OV101, also called gaboxadol or THIP, is an investigational therapy developed by Ovid Therapeutics to treat Angelman syndrome and Fragile X syndrome.

OV101 is a small molecule derived from a compound called muscimol, which is naturally found 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. In October 2017, the FDA extended this designation to treat Fragile X syndrome as well. Ovid also received two U.S. patents (expiring in 2035) for methods of treating Angelman syndrome using OV101.

How OV101 works

It is an oral medication that selectively activates GABA receptors that are located on the surface of nerve cells outside the synapse. A synapse is the 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 the nerves) and extra-synaptic receptors (away from the nerve terminal). OV101 binds specifically to the extrasynaptic GABA receptors.

GABA mainly dampens excessive neuronal activity, a process called tonic inhibition. Tonic inhibition is important since it allows a healthy human 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 extrasynaptic 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.

The selective binding of OV101 to the extrasynaptic GABA receptors restores tonic inhibition.

In preclinical studies, researchers observed that 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, who had been diagnosed with either Angelman or Fragile X syndrome. This open-label, single-arm, single dose study was designed to evaluate the safety, tolerabilit, and pharmacokinetics 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 OV101 was generally safe and well-tolerated.

These encouraging results led to the inclusion of adolescents in an ongoing Phase 2 study (NCT02996305) called the STARS trial, which aims to enroll about 75 patients, ages 13 to 49 years, with a confirmed diagnosis of Angelman syndrome. The randomized, double-blind, placebo-controlled trial aims to assess the safety and tolerability of OV101 as well as its effects on motor skills, maladaptive behavior, sleep and quality of life. The trial will recruit patients in the United States and Israel, and is expected to finish by November 2018.


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