Trial data support Ovid’s decision to stop its OV101 program in 2021

Ovid licensed OV101 to Healx in 2022 for testing in other diseases

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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OV101 (gaboxadol) fails to ease disease severity in children with Angelman syndrome (AS), according to recently published final results from the Phase 3 NEPTUNE trial.

The findings are overall consistent with previously reported top-line trial data from the treatment’s developer Ovid Therapeutics, which prompted the company to stop clinical development of OV101 in 2021.

Full trial results have now been published in the European Journal of Paediatric Neurology in a study, titled Gaboxadol in angelman syndrome: A double-blind, parallel-group, randomized placebo-controlled phase 3 study.”

Angelman patients exhibit symptoms of significant neurological dysfunction, including intellectual disability, speech impairments, movement problems, sleep disturbances, behavioral issues, and seizures.

Research indicates that these symptoms could arise from a lack of tonic inhibition in the brain, which, simply put, means nerve cells may become overactive and prone to firing when they shouldn’t.

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OV101 designed to activate subtype of GABA receptors in brain

OV101 was designed to activate a subtype of gamma-aminobutyric acid (GABA) receptors in the brain. These proteins mediate the effects of the inhibitory signaling molecule GABA, thus boosting tonic inhibition.

After being found to ease core symptoms of Angelman among children and adolescents in the Phase 2 STARS trial (NCT02996305), the global Phase 3 NEPTUNE trial (NCT04106557) was launched in 2019.

It enrolled 97 Angelman patients, ages 4-12, who were randomly assigned to receive a weight-based dose of oral OV101 or a placebo once daily for 12 weeks, or about three months. The treatment was taken as an oral capsule or sprinkled on semi-liquid food for patients who could not swallow the capsule whole.

An additional seven children, ages 2-3, received OV101 and were included in safety, but not efficacy, analyses.

The main goal was to assess changes on the Clinical Global Impression Improvement Angelman Syndrome (CGI-I-AS) scale after 12 weeks. The test is a seven-point scale that assesses six key areas affected in Angelman: expressive communication, receptive communication, fine and gross motor skills, behavior, and sleep.

A score of four on this scale indicates no change in disease severity with treatment, whereas decreasing scores indicate improvements and increasing scores reflect worsening symptoms.

Secondary goals included evaluating the proportion of patients with a CGI-I-AS of three or less, indicating at least a minimal improvement, and a score of two or less, which reflects much improvement.

On average, children were either moderately or markedly impaired at the study’s start.

No difference was observed in CGI-I-AS scores between the two groups after 12 weeks, with a mean score of 3.2 in the placebo group and 3.3 in the OV101 group, meaning that the trial failed to meet its main goal. By week 12, the most frequently reported score in either group was four, indicating no change in disease severity.

Likewise, no difference was observed in the proportion of responders with minimal improved status, occurring in 55% of the placebo group and 49% of the OV101 group, or much improved, seen in 27% of the placebo group and 26% of those given OV101.

No treatment efficacy was seen across a range of other clinical measures of disease severity.

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OV101 generally found to be safe across all ages

OV101 was generally found to be safe across all ages, with a similar profile as in previous reports.

Researchers cited high clinical response rates in the placebo group as one possible reason that the trial failed to meet its goal.

“Future AS development programs must anticipate placebo response rates and consider participant stratification based on clinical symptoms of interest, biomarkers, and more objective clinical outcome assessments to increase the likelihood of detecting treatment effects,” the team wrote.

Moreover, “questions remain as to the potential benefit of gaboxadol among specific subgroups with AS in light of benefits seen in the STARS trial but not in NEPTUNE,” the researchers added.

Ovid was also previously developing OV101 for fragile X syndrome, another neurodevelopmental disease. That clinical program was stopped simultaneously with the Angelman program.

More recently, Ovid licensed the therapy to Healx, which plans to develop it as part of a combination therapy for fragile X and other indications. It has not been reported whether Angelman will be one of those indications.