grateful to the patients, families, caregivers, clinicians, and researchers who made this trial possible,” Budur said.
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