Fenfluramine: possible new treatment for Lennox-Gastaut syndrome

Fenfluramine was associated with a sustained reduction in frequency of seizures resulting in drops for up to a year in patients with Lennox-Gastaut syndrome (LGS) in the open-label extension (OLE) of a phase 3 study. The novel treatment was generally well tolerated.

Fenfluramine (3-trifluoromethyl-N-ethylamphetamine) is a substituted amphetamine that is structurally similar to serotonin. It is thought to reduce seizures by acting as an agonist of specific serotonin receptors in the brain, including 5-HT1D, 5-HT2A, and 5-HT2C. Fenfluramine is used to treat seizures in patients with Dravet syndrome [1]. At the AAN 2022 meeting, an interim analysis of long-term safety and efficacy of fenfluramine in patients with LGS was presented. Dr Kelly Knupp (Children's Hospital Colorado, CO, USA) shared the results of the OLE (NCT03355209) of the randomised-controlled, phase 3 trial [2]. The results were published in JAMA Neurology [3].

In this study, fenfluramine 0.7 mg/kg/day given for 14 weeks led to a median reduction in seizures of 26.5%, while the reduction in the placebo group was 7.6% (estimated median difference -19.9%; P=0.0013).

At data cut-off for this interim analysis (19 October 2020), 247 patients participated in the OLE. Mean age was 14.3 years, a third were adults. They all started on fenfluramine at 0.2 mg/kg/day and were titrated to effectiveness/tolerability after 1 month. The 5 most common concomitant anti-seizure medications (ASMs) were valproate, clobazam, lamotrigine, levetiracetam, and rufinamide; 88.3% of patients received 2-4 concomitant ASMs.

After 3 months, patients experienced sustained clinically meaningful reduction in median frequency of seizures associated with a drop (“drop seizures”) between 39.4%–51.8%. This treatment effect of fenfluramine was sustained up to 12 months. A statistically significant change in median frequency of seizure subtypes from pre-randomisation baseline was observed after 1 year of treatment in the OLE:

• generalised tonic-clonic: -62.8%;
• tonic: -60.4%;
• atonic: -67.4%;
• tonic-atonic: -50.8%.

A total of 87 patients (51.2%) experienced ≥50% reduction in drop seizure frequency (see Figure). About half of the investigators and caregivers rated patients as much improved/very much improved. Dr Knupp added that fenfluramine was generally well tolerated. The 2 most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No case of valvular heart disease or pulmonary arterial hypertension was observed during the OLE. Dr Knupp concluded: “Fenfluramine may be an important new treatment option with a novel mechanism of action for patients with LGS.”

Figure: Responder rates for drop seizures in patients with LGS treated with fenfluramine at ∼1 year [2]



 

 

 

 

 

 

 

 

1. Simon K, et al. Curr Res Pharmacol Drug Discov. 2021;3:100078.
2. Knupp K, et al. Interim analysis of long-term safety and efficacy of FINTEPLA (fenfluramine) in patients with Lennox-Gastaut Syndrome. S13.010, AAN 2022, 02–07 April, Seattle, USA.
3. Knupp KG, et al. JAMA Neurol, May 02, 2022. DOI:10.1001/jamaneurol.2022.0829.

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Posted on 2 June 20222 June 2022