Ovid Therapeutics Inc. announced positive topline results from its Phase 1 study of OV329, a next-generation GABA-aminotransferase (GABA-AT) inhibitor being developed for drug-resistant epilepsies. The trial demonstrated statistically significant inhibition of GABA-AT across multiple biomarker measures, with the 5 mg dose showing 53% inhibition (p=0.0001) as measured by long-interval intracortical inhibition (LICI) on the abductor pollicis brevis muscle.
Superior Efficacy Profile Compared to Current Standard
OV329's inhibition exceeded that of therapeutic doses of vigabatrin (VGB), the current first-generation GABA-AT inhibitor. Prior studies found therapeutic doses of VGB (2-3 g) delivered approximately 35% inhibition relative to untreated baselines, while OV329 at 5 mg demonstrated 53% change in inhibition relative to participants' untreated baseline on the APB muscle.
"The results from this study provide unequivocal evidence that support the advancement of OV329 into further studies in patients with epilepsy," said Alexander Rotenberg, MD, PhD, Director of Neuromodulation at Boston Children's Hospital and professor of neurology at Harvard Medical School. "These early data confirm that OV329 is getting into the brain and exerting concentration-dependent inhibition, as shown by the highly significant correlation between OV329 blood exposure and long-interval intracortical inhibition."
Comprehensive Biomarker Analysis Confirms Target Engagement
The Phase 1 trial evaluated OV329 in 68 healthy volunteers, including 51 participants receiving active treatment and 17 receiving placebo, across single and multiple ascending dose cohorts with doses ranging from 1 mg to 5 mg. The study employed extensive biomarker analyses using transcranial magnetic stimulation (TMS) measured with electromyography (EMG) to assess established measures for evaluating anti-seizure medicines.
OV329 demonstrated increases in the cortical silent period (CSP), an additional measure of inhibition. In the 5 mg cohort, the drug prolonged the CSP in the first dorsal interosseous muscle from 124.08 ms at baseline to 137.00 ms at Day 7 (mean 12.90 ms; p=0.00012), compared to placebo which showed minimal change from 105.11 ms to 107.72 ms (mean 2.60 ms; p=0.54).
Magnetic resonance spectroscopy (MRS) measurements showed mean GABA levels increased in the medial parietal lobe by 7.13% after 7 days of dosing OV329 at 5 mg, compared to 0.24% in placebo. Although not statistically significant due to baseline variability, the findings are consistent with OV329's intended mechanism of action.
Favorable Safety Profile Without Ocular Complications
OV329 demonstrated a favorable safety and tolerability profile with all potentially treatment-related adverse events reported as mild and transient. Treatment-related adverse events included headache and drowsiness in the 2 mg cohort, and metallic taste in the 5 mg cohort.
Notably, extensive ophthalmic testing revealed no evidence of retinal changes during dosing and through Day 30, representing 21-23 days post-last dose. This finding was anticipated from preclinical studies demonstrating that OV329 enters and rapidly clears the brain plasma and tissue within one hour, whereas vigabatrin preferentially partitions and accumulates in the retina.
"OV329 was designed to deliver the benefits of a novel GABA-AT inhibitor while avoiding the challenges of existing medicines," said Dr. Jeremy Levin, chairman and chief executive officer of Ovid Therapeutics. "Our Phase 1 trial generated first-in-human data, supported by what we believe is the most extensive biomarker program in early seizure drug development, showing consistent results across multiple validated measures and demonstrating a clean ocular and overall safety profile."
Clinical Development Timeline and Pipeline Updates
Ovid plans to initiate a Phase 2a randomized placebo-controlled study evaluating OV329 in adult patients with drug-resistant focal onset seizures in Q2 2026, with completion expected in mid-2027. The company also intends to characterize OV329's anti-convulsant profile in an open-label seizure study.
Simultaneously, Ovid is advancing its portfolio of potassium-chloride cotransporter 2 (KCC2) direct activators. OV350, an intravenous KCC2 direct activator, is currently being studied in healthy volunteers with topline safety, tolerability and pharmacokinetic data anticipated in Q4 2025. The company plans to file for regulatory clearance for OV4071, its first oral KCC2 development candidate, in Q1 2026 and initiate Phase 1/1b studies in Q2 2026.
Mechanism of Action and Therapeutic Potential
OV329 works by reducing the activity of GABA-AT, thereby increasing levels of GABA in the brain and potentially suppressing neuronal hyperexcitability known to cause seizures. Low levels of GABA, the primary inhibitory neurotransmitter in the brain, have been linked to neuronal hyperexcitability. The drug is being developed for rare and treatment-resistant forms of epilepsy and seizures, including seizures associated with status epilepticus, tuberous sclerosis complex, infantile spasms, and conditions with focal onset seizures.
