perampanel and Lennox-Gastaut-Syndrome

There are currently five compounds (clobazam, felbamate, lamotrigine, topiramate, rufinamide) available for prescription with a demonstrated efficacy on drop seizures for Lennox-Gastaut syndrome (LGS). There are also currently new and under-investigation compounds. This paper gives an overview on these novel developments for LGS based on the lecture given at the French Chapter meeting of the International League Against Epilepsy (ILAE) held in Paris in October 2019. Five compounds were discussed. Epidiolex (cannabidiol) has been approved recently based on positive randomized control trials in LGS patients. Four drugs are under investigation according to a search on the 'clinicaltrials.gov' database. Perampanel and fenfluramine are both being studied in ongoing phase 3 studies. Two compounds are in an earlier stage of development with ongoing phase 1 and 2 studies: carisbamate and OV953. We summarized the publicly available data. Based on these drug development programs, we can expect that new compounds will become available for LGS in the next years, possibly resulting in new treatment paradigms.

Topics: Anticonvulsants; Cannabidiol; Drug Development; Drugs, Investigational; Fenfluramine; Humans; Lennox Gastaut Syndrome; Nitriles; Pyridones; Therapies, Investigational; Triazoles

This retrospective study assessed long-term effectiveness of add-on perampanel (PER) in patients with Lennox-Gastaut syndrome (LGS). Outcomes included time to PER failure and time to seizure relapse in responders. PER failure was defined as either discontinuation of PER or initiation of another treatment. Seizure relapse in responders was defined as occurrence of a seizure in seizure-free patients and increase of at least 50% in average monthly seizure frequency for those who were responders. Eighty-seven patients were included. Treatment failure occurred in 52 (59.8%) subjects at a median time of 12 months. Treatment failure was due to lack of efficacy in 27 (52.0%) patients, lack of tolerability in 14 (27.0%), and both reasons in 11 (21.0%). A slower titration was associated with a lower risk of PER failure compared to faster titration schedules, and the occurrence of adverse events increased the risk of treatment failure. Thirty-six patients (41.4%) were responders during a median follow-up of 11 months. Seizure relapse occurred in 13 of 36 (36.1%) patients after a median time of 21 months. The overall rate of seizure responders was 23 of 87 (26.4%) at the end of follow-up. This study provides real-world evidence on the effectiveness of PER as adjunctive treatment in LGS patients.

Topics: Anticonvulsants; Humans; Lennox Gastaut Syndrome; Retrospective Studies; Seizures; Treatment Outcome

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of syndromes, including Lennox-Gastaut syndrome (LGS), which are refractory to multiple therapies. Perampanel efficacy has been reported in LGS but further real-world evidence is needed in DEEs.. A multicenter, retrospective, 1-year observational study in patients with DEEs on adjuvant perampanel treatment was conducted to assess perampanel safety and effectiveness in this type of patients in a real-world setting. Seizure types [focal onset seizures (FOS), generalized tonic-clonic seizures (GTCS), tonic seizures (TS), atonic seizures (AtS), atypical absences (AA), and myoclonic seizures (MS)] and seizure clusters were divided in different frequency groups: daily, weekly, and monthly seizures, and absent or seizure freedom. Patients could have more than one seizure type. For each frequency group, group change and seizure freedom were analyzed.. Eighty-seven patients diagnosed with DEEs (45 males) of median age 22 [1-70] years were included. The most frequent DEEs were LGS (35.6%) and Lennox-like syndrome (37.9%). At baseline 20 patients had three to five types of seizures, 36 patients had two types of seizures and 31 patients had one predominant type of seizure. The mean number of seizure types per patient at baseline was 2.12 ± 0.97 which was reduced to 1.62 ± 0.91 at 12 months (p < 0.001). Overall, 51.7% of patients had a significant improvement in at least one seizure type. At baseline, 45 patients had GTCS, 42 FOS, 41 TS, 18 AA, 16 AtS, 11 MS, and 30 seizures clusters. Seizure freedom for each specific type at 12 months was significantly achieved by 35% of patients with GTCS (p < 0.001), 17% (p = 0.016) with TS and 37% with seizure clusters (p < 0.001). Patients achieved seizure freedom from other seizure types but with no statistical significance: 7% FOS-free, 28% AA-free, 6% Ats-free, and 18% MS-free. Regarding changes of group at 12 months, 22% of TS and 19% of FOS improved significantly to a group with lower seizure frequency (p = 0.004 and p = 0.02, respectively). In remaining groups (4% of GTCS, 11% of AA, 18% of Ats, 18% of MS, and 13% of seizure clusters), the improvement was not statistically significant. Twenty-nine patients discontinued perampanel: 18 (21%) due to AEs, 8 (9%) due to lack of efficacy, and 3 (3%) due to seizure worsening. Adverse events, mostly mild or moderate, were reported in 53% of patients, and irritability/mood changes (22%) and somnolence (17%) were the most frequent.. This is the first large-scale real-world study with perampanel across different seizure types in patients with DEEs. Perampanel was effective, especially in GTCS, TS, and FOS, as well as in seizure clusters. Perampanel was generally well-tolerated without unexpected AEs.

Topics: Adult; Anticonvulsants; Epilepsies, Myoclonic; Epilepsy, Generalized; Humans; Lennox Gastaut Syndrome; Male; Nitriles; Pyridones; Retrospective Studies; Seizures; Treatment Outcome; Young Adult

Perampanel (PER) was added to the anticonvulsant regimen of 71 patients with Lennox-Gastaut Syndrome (LGS) to evaluate its efficacy against seizures and its tolerability.. We evaluated at 3-month intervals 62 with pure LGS and 9 with LGS-like epileptic encephalopathy (28 females, 43 males, mean age 40.1 ± 11.5 yrs, median 38, range 20-71) in whom PER was introduced by 2 mg steps at 2- to 4-week intervals up to 6 mg/day, with possible dose reduction or increases after that. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed.. Mean PER exposure was 538.9 days ± 425 (median 429), with 44 patients (62 %) on PER at last follow-up. About 2/3 of patients were responders, including 35.2 % that had a ≥75 % decrease in their seizures. Among these 16.9 % had a ≥90 % decrease. No improvement was seen in 14 patients; 5 had a less than 50 % response, and 6 had seizure aggravation. Therefore, 25 (35.2 %) were considered non-responders. Half of the patients developed at least one side-effect. Significant negative changes in behavior were noted in 1/3 of the cases, including irritability (8.5 %) and aggressivity (7 %). Contrastingly, 4 patients reported positive behavioral and psychological well-being side-effects.. This retrospective, open-label study provides evidence that PER may significantly help in LGS. PER should be tried in LGS patients who are not satisfactorily controlled. Its use may be limited in some patients due to behavioral side-effects occurring, particularly at doses ≥ 6 mg/d.

Topics: Adult; Aged; Anticonvulsants; Female; Humans; Lennox Gastaut Syndrome; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Treatment Outcome; Young Adult

Report the use of perampanel treatment in children with Lennox-Gastaut syndrome (LGS).. We conducted a prospective study of 13 LGS patients (seven male; mean age, 12.8years) treated with adjunctive perampanel therapy. Perampanel was initiated at 2mg/day and titrated to a median maximum dose of 6mg/day.. After a mean follow-up duration of 10.8months (range, 1-24months), nine patients (69.2%) were responders (≥50% reduction in total seizure frequency) and nine (69.2%) were rated by their physician as "much improved" or "very much improved". Four patients (30.8%) discontinued perampanel due to the lack of efficacy (n=2) and seizure aggravation (n=2). No patients discontinued due to other adverse events (AEs). AEs were reported for six patients (46.2%) and comprised decreased activity/social interaction (n=3), behavior disturbance with agitation (n=2), and/or fatigue (n=2). All AEs became manageable after perampanel dosing was decreased. Improvements in cognitive function and/or behavior were reported for seven patients (53.8%). Introduction of perampanel allowed the dose reduction and/or discontinuation of other treatments in seven patients (53.8%).. Perampanel was efficacious and generally well tolerated as an adjunctive treatment for seizures associated with LGS, supporting further research in this area.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Cohort Studies; Female; Follow-Up Studies; Humans; Lennox Gastaut Syndrome; Male; Nitriles; Prospective Studies; Pyridones; Seizures; Treatment Outcome