Fragile X Archives - Green Market Report

StaffOctober 6, 2022

Zynerba Pharmaceuticals (Nasdaq: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for orphan neuropsychiatric disorders, today announced that the U.S. Patent and Trademark Office has issued Patent No. 11,458,110, titled “Treatment of Fragile X Syndrome With Cannabidiol,” which includes claims directed to methods of treating Fragile X syndrome with cannabidiol.

This new patent, which expires in 2038, is part of an expanding international intellectual property portfolio covering Zynerba’s transdermal cannabidiol product candidate, Zygel. There are currently four corresponding U.S. patents and one corresponding EU patent related to methods of treating Fragile X syndrome. Last year Green Market Report reported that Zynerba
published the results from its open-label Phase 2 BELIEVE (Open-Label Study to Assess the Safety and Efficacy of Zygel (ZYN002) Administered as a Transdermal Gel to Children and Adolescents with Developmental and Epileptic Encephalopathy) study in the Journal of the American Medical Association (JAMA) Network Open.

The study demonstrated a 58% median monthly reduction in seizures at month 5, and a 43.5% reduction over the 6.5 month study period (the primary efficacy endpoint). In addition, the parents/caregivers noted improvements in social or interpersonal engagement and irritability (77%); alertness, energy, and sleep (53%); and cognition or concentration (47%).

48 patients with a mean age of 10.5 years were enrolled in BELIEVE and included in the safety analysis. 60% had at least one treatment-related adverse event (AE) over the 6.5 month trial period and 96% of these AE’s were mild or moderate. During the treatment period, 10 patients (21%) reported serious adverse events (SAEs). Two SAEs were considered to be possible treatment-related: nonconvulsive status epilepticus and lower respiratory tract infection, in separate patients. All SAEs were resolved, and none resulted in an alteration of the study medication. The study warned that there was no control group and so it is impossible to know how much was due to the placebo effect and the desire for cannabis products to work.

Debra BorchardtJune 30, 2020

Some drugs work and at other times they don’t, which is the whole point of testing and the importance of trying to find solutions to patient conditions. Unfortunately for Zynerba Pharmaceuticals, Inc. (ZYNE) its latest top-line results from the 14-week pivotal CONNECT-FX (Clinical study of Cannabidiol (CBD) in Children and Adolescents with Fragile X) trial failed to produce the necessary threshold for positive results. The stock was selling off as a result of the news.

The Zygel CBD gel as a treatment for behavioral symptoms of Fragile X syndrome (FXS) in 212 patients did not achieve statistical significance versus placebo in the primary endpoint of improvement in the Social Avoidance subscale of the Aberrant Behavior Checklist – Community FXS (ABC-CFXS). Zynerba also said that Zygel also did not demonstrate statistical significance versus placebo in the three key secondary endpoints, which were the change from baseline to the end of the treatment period in the Irritability subscale score of the ABC-CFXS, the Socially Unresponsive/Lethargic subscale score of the ABC-CFXS and Improvement in Clinical Global Impression (CGI-I).

“This study identified a key population of patients who appear to benefit from treatment of their behavioral symptoms of FXS with Zygel,” said Randi J. Hagerman, MD, an investigator in the clinical trial and Medical Director and Endowed Chair in Fragile X Research at UC Davis MIND Institute and Distinguished Professor at the Department of Pediatrics at UC Davis School of Medicine. “Zygel has the potential to be an important therapeutic option for the most severely impacted patients with Fragile X.”

Study Results

While the drug wasn’t a statistical success, the company felt that enough patients responded positively that it wants to meet with the FDA to discuss a future path for the drug.

“The results from CONNECT-FX identified a significant patient population who responded well to Zygel and may provide us with a pathway towards licensure,” said Armando Anido, Zynerba’s Chairman and Chief Executive Officer. “We intend to discuss the results of the study with the FDA as soon as possible. On behalf of the entire Zynerba team, I want to sincerely thank the patients, families and investigators who participated in this study as well as the National Fragile X Foundation, the FRAXA Research Foundation, and the Fragile X Association of Australia for their assistance in this study.”

The company posted the following study details: Two hundred and forty-five (245) patients with Fragile X syndrome, confirmed with the full mutation of the FMR1 gene, were enrolled at 21 clinical sites in the United States, Australia, and New Zealand. Unknown to the patients and their caregivers, all patients were given placebo during the first two weeks (called a “placebo run-in” which is often used in neuropsychiatric clinical trials), and as a result 33 patients were not randomized. The remaining 212 patients were included in the Intent-to-Treat (ITT) population (Zygel: n=110; placebo: n=102) and were randomized to receive either trial drug or placebo for an additional 12 weeks. One patient did not receive study medication so 211 patients are included in the safety analysis (Zygel: n=109; placebo: n=102.) One patient did not have a post-baseline efficacy measure, resulting in 210 patients in the full analysis set (Zygel: n=109; placebo: n=101).

A pre-planned ad hoc analysis of the most severely impacted patients in the trial, as defined by patients having at least 90% methylation (“full methylation”) of the impacted FMR1 gene, demonstrated that patients receiving Zygel achieved statistical significance in the primary endpoint of improvement at 12 weeks of treatment in the Social Avoidance subscale of the ABC-CFXS compared to placebo (p=0.020). This group comprised 80% of the patients enrolled in the CONNECT-FX study. The Company believes that full methylation occurs in approximately 60% of the overall FXS patient population. Based on this analysis, Zynerba intends to meet with the FDA regarding a regulatory path forward for Zygel.