Fenfluramine, originally developed as an appetite suppressant, shows potential as an anti-epileptic therapy to reduce the seizure rate in Dravet syndrome patients, a review study suggests.
The study, “Individualized treatment approaches: Fenfluramine, a novel antiepileptic medication for the treatment of seizures in Dravet syndrome,” was published in the journal Epilepsy & Behavior.
Fenfluramine, sold under the brand name Pondimin (among others) was prescribed as an appetite suppressant until 1997. In the U.S., the medicine was removed from the market after reports linked it to heart problems and pulmonary hypertension.
The therapy’s appetite suppressant effects are connected to its ability to disrupt the storage and neuronal reuptake of serotonin, a neurotransmitter that plays an essential role in several functions including mood, memory, and appetite.
Early reports began to emerge in the 1980s of the potential utility of fenfluramine in epilepsy when researchers reported its use in certain neurological disorders such as self-induced photosensitive epilepsy.
In 1996, researchers treated a group of 11 children who were institutionalized with refractory epilepsy and self-induced seizures, most of which were photosensitive or pattern-sensitive seizures. Daily doses of fenfluramine added to their anti-epilepsy medicine regimen resulted in complete seizure control in seven patients and a greater than 75% reduction in seizure frequency in four patients during a median follow-up of five years.
Some of these patients had some of the typical features seen in Dravet syndrome patients, for which currently available therapies fail to achieve complete seizure control, and five out of the 11 patients were proven to carry a mutation in the SCN1A gene. This gene provides instructions for a sodium channel called NaV1.1s and is mutated in approximately 80 percent of all Dravet patients.
Later, these five patients were included in another group of 12 patients with confirmed Dravet syndrome. Fenfluramine was added to their anti-epileptic regimen for a mean duration of 11.3 years. Most of these patients experienced a reduction in the number of seizures, with seven patients becoming seizure-free for a mean of 6.6 years. Moreover, researchers detected no signs of cardiac problems or pulmonary hypertension.
“The most recent report from this cohort of 10 remaining patients describes an additional 5 years of follow-up, during which three patients were seizure-free and four additional patients had seizure-free intervals of at least 2 years,” the researchers wrote.
In 2011, a second group of Dravet patients received fenfluramine for a median of 1.5 years, ranging betwen 3.6 months and 5.1 years, treated with an average dose of 0.35 mg/kg/day.
Within three months of treatment with fenfluramine, the frequency of seizures decreased an average of 75%, from 15 to 1.5 seizures per month. This benefit was sustained in six patients who were treated for at least one year. Once again, no heart problems were detected.
“The clinical profile that has emerged with fenfluramine use in this cohort of patients with Dravet syndrome, a group of patients with seizures that are historically refractory to AED treatment, is unique both in terms of the magnitude of seizure reduction and the durability of effect over long periods of time,” the researchers said.
These early results prompted two ongoing, randomized, placebo-controlled Phase 3 trials (NCT02682927, NCT02826863), which are testing Zogenix’s low-dose fenfluramine liquid solution called ZX008 as an add-on treatment for Dravet syndrome.
Of note, ZX008 has been used as an add-on therapy by Dravet patients in Belgium for more than two decades under a government-sanctioned compassionate use program.
In total, 119 pediatric and young adult patients — ages 2-18 years — with Dravet syndrome were randomized to receive either a placebo or ZX008 administered as an oral solution.
Patients received one of two doses of ZX008, 0.2 mg/kg/day or 0.8 mg/ kg/day, for 14 weeks. The daily dose was divided in half and administered twice daily, 12 hours apart.
Patients randomized to ZX008 at 0.2 and 0.8 mg/kg/day showed a 33.7% and 63.9% decrease in monthly frequency of motor seizures, respectively, compared with the placebo group.
“A [more than] 50% reduction in monthly convulsive seizure frequency was seen by 70% of patients in the ZX008 0.8 mg/kg/day and in 41% of patients in the ZX008 0.2 mg/kg/day compared with 7.5% of patients in the placebo group,” the researchers wrote.
The rate of adverse effects was similar between the 0.8 mg/kg/day group and the placebo group — 10% and 12.5%, respectively.
Cardiac examinations before and during treatment with ZX008 revealed no signs of pulmonary hypertension.
With this data, the published experience of the treatment of Dravet syndrome with fenfluramine now includes 100 patients who have been treated from three months to 28 years without any cardiac problems.
Importantly, the daily doses used in Dravet syndrome patients — 5 mg to less than 30 mg/day — are below the 60 mg/day used to treat adults with obesity, which was associated with cardiac problems and pulmonary hypertension.
“These observations suggest a positive benefit–risk profile for the use of lower dose fenfluramine in children and young adults treated for Dravet syndrome compared with its use at higher doses in an adult population with obesity,” the researchers wrote.
Based one the various clinical results, the team believes that “fenfluramine may represent a novel and effective treatment for Dravet syndrome.”
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