Ovid Therapeutics' Pre-Clinical Study Shows OV329 Doesn't Accumulate in Animal Eyes Unlike Vigabatrin

A recent study by Ovid Therapeutics Inc. has shown significant findings regarding OV329, a next-generation anti-seizure medication. Unlike vigabatrin (VGB), the only FDA-approved GABA-aminotransferase (GABA-AT) inhibitor, OV329 did not accumulate in mouse retinas, eyes, or brain tissues. This was observed after 48 hours of continuous exposure, suggesting OV329’s potential for better ocular safety.

Presented at the Epilepsy Pipeline Conference, the study replicated previous research indicating VGB’s rapid accumulation in mouse tissues, including the retina and brain, even at subtherapeutic doses. On the contrary, OV329, administered at therapeutic doses, showed no signs of such accumulation. These findings align with previous studies where OV329 did not cause retinal tissue pathology in animal models, whereas VGB led to retinal cell degradation.

Dr. Zhong Zhong, Chief Scientific Officer of Ovid Therapeutics, emphasized that OV329’s features—potency, rapid tissue clearance, and a prolonged pharmacodynamic effect—may enable it to provide an anticonvulsant effect at safer, non-sedative doses without the ocular side effects associated with VGB. OV329 is designed to inhibit GABA-AT efficiently and clear the tissue quickly, reducing the risk of ocular toxicity.

The study employed continuous infusion via a subcutaneous osmotic pump in mice, with OV329 tested at 5 mg/kg/day compared to 80 mg/kg/day for VGB. OV329 concentrations in target tissues were either below the quantification limit or undetectable, reinforcing its ability to clear from the body without accumulating. VGB, on the other hand, was confirmed to accumulate in the eye at sub-therapeutic doses and was linked to ocular toxicity at therapeutic levels in humans.

OV329’s short half-life of 1.5 hours and quick tissue elimination properties contribute to its reduced risk of ocular accumulation. Previous studies have shown VGB’s tendency to accumulate in the retina, visual cortex, and brain with significant retina/plasma ratios. Moreover, VGB's active S-(+) enantiomer preferentially accumulates in tissues, indicating potential off-target effects.

Ovid Therapeutics is on track to complete a Phase 1 trial of OV329 in healthy volunteers by late 2024. This trial will evaluate safety and include biomarkers for target engagement and evidence of clinical effect using magnetic resonance spectrometry and transcranial magnetic stimulation.

OV329 is being developed for treating rare and resistant forms of epilepsy and seizures, including those associated with tuberous sclerosis complex and infantile spasms. By inhibiting GABA-AT, OV329 increases levels of GABA, the brain's inhibitory neurotransmitter, thereby reducing neuronal hyperexcitability and suppressing seizures.

OV329 aims to improve upon VGB, which is limited by a Black Box warning for causing irreversible bilateral peripheral visual field constriction in some patients. OV329 has shown to be significantly more potent than VGB and possesses favorable tissue clearance characteristics while delivering prolonged effects, potentially strengthening inhibitory neurotransmission.

Ovid Therapeutics is a biopharmaceutical company dedicated to improving the lives of individuals affected by rare epilepsies and brain conditions. The company is advancing a pipeline of novel, targeted small molecule candidates addressing neuronal hyperexcitability and other neurological symptoms. Key projects include OV888/GV101, a ROCK2 inhibitor for cerebral cavernous malformations, OV329 for treatment-resistant seizures, and OV350 for epilepsy and psychiatric conditions.