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In a phase 3 trial, fenfluramine, which was withdrawn from the market in 1997 due to safety concerns about heart valve complications, was safe and effective for reducing seizures in children with Dravet syndrome. The study author and independent experts called for longer-term studies of the drug.

Children and adolescents with Dravet syndrome who took oral fenfluramine in addition to other antiepileptic drugs (AEDs) were 54 percent less likely to experience a seizure than those on placebo, according to a study in the December 2, 2019, online issue of JAMA Neurology.

In addition, the seizure-free period was longer in children on fenfluramine.

Dravet syndrome is a difficult-to-treat epilepsy disorder, so it's exciting to see that a handful of kids (five) were nearly seizure-free (with one seizure or less) during the 12-week maintenance period, the study investigator Kelly G. Knupp, MD, MSCS, FAES, associate professor of pediatrics and neurology at Children's Hospital Colorado at the University of Colorado in Denver told Neurology Today.

We were also pleased to see no adverse cardiac events, especially valvular heart disease and pulmonary hypertension, which were reasons fenfluramine was withdrawn from the market in 1997. This is similar to the Belgium experience, [an open label extension study], but I think that this will require careful monitoring in the future. If the cardiac findings are rare or time-dependent, there has not yet been enough patient exposure yet to identify them, said Dr. Knupp.

She noted that fenfluramine was originally approved as an appetite suppressant. Given that, we were not surprised that decreased appetite and weight-loss were the most common side-effect, said Dr. Knupp.

The Zogenix-funded phase 3 study confirms the findings from an earlier phase 3 trial of the drug in children with Dravet syndrome.

Zogenix submitted a new drug application to the US Food and Drug Administration (FDA) with the data from the two trials and an interim analysis from an ongoing open-label extension study.

In November 2019, the FDA announced that it granted the Zogenix application priority review with a six-month deadline. The federal agency has set a Prescription Drug User Fee Act target action date of March 25, 2020 for fenfluramine, according to a statement from the company.

Given these promising findings, we hope that fenfluramine will be available so we can treat more children and young people with Dravet syndrome, said Dr. Knupp.

An estimated 12,000 individuals in the United States have the syndrome associated with poorly-controlled frequent convulsive seizures, which increases their risk of disability and premature death, Dr. Knupp said.

The randomized, placebo-controlled study evaluated the safety and efficacy of twice-daily fenfluramine added to stiripentol, plus valproate or clobazam, in children diagnosed with Dravet syndrome.

The previous randomized, controlled study only examined fenfluramine because the researchers lacked pharmacokinetic data to evaluate dosage modifications needed to compensate for an expected fenfluramine-stiripentol drug interaction, according to the paper.

Patients with poorly controlled seizures on AED regimens were enrolled at approximately 28 sites in Canada, France, Germany, the Netherlands, Spain, the United Kingdom, and the United States.

Eighty-seven patients with a mean age of 9.1 years (ages 2 to 18) and a mean baseline frequency of about 25 convulsive seizures monthly were randomized to fenfluramine or placebo.

After a six-week randomization period to establish the baseline frequency of at least six convulsive seizures, the medication dose was titrated for three weeks from a starting dose of 0.2mg/kg daily in two equal doses to 0.4 mg/kg daily (with a maximum of 17 mg/kg daily). The dose was maintained for 12 weeks when the study ended. The total study period was 21 weeks.

The children receiving fenfluramine experienced a 54 percent reduction in their average monthly convulsive seizure frequency compared with the children on placebo during the 21-week trial.

Also, 54 percent (23 of 43) of patients on fenfluramine experienced a 50 percent or greater reduction in the average monthly convulsive seizure frequency compared with 5 percent (two of 44) on placebo. The fenfluramine group also had a median of 22 seizure-free days compared with a median of 13 seizure-free days in the placebo group.

The most common adverse events in the fenfluramine group were decreased appetite, fatigue, diarrhea, and pyrexia.

The main limitation of the study was its short duration. We don't know if these findings will hold up in two to five years, which is important given the drug was withdrawn for safety reasons in the 1990s, said Dr. Knupp.

In the meantime, many children from both phase 3 trials are continuing to take fenfluramine in an open-label trial that will shed further light on the drug's safety.

The most important finding is that in yet another study fenfluramine has demonstrated very potent antiseizure effects in children with Dravet syndrome. The novel finding is that this effect is also true for children already taking stiripentol, said Orrin Devinsky, MD, FAAN, professor of neurology, neurosurgery, and psychiatry at NYU Langone School of Medicine and director of NYU Langone's Comprehensive Epilepsy Center, in an email.

The study provides even more compelling evidence that fenfluramine is a very effective medication in this population, Dr. Devinsky said.

We have studied fenfluramine and have found it one of the most efficacious drugs we have ever used, he added.

Dr. Devinsky noted that the medication is safe; he pointed out that discontinuation rates of children were low, at less than 10 percent, due to their experiencing side-effects such as weight loss due to decreased appetite.

This is an exciting new possibility. I was surprised by how effective fenfluramine was in children who had failed any number of medications before. This is significant because frequent seizures are a strong risk factor for unexpected death in epilepsy, said David Gloss, MD, FAAN, chair of neurology at Charleston Area Medical Center in West Virginia, who was not involved in the study.

Dr. Gloss said the benefits of having the drug available to treat such a treatment-resistant condition as Dravet syndrome may outweigh the harms of possible side-effects.

We are always concerned about side-effects but I think most parents of children with this syndrome would be less concerned about weight-loss or fatigue than the frequency and risk of uncontrolled convulsive seizures. I am always transparent with parents about the side-effects and let them decide.

Dr. Gloss would like to see the FDA approve the drug. Based on the study results, I think that it's safe and effective enough for practitioners to start using. But, because of the small sample size, it's not clear yet whether it will be a gamechanger. I would like to see the results of a larger ideally longer study first.

Dr. Knupp has received research funding from the Pediatric Epilepsy Research Foundation, West Therapeutics, and Zogenix. She has received consulting fees from Zogenix, BioMarin, Biocodex, Stoke, Encoded, and fees for serving on the data safety monitoring board for GW Pharma. Dr. Devinsky receives grant support from NINDS, the National Institute of Mental Health, the Department of Defense Multidisciplinary University Research Initiative, Centers for Disease Control and Prevention, and National Science Foundation. He has equity and/or receives compensation from Privateer Holdings, Tilray, Receptor Life Sciences, Qstate Biosciences, Tevard, Empatica, Engage, Egg Rock/Papa & Barkley, Rettco, SilverSpike, and California Cannabis Enterprises. He has also received consulting fees from GW Pharma, Cavion and Zogenix. Dr. Gloss disclosed no competing interests.

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