OV329 and GABA-aminotransferase inhibition
overview
OV329 is a next-generation GABA-aminotransferase (GABA-AT) inhibitor being developed as a potential medicine for rare and treatment-resistant forms of epilepsy and seizures. Ovid believes OV329 is significantly more potent than prior GABA-AT inhibitors which may confer seizure reduction efficacy, enhanced safety, and lower dosing.
mechanism of action
γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain and is primarily catabolized by the enzyme GABA aminotransferase (GABA-AT). Low levels of GABA in the brain have been linked to neuronal hyperexcitability, which can lead to seizures. OV329 inhibits GABA-AT activity, thereby increasing GABA levels in the brain, resulting in suppression of neuronal hyperexcitability associated with seizures. OV329 may be a best-in-class GABA-AT inhibitor that could offer enhanced efficacy with an improved benefit-risk profile.
development
OV329 is currently in a Phase 1 study with healthy volunteers to evaluate the safety, pharmacokinetic profile and target engagement associated with single and repeated oral doses of OV329. The Phase 1 study will measure two potential biomarkers for target engagement via magnetic resonance spectroscopy (MRS) and transcranial magnetic stimulation (TMS). Ovid is also exploring acute treatment options with a potential IV formulation of OV329.
Prior evaluation of OV329 in preclinical seizure and epilepsy models indicate that OV329 significantly reduced focal and generalized seizures, including pharmaco-resistant seizure phenotypes. Improvement in seizure outcomes could be achieved with repeated, low dosing which have correlated with increases in brain GABA levels and tonic inhibitory neuronal signaling.
For additional information on OV329 non-clinical data, please click here.
potential indications
Initial clinical development may include tuberous sclerosis complex (TSC), infantile spasms (IS), status epilepticus, and/ or other focal seizure related disorders. See below to learn about tuberous sclerosis complex and infantile spasms.
Tuberous sclerosis complex (TSC) is a genetic disease that can be inherited from one parent with TSC or can result from a spontaneous genetic mutation
TSC can cause tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin, and lungs. The aspects of TSC that most strongly impact quality of life are generally associated with the brain: seizures, developmental delay, intellectual disability, and autism spectrum disorder
One of the earliest forms of epilepsy that can occur in those diagnosed with TSC is infantile spasms. Infantile spasms can begin anytime in the first 2 years, but often peak between 4 and 6 months of age. They occur in 1 in 2,000 children from many different causes and in up to 35% of children with TSC1
Reference: 1. Tuberous Sclerosis Alliance. Accessed February 18, 2021. https://www.tsalliance.org