Fenfluramine: potential new label for rare type of epilepsy?

The amphetamine derivative fenfluramine, previously marketed as an appetite suppressant to manage obesity, delivers a different promise in a new phase III trial by showing its anti-epileptic potential in children and young adults with Dravet syndrome.

Despite previous accounts on the anti-epileptic activity of fenfluramine, these were only small case reports and observational studies, noted the researchers. [Ther Adv Neurol Disord 2015;8:328-338] “This study was the first randomized, double-blind, placebo-controlled clinical trial to assess the safety and efficacy of fenfluramine [in this patient setting. Our findings] suggest that the use of low-dose fenfluramine … added to existing anti-epileptic therapy could be effective in reducing the frequency of convulsive seizures in patients with Dravet syndrome.”

A disabling, refractory, childhood-onset, developmental epileptic encephalopathy characterized by a high seizure burden along with significant neurodevelopmental, motor, and behavioural comorbidities, Dravet syndrome is marked by high mortality rates due to status epilepticus and sudden unexpected death in epilepsy. [Epilepsy Res 2016;128:43-47] The disease characteristics entail a high humanistic and economic impact, hence the high unmet need for new and better treatment strategies, noted the researchers. [Dev Med Child Neurol 2018;60:63-72; Epilepsy Behav 2018;80:109-113]

Researchers merged datasets of two phase 3 trials. Following a 6-week observation phase to determine baseline monthly convulsive seizure* frequency (MCSF), 119 participants (mean age 9 years, 54 percent male) were randomized 1:1:1 to receive fenfluramine daily at a dose of either 0.7 or 0.2 mg/kg or placebo on top of existing anti-epileptic agents**. [Lancet 2019;394:2243-2254]

During the 14-week treatment period, fenfluramine 0.7 and 0.2 mg/kg recipients had greater reductions in mean MCSF compared with placebo-treated patients (estimated difference from placebo, -62.3 percent; p<0.0001 [0.7 mg/kg] and -32.4 percent; p=0.0209 [0.2 mg/kg]).

The achievement of seizure freedom (8 percent of participants in each fenfluramine arm) further illustrates the drug’s efficacy. No placebo recipient achieved 100-percent reduction in CSF.

Nearly all fenfluramine recipients reported adverse events (AEs; 95 percent of participants in each arm), the most common being diarrhoea, somnolence, pyrexia, reduced appetite, weight loss, and nasopharyngitis. The incidence of serious AEs ranged from 10 to 13 percent across all arms, the most common being hospital admission for status epilepticus. No deaths were reported.

Cardiovascular implications

Cardiovascular (CV) safety is an important outcome measure in this patient setting in light of the cardiac valvulopathy and pulmonary arterial hypertension (PAH) found to be associated with high doses of fenfluramine (up to 220 mg/day). [N Engl J Med 1997;337:581-588; N Engl J Med 1996;335:609-616]

These controversial CV effects led to the drug’s withdrawal from the global market in 1997. [Crit Rev Toxicol 2016;46:477-489] Following which, approval for compassionate use was granted by the Belgian government in 2002 to allow Dravet syndrome patients to receive fenfluramine under a treatment protocol, said the researchers.

Increased dose and treatment duration were identified as risk factors for valvulopathy. [BMC Med 2008;6:34; BMC Cardiovasc Disord 2003;3:5] In the current trial however, low fenfluramine doses were used (≤26 mg/day). Save for the findings of trace mitral or aortic regurgitation which are apparently “physiologic and normal” in this patient subset, [J Am Soc Echocardiogr 2017;30:303-371; Eur J Echocardiogr 2010;11:307-332] echocardiographic exams revealed normal valvular function with no signs of PAH across all patient subgroups throughout the trial.

However, the short trial period may have limited the findings, hence the need for longer-term studies to ascertain the CV safety of fenfluramine, as well as its impact on nonseizure endpoints (ie, executive function, quality of life), noted the researchers.

“[Overall, our findings show that low-dose] fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or PAH. [Therefore,] fenfluramine could be an important new treatment option for patients with Dravet syndrome,” concluded the researchers.