GABA-AT Inhibitor OV329 Shows Safety, Preliminary Target Engagement in Phase 1 Study

A recently presented phase 1 single-ascending (SAD) and multiple-ascending dose (MAD) trial, Ovid Therapeutics’ OV329, a potent next generation GABA-amino transferase (AT) inhibitor, was considered well tolerated and safe, with effects seen on GABA-mediated transcranial magnetic stimulation (TMS) measures of cortical inhibition. The drug is expected to be tested in a phase 2a randomized, placebo-controlled trial in adults with drug-resistant focal onset seizures in Q2 of 2026.

OV329 is a selective inhibitor of GABA-AT, the enzyme responsible for GABA breakdown, and by blocking GABA-AT it increases brain GABA levels to reduce neuronal hyperexcitability and suppress seizures—a mechanism that may position it as a best-in-class therapy. The phase 1 study, a double-blind, placebo-controlled trial, featured 68 healthy adults across 3 sites in the U.S. and Australia testing 4 SAD cohorts or 3 MAD cohorts of OV329.

Presented at the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9 in Atlanta, Georgia, OV329 was shown to be safe and well-tolerated at all doses, with no clinically significant changes in vitals, physical/neurological exam, ECGs, or laboratory findings. Led by Amanda Banks, chief development officer at Ovid, there were no clinically significant ophthalmologic changes, and treatment-emergent AEs possibly related to the study drug were mild or moderate, including headache, drowsiness, and metallic taste.

OV329 showed predictable serum exposure across the 1–5 mg dose range, reaching peak levels at 1 hour and achieving steady state by Day 3. TMS-based biomarkers demonstrated dose-dependent increases in long-interval intracortical inhibition at 3 mg and 5 mg (P < 0.05), mirroring the inhibitory profile seen with vigabatrin, and the cortical silent period was similarly prolonged in these cohorts after accounting for random effects (P < 0.05). In contrast, short-interval intracortical inhibition, a GABA_A-mediated measure typically unaffected by vigabatrin, remained unchanged with OV329.

Biomarker Data

Nearly 2 months before the AES presentation, Ovid announced positive data from the phase 1 study, including insights into the biomarker, safety, and tolerability results. Here, data revealed that OV329 produced robust GABAergic inhibition across multiple TMS biomarkers, with the 5-mg dose yielding a 53% increase in long-interval intracortical inhibition (LICI 150 ms; P = 0.0001) in the APB muscle and a 44.3% increase in the FDI, while placebo showed no meaningful change.

Overall, the magnitude of inhibition exceeded that reported for therapeutic doses of vigabatrin (2–3 g), which produce roughly 35% LICI increases, underscoring OV329’s potent engagement of cortical inhibitory circuits. OV329 also significantly prolonged the cortical silent period in both the FDI (mean +12.9 ms; P = 0.00012) and APB (mean +7.88 ms; P = 0.026), whereas placebo showed minimal change, further reinforcing the drug’s strong inhibitory neurophysiologic signature.

Consistent with these electrophysiologic findings, OV329 at 5 mg increased medial parietal GABA concentrations by 7.13% after 7 days of dosing, compared with 0.24% in the placebo group, aligning with the drug’s mechanism of enhancing cortical GABAergic tone despite baseline variability limiting statistical significance. Exploratory EEG analyses also showed shifts in brainwave activity suggestive of increased inhibition, supporting OV329’s emerging profile as a potent modulator of GABAergic pathways.

Looking Forward

Ovid is currently engaging sites and regulators, with the intention to launch a phase 2a randomized, placebo-controlled trial evaluating OV329 in adult patients with drug-resistant focal onset seizures in Q2 2026. While that study waits completion in 2027, the company also is putting on another open-label seizure trial to further characterize OV329’s anti-convulsant profile.

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REFERENCES
1. Tsai J, Rotenberg A, Rogasch NC, et al. OV329, a Potent Next Generation GABA-AT Inhibitor, is Well-tolerated and Produces GABA-ergic Cortical Inhibition in a Phase 1 SAD/MAD Study in Healthy Volunteers. Presented at: 2025 AES Annual Meeting; December 5-9; Atlanta, Georgia. Abstract 2.451.
2. OV329 and GABA-aminotransferase inhibition. Ovid Therapeutics. Accessed December 7, 2025. https://ovidrx.com/our-science/programs/ov329/
3. Ovid announces positive topline results for the next-generation GABA-aminotransferase inhibitor, OV329, that demonstrate strong inhibitory activity and a potential best-in-category safety profile. News release. October 3, 2025. Accessed December 7, 2025. https://investors.ovidrx.com/news/news-details/2025/Ovid-announces-positive-topline-results-for-the-next-generation-GABA-aminotransferase-inhibitor-OV329-that-demonstrate-strong-inhibitory-activity-and-a-potential-best-in-category-safety-profile/default.aspx