Elsevier

Epilepsy & Behavior

Volume 124, November 2021, 108275
Epilepsy & Behavior

Safety and efficacy of rufinamide in children and adults with Lennox-Gastaut syndrome: A post hoc analysis from Study 022

https://doi.org/10.1016/j.yebeh.2021.108275Get rights and content

Highlights

  • The first symptoms of LGS usually appear during early childhood.

  • LGS is an electro-clinical entity, often challenging to diagnose early and treat.

  • Rufinamide is indicated for adjunctive treatment of patients with LGS aged ≥1 year.

  • This post hoc analysis assessed rufinamide in LGS patients aged <16 and ≥16 years.

  • Rufinamide was well tolerated and improved seizure control, irrespective of age.

Abstract

Background

Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy with the first symptoms usually appearing during early childhood. Due to the highly variable underlying etiologies, LGS cannot be considered as one disease but as an electro-clinical entity, often challenging to diagnose early and treat accordingly. The anti-seizure medication, rufinamide, is indicated for the adjunctive treatment of patients with LGS aged ≥1 year. This post hoc analysis assessed the safety and efficacy of adjunctive rufinamide for total and tonic-atonic seizures during Study 022 in children (aged <16 years) and adults (aged ≥16 years).

Methods

Randomized, placebo-controlled, phase III Study 022 included patients with a diagnosis of LGS and a history of multiple seizure types (including tonic-atonic or astatic seizures and atypical absence seizures; ≥90 seizures in the month prior to baseline). Assessments included monitoring of treatment-emergent adverse events (TEAEs), percent change in tonic-atonic seizure frequency/28 days during the double-blind phase relative to study baseline (a primary endpoint), and percentage of patients with ≥25%, ≥50%, or ≥75% reduction in seizure frequency relative to baseline.

Results

Of 138 enrolled patients, 74 received rufinamide (<16 years, n = 49 [66%]) and 64 received placebo (<16 years, n = 43 [67%]). Incidence of TEAEs was generally similar between age groups. The frequency (per 28 days) of tonic-atonic seizures was reduced with rufinamide (vs. placebo) in both younger and older patients: age <16 years (−41% vs. −6%), age ≥16 years (−55% vs. +16%) (p < 0.025; both age groups). In patients aged <16 years receiving rufinamide, 38% and 17% achieved ≥50% and ≥75% reductions in tonic-atonic seizure frequency vs. 18% and 3% with placebo, respectively. Corresponding responder rates for patients aged ≥16 years were 52% and 32% (rufinamide) vs. 15% and 5% (placebo), respectively.

Conclusions

In this post hoc analysis, adjunctive rufinamide was well tolerated and improved seizure control in patients with LGS, irrespective of age.

Introduction

Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy, which, in the majority of cases, manifests in children most commonly before the age of 8 years [1], [2], [3], but can also, more rarely, first present in adulthood [2], [4]. The syndrome was first described in 1966 [1] and is characterized by three key features: multiple seizure types (including tonic, atonic, tonic-atonic, and atypical absence seizures); the presence of diffuse slow spike–wave activity during wakefulness detected by electroencephalogram (EEG); and intellectual disability [1], [5]. However, these characteristics are not always present at onset and may develop over time. Furthermore, due to the highly heterogeneous underlying etiology of LGS (genetic, structural, combinations of structural and genetic [e.g., tuberous sclerosis], or unknown), this syndrome cannot be considered as one disease, but rather an electro-clinical entity. Taken together, this often makes early and accurate diagnosis of LGS challenging [4], [5], [6].

To date, four therapeutic anti-seizure medication (ASM) options have received US Food and Drug Administration and European Medicines Agency approval for the treatment of seizures associated with LGS; these are cannabidiol, lamotrigine, rufinamide, and topiramate [7], [8], [9], [10], [11], [12], [13], [14]. In the US, clobazam and felbamate are also indicated for LGS [15], [16]. Furthermore, carisbamate, fenfluramine, perampanel, and soticlestat are under development/being evaluated for the treatment of LGS (source: clinicaltrials.gov search, June 2021). This manuscript focuses on rufinamide, which is indicated for use as adjunctive treatment of seizures associated with LGS in patients aged ≥1 year [12].

The safety and efficacy of rufinamide has been demonstrated in two phase III studies and their open-label extensions in patients aged 4 to 30 years [17], [18], [19], [20]. In addition, a long-term phase III study of rufinamide treatment in patients with LGS aged 1 to <4 years showed that adjunctive rufinamide is well tolerated in pediatric patients, with similar behavioral outcomes to other ASMs [21]. The aim of this post hoc analysis of data from Study 022 was to assess the safety and efficacy of adjunctive rufinamide for the treatment of children (aged <16 years) and adults (aged ≥16 years) with LGS, which has not been previously reported in detail.

Section snippets

Methods

Full methods of Study 022 have been published previously [17]. Briefly, Study 022 was a randomized, double-blind, placebo-controlled, multicenter phase III study comprising a 28-day baseline period followed by an 84-day treatment period (14-day titration period and 70-day maintenance period). Patients aged 4 to 30 years with LGS and a history of multiple seizure types (including tonic-atonic or astatic seizures and atypical absence seizures with ≥90 seizures/month in the month prior to

Patients

Of a total of 138 patients, 74 patients received rufinamide (<16 years: n = 49; ≥16 years: n = 25) and 64 received placebo (<16 years: n = 43; ≥16 years: n = 21) during the core study and were included in this analysis. Patient demographics at baseline were generally similar between treatment groups (Table 1).

Patients aged <16 years were exposed to rufinamide for a mean (standard deviation [SD]) of 79.2 (21.2) days, compared with 81.5 (17.2) days for patients receiving placebo. For patients

Discussion

Adjunctive rufinamide has demonstrated favorable safety and efficacy for the treatment of total and tonic-atonic seizures in patients with LGS in Study 022 [17]. In this post hoc analysis from Study 022, rufinamide was generally well tolerated and efficacious in patients with LGS, irrespective of patient age. A slightly higher number of children discontinued rufinamide due to a TEAE or reported a serious TEAE compared with adults, which may be due to younger patients being more closely

Conclusions

Overall, these data confirm that rufinamide is efficacious and well tolerated in the treatment of seizures in both children (aged <16 years) and adults (≥16 years) with LGS. The limitation of seizures being recorded in seizure diaries alone without supporting EEG data should be noted.

Funding

Study 022 was sponsored by Eisai Inc. and conducted by Novartis Pharmaceuticals.

Disclosures

Alexis Arzimanoglou, authorized by his institution collaborations, has served as an advisor, consultant, or speaker for Amzell, Arvelle, Biomarin, Eisai, GW Pharmaceuticals, Sanofi, Shire, Takeda, UCB Pharma, and Zogenix. He has received authorship royalties from Elsevier, JLE publications, McKeith Press, and Wiley publications. He has also received research and educational grants, paid to his institution, from Caixa Bank Foundation – Spain Foundation (Spain), Eisai, the European Commission, GW

Acknowledgements

Medical writing support, under the direction of the authors, was provided by Laura George, PhD, on behalf of CMC AFFINITY, McCann Health Medical Communications, funded by Eisai Inc., in accordance with Good Publication Practice (GPP3) guidelines.

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