OV101 (gaboxadol or THIP) is a small molecule, orally available, developed by Ovid Therapeutics. It was being investigated as a potential therapy for Angelman syndrome and fragile X syndrome, the most common genetic cause of inherited intellectual disability and autism spectrum disorders.

Due to a lack of efficacy shown in an Angelman’s Phase 3 clinical trial, the company decided to discontinue OV101’s development for both conditions.

How does OV101 work?

OV101 is a small molecule derived from muscimol, a compound naturally present in a mushroom named Amanita muscaria.

It works by selectively activating GABA receptors at the surface of nerve cells, specifically those located outside synapses (extra-synaptic). Synapses are the point of contact between two nerve cells where they communicate via chemical messengers called neurotransmitters.

GABA is a neurotransmitter that mainly dampens excessive neuronal activity, a process called tonic inhibition, which is essential to prevent the brain from becoming overloaded with signals and losing its ability to distinguish important information from background noise.

People with Angelman and fragile X syndromes typically show abnormally low levels of extra-synaptic GABA that ultimately reduce tonic inhibition. As such, disrupted tonic inhibition is thought to be the underlying cause of these neurodevelopmental disorders.

By selectively activating extra-synaptic GABA receptors, OV101 is expected to restore tonic inhibition, ultimately reducing symptoms of Angelman and fragile X.

This was supported by preclinical studies showing that the experimental therapy lessened symptoms in animal models of both Angelman and fragile X syndromes.

OV101 in clinical trials

Ovid successfully completed an open-label Phase 1 clinical trial (NCT03109756), which evaluated OV101’s safety, tolerability, and pharmacokinetics in seven boys and five girls, ages 13 to 17, with either Angelman or fragile X syndrome. (Pharmacokinetics refers to the therapy’s movement into, through, and out of the body.)

Data showed that the pharmacokinetic profile of OV101 in adolescents with Angelman and fragile X syndrome was similar to that in young adults, and that the therapy was generally safe, with patients tolerating it well.

These encouraging results led to the launch of a placebo-controlled Phase 2 trial, called STARS (NCT02996305), in 78 adolescents and adults, ages 13 to 49, with Angelman’s.

Participants were assigned randomly to receive either OV101 once daily (15 mg at night), OV101 twice daily (10 mg in the morning and 15 mg at night), or a placebo twice a day, for 12 weeks.

Results showed that OV101 significantly improved patients’ sleep, motor function, and communication abilities while reducing anxiety. The therapy was generally safe, with most side effects being mild, and with no group differences in adverse rates.

The international Phase 3 NEPTUNE trial (NCT04106557) was designed to further evaluate OV101’s safety and effectiveness in a larger Angelman’s patient population. The trial recruited 104 children (97 ages 4–12 years, and seven ages 2–3) with Angelman syndrome in the U.S., Australia, Germany, Israel, and the Netherlands. Researchers assigned the children randomly to either OV101 or a placebo once a day for three months.

In December 2020, Ovid announced that NEPTUNE failed to meet its main goal of showing that OV101 was significantly superior to placebo at generally improving patients’ conditions, as assessed with the Clinical Global Impression-Improvement Angelman syndrome (CGI-I-AS) scale. CGI-I-AS is a seven-point scale that assesses patients’ changes across five key areas, specifically communication, fine and gross motor skills, behavior, and sleep.

Top-line data showed that OV101-treated children had a 0.7-point improvement on the scale, compared with a 0.8-point improvement in those given a placebo. Results of the trial’s secondary goals, which included changes in sleep, communication, motor function, socialization, daily living skills, and behavior, have not been disclosed.

The therapy was reported to be generally well-tolerated during the trial, with no significant safety issues.

Based on those Phase 3 results, Ovid decided to fully stop the development of OV101 for both Angelman and fragile X syndromes.

An open-label extension trial, called ELARA (NCT03882918), evaluating the therapy’s long-term effects in patients who participated in the previous Phase 1 or 2 trials of OV101, is likely to have stopped, as evidenced by the status in the trial’s page.

Additional information

The U.S. Food and Drug Administration (FDA) granted OV101 orphan drug designation in September 2016 for treating Angelman syndrome, and then extended the designation to fragile X syndrome in October 2017. The therapy also received FDA’s rare pediatric disease designation in June 2020.

Ovid received two U.S. patents (expiring in 2035) for methods of treating Angelman syndrome using OV101.


Last updated: May 7, 2021


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