eNeuro Publishes Findings on the Anti-Convulsant Properties of OV329 and Its Potential Effectiveness in Treatment-Resistant Seizures

2024-07-12

Sustained exposure to OV329 in preclinical models reduced GABA-aminotransferase (GABA-AT) activity, increased steady state GABA levels in the brain, and induced phasic and tonic inhibition

OV329 demonstrated anti-convulsant effects in mice, reducing the severity of status epilepticus and preventing the development of benzodiazepine-resistant seizures

OV329 was shown to have a higher potency (as measured by IC50) for the GABA-AT target than published studies of vigabatrin, an FDA-approved GABA-AT inhibitor

July 10, 2024 -- Ovid Therapeutics Inc. (NASDAQ: OVID), a biopharmaceutical company dedicated to improving the lives of people affected by rare epilepsies and brain conditions, announced that eNeuro, a peer-reviewed, open-access journal from the Society for Neuroscience published several preclinical studies validating OV329’s mechanism of action and anti-convulsant properties.

OV329 is a rationally designed, next-generation GABA-AT inhibitor in development by Ovid for the potential treatment of drug-resistant seizures. OV329 is intended to have higher potency and preferable safety and dosing relative to the available medicine in this class. To support OV329’s clinical development, the preclinical studies published in eNeuro were conducted jointly by the Department of Neuroscience at Tufts University School of Medicine, the Department of Neuroscience, Physiology and Pharmacology at the University College London and Ovid.

“These preclinical studies provide further support that OV329 has a differentiated profile from prior anti-convulsant therapies and may have the potential to deliver robust and sustained seizure reduction,” said Zhong Zhong, Ph.D., Chief Scientific Officer of Ovid Therapeutics. “OV329 was designed for better selectivity and improved safety relative to established GABA-AT inhibitors. These encouraging results provide us with further confidence of what we may hope to see in patients with refractory seizures.”

PUBLICATION HIGHLIGHTS

Sustained exposure to low doses of OV329 delivered reduced GABA-AT activity and increased GABA accumulation in mouse brains. Mice treated with OV329 at 5 mg/kg every 24 hours for six days showed significantly reduced GABA-AT activity in the brain to 62.6 ± 4.4% of control (vehicle: 100.0 ± 2.7%; n=6 mice per experimental group; two tailed unpaired t-test). In parallel, treatment with OV329 significantly increased GABA levels to 134.0 ± 7.2% of control (vehicle: 100.0 ± 5.9%; n=6 mice per group; two-tailed unpaired t-test) as measured using liquid chromatography coupled with mass spectroscopy.

Repeat, low doses of OV329 delivered synaptic and extra synaptic inhibition in mice suggesting it may provide sustained anti-convulsant activity. Mice consistently treated with a low dose of 0.5 mg/kg of OV329 over six days were shown to experience phasic (synaptic) and tonic (extra synaptic) inhibition as compared to placebo. These findings, which were measured by electrophysiological recordings, may differentiate OV329 from other anti-convulsant medicines and suggest the potential to provide broad inhibitory neurotransmission.

Sustained doses of OV329 reduced the severity of status epilepticus (SE) and prevented development of benzodiazepine resistance in a mouse model with similarities to SE patients. In a kainic acid-induced SE mouse model, which has similarities to patients in a state of SE, electroencephalogram (EEG) recordings demonstrated that OV329 significantly reduced the EEG power of SE when compared with placebo (vehicle: 2.0 ± 0.3 times 10-6 V2 compared to OV329: 0.9 ± 0.2 times 10-6 V2; two-tailed Welch’s t test; p=0.005; N=6 mice). Additional findings using this benzodiazepine resistant model showed that mice pre-treated with OV329 were able to restore the anti-convulsant effects of diazepam.

OV329 was shown to have superior potency (as measured by IC50) to the GABA-AT target than published results for vigabatrin (VGB). OV239 had an IC50 of 104.1 nM for GABA-AT, while the published IC50 for VGB was 183.8 µM.

Collectively, the studies published in eNeuro reinforce prior findings, which suggest OV329 is a potent, highly selective GABA-AT inhibitor. OV329 appears to increase GABA levels in animal brains through both phasic and tonic inhibition, which indicates that it may have the potential to deliver sustained anti-seizure properties at very low doses in humans. Additionally, cumulative and single doses of OV329 have been shown to reduce the severity of SE and restore the effectiveness of diazepam in an acute benzodiazepine-resistant seizure mouse model.

The authors note that the safety profile of OV329 is believed to differentiate it from VGB, a previously approved GABA-AT inhibitor. VGB, has a known toxicity and is associated with visual field loss. The underlying mechanisms of VGB’s toxicity may result from the high daily dose, poor blood brain barrier permeability, low activation efficiency and possible off-target effects. OV329 was rationally designed to be more potent and specific with the desire to avert these safety challenges. Specifically, OV329 exhibits a marked increase (200 - 1000 fold) in potency for GABA-AT compared to VGB, it demonstrates the potential for faster tissue clearance than VGB but with a prolonged pharmacodynamic effect, and it does not irreversibly inhibit GABA-AT activity.

Full-text of the OV329 publication in eNeuro is available here.

About OV329

OV329 is a potential next-generation GABA-AT inhibitor being developed for the potential treatment of rare and treatment-resistant forms of epilepsy and seizures, such as seizures associated with status epilepticus, tuberous sclerosis complex, infantile spasms and conditions with focal onset seizures. Low levels of GABA, the primary inhibitory neurotransmitter in the brain, have been linked to neuronal hyperexcitability. OV329 is believed to work by reducing the activity of GABA-AT, thereby increasing levels of GABA in the brain, and potentially suppressing neuronal hyperexcitability known to cause seizures. OV329 may be a potential best-in-class GABA-AT inhibitor.

About Ovid Therapeutics

Ovid Therapeutics Inc. is a New York-based biopharmaceutical company that is dedicated to meaningfully improving the lives of people affected by certain epilepsies and brain conditions with seizure symptoms. The Company is advancing a pipeline of novel, targeted small molecule candidates that modulate the intrinsic and extrinsic factors involved in neuronal hyperexcitability causative of seizures and other neurological symptoms. Ovid is developing: OV888/GV101 capsule, a potent and highly selective Rho-associated coiled-coil containing protein kinase 2 inhibitor capsule, for the potential treatment of cerebral cavernous malformations and other rare central nervous system diseases; OV329, a GABA-AT inhibitor, a potential therapy for treatment-resistant seizures; and OV350, a direct activator of the KCC2 transporter, for the potential treatment of epilepsies and other psychiatric conditions. For more information about these and other Ovid research programs, please visit www.ovidrx.com.

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