Abstracts

Rationale: Padsevonil (PSL; UCB0942) is an investigational, dual-acting antiepileptic drug showing high and moderate binding affinity to synaptic vesicle 2 proteins and the benzodiazepine site of the GABAA receptor, respectively. Here, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of PSL evaluated in 2 first-in-human studies with healthy volunteers. Methods: Single (N01360) and multiple (N01386) rising oral doses were administered in 2 randomized, placebo-controlled trials to healthy male and female volunteers. In N01360, two alternating panels of 8 individuals received the following doses or matching placebo (6:2), orally after an overnight fast: 10, 30, 100, 200, 350, 490mg. In N01386, 4 successive groups of 12 individuals received PSL at 100, 200, 300, and 400mg or matched placebo (10:2) as single, then twice daily doses for 12 days. Drug concentrations (PSL and its metabolites) were determined after single dose and at the end of treatment. Safety monitoring included vital signs, adverse events (AEs), ECGs (12-lead, Holter and telemetry), and clinical laboratory tests. Potential CNS effects were explored using a range of cognitive and motor performance tests (choice reaction time, digit vigilance, immediate and delayed word recall, saccadic eye movement, Karolinska sleepiness scale, pharmaco-EEG, ARCI-49 questionnaire, Bond and Lader visual analogue rating scale). Results: Single doses of 10 to 490mg and multiple doses of 100, 200, 300, and 400mg of PSL were generally well tolerated. Transient, self-limiting CNS AEs (fatigue, somnolence, dizziness) occurred with increasing intensity at higher doses but attenuated with repeated doses. One serious AE – delirium, occurring 2 days after full treatment period – was attributed to study drug. One individual withdrew due to AE (fatigue). Transient cardiac rhythm disturbances were noted in 3 individuals (not attributed to study drug after independent cardiologist assessment). The PK profile for PSL demonstrated high interindividual variability. After single dose, Cmax and AUC values for both parent and metabolites increased linearly with dose and a biphasic disposition with a terminal elimination half-life of ~6h was noted. Parent renal excretion was negligible. The apparent clearance of PSL decreased after repeat dosing, resulting in an increase in exposure. Steady state was reached after 2-3 days of dosing. There were no adverse findings on clinical examination/labs. The maximum tolerated dose of PSL was 800mg/day. At the highest doses (≥400mg/day), transient reductions were seen in memory, alertness, psychomotor performance, and vigilance (consistent with a GABAA-mediated effect in addition to sustained SV2A effects), that attenuated with repeated dosing. Conclusions: PSL was generally well tolerated in healthy volunteers. Effects on performance were generally consistent with those of CNS drugs with GABAergic and SV2 activity. The safety, tolerability, and PK profile of PSL supports the intended bid dosing regimen required for evaluation of efficacy in Phase II trials. Funding: UCB Pharma-sponsored.