Ovid Therapeutics Announces Positive Topline Results from the Phase 2 ROCKET Trial of OV101 for the Treatment of Fragile X Syndrome
- OV101 met the study’s primary objective of safety and tolerability
- OV101 produced statistically significant reductions in behavioral and functional symptoms in individuals with Fragile X syndrome
- Results support the continued development of OV101 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 (
“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.
“Developing treatment options in Fragile X syndrome has historically been challenging, and there continues to be a high unmet medical need,” said
About the Phase 2 ROCKET Trial
The 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 Tolerability
The 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 Results
The 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,
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)
|60.5 (18.08)||-20.0 (22.7)||21.7% (23.25) (p=0.1763)|
|BID (n=5)||60.0 (34.26)
|52.6 (44.01)||-8.8 (6.57)||24.5% (21.99) (p=0.0402)|
|TID (n=6)||62.1 (18.91)
|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 (
A statistically significant improvement in the mean
Table 2: Mean change (and standard deviation, SD) in
|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)
|20.7 (10.09)||-10.5 (12.24)||-22.6% (42.08) (p=0.0897)|
|BID (n=7)||20.1 (9.00)
|15.4 (9.85)||-4.1 (5.64)||-18.9% (27.633) (p=0.1000)|
|TID (n=7)||26.1 (9.13)
|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
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%).
The 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
Based on the results reported today,
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 (
The Anxiety, Depression, and Mood Scale (
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 Syndrome
Fragile 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
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.
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Source: Ovid Therapeutics Inc.