OV101 Demonstrates Efficacy in CGI-I Measurements for Angelman Syndrome


The once-daily 15-mg dose resulted in a significant 12-week improvement for patients with the rare condition.

Dr Rob Thibert

Ron Thibert, DO, MsPH, chairperson, STARS clinical trial steering committee, director, Angelman syndrome clinic at MassGeneral Hospital for Children, and an assistant professor at Harvard Medical School

Ron Thibert, DO, MsPH

Ovid Therapeutics has announced that the phase II trial of its investigational therapy for Angelman syndrome, OV101 (Gaboxadol), has achieved its prespecified endpoint.

The randomized, double-blind, placebo-controlled trial revealed a robust improvement in the once-daily arm compared to control in the first efficacy endpoint of the physician-rated clinical global impressions of improvement (CGI-I) measurement (P = .0006). The positive topline results of the STARS trial will be presented by Matthew During, MD, DSc, at the 2018 Angelman Syndrome Foundation/Duplication15q Research Symposium in Chapel Hill, North Carolina.

“We are excited by these data, as this is the first demonstration of [a] positive clinical effect on overall symptomology in Angelman syndrome,” said Jeremy Levin, DPhil, MB, BChir, chairman and chief executive officer of Ovid Therapeutics, in a statement. “In collaboration with the Angelman community, we designed a robust study to evaluate prespecified endpoints that may pave the way for a registrational pathway for a disorder that has no previously approved medicines. These data are a tribute to the patients and their families, and we thank them.”

The trial included 88 patients with Angelman syndrome and randomized them to 3 groups: 2 intervention arms in which patients received either a once-daily dose of OV101 (n = 27) or a twice-daily dose of OV101 (n = 28), and a control arm in which patients received placebo (n = 27). After 12 weeks, 66.7% (n = 38) of the therapy-treated patients overall improved in CGI-I measurements, compared to 39.3% (n = 11) in the control group (P = .0206).

The mean change CGI-I symptoms score at week 12 was 3.00 in the once-daily arm, 3.58 in the twice-daily arm, and 3.79 in the placebo arm. The twice-daily group was not statistically significant (P = .3446), but both the once-daily (P = .0006) and the pooled treatment groups (P = .0103) were, compared to placebo.

In a post-hoc analysis of patients who were “much” or “minimally” improved—denoted by a CGI-I score of ≤3—the data suggest that in comparison with older age groups, younger patients who received a once-daily dose had the greatest response to OV101. In total, 83% of those aged 13-17 years and 18-24 years met that mark in the once-daily group compared to 29% and 58%, respectively, with placebo. Of those aged 25-49, 70% met those criteria in the treatment group, compared to 22% with placebo.

Additionally, Ovid announced that data on a prespecified subset of scales across behavior, sleep, and gait were also conducted, which did not show significant differences from placebo. These data will be relayed at a later point, according to the company.

In terms of safety, the therapy was well-tolerated. The most common adverse events (AEs), occurring in ≥5% of patients, with OV101 were vomiting (once-daily, 17.2%; twice daily, 17.2%), somnolence (once-daily, 17.2%; twice daily, 10.3%), irritability (once-daily, 10.3%; twice daily, 17.2%), aggression (once-daily, 13.8%; twice daily, 3.4%), and pyrexia (once-daily, 24.1%; twice daily, 3.4%). Compared to placebo, pyrexia, rash, seizure, enuresis, and myoclonic epilepsy occurred more often with OV101.

Serious AEs of seizure were reported in 2 patients: 1 in the once-daily OV101 arm, and 1 in the twice-daily arm. The former was deemed as unassociated with the study drug, while the latter was noted by investigators as possibly related.

“These initial data from the STARS study are encouraging, particularly the statistically significant improvement in overall symptoms that we see in the CGI-I scale in the once-daily dosing group. Angelman syndrome is a complex disorder, and the CGI-I scale captures the totality of global neurological deficits and helps to define the impact of medicines on the individual and their families,” said Ron Thibert, DO, MsPH, chairperson, STARS clinical trial steering committee, director, Angelman syndrome clinic at MassGeneral Hospital for Children, and an assistant professor at Harvard Medical School, in a statement.

Thibert added that the data are the first to reveal a compound that specifically targets Angelman syndrome having a clinical effect, and that Ovid Therapeutics is the first company to conduct a double-blind, placebo-controlled study for the condition, which Thibert said provided “important clinical and scientific data.”

“Based on these data, I believe OV101 has the potential to offer a clinically meaningful benefit specific to people living with Angelman syndrome,” Thibert said.

The therapy targets impaired tonic inhibition, which is most commonly caused by a UBE3A genetic disruption. Currently, no therapies are approved by the FDA for Angelman syndrome.

A discussion with regulatory agencies is planned to determine the next registrational pathway steps. Later this year, Ovid is planning an open-label extension trial, ELARA, which will enroll patients who participated in prior trials of OV101 for 1-year, using once-daily dosing to assess long-term safety and tolerability, with some efficacy measures.

“The STARS study was designed to provide information to allow us to progress the development of OV101,” said Amit Rakhit, M.D., MBA, chief medical and portfolio management officer of Ovid Therapeutics. “With these findings, we have advanced our understanding of relevant endpoints to evaluate key symptoms of Angelman syndrome. Furthermore, we demonstrated that a once-daily dose of OV101 could be sufficient to drive clinically meaningful benefit to patients. We look forward to discussing the data with regulatory authorities to inform our future development plans.”


Ovid Therapeutics Announces Positive Topline Data from Phase 2 STARS Trial of OV101 for the Treatment of Angelman Syndrome [press release]. New York: Ovid Therapeutics; August 6, 2018. globenewswire.com/news-release/2018/08/06/1547345/0/en/Ovid-Therapeutics-Announces-Positive-Topline-Data-from-Phase-2-STARS-Trial-of-OV101-for-the-Treatment-of-Angelman-Syndrome.html. Accessed August 6, 2018.

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