Fenfluramine reduces seizure occurrence in patients with Lennox-Gastaut syndrome, JAMA says

Australia: Fenfluramine, as compared to placebo, offered a considerably higher reduction in drop seizures in individuals with Lennox-Gastaut syndrome (LGS) and may be a particularly favorable alternative in people who have generalized tonic-clonic seizures, says an article published in the Journal of American Medical Association - Neurology. 

Patients with Lennox-Gastaut syndrome, a severely debilitating, treatment-resistant developmental and epileptic encephalopathy, require new therapy alternatives. As a result, Kelly G. Knupp and colleagues undertook this research to assess the effectiveness and safety of fenfluramine in LGS patients.

This parallel-group, multicenter, placebo-controlled, double-blind, randomized clinical study lasted 20 weeks, from November 27, 2017 to October 25, 2019. Patients in the study ranged in age from 2 to 35 years old, had a verified diagnosis of LGS, and had two or more drop seizures each week throughout the four-week baseline period. Patients were randomly assigned to either a 0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) fenfluramine dosage or a placebo. Patients were given their randomized dosage for 12 weeks after titration (2 weeks). The primary effectiveness end measure was the % difference from baseline in drop seizure frequency in individuals receiving 0.7 mg/kg/d fenfluramine vs placebo.

The key findings of this study were as follows:

1. In total 263 patients were randomly assigned to one of three groups: 0.7 mg/kg/d fenfluramine (n = 87), 0.2 mg/kg/d fenfluramine (n = 89), or placebo (n = 87).

2. The 0.7-mg/kg/d fenfluramine group had a 26.5% reduction in drop seizures, the 0.2-mg/kg/d fenfluramine group had a 14.2% reduction, and the placebo group had a 7.6% reduction.

3. The trial's primary effectiveness end goal was met: patients in the 0.7-mg/kg/d fenfluramine group had a 19.9% average estimated difference in drop seizures from baseline compared to placebo.

4. More individuals in the 0.7-mg/kg/d fenfluramine group had a 50% or higher response.

5. More patients in the 0.7-mg/kg/d fenfluramine group received a considerably better or very much improved rating on the Clinical Global Impression of Improvement measure than patients in the placebo group, according to site investigators and caregivers.

6. The seizure subtype that appeared most responsive to fenfluramine was a generalized tonic-clonic seizure, with a 45.7% decrease in frequency in the 0.7-mg/kg/d fenfluramine group and a 58.2% decrease in the 0.2-mg/kg/d fenfluramine group compared to a 3.7% increase in the placebo group.

7. The most prevalent treatment-emergent adverse events were loss of appetite, somnolence, and weariness.

8. There were no reports of valvular heart disease or pulmonary arterial hypertension.

In conclusion, fenfluramine was usually well tolerated, with safety ratings comparable to those described in earlier RCTs and OLE studies for the short- and long-term treatment of DS, with no reports of valvular heart disease or pulmonary arterial hypertension.

Reference:

Knupp KG, Scheffer IE, Ceulemans B, et al. Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial. JAMA Neurol. Published online May 02, 2022. doi:10.1001/jamaneurol.2022.0829