RESUMO
OBJECTIVE: To characterize efficacy, safety/tolerability, and pharmacokinetics of padsevonil (PSL) administered concomitantly with ≤3 antiseizure medications (ASMs) for observable focal seizures in adults with drug-resistant epilepsy in two multicenter, randomized, double-blind, placebo-controlled, parallel-group trials. METHODS: The phase 2b dose-finding trial (EP0091/NCT03373383) randomized patients 1:1:1:1:1 to PSL 50/100/200/400 mg or placebo twice daily (b.i.d.). The phase 3 efficacy trial (EP0092/NCT03739840) randomized patients 1:1:1:1 to PSL 100/200/400 mg or placebo b.i.d. Patients with observable (focal aware with motor symptoms, focal impaired awareness, focal to bilateral tonic-clonic) focal seizures for ≥3 years, experiencing them ≥4 times per 28 days including during the 4-week baseline period despite treatment with ≥4 lifetime ASMs including current ASMs, were enrolled. RESULTS: In EP0091 and EP0092, 410 and 231 patients, respectively, were randomized and received at least one dose of trial medication. In patients in EP0091 on PSL 50/100/200/400 mg b.i.d. (n = 80/82/81/81, respectively) versus placebo (n = 81), outcomes included percentage reductions over placebo in observable focal seizure frequency during the 12-week maintenance period: 17.2%, 19.1% (p = 0.128), 19.2% (p = 0.128), 12.4% (p = 0.248); 75% responder rates (p-values for odds ratios): 13.8%, 12.2% (p = 0.192), 11.1% (p = 0.192), 16.0% (p = 0.124) versus 6.2%; 50% responder rates: 33.8% (p = 0.045), 31.7% (p = 0.079), 25.9% (p = 0.338), 32.1% (p = 0.087), versus 21.0%; TEAEs were reported by 82.7% (67/81), 78.3% (65/83), 74.4% (61/82), 90.1% (73/81) versus 78.3% (65/83). In patients in EP0092 on PSL 100/200/400 mg b.i.d. (n = 60/56/56, respectively) versus placebo (n = 54), outcomes included percentage reductions over placebo: -5.6% (p = 0.687), 6.5% (p = 0.687), 6.3% (p = 0.687); 75% responder rates: 15.3% (p = 0.989), 12.5% (p = 0.989), 14.3% (p = 0.989) versus 13.0%; 50% responder rates: 35.6% (p = 0.425), 33.9% (p = 0.625), and 42.9% (p = 0.125) versus 27.8%; TEAEs were reported by 80.0% (48/60), 78.9% (45/57), 83.1% (49/59) versus 67.3% (37/55). SIGNIFICANCE: In both trials, the primary outcomes did not reach statistical significance in any PSL dose group compared with placebo. PSL was generally well tolerated, and no new safety signals were identified.
