Efficacy and safety of adjunctive padsevonil in adults with drug‐resistant focal epilepsy: Results from two double‐blind, randomized, placebo‐controlled trials
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‐cont...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-12-01
|
| Series: | Epilepsia Open |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/epi4.12656 |
| _version_ | 1797987968075431936 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Michael Rademacher |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T07:56:31Z |
| format | Article |
| id | doaj.art-f7b64484d7ee4361b1b24f205981fd0f |
| institution | Directory Open Access Journal |
| issn | 2470-9239 |
| language | English |
| last_indexed | 2024-04-11T07:56:31Z |
| publishDate | 2022-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Epilepsia Open |
| spelling | doaj.art-f7b64484d7ee4361b1b24f205981fd0f2022-12-22T04:35:55ZengWileyEpilepsia Open2470-92392022-12-017475877010.1002/epi4.12656Efficacy and safety of adjunctive padsevonil in adults with drug‐resistant focal epilepsy: Results from two double‐blind, randomized, placebo‐controlled trialsMichael Rademacher0Manuel Toledo1Wim Van Paesschen2Kore K. Liow3Ivan G. Milanov4Maria‐Luise Esch5Nan Wang6Merran MacPherson7William J. Byrnes8Timothy D. C. Minh9Elizabeth Webster10Konrad J. Werhahn11Department of Epileptology University of Bonn Medical Center Bonn GermanyEpilepsy Unit, Neurology Department Vall d'Hebron University Hospital Barcelona SpainDepartment of Neurology University Hospitals Leuven Leuven BelgiumComprehensive Epilepsy Center Hawaii Pacific Neuroscience Honolulu Hawaii USAMedical University of Sofia Sofia BulgariaUCB Pharma Monheim am Rhein GermanyUCB Pharma Morrisville North Carolina USAUCB Pharma Slough UKUCB Pharma Morrisville North Carolina USAUCB Pharma Morrisville North Carolina USAUCB Pharma Morrisville North Carolina USAUCB Pharma Monheim am Rhein GermanyAbstract 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.https://doi.org/10.1002/epi4.12656antiepileptic drugantiseizure medicationdual mechanism of actionfocal seizuresynaptic vesicle protein 2tolerability |
| spellingShingle | 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 Efficacy and safety of adjunctive padsevonil in adults with drug‐resistant focal epilepsy: Results from two double‐blind, randomized, placebo‐controlled trials Epilepsia Open antiepileptic drug antiseizure medication dual mechanism of action focal seizure synaptic vesicle protein 2 tolerability |
| title | Efficacy and safety of adjunctive padsevonil in adults with drug‐resistant focal epilepsy: Results from two double‐blind, randomized, placebo‐controlled trials |
| title_full | Efficacy and safety of adjunctive padsevonil in adults with drug‐resistant focal epilepsy: Results from two double‐blind, randomized, placebo‐controlled trials |
| title_fullStr | Efficacy and safety of adjunctive padsevonil in adults with drug‐resistant focal epilepsy: Results from two double‐blind, randomized, placebo‐controlled trials |
| title_full_unstemmed | Efficacy and safety of adjunctive padsevonil in adults with drug‐resistant focal epilepsy: Results from two double‐blind, randomized, placebo‐controlled trials |
| title_short | Efficacy and safety of adjunctive padsevonil in adults with drug‐resistant focal epilepsy: Results from two double‐blind, randomized, placebo‐controlled trials |
| title_sort | efficacy and safety of adjunctive padsevonil in adults with drug resistant focal epilepsy results from two double blind randomized placebo controlled trials |
| topic | antiepileptic drug antiseizure medication dual mechanism of action focal seizure synaptic vesicle protein 2 tolerability |
| url | https://doi.org/10.1002/epi4.12656 |
| work_keys_str_mv | AT michaelrademacher efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials AT manueltoledo efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials AT wimvanpaesschen efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials AT korekliow efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials AT ivangmilanov efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials AT marialuiseesch efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials AT nanwang efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials AT merranmacpherson efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials AT williamjbyrnes efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials AT timothydcminh efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials AT elizabethwebster efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials AT konradjwerhahn efficacyandsafetyofadjunctivepadsevonilinadultswithdrugresistantfocalepilepsyresultsfromtwodoubleblindrandomizedplacebocontrolledtrials |