Zygel Led to Meaningful Behavioral Improvements in Certain Youngsters

Zynerba Pharmaceuticals’ experimental cannabidiol (CBD) gel Zygel results in statistically significant and clinically meaningful reductions in behavioral symptoms in children and adolescents with fragile X syndrome (FXS) and a fully methylated FMR1 gene, according to data from the Phase 2/3 CONNECT-FX trial.

DNA methylation is a biochemical modification that “turns off” genes,  preventing the production of the respective protein. In this case, methylation of 90% or more of the FMR1 gene (classified as full methylation) is associated with a complete absence of the FMRP protein and greater disease severity.

The results suggest that the degree of FMR1 methylation may influence treatment responses among fragile X patients and that Zygel may be an effective treatment for those with full methylation, who the company believes account for 60% of all cases.

Zynerba plans to confirm Zygel’s therapeutic potential specifically in this subset of patients in an upcoming pivotal trial, expected to begin before the year’s end. If positive, the results are expected to further support a regulatory application to the U.S. Food and Drug Administration (FDA) seeking the therapy’s approval for this specific group of fragile X patients.

CONNECT-FX findings, along with the rationale behind the thresholds for clinically meaningful behavioral changes in the Aberrant Behavior Checklist — Community FXS (ABC-CFXS) subscales, were presented recently through two posters at the Society of Biological Psychiatry 2021 Virtual Meeting, held April 29–May 1.

“We believe these data demonstrate the ABC-CFXS subscales capture behaviors that are impactful and meaningful in clinical trials of children with FXS [fragile X syndrome],” Joseph M. Palumbo, MD, Zynerba’s chief medical officer, said in a press release.

“Therefore, we remain confident that these subscales are fit for purpose for measuring clinical trial endpoints in FXS,” Palumbo added.

Applied to the shoulder or upper arm, Zygel is designed to deliver controlled amounts of a purified form of CBD, the major non-psychoactive cannabinoid (active component) in the cannabis plant, into the bloodstream through the skin.

CBD mimics the body’s natural cannabinoids that modulate the endocannabinoid system, which is associated with some of the behavioral abnormalities that characterize fragile X.

The Phase 2/3 CONNECT-FX study (NCT03614663) evaluated the safety and effectiveness of Zygel in 212 fragile X patients, ages 3 to 17, who were recruited at sites in the U.S., Australia, and New Zealand. It is the largest controlled study ever performed in fragile X patients, according to Zynerba.

Participants, with a mean age of 9.4 years and most (70%) being males, were assigned randomly to receive either Zygel (250 or 500 mg, based on the person’s weight) or a placebo every day for 12 weeks, in addition to standard care.

Top-line data showed the trial failed to meet its main goal of demonstrating that Zygel significantly reduced social avoidance behaviors, as assessed with the ABC-CFXS social avoidance subscale, relative to placebo.

ABC-CFXS is a validated measure of behavioral abnormalities common in fragile X, including social avoidance, irritability, hyperactivity, and inappropriate speech.

However, significant benefits were observed among patients with a full methylation of FMR1 and more severe symptoms (80% of all participants), who showed a two-times greater reduction in social avoidance behaviors than those given a placebo (by 40% vs. 21.1%).

Compared with placebo, Zygel did not significantly improve scores of other ABC-CFXS subscales and of the Clinical Global Impression-Improvement scale (CGI-I) — used as secondary goals — in this subset of patients.

Poster presentations

Now, Zynebra and trial researchers presented data showing that the investigational gel led to clinically meaningful reductions in social avoidance behavior and irritability, as well as significant improvements in CGI-I behavioral subdomains in this subset of patients.

In the poster, “Cannabidiol in Fragile X Syndrome (FXS): Proposed Mechanism of Action Translates Into Meaningful Clinical Benefits (CONNECT-FX [ZYN2-CL-016]),” researchers explained how they defined thresholds for clinically meaningful changes in the ABC-CFXS Social Avoidance, Irritability, and Socially Unresponsive/Lethargic subscales.

These thresholds were based on FDA recommendations for caregiver-reported outcomes and interviews with 25 caregivers of fragile X patients.

They were determined by analyzing the mean change in these subscales in patients with improvements in at least one category of the Caregiver Global Impression of Severity, which was classified as meaningful or important by caregivers.

Results showed that clinically meaningful improvements in the ABC-CFXS included a reduction of three or more points in the Social Avoidance subscale, nine or more points in the Irritability subscale, and five or more points in the Socially Unresponsive/Lethargic subscale.

“These thresholds serve as a basis for evaluating clinically meaningful treatment effects at the individual patient level in clinical trials of children and adolescents with FXS as demonstrated for [Zygel] in CONNECT-FX,” the researchers wrote.

In the poster “A Pivotal Study of ZYN002 Cannabidiol Transdermal Gel in Children and Adolescents With Fragile X Syndrome (CONNECT-FX [ZYN2-CL-016]),” researchers presented CONNECT-FX results, such as those based on the newly defined ABC-CFXS thresholds, of fragile X patients with a full methylation of FMR1.

Data showed that a significantly greater proportion of Zygel-treated patients achieved a meaningful drop in ABC-CFXS subscales of Social Avoidance (58.2% vs. 40.6%) and Irritability (40.3% vs. 23.8%).

In addition, reductions in social avoidance and isolation, and in irritable and disruptive behaviors, as well as improvements in social interactions were reported significantly more often by caregivers of Zygel-treated patients than by those of patients on a placebo.

These findings suggest that Zygel provided meaningful reductions in behavioral symptoms of children and adolescents with fragile X and a full methylation of the FMR1 gene.

“These results may represent an important step forward in further understanding FXS and the importance of methylation of the FMR1 gene,” the researchers wrote, adding that Zygel’s beneficial effects also are being confirmed in CONNECT-FX’s open-label extension study (NCT03802799), in which all patients are receiving the therapy for up to one year.