Open‐label study to investigate the safety and efficacy of adjunctive perampanel in pediatric patients (4 to <12 years) with inadequately controlled focal seizures or generalized tonic‐clonic seizures

Abstract

Objective: Study 311 (NCT02849626) was a global, multicenter, open-label, singlearm study that assessed safety, tolerability, pharmacokinetics, and pharmacokinetics/ pharmacodynamics of once-daily adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with focal seizures (FS) (with/without focal to bilateral tonic-clonic seizures [FBTCS]) or generalized tonic-clonic seizures (GTCS). Methods: In the 311 Core Study, a 4-week Pre-treatment Period (Screening/Baseline) preceded a 23-week Treatment Period (11-week Titration; 12-week Maintenance)and 4-week Follow-up. Endpoints included safety/tolerability (primary endpoint), median percent change in seizure frequency per 28 days from Baseline (Treatment Period), and 50% responder and seizure-freedom rates (Maintenance Period). Patients were stratified by age (4 to <7; 7 to <12 years) and concomitant enzyme-inducing anti-seizure drug (EIASD) use. Results: One hundred eighty patients were enrolled (FS, n = 149; FBTCS, n = 54; GTCS, n = 31). The Core Study was completed by 146 patients (81%); the most common primary reason for discontinuation was adverse event (AE) (n = 14 [8%]). Mean (standard deviation) daily perampanel dose was 7.0 (2.6) mg/day and median (interquartile range) duration of exposure was 22.9 (2.0) weeks. The overall incidence of treatment-emergent AEs (TEAEs; 89%) was similar between patients with FS (with/ without FBTCS) and GTCS. The most common TEAEs were somnolence (26%) and nasopharyngitis (19%). There were no clinically important changes observed for cognitive function, laboratory, or electrocardiogram (ECG) parameters or vital signs.Median percent reductions in seizure frequency per 28 days from Baseline were as follows: 40% (FS), 59% (FBTCS), and 69% (GTCS). Corresponding 50% responder and seizure-freedom rates were as follows: FS, 47% and 12%; FBTCS, 65% and 19%; 126 | FOGARASI et Al. | 127 FOGARASI et Al.

Exploring the Evidence for Broad-Spectrum Effectiveness of Perampanel: A Systematic Review of Clinical Data in Generalised Seizures

“…In a post-hoc analysis of the RCT, seizure outcomes in patients with absence seizures were explored [17]. Results were inconclusive, as the study was designed to study changes in PGTCS frequency and did not have sufficient 3 interventional non-randomised trials (NCT02849626 [9]; and 2 with no study ID [11,12]) N = 31 [9]; N = 17 [11]; [11,12] Median % reduction from baseline PGTCS frequency:…”

“…69% [9] and 74% [12] Responder rates ranged from 64% [9] to 100% [11] Seizure freedom rate: 55% [9] TEAEs suggestive of seizure worsening: 1/31 'seizure cluster'; 1/31 'epilepsy' (serious TEAE) [9] Seizure worsening (subjective or objective) in 2/6 patients with Lafora disease [12] TEAEs in 26/31 (84%); leading to discontinuation in 3/31 (10%) [9] AEs not reported separately for patients in PGTCS in other studies…”

X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

“…In the case of GLUA3 loss-of-function variants there are no FDA or MDA approved treatment options, however in the case of GoF variants, one drug is available: Perampanel (PER) which is an orally active, selective, non-competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor agonist [43]. Although there are several publications describing the safety and efficacy of PER for individuals with epilepsy [43][44][45], there are no similar data available in individuals with GRIA3 GoF variants. An empirical antiepileptic treatment in monogenic disorders including GRIA3-deficiency is often found ineffective, may cause unwanted side effects and thus ultimately result in a diminished quality of life.…”

Alternatives to valproate in girls and women of childbearing potential with Idiopathic Generalized Epilepsies: state of the art and guidance for the clinician proposed by the Epilepsy and Gender Commission of the Italian League Against Epilepsy (LICE)

“…In 31 patients with GTCSs, the median percent reduction in seizure frequency from baseline was 69%; the 50% responder and SF rates were 64% and 55% respectively. Safety and tolerability were confirmed [75].…”