Efficacy and Safety of Fenfluramine in the Treatment of Lennox-Gastaut Syndrome – An Overview of Current Knowledge

Introduction

Lennox-Gastaut syndrome is a severe developmental and epileptic encephalopathy beginning in childhood characterized by seizures refractory to pharmacotherapy (including tonic/atonic seizures with falls) and intellectual impairment. Fenfluramine has recently been approved as an adjunctive anticonvulsant treatment for LGS in the USA, EU, and UK. Based on a systematic literature review in the MEDLINE, Embase, and ClinicalTrials.gov databases up to December 2023, an overview of current evidence on the benefits and risks of this therapy was created.

Findings from Phase II Study

An open-label Phase II study (NCT02655198) evaluated the efficacy and safety of fenfluramine in 13 children and adolescents aged 3–17 years with LGS over 20 weeks with a 15-week extension. Enrolled patients had to have ≥ 4 seizures in the past 4 weeks while on ≥ 2 antiseizure medications (ASMs). FFA was administered twice daily at a dose of 0.2 mg/kg/day, increasing up to 0.8 mg/kg/day or 30 mg/day without changing other ASMs.

Ten participants completed the study with a median maintenance dose of 0.4 mg/kg/day. After 20 weeks of treatment, their seizure frequency decreased from 61 to 22 per month (a 60% reduction). Treatment response (at least a 50% reduction in seizure frequency) was achieved in 8 patients, and 3 patients had a reduction of more than 75%. Nine patients participated in the study extension, with a 58% reduction in convulsive seizure frequency at the end of the follow-up, 6 patients achieved a ≥ 50% reduction, and 3 patients a ≥ 75% reduction in seizure frequency. Adverse events (AEs) included decreased appetite (31%), decreased alertness (15%), sleep disorder, fatigue, and drowsiness (8%). Two patients discontinued treatment due to AEs. No signs of valvular heart disease or pulmonary hypertension were observed.

Findings from Phase III Study and Its Open-Label Extension

A double-blind, randomized, placebo-controlled Phase III study (NCT03355209) enrolled 263 patients with LGS aged 2–35 years. They had to have ≥ 2 seizures with falls in the past 4 weeks and be on 1–4 ASMs. Adding FFA to the ASMs resulted in a 26.5% reduction in mean seizure frequency from 77/month at 0.7 mg/kg/day, 14.2% at 0.2 mg/kg/day, and 7.6% with placebo after 14 weeks. The proportion with a 50% reduction in seizure frequency, which was 10% with placebo, reached 25% with FFA 0.7 mg/kg/day (p = 0.02) and 28% with FFA 0.2 mg/kg/day (p = 0.005). The most common AEs were decreased appetite (22%), drowsiness (13%), and fatigue (13%). Clinically significant weight loss (≥ 7%) was reported in 8% of patients with FFA at 0.7 mg/kg/day and 2% at 0.2 mg/kg/day and with placebo. Six patients discontinued FFA due to AEs.

The one-year open-label extension of this study showed a significant median reduction in the number of seizures with falls by 28.6% (p < 0.0001) and non-fall seizures by 45.9% (p = 0.0038). This reduction was comparable in both adults and children. At least a 50% reduction in seizure frequency was achieved in 31.1% of those treated. The decreased seizure frequency persisted in some patients for up to 21 months. The most common AEs included decreased appetite (16.2%) and fatigue (13.4%). Of the 247 individuals who experienced a ≥ 7% weight loss with FFA, 33% regained their original weight. No instances of heart valve damage or pulmonary hypertension were detected.

Additional Effects of Fenfluramine

A post hoc analysis of the described Phase III study showed clinically significant improvements in cognitive regulation and overall scores of executive function subdomains as rated by parents using the BRIEF (Behavior Rating Inventory of Executive Function) tool in 27% of children and 25% of adolescents treated with FFA compared to 13% and 11% of those on placebo, respectively, which was statistically significant. A separate analysis showed similar improvement in adults, more likely with a higher FFA dose (0.7 mg/kg/day).

An aggregated analysis of studies with FFA and data from patients with Dravet syndrome treated in the early access program in the USA and Europe indicated a lower incidence of SUDEP with FFA compared to historical results. For patients with LGS, such analysis results are not yet available, but preclinical models suggest a potential reduction in SUDEP risk.

Safety Profile

Fenfluramine was withdrawn from the market for obesity treatment (often in combination with phentermine) in 1997 due to the risk of heart valve disease and pulmonary hypertension. However, in LGS treatment, phentermine is administered at significantly lower doses (usually < 26 mg/day compared to 60-120 mg/day in obesity treatment). No cases of heart valve disease have been detected in clinical trials at doses used in anticonvulsant treatment. The product summary indicates that before starting FFA, echocardiographic examination should be performed to exclude pre-existing valvular disease and pulmonary hypertension. Follow-up echocardiography is recommended every 6 months for the first 2 years and then once yearly and 3-6 months after discontinuing FFA.

A small percentage of children and adults may experience ≥ 7% weight loss with fentermine treatment, but it usually stabilizes during treatment.

Plasma concentration of FFA shows interindividual variability. There is an association between concentration and the occurrence of fatigue and drowsiness. Therefore, clinical monitoring of plasma drug levels, administration of lower doses in older patients, and monitoring plasma levels in patients with fatigue and drowsiness are recommended.

Conclusion

Fenfluramine has proven effective in reducing the frequency of seizures with falls in patients with LGS in both short-term and long-term clinical studies. No cases of valvular heart disease or pulmonary hypertension were detected at doses < 26 mg/day. The drug may also help improve cognitive function in patients with LGS and has the potential, similar to Dravet syndrome, to reduce the risk of SUDEP. It can thus be beneficial for both adults and children with LGS who do not respond adequately to other anticonvulsants.

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Source: Besag F. M. C., Vasey M. J., Chin R. F. M. Evaluating fenfluramine hydrochloride as an oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome. Expert Rev Neurother 2024 Mar; 24 (3): 235–249, doi: 10.1080/14737175.2024.2313548.