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
Ca
nnabidiol (CBD) in Childr
en and
Adoles
cen
ts 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.
|
PlaceboN=101 |
ZygelN=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.
|
PlaceboN=76 |
ZygelN=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.
About Fragile X Syndrome (FXS)
Fragile X syndrome is a rare genetic developmental
disability that is the leading known cause of both inherited
intellectual disability and autism spectrum disorder, affecting 1
in 3,600 to 4,000 males and 1 in 4,000 to 6,000 females. It is the
most common inherited intellectual disability in males and a
significant cause of intellectual disability in females, and the
leading genetic cause of autism spectrum disorder (ASD). The
disorder negatively affects synaptic function, plasticity and
neuronal connections, and results in a spectrum of intellectual
disabilities and behavioral symptoms, such as social avoidance and
irritability. In the US, there are about 71,000 people
suffering with FXS, approximately 60% of whom have full methylation
of the FMR1 gene.
FXS is caused by a mutation in FMR1, a gene which
modulates a number of systems, including important effects on the
endocannabinoid system, and most critically, codes for a protein
called FMRP. This protein helps regulate the production of other
proteins and plays a role in the development of synapses,
which are critical for relaying nerve impulses, and in regulating
synaptic plasticity. The FMR1 mutation manifests as multiple
repeats of a DNA segment, known as the CGG triplet repeat. In most
neurotypical people, the FMR1 gene correctly codes for the FMRP
protein. In neurotypical individuals, there are CGG repeats, but
these repeats only occur between 5 and 40 times. As a result, FMRP
is manufactured at levels that enable control over behaviors like
social avoidance and anxiety. In people with full mutation of the
Fragile X gene, the CGG segment is repeated more than 200 times and
in most cases causes the FMR1 gene to not function. However, the
methylation of the FMR1 gene also plays a role in determining
functionality of the gene. At greater than 90% methylation, which
is considered “full methylation”, the FMR1 gene is silenced,
therefore, no FMRP is produced, and the systems and processes that
are expected to be affected by FMRP become dysregulated.
People with genetically confirmed full mutation
Fragile X and full methylation of their FMR1 gene are generally the
most severely impacted by the disorder.
About Zynerba Pharmaceuticals,
Inc. Zynerba Pharmaceuticals is the leader in
pharmaceutically-produced transdermal cannabinoid therapies for
rare and near-rare neuropsychiatric disorders. We are committed to
improving the lives of patients and their families living with
severe, chronic health conditions including Fragile X syndrome,
autism spectrum disorder, 22q11.2 deletion syndrome, and a
heterogeneous group of rare and ultra-rare epilepsies known as
developmental and epileptic encephalopathies. Learn more at
www.zynerba.com and follow us on Twitter at
@ZynerbaPharma.
Statistical Analysis Method
Inferential statistics for the primary endpoint are
based on a linear mixed model for repeated measures (MMRM)
including categorical effects for gender, region, treatment and
week, treatment-by-week interaction, baseline score, and baseline
score-by-week interaction. Inference for the primary endpoint in
the subgroups defined by FMR1 status are also based on the primary
model, and include the appropriate terms for subgroup
interactions.
Cautionary Note on Forward-Looking
Statements
This press release contains forward-looking
statements within the meaning of The Private Securities Litigation
Reform Act of 1995. We may, in some cases, use terms such as
“predicts,” “believes,” “potential,” “proposed,” “continue,”
“estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,”
“could,” “might,” “will,” “should” or other words that convey
uncertainty of future events or outcomes to identify these
forward-looking statements. Such statements are subject to numerous
important factors, risks and uncertainties that may cause actual
events or results to differ materially from the Company’s current
expectations. Management’s expectations and, therefore, any
forward-looking statements in this press release could also be
affected by risks and uncertainties relating to a number of other
factors, including the following: the Company’s cash and cash
equivalents may not be sufficient to support its operating plan for
as long as anticipated; the Company’s ability to obtain additional
funding to support its clinical development programs; the results,
cost and timing of the Company’s clinical development programs,
including any delays to such clinical trials relating to enrollment
or site initiation; clinical results for the Company’s product
candidates may not be replicated or continue to occur in additional
trials and may not otherwise support further development in a
specified indication or at all; actions or advice of the U.S. Food
and Drug Administration and foreign regulatory agencies may affect
the design, initiation, timing, continuation and/or progress of
clinical trials or result in the need for additional clinical
trials; the Company’s ability to obtain and maintain regulatory
approval for its product candidates, and the labeling under any
such approval; the Company’s reliance on third parties to assist in
conducting pre-clinical and clinical trials for its product
candidates; delays, interruptions or failures in the manufacture
and supply of the Company’s product candidates the Company’s
ability to commercialize its product candidates; the size and
growth potential of the markets for the Company’s product
candidates, and the Company’s ability to service those markets; the
Company’s ability to develop sales and marketing capabilities,
whether alone or with potential future collaborators; the rate and
degree of market acceptance of the Company’s product candidates;
the Company’s expectations regarding its ability to obtain and
adequately maintain sufficient intellectual property protection for
its product candidates; the timing and outcome of current and
future legal proceedings; and the extent to which health epidemics
and other outbreaks of communicable diseases, including COVID-19,
could disrupt our operations or adversely affect our business and
financial conditions. This list is not exhaustive and these and
other risks are described in the Company’s periodic reports,
including the annual report on Form 10-K, quarterly reports on Form
10-Q and current reports on Form 8-K, filed with or furnished to
the Securities and Exchange Commission and available
at www.sec.gov. Any forward-looking statements that the
Company makes in this press release speak only as of the date of
this press release. The Company assumes no obligation to update
forward-looking statements whether as a result of new information,
future events or otherwise, after the date of this press
release.
Zynerba ContactWilliam Roberts,
Vice President, Investor Relations and Corporate
CommunicationsZynerba Pharmaceuticals484.581.7489
robertsw@zynerba.com
Media contactMolly DevlinEvoke
KYNE215.928.2199Molly.Devlin@evokegroup.com
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