Abstracts

Rationale: Padsevonil (PSL; UCB0942) is an antiepileptic drug candidate that combines high affinity synaptic vesicle 2A binding with partial agonism at the benzodiazepine site of the GABAA receptor (Wood et al., AES 2017). Activity across 10 preclinical animal models indicated broad-spectrum efficacy of PSL, with full seizure protection seen in the amygdala kindling model at concentrations corresponding to clinical doses (Kaminski et al., AES 2017). We evaluated efficacy, safety, and tolerability of adjunctive PSL in adults with drug-resistant focal seizures. Methods: A double-blind, placebo (PBO)-controlled, phase II trial (EP0069; NCT02495844) was conducted in adults (≥18 years) with uncontrolled, frequent focal seizures (≥4 observable seizures/week), who had failed to attain seizure-control on ≥4 antiepileptic drug (AED) regimens, and were on stable dose of ≥1 AED. After 2-week prospective baseline, patients were randomized (1:1) to PSL/PBO and entered 3-week double-blind inpatient period (Figure). In the PSL arm, treatment was initiated at 100 mg/day and doses were up-titrated to 800mg/day (400mg bid) over 1 week, followed by a 2-week inpatient maintenance. In the PBO arm, 2-week maintenance was followed by up-titration to 800mg/day PSL in week 3. All patients continued on PSL in an 8-week open-label outpatient period. Primary efficacy outcome was 75% responder rate (≥75% reduction in seizure frequency) from 2-week baseline to 2-week inpatient maintenance. The first secondary efficacy outcome was median reduction in seizure frequency. Safety outcomes included treatment-emergent adverse events (TEAEs) with PSL (pooled for PSL arm and PBO arm [week 3 onwards]). Results: 55 patients were randomized (PSL: 28; PBO: 27). The median weekly focal seizure frequency at baseline was 8.24 (Table). During the 2-week inpatient maintenance, 8/26 (30.8%) patients on PSL vs 3/27 (11.1%) on PBO were ≥75% responders (odds ratio: 4.14; p=0.0679). Median percent reduction in weekly focal seizure frequency was 53.7% with PSL vs 12.5% with PBO (median difference: 34.0; 95% CI: 3.0, 67.5). Two patients on PSL and 1 on PBO were seizure-free. Two patients discontinued PSL; 1 due to AEs (dysphoria & mood swings) and 1 due to other reasons (non-drug related medical reasons). 53/55 patients continued to outpatient period (open-label PSL treatment); 3 discontinued due to lack of efficacy and 50 completed the trial. During the last 4 weeks of outpatient PSL treatment, 16/51 (31.4%) patients were ≥75% responders. Median percent reduction in weekly focal seizure was 55.2% (n=51). No patients were seizure-free. Overall, 50/55 (90.9%) reported TEAEs with PSL, most commonly somnolence (25 [45.5%]), dizziness (24 [43.6%]), and headache (14 [25.5%]). Two patients (3.6%) had serious TEAEs (status epilepticus [n=1]; impaired judgment, delirium, dysphoria [n=1]) and 18 (32.7%) had TEAEs that required a dose change. Conclusions: A meaningful reduction in seizure frequency was observed with PSL vs PBO in adults with drug-resistant focal seizures. Funding: UCB Pharma-sponsored.