OV101, also gaboxadol or THIP, is an investigational therapy that Ovid Therapeutics is developing to treat Angelman syndrome and fragile X syndrome.

OV101 is an oral small molecule derived from a compound called muscimol, which is found naturally in a mushroom (Amanita muscaria).

The U.S. Food and Drug Administration (FDA) granted OV101 orphan drug designation in September 2016 to treat Angelman syndrome. The agency extended this designation to treat fragile X syndrome in October 2017. The FDA further granted OV101 rare pediatric disease designation in June 2020.

How does OV101 work?

OV101 is an oral medication that selectively activates GABA receptors that are located on the surface of nerve cells outside the synapse. A synapse is a narrow space between two nerve cells where they communicate via chemical messengers called neurotransmitters.

GABA is a neurotransmitter that acts on two types of receptors: synaptic receptors (between two nerve cells) and extra-synaptic receptors (away from the nerve cell terminal). OV101 binds specifically to the extra-synaptic GABA receptors.

GABA mainly dampens excessive neuronal activity, a process called tonic inhibition. Tonic inhibition is important because it allows the brain to correctly recognize excitatory and inhibitory neurological signals without being overloaded.

Disruption of tonic inhibition is thought to be the underlying cause of neurodevelopmental disorders such as Angelman and fragile X syndromes. These disorders mainly involve abnormally reduced levels of extra-synaptic GABA that ultimately lower tonic inhibition. This causes the brain to become overloaded with signals and thus lose the ability to differentiate important information from background noise.

Researchers hope that the selective binding of OV101 to the extra-synaptic GABA receptors will restore tonic inhibition. In preclinical studies, OV101 improved symptoms of both Angelman and fragile X syndromes.

OV101 in clinical trials

Ovid successfully completed a Phase 1 clinical trial (NCT03109756) that enrolled seven boys and five girls, ages 13 to 17, with either Angelman or fragile X syndrome. This open-label, single-arm, single-dose study evaluated the safety, tolerability, and pharmacokinetics (movement in the body) of OV101.

The results showed that the pharmacokinetic profile of OV101 in adolescents with Angelman and fragile X syndrome was similar to that observed in young adults. They also demonstrated that the treatment was generally safe and patients tolerated it well.

Those encouraging results led to the inclusion of adolescents in the Phase 2 STARS trial (NCT02996305). This randomized, double-blind, placebo-controlled trial enrolled 78 participants, ages 13 to 49 years, with a confirmed diagnosis of Angelman syndrome. Results showed that OV101 improved sleep, motor function, and communication abilities, while reducing anxiety. The results also indicated that OV101 is generally safe. Most adverse events (side effects) were mild, and there were no differences between treatment groups.

Researchers are further evaluating OV101 in the Phase 3 clinical trial (NCT04106557) called NEPTUNE. The trial is recruiting up to 95 children (ages 2–12 years) with Angelman syndrome in the U.S., Australia, Germany, Israel, and the Netherlands. Participants are randomly receiving either OV101 or a placebo by mouth once per day for 12 weeks. It is scheduled to be complete in December 2020.

Additional information

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


Last updated: June 24, 2020


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