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
Abstract number :
2.451
Submission category :
2. Translational Research / 2A. Human Studies
Year :
2025
Submission ID :
1363
Source :
www.aesnet.org
Presentation date :
12/7/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Julia Tsai, PhD – Ovid Therapeutics, Inc
Alexander Rotenberg, MD, PhD – Boston Children’s Hospital, Harvard Medical School
Nigel C Rogasch, PhD – University of Adelaide
Wei-Yeh Liao, PhD – University of Adelaide
Shruti Raja, MD, MHS – Duke Early Phase Research Unit, Duke University School of Medicine
Matthew Jung, BA – Ovid Therapeutics, Inc
Amanda Yaari, BA – Ovid Therapeutics, Inc
Amanda Banks, MD – Ovid Therapeutics, Inc
Rationale: GABA-amino transferase (GABA-AT) catabolizes GABA, the primary inhibitory neurotransmitter in the adult CNS. OV329 is a highly potent investigational GABA-AT inhibitor with the potential to be a next-generation antiseizure drug. OV329 elevates GABA levels, thereby enhancing inhibitory neurotransmission to suppress treatment-resistant seizures in 9 animal models. A Phase 1 ascending, single and multiple dose(s), double-blind, randomized, placebo-controlled study was conducted to assess the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamic (PD) activity of OV329 in healthy adults.
Methods: 68 healthy participants (42 male, 26 female) were enrolled at 3 sites in the U.S. and Australia into one of 4 single ascending dose (SAD) cohorts or 3 multiple ascending dose (MAD) cohorts. Participants in SAD cohorts received one dose of oral OV329 or placebo and were followed for 3 days in-patient and returned on Day 7 for follow up. Participants in the MAD cohorts received one dose of OV329 or placebo daily for 7 days, remained in-patient until Day 9, and returned for follow up on Days 14 and 30. Safety assessments included adverse events (AEs), vital signs, physical/neurological exams, electrocardiograms (ECGs), laboratory tests, ophthalmologic assessments (including visual acuity, visual field perimetry, optical coherence tomography, and fundus photography), and the Columbia Suicide Severity Rating Scale (CSSRS). Blood and urine PK samples were obtained. Exploratory biomarkers assessed potential PD effects, including transcranial magnetic stimulation (TMS) metrics that were previously used to study a 1st-generation GABA-AT inhibitor, vigabatrin (VGB).
Results: OV329 was safe and well-tolerated at all doses. No clinically significant changes in vitals, physical/neurological exam, ECGs, laboratory, or CSSRS results were deemed related to study drug. There were no clinically significant changes in ophthalmologic parameters. Treatment emergent AEs possibly related to study drug were mild or moderate in severity and included headache, drowsiness and metallic taste. OV329 serum concentration increased predictably from 1 to 5 mg with Tmax at 1 hr and steady state achieved by Day 3. Paired-pulse TMS-derived biomarkers indicated selective concentration-dependent increases in long-interval intracortical inhibition (LICI) after 3 mg and 5 mg dosing of OV329 (p< 0.05)
Translational Research