Daily treatment with Fintepla (a low-dose oral solution of fenfluramine), an investigational therapy by Zogenix, significantly reduces seizure frequency in children and teenagers with Dravet syndrome while demonstrating safety, according to a merged analysis of two Phase 3 trials.
When given daily in addition to existing antiepileptic medications to patients ages 2 to 18, Fintepla at its higher dose of 0.7 mg/kg lowered the monthly frequency of seizures from a median of almost 21 before treatment to five after treatment.
Although more safety data is needed, researchers believe that Fintepla (previously called ZX008) could be an important new treatment option for people with Dravet syndrome.
An application to approve Fintepla to treat Dravet is currently under review by the U.S. Food and Drug Administration (FDA).
Results of the analysis were detailed in the study, “Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial,” recently published in The Lancet.
Fintepla’s active ingredient — fenfluramine — was originally developed as an appetite suppressant to treat obesity. It was withdrawn from the U.S. market in 1997 after reports of cardiovascular side effects, including heart valve disease and pulmonary hypertension (high blood pressure in the arteries of the lungs) in patients given doses of up to 220 mg per day.
Small studies and up to 30 years of compassionate use in Belgium provided evidence that fenfluramine taken daily at a low dose can lower the number of epileptic seizures without causing problems related to the heart.
The agent’s antiepileptic and appetite suppressing properties are thought to rely on its ability to increase serotonin levels in the brain.
Zogenix is developing a low-dose, oral solution of fenfluramine hydrochloride, under the brand name Fintepla, to treat seizures associated with Dravet syndrome, a rare and severe form of epilepsy with a great need for effective treatments. Fintepla is sugar-free to make it compatible with a ketogenic diet.
The company is running two identical randomized, double-blind, Phase 3 clinical trials (NCT02682927 and NCT02826863) to address the safety and efficacy of Fintepla used in combination with existing antiepileptic agents in children and young adults with Dravet syndrome.
One trial is being conducted in the U.S. and Canada, and the other at several sites in Europe, Australia and Japan. This last study is currently recruiting, and more information can be found here.
Researchers now pooled results from the two trials and analyzed them together. They included a total of 119 patients ages two to 18 (average age of 9).
Patients were randomized to either placebo (40 people), Fintepla at 0.2 mg/kg per day (39) or 0.7 mg/kg per day (40, a maximum daily dose of 26 mg/day), administered twice daily with food for 14 weeks.
Both doses of fenfluramine being tested are comparable to those used in Belgium.
The trial’s primary goal (or endpoint) was to assess if high study dose Fintepla was able to lower the frequency of convulsive seizures — hemiclonic, tonic, clonic, tonic-atonic, generalized tonic-clonic, and focal seizures with clearly observable motor signs — compared to placebo.
Data showed that patients given Fintepla at 0.7 mg/kg daily experienced a median reduction of 74.9% in the monthly frequency of seizures — lowering a median of 20.7 seizures before treatment to 4.7 during treatment.
Patients on the lower study dose had a median monthly seizure reduction of 42.3% — from 17.5 before treatment to 12.6 during the trial — while those on placebo had a 19.2% reduction.
The study met its primary efficacy endpoint, with the highest dose of Fintepla resulting in a 62.3% greater reduction in the mean number of monthly convulsive seizures compared with placebo.
In terms of safety, 21% to 38% of patients using Fintepla reported a lesser appetite. Other common side effects were diarrhea, fatigue, lethargy, sleepiness and weight loss.
No incidence of dangerous heart-related problems associated with a higher study dose of fenfluramine were observed. Echocardiographic scans showed no heart valve problems in all treated patients, and no signs of pulmonary hypertension were seen.
Researchers noted, however, that cardiac safety needs to be further confirmed in longer studies.
“The results from this study are tremendously encouraging in reducing the magnitude and duration of seizures in our patients with Dravet syndrome,” Joseph Sullivan, MD, director of the Pediatric Epilepsy Center of Excellence at the UCSF Benioff Children’s Hospital, and a principal study investigator, said in a press release.
“If future outcomes are as positive, it could help clinicians set new standards of care for a treatment-resistant disease like Dravet syndrome, in which frequent debilitating seizures and significant cognitive and functional impairments are the norm,” he added.
“[W]e are excited to see the continued signs of safety and efficacy of our investigational drug, Fintepla, used in Dravet syndrome patients over time in our ongoing open-label extension study and look forward to continuing to work with regulators to advance Fintepla as a potential new treatment option,” said Stephen J. Farr, PhD, president and CEO of Zogenix.
After a first rejection by the FDA — due to incomplete submission of early studies and accuracy problems in one of its clinical datasets — Zogenix resubmitted a new drug application (NDA) requesting Fintepla’s approval and that filing was accepted for review by the FDA in September.
The new submission was backed by data from the two Phase 3 trials, and preliminary analysis of an ongoing open-label extension study (NCT02823145) that includes 232 patients already treated for up to two years.
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