Ovid Therapeutics Inc. (NASDAQ: OVID), a biopharmaceutical
company committed to developing medicines that transform the lives
of people with rare neurological diseases, today announced positive
topline results from the signal-finding Phase 2 ROCKET trial of
OV101 (gaboxadol), a novel delta (δ)-selective GABAA receptor
agonist, in males with Fragile X syndrome. Fragile X syndrome is
the most common inherited form of intellectual disability and
autism, with no approved therapies. In addition, Ovid today
provided preliminary findings from SKYROCKET, a non-drug
interventional study in Fragile X syndrome.
The ROCKET trial was a signal-finding, randomized, double-blind,
parallel-group trial to evaluate the safety, tolerability and
efficacy of OV101 in males ages 13 to 22 with a confirmed diagnosis
of Fragile X syndrome. The primary objective of the study was to
assess the safety and tolerability of OV101 over 12 weeks of
treatment in three different active dose arms. The secondary
objective was to evaluate changes in behavior after 12 weeks of
treatment. A total of 23 participants were randomized into the
study across three active-arm dose cohorts: OV101 5 mg once-daily
(QD), OV101 5 mg twice-daily (BID), and OV101 5 mg
three-times-daily (TID).
OV101 met its primary objective and appeared to be well
tolerated over 12 weeks of treatment with no serious adverse events
reported across all three dose cohorts. OV101 demonstrated a
statistically significant effect on secondary behavioral endpoints
in the three combined study groups as follows: 26.2% mean
improvement in the Aberrant Behavior Checklist-Community for
Fragile X syndrome (ABC-CFXS) total score from baseline to week 12
(p=0.002); and a 21.6% mean improvement in the Anxiety, Depression
and Mood Scale (ADAMS) total score from baseline to week 12
(p=0.004). Statistically significant improvements were also
observed across various ABC-CFXS and ADAMS subscales. In addition,
OV101 demonstrated a statistically significant mean reduction of
0.4 in the Clinical Global Impressions Severity scale (CGI-S) total
score (p=0.002) from baseline to week 12.
“The data from the ROCKET trial demonstrate that OV101 may have
a meaningful effect on improving the lives of some individuals
living with Fragile X syndrome,” said Dr. Elizabeth Berry-Kravis,
Professor of Pediatrics and Neurological Sciences and Co-Director
of the Molecular Diagnostics Section of the Genetic Laboratory at
Rush University Medical Center. “Fragile X is a challenging
neurodevelopmental genetic condition, with complex symptomatology
that significantly impacts patients and their families. I am
encouraged by the safety results of this Phase 2 study of OV101 and
am excited to further investigate its therapeutic potential in
patients living with Fragile X syndrome.”
“Developing treatment options in Fragile X syndrome has
historically been challenging, and there continues to be a high
unmet medical need,” said Amit Rakhit, M.D., MBA, President and
Chief Medical Officer of Ovid Therapeutics. “This was the first
interventional clinical study of OV101 in the Fragile X population,
and we are encouraged by the safety profile and the positive
efficacy signals we see across multiple behavior domains from this
small, active-arm study. Lower and middle dosing regimens appear to
be superior to the higher, three-times-daily dose, which is
consistent with the emerging profile of OV101. We are in the
process of further evaluating which specific dose to advance in
future studies, and we look forward to moving this program forward
to discussions with regulators to determine next steps for the
development of OV101 in the Fragile X indication.”
About the Phase 2 ROCKET TrialThe Phase 2
ROCKET trial was a signal-finding, randomized, double-blind,
parallel-group trial to evaluate the safety, tolerability and
efficacy of OV101 in males between ages 13 to 22 with a confirmed
diagnosis of Fragile X syndrome. There were no females included in
the study. The study randomized 23 participants across three
active-arm dose cohorts: OV101 5 mg once-daily (n=7), OV101 5 mg
twice-daily (n=8), and OV101 5 mg three-times-daily (n=8). The
majority of treated patients were Caucasian (87%), and the mean age
was 17 years. All participants in the study had a baseline CGI-S
score of ≥ 4, with a mean baseline CGI-S score of ≥5, as well as an
intelligence quotient (IQ) of <75, which corresponds to a
relatively more severely impaired population of individuals with
Fragile X syndrome. Three participants discontinued participation
in the study—one for an adverse event (increased agitation) in the
twice-daily arm, and two voluntarily withdrew for either
noncompliance with study drug (once-daily arm) or increased
agitation at study clinic visits (three-times-daily arm).
Compliance with the study drug was high (95%).
Primary Endpoint: Safety and TolerabilityThe
study met its primary endpoint of safety and tolerability, and
OV101 appeared to be well tolerated over 12 weeks of treatment
across all three dose cohorts. There were no serious adverse events
or deaths reported in the study. The most common adverse events
(AEs) included diarrhea (9%), irritability (9%), headache (13%),
and upper respiratory infections (18%), with the majority of AEs
reported as mild in severity (94%).
Topline Efficacy Endpoint ResultsThe secondary
objective of the study was to evaluate changes in behavior after 12
weeks of treatment with three different doses of OV101. Data from
the ABC-CFXS, ADAMS, CGI-S, and CGI-I rating scales are shown
below.
Aberrant Behavior Checklist-Community for Fragile X Syndrome
(ABC-CFXS):A statistically significant improvement in the
ABC-CFXS total score was observed from baseline to week 12 in
the combined study groups.
Table 1: Mean change (and standard deviation, SD) in ABC-CFXS
total score vs. baseline
|
Baseline (n=17)** |
Week 12 |
Change |
% Improvement (p value) |
Study Population (n=15)* |
65.7 (26.26) |
52.3 (30.42) |
-15.5 (15.52) |
26.2% (23.16) (p=0.0017) |
QD (n=4) |
80.5 (24.93) (n=4) |
60.5 (18.08) |
-20.0 (22.7) |
21.7% (23.25) (p=0.1763) |
BID (n=5) |
60.0 (34.26) (n=6) |
52.6 (44.01) |
-8.8 (6.57) |
24.5% (21.99) (p=0.0402) |
TID (n=6) |
62.1 (18.91) (n=7) |
46.7 (27.46) |
-18.2 (16.17) |
30.7% (27.33) (p=0.0402) |
*Sample size (n) was different in study population due to
patients who discontinue later in the study** Individuals with
minimal behavior symptoms as measured by the ABC-C scale (defined
as baseline ABC-C total score <=16) were prespecified to be
excluded from this planned analysis. Six individuals from the total
cohort of 23 patients met this exclusion criteria.
In the ABC-CFXS subscales, patients in the three combined
dose cohorts (n=15) showed statistically significant improvements
from baseline to week 12 in lethargy/social withdrawal (38%
improvement; p=0.001), hyperactivity (29% improvement; p=0.005),
stereotypic behavior (21% improvement; p=0.01), and irritability
(20% improvement; p=0.03) subscales. Percent change from baseline
to week 12 on social avoidance (12% improvement; p=0.2499) and
inappropriate speech (18% improvement; p=0.3216) subscales showed
improvements but were not statistically significant.
Anxiety, Depression and Mood Scale (ADAMS):A statistically
significant improvement in the mean ADAMS total score was observed
from baseline to week 12 in the combined study groups.
Table 2: Mean change (and standard deviation, SD) in ADAMS score
vs. baseline
|
Baseline (n=23) |
Week 12 |
Change |
% Change (p value) |
Study Population (n=20)* |
24.7 (12.07) |
18.3 (9.47) |
-7.0 (9.54) |
-21.6% (31.700) (p=0.0039) |
QD (n=6) |
28.4 (17.19)(n=7) |
20.7 (10.09) |
-10.5 (12.24) |
-22.6% (42.08) (p=0.0897) |
BID (n=7) |
20.1 (9.00)(n=8) |
15.4 (9.85) |
-4.1 (5.64) |
-18.9% (27.633) (p=0.1000) |
TID (n=7) |
26.1 (9.13)(n=8) |
19.0 (9.29) |
-6.9 (10.48) |
-23.3% (30.488) (p=0.1341) |
*Sample size (n) was different in baseline population due to
patients who discontinue later in the study
In the ADAMS subscales, patients also showed statistically
significant mean improvements (SD) from baseline to week 12 in
manic/hyperactive behavior (−1.7 (1.95); p=0.001), social avoidance
(−2.2 (3.47); p=0.01) and general anxiety (−2.5 (2.87); p=0.001)
subscales. Changes from baseline to week 12 on the compulsive
behavior (−0.6 (1.98); p=0.1921) and the depressed mood (−0.1
(2.69); p=0.8699) subscales were not statistically significant.
Clinical Global Impression Scale-Severity (CGI-S) and
Improvement (CGI-I): A statistically significant improvement
was observed in the mean (SD) CGI-S total score (−0.4 (0.50);
p=0.002) from baseline to week 12. In the CGI-S subscales,
statistically significant mean improvements were observed from
baseline to week 12 in the communication (−0.6 (0.68); p=0.001),
anxiety (−0.5 (0.76); p=0.008), attention deficit hyperactivity
disorder (−0.5 (0.83); p= 0.025), and activities of daily living
(−0.3 (0.57); p=0.03) domains. Change from baseline to week 12 on
the disruptive behavior (−0.7 (1.59); p=0.06) and repetitive and
restrictive behaviors (−0.2 (0.49); p=0.1864) subscales did not
reach statistical significance. Additionally, compared to the
baseline measurement, 60% of participants who received OV101 were
identified as CGI-I responders at week 12 (defined as improvement
in the CGI-I by a response of “2-Much Improved” (40%), or
“3-Minimally Improved” (20%).
SKYROCKETThe SKYROCKET trial was a
non-interventional study evaluating the appropriateness of multiple
scales used in Fragile X syndrome and was conducted in parallel to
the ROCKET study. The study enrolled 13 males ages 8 to 29 years
(mean age 17 years) with a confirmed diagnosis of Fragile X
syndrome.
The primary objective was to evaluate the suitability and
reliability of different scales for the assessment of behavior,
sleep, and functioning and also to determine which tools would be
the most appropriate for future interventional clinical efficacy
trials of individuals with Fragile X syndrome.
The participating clinicians and caregivers were aware that the
trial was non-interventional. The mean changes from baseline to
week 12 were evaluated in the ABC-C total and subscale scores, the
ADAMS subscale scores, and the CGI-S subscale scores, as well as
the mean change in CGI-I scores at week 12. Other exploratory
scales were also assessed. High variability was seen among
caregiver-administered assessments (ABC-C, ADAMS) compared to
clinician-assessed scales (CGI-I, CGI-S). The
caregiver-administered assessments showed a placebo response as
seen with previous Fragile X syndrome trials. In these other
trials, placebo response rates were highly
variable. Therefore, the SKYROCKET trial data will help inform
future study design, including potential endpoints and measures to
mitigate placebo response.
Next StepsBased on the results reported today,
Ovid Therapeutics believes that OV101 has the potential to
represent a compelling new therapeutic option for individuals with
Fragile X syndrome. Given the lack of an approved medication and
the high unmet need in Fragile X syndrome, the Company plans to
request meetings with regulatory authorities to discuss the
development path and registration pathway for OV101 for the
treatment of Fragile X syndrome.
About the Aberrant Behavior Checklist-Community Scale
for FXS (ABC-CFXS)The Aberrant Behavior
Checklist-Community for FXS (ABC-CFXS) is a scale used to measure
caregiver assessment of maladaptive behavior. Factor analytic
examination of the Aberrant Behavior Checklist-Community (ABC-C)
within a Fragile X syndrome (FXS) population yields a 6-factor
solution consisting of the following maladaptive behavior domains:
social avoidance, stereotypic behavior, lethargy/social withdrawal,
irritability, hyperactivity, and inappropriate speech. Items are
rated on a 4-point Likert scale ranging from 0 “not a problem at
all” to 3 “the problem is severe in degree.”
About the Anxiety, Depression, and Mood Scale
(ADAMS)The Anxiety, Depression, and Mood Scale (ADAMS) is
a factor-derived measure of anxiety and mood symptoms that has been
validated in individuals with FXS. Caregivers are asked to rate the
frequency and severity of 28 items on a scale of 0 “not a problem”
to 3 “severe problem.” The ADAMS produces a total score and 5
subscale scores: manic/hyperactive behavior, depressed mood, social
avoidance, general anxiety, and obsessive/compulsive behavior.
About the Clinical Global Impression Scale-Severity
(CGI-S) and Improvement (CGI-I)The CGI was developed for
clinicians in clinical trials to assess a patients’ global
functioning before and after an intervention. At baseline,
clinicians rate the severity of the patient’s current symptoms
(CGI-S), while during the study, clinicians assess the CGI-S, as
well as how much the patient’s illness has changed (improved or
worsened) relative to the baseline state (CGI-I) using 7-point
Likert-type scales. The CGI-S in the ROCKET/SKYROCKET trials has
been adapted to capture specific characteristics commonly present
in the FXS population, including the subdomains of anxiety, ADHD,
communication/connectedness, repetitive and restrictive behavior,
disruptive behavior, and activities of daily living. Lower scores
on the CGI-S reflect better functioning (less severe), while lower
scores on the CGI-I reflect greater improvements in symptoms. The
CGI is well-validated and correlates with other standardized
measures of psychiatric severity.
About Fragile X SyndromeFragile X syndrome is
the most common inherited form of intellectual disability and
autism, with a prevalence of 1 in 3,600 to 4,000 males and 1 in
4,000 to 6,000 females in the United States. Individuals with
Fragile X syndrome often have a range of behavioral challenges,
such as cognitive impairment, anxiety, mood swings, hyperactivity,
attention deficit, poor sleep, self-injury and heightened
sensitivity to various stimuli, such as sound. Additionally,
individuals with Fragile X syndrome are prone to comorbid medical
issues including seizures and sleep disturbance. Fragile X syndrome
results from mutations in the FMR1 gene, which blocks expression of
the Fragile X Mental Retardation Protein (FMRP), an important
protein in GABA synthesis. There are no FDA-approved therapies for
Fragile X syndrome, and treatment primarily consists of behavioral
interventions and pharmacologic management of symptoms.
In studies of individuals with Fragile X syndrome and
experimental models, extrasynaptic GABA levels are abnormally
reduced, and there is also dysregulation of GABA receptors. This
ultimately contributes to a decrease in tonic inhibition, causing
the brain to become inundated with signals and lose the ability to
separate background noise from critical information.
About OV101 (gaboxadol)OV101 is believed to be
the only delta (δ)-selective GABAA receptor agonist in development
and the first investigational drug to specifically target the
disruption of tonic inhibition, a central physiological process of
the brain that is thought to be the underlying cause of certain
neurodevelopmental disorders. OV101 has been demonstrated in
laboratory studies and animal models to selectively activate the
δ-subunit of GABAA receptors, which are found in the extrasynaptic
space (outside of the synapse), and thereby impact neuronal
activity through modulation of tonic inhibition.
Ovid is developing OV101 for the treatment of Angelman syndrome
and Fragile X syndrome to potentially restore tonic inhibition and
thereby address several core symptoms of these disorders. In both
these syndromes, the underlying pathophysiology includes disruption
of tonic inhibition modulated through the δ-subunit of GABAA
receptors. In preclinical studies, it was observed that OV101
improved symptoms of Angelman syndrome and Fragile X syndrome. This
compound has also previously been tested in more than 4,000
patients (more than 1,000 patient-years of exposure) and was
observed to have favorable safety and bioavailability profiles.
Ovid is conducting a pivotal Phase 3 clinical trial with OV101 in
Angelman syndrome (NEPTUNE) and has completed a Phase 2
signal-finding clinical trial with OV101 in Fragile X syndrome
(ROCKET).
The FDA has granted Orphan Drug and Fast Track designations for
OV101 for both the treatment of Angelman syndrome and Fragile X
syndrome. The European Commission (EC) has granted orphan drug
designation to OV101 for the treatment of Angelman syndrome. The
U.S. Patent and Trademark Office has granted Ovid patents directed
to methods of treating Angelman syndrome and Fragile X syndrome
using OV101. The issued patents expire in 2035 without regulatory
extensions.
About Ovid TherapeuticsOvid Therapeutics Inc.
is a New York-based biopharmaceutical company using its
BoldMedicine® approach to develop medicines that transform the
lives of patients with rare neurological disorders. Ovid has a
broad pipeline of potential first-in-class medicines. The Company’s
most advanced investigational medicine, OV101 (gaboxadol), is
currently in clinical development for the treatment of Angelman
syndrome and Fragile X syndrome. Ovid is also developing OV935
(soticlestat) in collaboration with Takeda Pharmaceutical Company
Limited for the potential treatment of rare developmental and
epileptic encephalopathies (DEE). For more information on Ovid,
please visit http://www.ovidrx.com/.
Forward-Looking Statements This press release
includes certain disclosures that contain “forward-looking
statements,” including, without limitation, statements regarding:
advancing and commercializing Ovid’s product candidates, progress,
timing, scope and the development and potential
benefits of Ovid’s product candidates; and the
anticipated reporting schedule of clinical data regarding Ovid’s
product candidates. You can identify forward-looking statements
because they contain words such as
“will,” “appears,” “believes” and “expects.”
Forward-looking statements are based on Ovid’s current expectations
and assumptions. Because forward-looking statements relate to the
future, they are subject to inherent uncertainties, risks and
changes in circumstances that may differ materially from those
contemplated by the forward-looking statements, which are neither
statements of historical fact nor guarantees or assurances of
future performance. Important factors that could cause actual
results to differ materially from those in the forward-looking
statements include uncertainties in the development and
regulatory approval processes, and the fact that initial
data from clinical trials may not be indicative, and are not
guarantees, of the final results of the clinical trials and are
subject to the risk that one or more of the clinical outcomes may
materially change as patient enrollment continues and/or more
patient data become available. Additional risks that could cause
actual results to differ materially from those in the
forward-looking statements are set forth in Ovid’s filings with
the Securities and Exchange Commission under the caption
“Risk Factors”. Such risks may be amplified by the COVID-19
pandemic and its potential impact on Ovid’s business and
the global economy. Ovid assumes no obligation to update
any forward-looking statements contained herein to reflect any
change in expectations, even as new information becomes
available.
Contacts
Investors and Media:Ovid Therapeutics
Inc.Investor Relations & Public Relationsirpr@ovidrx.com
Or
Investors: Steve KlassBurns McClellan,
Inc.sklass@burnsmc.com (212) 213-0006
Media: Katie Engleman 1AB katie@1abmedia.com
(919) 333-7722
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