Seletracetam Revisited: A Missed Opportunity for Effective Epilepsy Therapy

Seletracetam (SEL) is a second-generation racetam derivative of the benchmark antiseizure medication (ASM) levetiracetam, discovered in a drug discovery program conducted by UCB Pharma in the early 2000s to optimize binding to synaptic vesicle glycoprotein 2A (SV2A), the main target of levetiracetam. SEL (administered orally) reached phase IIa clinical trials, but its further development was stopped, and its patent expired in 2021. In preclinical studies, SEL showed very potent seizure suppression in several acquired and genetic epilepsy models, with high CNS tolerability. Phase I human studies indicated rapid and extensive oral absorption (> 90% bioavailability), linear pharmacokinetics, and an elimination half-life of about 8 h, with mostly mild to moderate CNS adverse events. Several phase IIa trials found SEL to be effective and to have a good safety profile in patients with photosensitive epilepsy and drug-resistant focal epilepsy. A unique aspect of SEL is its high potency and water solubility that-unlike any other non-benzodiazepine (non-BDZ) ASMs-allows it to be formulated at therapeutic doses in a very low liquid volume suitable for intranasal administration and potential use in acute seizure rescue therapy. The US-based company PrevEp, Inc. (Bethesda, MD) filed a new US patent application in 2024, followed by a worldwide Patent Cooperation Treaty (PCT) application in 2025 on intranasal and orobuccal SEL formulations and new medical uses as the first potential non-BDZ rescue treatment of acute repetitive seizures and rapid epileptic seizure termination (REST). The clinical development of this novel formulation is derisked by the favorable oral SEL administration phase I and phase IIa clinical data. SEL offers several important advantages for rescue treatment in comparison with BZDs. It is only moderately sedative even at the highest doses tested orally, does not cause respiratory depression, and has no addictive potential. Thus, SEL has the potential to become the first non-BDZ acute rescue therapy. Because SEL has never been approved for use in humans, it is a new chemical entity (NCE). In this review, we describe the pharmacology of SEL, its clinical profile after oral administration, and the development of the new intranasal formulation, including first-in-human data.