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

The treatment is an oral small molecule derived from a compound called muscimol, which is found naturally in a mushroom named Amanita muscaria.

The U.S. Food and Drug Administration (FDA) granted OV101 orphan drug designation in September 2016 to treat Angelman syndrome, and then extended the designation to fragile X syndrome in October 2017. OV101 was given a rare pediatric disease designation in June 2020.

How does OV101 work?

OV101 is a medication that selectively activates GABA receptors present 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.

Researchers think that the disruption of tonic inhibition is 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 in animal models 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 in young adults. The treatment was found to be generally safe, with patients tolerating it well.

Those encouraging results led to the inclusion of patients in the Phase 2 STARS trial (NCT02996305). This randomized, double-blind, placebo-controlled trial enrolled 78 participants, ages 13 to 49, with a 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 side effects were mild, and there were no differences between treatment groups.

Researchers further evaluated OV101 in a Phase 3 clinical trial (NCT04106557) called NEPTUNE. The trial recruited 97 patients, 4 to 12 years of age, and seven children, ages 2 to 3, with Angelman syndrome in the U.S., Australia, Germany, Israel, and the Netherlands. Researchers randomly assigned participants to either OV101 or a placebo once per day for 12 weeks. Ovid announced in December 2020 that the trial did not meet its primary goal of showing a difference between the treatment group and placebo group in changes in score on the clinical global impression-improvement-Angelman syndrome (CGI-I-AS) scale. The treatment group showed a 0.7 point improvement on the scale while the placebo group showed a 0.8 point improvement. Researchers are still analyzing the secondary goals of the trial. They will discuss the final results with the FDA to determine the next steps for OV101.

Ongoing clinical trials

The company said it will still continue to offer OV101 to patients enrolled in its open-label extension trial called ELARA (NCT03882918). ELARA is still recruiting participants in the U.S. and Israel. Researchers expect to have results from this trial in the first quarter of 2021.

Additional information

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


Last updated: Dec. 14, 2020


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