Evaluating fenfluramine hydrochloride as an oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome

ABSTRACT

Introduction

Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by treatment-refractory seizures, including tonic/atonic ‘drop’ seizures, and intellectual impairment and slow spike-wave discharges on the electroencephalogram. Fenfluramine, previously prescribed as a weight-loss drug but then withdrawn, has recently been approved in the US, EU, and UK for the adjunct treatment of seizures associated with LGS.

Areas covered

The authors review the efficacy and safety findings from clinical trials of fenfluramine in LGS. The authors then discuss the evidence for adverse effects that may be of particular concern to fenfluramine, namely cardiac abnormalities, and weight loss, in the context of the use of fenfluramine for the treatment of the refractory seizures in LGS.

Expert opinion

Fenfluramine has demonstrated efficacy in reducing the frequency of seizures in LGS, notably drop seizures, in short-term and long-term clinical trials. Valvular heart disease and pulmonary hypertension have not been reported at the low doses (≤26 mg/day) used in these studies, however, data are limited. Due to its novel mechanism of action, fenfluramine may be of benefit in LGS which has not responded adequately to other antiseizure medications. However, none of these medications, including fenfluramine, achieves the ultimate goal of seizure freedom in most cases.

KEYWORDS:

• Fenfluramine
• Lennox-Gastaut syndrome
• efficacy
• safety
• valvulopathy
• pulmonary hypertension
• drop attack
• developmental and epileptic encephalopathy

Article highlights

• LGS is a severe childhood-onset developmental and epileptic encephalopathy characterized by treatment-refractory seizures.

• In a single placebo-controlled trial in adults and children with LGS, adjunct fenfluramine at a dose of 0.7 mg/kg reduced the frequency of drop seizures by 26.5% after 14 weeks, compared to a reduction of 7.6% with placebo.

• Decreases in drop seizure frequency were maintained for up to 21 months in some individuals in an open-label extension trial.

• No cases of valvular heart disease of pulmonary hypertension have been detected at the dose levels used in trials of fenfluramine for the treatment of seizures.

• The available evidence suggests fenfluramine is a safe and effective adjunct treatment for seizures in LGS, but data remain limited.

Declaration of interest

RFM Chin was a principal investigator in a GWPharma sponsored trial of cannabidiol for the treatment of Lennox Gastaut syndrome. He has provided paid consultancy for GWPharma and Zogenix, and received travel grants from GWPharma, Zogenix, Esai, and UCB. He has shares in RIZE Medical Cannabis & Life Sciences UCITS ETF. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.