Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy: Results from two double-blind, randomized, placebo-controlled trials

Michael Rademacher, Manuel Toledo, Wim Van Paesschen, Kore K Liow, Ivan G Milanov, Maria-Luise Esch, Nan Wang, Merran MacPherson, William J Byrnes, Timothy D C Minh, Elizabeth Webster, Konrad J Werhahn, Michael Rademacher, Manuel Toledo, Wim Van Paesschen, Kore K Liow, Ivan G Milanov, Maria-Luise Esch, Nan Wang, Merran MacPherson, William J Byrnes, Timothy D C Minh, Elizabeth Webster, Konrad J Werhahn

Abstract

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.

Keywords: antiepileptic drug; antiseizure medication; dual mechanism of action; focal seizure; synaptic vesicle protein 2; tolerability.

Conflict of interest statement

Michael Rademacher has received consultancy fees for reviewing the clinical study reports of these trials and participation in investigator meetings from UCB Pharma. Manuel Toledo has received grants and consultation honoraria from Arvelle Therapeutics, BIAL, Eisai, Esteve, Exeltis, GW Pharmaceuticals, Sanofi, and UCB Pharma. Wim Van Paesschen has received consultancy fees for participation in advisory boards for UCB Pharma. Kore K. Liow has received research support from Acadia, Aquestive Therapeutics, Biogen, Cerevel Therapeutics, Eisai, Engage Therapeutics, Idorsia, LivaNova, NeuroDerm, Novartis, SK Life Science, UCB Pharma, and Xenon Pharmaceuticals. Ivan G. Milanov has no conflicts of interest to disclose. Nan Wang was an employee of UCB Pharma at the time this trial was conducted and is currently affiliated with TechData Service Company LLC. Elizabeth Webster was an employee of UCB Pharma at the time this trial was conducted. Maria‐Luise Esch, Merran MacPherson, William J. Byrnes, Timothy D. C. Minh, and Konrad J. Werhahn are salaried employees of UCB Pharma and receive stock or stock options from their employment. Funding for writing support was provided by UCB Pharma.

© 2022 UCB BioSciences GmbH. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1
FIGURE 1
Efficacy outcomes of patients randomized to placebo or PSL by randomized dose group for observable focal seizures over the 12‐week maintenance period in the dose‐finding trial (EP0091; full analysis set): (A) change from baseline in log‐transformed observable focal seizure frequency as percentage reductions over placebo; (B) 75% responder rate; (C) 50% responder rate; (D) median percentage reduction from baseline in focal seizures per 28 days. For the primary outcomes (percentage reductions over placebo in observable focal seizure frequency and 75% responder rates), statistical comparison of the PSL 50 mg b.i.d. dose group to placebo was provided only if the other three higher doses were significant. ASM, antiseizure medication; b.i.d., twice daily; PSL, padsevonil.
FIGURE 2
FIGURE 2
Efficacy outcomes of patients randomized to placebo or PSL by randomized dose group for observable focal seizures over the 12‐week maintenance period in the phase 3 efficacy trial (EP0092; full analysis set): (A) change from baseline in log‐transformed observable focal seizure frequency as percentage reductions over placebo; (B) 75% responder rate; (C) 50% responder rate; (D) median percentage reduction from baseline in focal seizures per 28 days. ASM, antiseizure medication; b.i.d., twice daily; PSL, padsevonil.

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