Zynerba Pharma (ZYNE) Pivotal CONNECT-FX Trial of Zygel in Fragile X Syndrome Did Not Achieve Statistical Significance
Zynerba Pharmaceuticals, Inc. (NASDAQ: ZYNE), the leader in innovative pharmaceutically-produced transdermal cannabinoid therapies for rare and near-rare neuropsychiatric disorders, today announced top line results from the 14-week pivotal CONNECT-FX (Clinical study of Cannabidiol (CBD) in Children and Adolescents with Fragile X) trial. The multi-national, randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of Zygel™ CBD gel as a treatment in for behavioral symptoms of Fragile X syndrome (FXS) in 212 patients.
Zygel 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). 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).
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.
“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.”
“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.”
CONNECT-FX Patient Disposition
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).
Baseline Demographics
Select baseline demographics for the ITT population are as follows:
| Placebo | Zygel | Total | |
| n | 102 | 110 | 212 |
| Age (years) | 9.8 | 9.6 | 9.7 |
| Sex – Males | |||
| n | 78 | 81 | 159 |
| % | 76% | 74% | 75% |
| Weight – kg | |||
| Median | 34.3 | 36.8 | 35.7 |
| Range – Min, Max | 15.6, 104.7 | 14.6, 87 | 14.6, 104.7 |
| >35 kg, % | 48.0% | 55.5% | 51.9% |
| Baseline psychoactive medications, % | 66% | 57% | 62% |
Primary and Key Secondary Endpoints - Full Analysis Set
The results of CONNECT-FX in the full analysis population for the primary and key secondary endpoints are summarized below.
| Placebo N=101 | Zygel N=109 | ||||||
| Endpoint | Baseline Mean | Week 12 Mean Change | Baseline Mean | Week 12 Mean Change | Treatment Difference* | Odds Ratio | Treatment P-Value |
| ABC-CFXS Social Avoidance Subscale | 7.24 | -2.29 | 7.12 | -2.68 | -0.39 | NS | |
| ABC-CFXS Irritability Subscale | 27.65 | -4.14 | 28.49 | -5.88 | -1.74 | NS | |
| ABC-CFXS Socially Unresponsive / Lethargy Subscale | 12.82 | -3.14 | 13.42 | -3.50 | -0.36 | NS | |
| CGI-I at week 12 (Much and Very Much Improved) | - | 15.9% | - | 20.2% | 1.33 | NS | |
NS = Not statistically significant
*A negative treatment difference demonstrates that Zygel patients improved versus placebo
Pre-Planned Ad Hoc Analysis of Patients with Full Methylation of the FMR1 Gene
The Company performed a pre-planned ad hoc analysis of the ITT population (n= 212) to evaluate the effect of Zygel versus placebo according to severity of baseline disease as defined by patients having full methylation of the impacted FMR1 gene. Patients with genetically confirmed full mutation Fragile X and full methylation of their impacted FMR1 gene are generally the most severely impacted by the disorder. Within the CONNECT-FX trial, this was corroborated with patients in the analysis at baseline having higher anxiety, lower IQ, lower adaptive function, and more severe autism as compared to patients without a fully methylated FMR1 gene. One hundred and sixty nine (169) patients met the criterion of full methylation of the FMR1 gene. One patient was not treated and one did not have a post-baseline efficacy measure, resulting in 167 patients (Zygel: n=91; placebo: n=76).
Baseline demographics for patients with full methylation of the FMR1 gene are shown below.
| Placebo | Zygel | Total | |
| n | 77 | 92 | 169 |
| Age (years) | 9.6 | 9.2 | 9.4 |
| Sex – Males | |||
| n | 54 | 65 | 119 |
| % | 70% | 71% | 70% |
| Weight – kg | |||
| Median | 33.9 | 35.7 | 35.0 |
| Range – Min, Max | 15.6, 104.7 | 14.6, 87.0 | 14.6, 104.7 |
| >35 kg, % | 45.5% | 53.3% | 49.7% |
| Baseline psychoactive medications, % | 65% | 54% | 59% |
Primary and Key Secondary Endpoints - Patients with Full Methylation of the FMR1 Gene
The results of CONNECT-FX in the analysis set of patients with full methylation of the FMR1 gene across the primary and key secondary endpoints are summarized below.
| Placebo N=76 | Zygel N=91 | ||||||
| Endpoint | Baseline Mean | Week 12 Mean Change | Baseline Mean | Week 12 Mean Change | Treatment Difference** | Odds Ratio | Treatment P-Value |
| ABC-CFXS Social Avoidance Subscale | 7.18 | -1.99 | 7.12 | -2.99 | -1.0 | 0.020* | |
| ABC-CFXS Irritability Subscale | 28.00 | -4.13 | 29.36 | -6.43 | -2.30 | 0.091 | |
| ABC-CFXS Socially Unresponsive / Lethargy Subscale | 13.17 | -2.74 | 13.30 | -3.91 | -1.17 | 0.135 | |
| CGI-I at Week 12 (Any Improvement) | - | 35.7% | - | 51.1% | 1.88 | 0.056 | |
*Statistically significant vs. placebo
**A negative treatment difference demonstrates that Zygel patients improved versus placebo
The median improvement in the Social Avoidance subscale of the ABC-CFXS after twelve weeks of treatment was 40.0% for patients on Zygel and 21.1% for patients on placebo.
The interaction test of heterogeneity for the Social Avoidance subscale was statistically significant (p=0.002), which means that the difference in treatment effects between the subgroups was statistically significant.
Safety Data
Zygel was very well tolerated in CONNECT- FX, and the safety profile was consistent with previously released data from other Zygel clinical trials. No safety signal was identified. Approximately half (54%) of the 211 patients included in the safety population experienced a treatment emergent adverse event (any event, whether unrelated or related to study drug), all of which were mild or moderate. The frequency of treatment emergent adverse events was similar across treatment groups (58% of patients on Zygel, 50% of patients on placebo). There were no serious or severe adverse events reported during the study. There were seven total psychiatric disorder TEAEs, five of which were in the placebo group.
Only 15 (7%) patients experienced a treatment-related adverse event (20 events total); 11 patients on Zygel experienced 14 treatment-related TEAEs, while four patients on placebo experienced six treatment-related TEAEs. The most common treatment-related TEAE was application site pain (Zygel: 6.4%; placebo: 1.0%).
Laboratory values for chemistry and hematology were comparable between the placebo and Zygel treatment groups, and there were no clinically relevant abnormalities in either group. Specifically, there were no clinically significant liver function tests.
Upcoming Corporate Milestones
- Fragile X syndrome: Meet with the FDA to discuss CONNECT-FX results as soon as possible.
- Developmental and epileptic encephalopathies (DEE): The results of discussions with FDA on the positive Phase 2 BELIEVE results and the clinical path forward are expected in 3Q2020.
- Autism spectrum disorder (ASD): Zynerba intends to meet with FDA to discuss the positive Phase 2 BRIGHT trial results and clinical path forward in 2H2020.
- 22q11.2 deletion syndrome (22q): As a result of COVID-19 travel restrictions in Australia, top line Phase 2 data from the INSPIRE trial are now expected in 4Q2020.
Conference call information
Zynerba management will host a live conference call and webcast today at 8:30 am Eastern Time to discuss the results of this clinical trial. The call can be accessed by dialing (866) 573-0180 (U.S. and Canada) or (430) 775-1345 (international) and referencing conference ID 9953448. To access the live webcast or the replay, visit the investor page of the Company’s website at http://ir.zynerba.com/. The webcast will be recorded and available on the Company’s website for 30 days.