Core Insights - Ovid Therapeutics Inc. announced positive topline results from its Phase 1 study of OV329, a next-generation GABA-aminotransferase inhibitor aimed at treating drug-resistant epilepsies, demonstrating a favorable safety and tolerability profile [1][2][6] Trial Design - The Phase 1 trial involved 68 healthy volunteers, with 51 receiving active treatment and 17 receiving placebo, testing doses from 1 mg to 5 mg [3] - Safety, tolerability, pharmacokinetic, and pharmacodynamic activities were assessed, including rigorous ophthalmic evaluations and extensive exploratory biomarker analyses [3][4] Biomarker and Efficacy Results - OV329 showed significant GABAergic inhibition, with a 53% increase in inhibition at the 5 mg dose as measured on the abductor pollicis brevis muscle [8] - The study confirmed OV329's ability to penetrate the brain and engage its target, achieving biological modulation consistent with elevated GABA levels [4][8] - After 7 days of dosing at 5 mg, mean GABA levels increased by 7.13% in the medial parietal lobe compared to 0.24% in placebo [8] Safety and Tolerability - The safety profile of OV329 was favorable, with all treatment-related adverse events reported as mild and transient, and no evidence of ophthalmic or retinal changes observed [6][9] - Extensive ophthalmic tests showed no adverse effects, contrasting with existing treatments like vigabatrin, which can accumulate in the retina [6] Future Development Plans - Ovid plans to advance OV329 into a Phase 2a study for drug-resistant focal onset seizures, expected to start in Q2 2026 [10] - The company is also progressing its KCC2 direct activator portfolio, with several regulatory and clinical milestones anticipated in the next 12 months [10][11]

OV329 Program & Clinical Development - OV329 is a next-generation GABA-aminotransferase inhibitor being developed for neuronal hyperexcitability and seizures[27] - Phase 1 topline results for OV329, including biomarker data, are expected in Q3 2025[20, 16] - A Phase 2a trial in patients with focal-onset seizures is planned to start in Q1 2026, with topline results expected in Q1 2027[20] - Phase 1 trial includes single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, with a total of 64 participants (48 receiving active treatment)[90] Biomarker Strategy - The OV329 Phase 1 trial incorporates a comprehensive biomarker strategy using magnetic resonance spectroscopy (MRS), transcranial magnetic stimulation (TMS), and electroencephalogram (EEG) to assess target engagement and pharmacodynamic effects[43, 45] - MRS will measure GABA concentrations in the medial parietal lobe to validate target engagement[45] - TMS will assess cortical excitability and brain circuit function, with metrics like cortical silent period (CSP) and paired-pulse long-interval intracortical inhibition (LICI)[45] - EEG will measure brain waves linked to inhibitory (GABAergic) activity, focusing on high and low frequencies[45] - Targeted directional changes in TMS biomarkers are anticipated, with increases in CSP and LICI, consistent with the effects of therapeutic vigabatrin[74] Market Opportunity - The company estimates a >$1 billion market opportunity for OV329 in drug-resistant epilepsy (DRE), targeting 65,000 adults with focal onset seizures and a price of $16,000 per year[38] - There is a substantial opportunity within the developmental epileptic encephalopathies (DEE) segment, with a potential market of ~20,000 patients and an average price of $60,000 per year, representing a >$1 billion market[116] Safety & Tolerability - In the Phase 1 trial, no treatment-related adverse events (AEs) or serious adverse events (SAEs) were observed in 30 treated participants, with headache being the most common AE[95, 94] - Comprehensive ocular safety metrics in Phase 1 showed no vision or ocular findings associated with OV329 treatment[96] - Preclinical studies show OV329 does not accumulate in the retina, unlike vigabatrin, suggesting a differentiated safety profile[107, 109]