Dravet syndrome: Fenfluramine effective and safe when added to stiripentol
A multicentre, double-blind, placebo-controlled, phase III randomized clinical trial (RCT) has found add-on fenfluramine to significantly reduce monthly convulsive seizure frequency in patients with Dravet syndrome (DS) whose condition was insufficiently controlled with stiripentol-containing antiepileptic drug (AED) regimens.
Results from Study 1, a phase III, placebo-controlled RCT, demonstrated that fenfluramine provided a significantly greater reduction in monthly convulsive seizure frequency (MCSF) vs placebo, but patients receiving stiripentol were excluded. [Lagae L, et al, AES 2017, poster 2.434] “Given the widespread use of stiripentol for DS, it is important to assess the benefit and tolerability of add-on fenfluramine in stiripentol-containing AED regimens,” wrote the researchers.
A total of 87 DS patients (mean age, 9.1 years; 57 percent boys; mean baseline MCSF, 25) receiving stiripentol-containing AED regimens across sites in Canada, France, Germany, the Netherlands, Spain, UK, and the US were randomized to receive fenfluramine 0.4 mg/kg/d (n=43) or placebo (n=44). [JAMA Neurol 2019, doi: 10.1001/jamaneurol.2019.4113]
The study achieved its primary efficacy objective: patients randomized to fenfluramine attained an estimated 54.0 percent (95 percent confidence interval [CI], 35.6 percent to 67.2 percent) greater reduction in mean MCSF between the baseline and titration and maintenance periods than those who received placebo (p<0.001). Patients in the fenfluramine vs placebo group also experienced significantly longer seizure-free intervals (median, 22.0 days vs 13.0 days; p=0.004).
The median percentage reduction from baseline in MCSF in the fenfluramine vs placebo group was 63.1 percent vs 1.1 percent during the titration and maintenance periods (p<0.001). The median number of convulsive seizure-free days was significantly higher in patients treated with fenfluramine than placebo (median, 24.4 days vs 20.3 days; p=0.001).
“Significantly more patients in the fenfluramine group had clinically meaningful improvements in clinical global impression scores,” wrote the researchers. At the end of the treatment and maintenance period, 44 percent of investigators rated patients in the fenfluramine group as much improved or very much improved vs 16 percent for the placebo group (p=0.008).
“The magnitude of treatment outcome is highlighted by the fact that significantly more patients receiving add-on fenfluramine vs placebo experienced reductions in MCSF that were clinically meaningful (≥50 percent MCSF reduction, 54 percent vs 5 percent of patients) and profound (≥75 percent MCSF reduction, 35 percent vs 2 percent of patients), which are magnitudes of response not commonly seen in DS,” emphasized the researchers.
The most common treatment-emergent adverse events (TEAE) in the fenfluramine group included decreased appetite, pyrexia, fatigue, and diarrhoea. TEAE-associated discontinuations occurred in three patients. Two patients (4.5 percent) receiving placebo and nine patients (20.9 percent) receiving fenfluramine experienced weight decreases of ≥7 percent from baseline. “Of these patients, five were also receiving topiramate [another AED with anorectic properties],” noted the researchers. “Importantly, no patient developed valvular heart disease or pulmonary arterial hypertension, and all echocardiograms in all patients demonstrated normal valve function without observation of abnormal valve morphology,” they added.
“Fenfluramine may represent an important, effective new treatment option for patients with DS and seizures inadequately controlled on stiripentol-inclusive AED regimens,” concluded the researchers.