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.