eNeuro Reports on OV329's Anti-Convulsant Properties for Treatment-Resistant Seizures

Ovid Therapeutics Inc., a biopharmaceutical company focused on rare epilepsies and brain conditions, announced that the peer-reviewed journal eNeuro has published several preclinical studies validating the efficacy and mechanism of action of their new drug candidate, OV329. This drug is a next-generation GABA-aminotransferase (GABA-AT) inhibitor that shows promising potential in treating drug-resistant seizures.

OV329 has been designed to offer higher potency and improved safety compared to existing GABA-AT inhibitors. The studies, conducted collaboratively by scientists from Tufts University School of Medicine, University College London, and Ovid, reveal significant findings supporting OV329's clinical potential. According to Dr. Zhong Zhong, Chief Scientific Officer of Ovid Therapeutics, these studies indicate that OV329 has a differentiated profile and could provide robust and sustained seizure reduction.

In preclinical trials, sustained exposure to OV329 led to reduced GABA-AT activity and increased GABA levels in the brains of mice. Specifically, mice treated with OV329 at a dose of 5 mg/kg every 24 hours for six days exhibited significantly reduced GABA-AT activity in the brain, reaching 62.6% of control levels. Simultaneously, GABA levels increased to 134% of control levels, as measured using liquid chromatography and mass spectrometry.

Additionally, low doses of OV329 were shown to induce both synaptic and extra-synaptic inhibition in mice, suggesting the drug's potential for sustained anti-convulsant activity. Mice given 0.5 mg/kg of OV329 over six days experienced phasic (synaptic) and tonic (extra-synaptic) inhibition, differentiating OV329 from other anti-convulsant medications by providing broad inhibitory neurotransmission.

The studies also demonstrated that OV329 could reduce the severity of status epilepticus (SE) and prevent the development of benzodiazepine-resistant seizures. In a mouse model induced with kainic acid to mimic SE, OV329 significantly lowered the electroencephalogram (EEG) power of SE compared to placebo. Mice pre-treated with OV329 were able to restore the anti-convulsant effects of diazepam, a benzodiazepine, showcasing the drug's potential in treating benzodiazepine-resistant seizures.

Notably, OV329 was found to have superior potency for the GABA-AT target than vigabatrin (VGB), an FDA-approved GABA-AT inhibitor. OV329's IC50 for GABA-AT was 104.1 nM, considerably lower than VGB’s published IC50 of 183.8 µM, indicating higher potency.

These findings reinforce previous research suggesting that OV329 is a potent, highly selective GABA-AT inhibitor. By increasing GABA levels in animal brains through both phasic and tonic inhibition, OV329 shows the potential to provide sustained anti-seizure properties at low doses in human patients. Moreover, the drug has been shown to reduce the severity of SE and restore diazepam efficacy in an acute benzodiazepine-resistant seizure model.

OV329's safety profile also appears to differentiate it from VGB, which is associated with significant toxicity and visual field loss. VGB's toxicity is believed to stem from high daily doses, poor blood-brain barrier permeability, low activation efficiency, and possible off-target effects. OV329 was designed to be more potent and specific, aiming to avoid these safety issues. It demonstrates higher potency for GABA-AT, faster tissue clearance, a prolonged pharmacodynamic effect, and does not irreversibly inhibit GABA-AT activity.

Overall, OV329 represents a promising new therapeutic candidate for treating rare and treatment-resistant forms of epilepsy and seizures. By reducing GABA-AT activity and increasing GABA levels in the brain, OV329 has the potential to suppress neuronal hyperexcitability and provide effective seizure control.