FDA Approves New Therapy for Dravet Syndrome

FDA Press Release

On June 25, 2020, the U.S. Food and Drug Administration approved Fintepla® (fenfluramine) for the treatment of seizures associated with Dravet syndrome in patients age 2 and older.

“Dravet syndrome is a debilitating disease that takes a tremendous toll on both patients and their families,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Fintepla offers an additional effective treatment option for the treatment of seizures associated with Dravet syndrome. The FDA will continue to work with companies on drug development for Dravet syndrome and other types of epilepsy.”

The effectiveness of Fintepla for the treatment of seizures associated with Dravet syndrome was demonstrated in two clinical studies in 202 subjects between ages 2 and 18. The studies measured the change from baseline in the frequency of convulsive seizures. In both studies, subjects treated with Fintepla had significantly greater reductions in the frequency of convulsive seizures during the trials than subjects who received placebo (inactive treatment). These reductions were seen within 3-4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.

Fintepla labeling includes a boxed warning stating the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH). Because of these risks, patients must have cardiac monitoring using echocardiograms performed before treatment, every six months during treatment, and once three to six months after treatment is discontinued. If the echocardiogram shows signs of VHD, PAH, or other cardiac abnormalities, health care professionals must consider the benefits and risks of continuing treatment with Fintepla for the patient.

Because of the risks of VHD and PAH, Fintepla is available only through a restricted drug distribution program, under a risk evaluation and mitigation strategy (REMS). The Fintepla REMS requires health care professionals who prescribe Fintepla and pharmacies that dispense Fintepla to be specially certified in the Fintepla REMS and that patients be enrolled in the REMS. As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive Fintepla.

The most common adverse reactions in clinical studies were decreased appetite; drowsiness, sedation and lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue or lack of energy; ataxia (lack of coordination), balance disorder, gait disturbance (trouble with walking); increased blood pressure; drooling, salivary hypersecretion (saliva overproduction); pyrexia (fever); upper respiratory tract infection; vomiting; decreased weight; risk of falls; and status epilepticus.

The FDA granted this application Priority Review. Fintepla received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Fintepla to Zogenix, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Body Cooling May Shorten Refractory Seizures in Dravet and Other Epilepsies

Summary

A study published in the Biomedical Journal shows that therapeutic hypothermia — based on lowering the body’s temperature — can shorten the duration of long-lasting seizures in drug-resistant forms of epilepsy, including Dravet syndrome.

Refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) are two of the most severe types of drug-resistant convulsive seizures. RSE seizures are those lasting more than one hour despite treatment with first- and second-line AEDs, while SRSE seizures last or return over a period of more than 24 hours after the patient is placed under general anesthesia. Both RSE and SRSE seizures are normally managed with anesthetic agents like propofol, midazolam, barbiturate, or ketamine, but these medications achieve a therapeutic effect in only 64–78% of patients. Thus, alternative therapeutic approaches with better efficacies are needed for patients with RSE/SRSE,” the researchers wrote.

Therapeutic hypothermia (TH), a form of therapy used to prevent organ and neuronal damage, has previously been used as a complementary treatment for RSE seizures.

However, studies assessing TH’s effectiveness in controlling seizures have had variable results, particularly those concerning children. Thus, a team of researchers in Taiwan carried out a retrospective study to compare clinical outcomes between a group of children experiencing RSE/SRSE seizures and given TH therapy with a group who were not.

Children given therapeutic hypothermia as an add-on therapy had shorter seizures compared to those who only received anticonvulsants (an average of 24 hours vs. 96 hours). Moreover, children in the TH group had milder neurological impairments compared with those in the control group, indicative of better long-term clinical outcomes. Later chronic refractory epilepsy was reported in less than half (45%) of the TH group children, whereas all in the control group developed this form of epilepsy after one year of follow-up. Duration of stay in a pediatric intensive care unit was similar in both groups.

According to the researchers, therapeutic hypothermia was found to be “safe for use in pediatric patients with RSE/SRSE.” This study shows that “shortened seizure durations in the acute symptomatic phase of SE can reduce the occurrence of post-status epilepticus epilepsy and improve patients’ long-term functional outcomes.”

Importance of Prompt Diagnosis in Pediatric Epilepsy Outcomes

Abstract

Purpose: Recognition of childhood epilepsy has improved worldwide, and children with epilepsy require immediate healthcare evaluation and monitoring. The interval between the onset of the first seizures and pediatric neurology assessment may influence the epilepsy outcome at follow-up assessments. This study aimed to assess the quality of medical care for children with first seizure onset and determine the impact of pediatric neurology clinic waiting times on epilepsy outcomes.

Methods: This was a retrospective cohort study based on chart reviews and included patients who underwent their first seizure evaluation at the Royal University Hospital in Saskatoon, Canada between January 1, 2012 and December 31, 2015. Waiting time (the time interval between seizure onset and the first clinical assessment) and baseline factors were examined in relation to epilepsy outcome on follow-up.

Results: Of a total 1157 patients evaluated for epilepsy for the period 2012-2015, 197 patients (~17%) had unprovoked seizures and were eligible for this study. The average age of the patients at seizure onset was 5.6 years, with average waiting and follow-up times of 4.33 months and 20.9 months, respectively. Shorter waiting times in the clinic led to a more favorable seizure outcome. Of the 197 assessed at the last seizure assessment, 132 (67%) patients had a favorable epilepsy outcome with no seizures at follow-up appointments and 65 (33%) showed an unfavorable epilepsy outcome with persistent seizures at follow-up appointments.

Conclusion: Early assessment of first seizure onset is crucial for the management of children with epilepsy. Waiting time and other factors may influence epilepsy outcome and thus represent opportunities to improve standard medical care.

Doctor sits with little boy in the hospital bed, showing him information on a tablet.

Importance of Prompt Diagnosis in Pediatric Epilepsy Outcomes

Abstract, published in Seizure

Purpose: Recognition of childhood epilepsy has improved worldwide. Children with epilepsy require immediate healthcare evaluation and monitoring. The interval between the onset of the first seizures and pediatric neurology assessment may influence the epilepsy outcome at follow-up assessments. This study aimed to assess the quality of medical care for children with first seizure onset and determine the impact of pediatric neurology clinic waiting times on epilepsy outcomes.

Results: Of a total 1157 patients evaluated for epilepsy for the period 2012-2015, 197 patients had unprovoked seizures and were eligible for this study. The average age of the patients at seizure onset was 5.6 years, the average waiting time was 4.33 months, and the average follow-up time was 20.9 months. Shorter waiting times in the clinic led to a more favorable seizure outcome. Of the 197 assessed at the last seizure assessment, 132 (67 %) patients had a favorable epilepsy outcome with no seizures at follow-up appointments and 65 (33 %) showed an unfavorable epilepsy outcome with persistent seizures at follow-up appointments.

Conclusion: Early assessment of first seizure onset is crucial for the management of children with epilepsy. Waiting time and other factors may influence epilepsy outcome and represent opportunities to improve standard medical care.

Autism and Seizures May Share Roots in Development

Early behavioral signs predict seizures in autistic children, according to a new study.

Previous work has shown that 5 to 46 percent of people with autism experience seizures. And autistic adults with epilepsy have, on average, less cognitive ability and weaker daily living skills than their autistic peers who do not have seizures.

The new study shows that people with autism who begin having seizures during childhood show small but significant behavioral differences before they ever experience a seizure, compared with those who do not develop epilepsy. They score lower than their peers on measures of quality of life and adaptive behaviors, which include communication, daily living skills, socialization and motor skills. They score higher on a measure of hyperactivity.

The results suggest that seizures and certain behavioral issues in autism could have common origins, says co-lead investigator Jamie Capal, associate professor of pediatrics and neurology at the University of North Carolina at Chapel Hill.

“I think it really does show us that in individuals with autism who eventually have epilepsy, there is some shared mechanism early on that we just haven’t been able to identify,” Capal says.

A blond woman cradles her infant in her arms, trying to soothe them.

Levetiracetam (Keppra®) Versus Phenobarbital (Solfoton®) for Seizures in Newborn Children: A Randomized Controlled Trial

Abstract, published in Pediatrics

BACKGROUND AND OBJECTIVES: There are no US Food and Drug Administration–approved therapies for neonatal seizures, which are seizures that occur in newborn children. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in newborn children. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures.

METHODS: The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment for neonatal seizures of any cause. The primary outcome measure was complete seizure freedom for 24 hours, assessed by independent review of the pattern of brain waves by 2 neurophysiologists.

RESULTS: Eighty percent of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam. A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. Although more adverse effects were seen in subjects randomly assigned to phenobarbital, they were not statistically significant.

CONCLUSIONS: In this phase IIb study, phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.

A mother sits beside he son, consoling him after school.

Study Shows that Mothers, Not Fathers, Bear More of the Impact of Caring for a Child with Dravet Syndrome

Abstract, published in Epilepsy & Behavior

Background: The aim of this study was to understand the impact of Dravet syndrome (DS) on patients with Dravet syndrome and their families, with a focus on the social and economic impact on both mothers and fathers.

Results: Survey responses were available for 91 patients (median age 7.6 years). Total seizure frequency varied from less than 1 to greater than 8 seizures per month, with tonic–clonic and myoclonic being the most frequent seizure types. DS adversely affected concentration, school learning, appetite, sleep, and overall behavior.

Compared with the general population, more parents were married and had higher educational achievement, while monthly net income was similar. Preparation of medication was generally done by the mother and father or the mother only. Most caregivers reported very low or no difficulty with treatment preparation and low or no risk of error. Parents typically spent < 30 min per day on treatment preparation and administration and around 4 hours per week for attending therapy appointments. Although most patients and parents were perceived to have good general health, mothers had a worse perception of their own general health than fathers. Compared with fathers, mothers reported a greater impact of caring for a child with DS on their social life, relationships with family and friends, time and energy, and professional life.

Conclusion: Families caring for a child with Dravet syndrome experience considerable social and economic impact, with an apparent greater burden of care on the mother than the father.

Epilepsy Research Findings: May 2020

In this month’s epilepsy research news, we highlight an unexpected health benefit of epilepsy neurostimulators and report on a potential explanation for the effectiveness of fenfluramine in Dravet syndrome. We also present a study suggesting that people who have achieved long-term seizure freedom should speak with their doctors more often about the possibility of weaning off medications to reduce unnecessary drug burdens.

In addition, given the impact that the COVID-19 pandemic is having on all our lives, we feature two COVID-19 related articles: one examines the psychological well-being of people with epilepsy and the other highlights recommendations for patients, caregivers, and clinicians from a group of well-known neurologists.

Finally, we encourage you to participate in ongoing research about COVID-19’s impact on the rare disease community. Patients and caregivers who take this survey will help the rare disease research community shed light on their needs during the COVID-19 pandemic and future health crises.

Summaries of these articles are presented below:

Research News

  • Neurostimulators and Psychiatric Disorders: Brain wave recordings from responsive neurostimulator systems allow physicians to differentiate seizure-induced neurobehavioral symptoms from those caused by comorbid psychiatric disorders such as anxiety, depression, and psychosis. This additional information can help guide medication or therapy changes to target the psychiatric illness itself instead of similar symptoms brought on by the seizures themselves. Learn More
  • Fenfluramine and Dravet Syndrome: Researchers may have discovered how fenfluramine, which is currently being investigated as an add-on therapy to reduce seizures in people with Dravet syndrome, also seems to promote long-term improvements in cognition, behavior and emotional control. The beneficial effects of seizure reduction and cognitive enhancement may result from the drug’s synergistic effect on two different proteins found on the surface of nerve cells. Learn More
  • Antiseizure Drug (ASD) Withdrawal: A Norwegian survey found that people who have achieved long-term seizure-freedom are not talking to their doctors often enough about a plan for discontinuing drug treatment. This suggests that many patients may be living with an unnecessary drug burden. Learn More
  • COVID-19 and Psychological Distress: A study conducted at the epilepsy center of West China Hospital showed that people with epilepsy suffered from significantly more psychological distress compared to controls. The research found that independent predictors of this distress are time spent paying attention to COVID-19 and a diagnosis of drug-resistant epilepsy. Learn More
  • COVID-19, Epilepsy Management, and Safety: Leading neurologists published two key suggestions on caring for people with epilepsy during the COVID-19 pandemic. First, as much care as possible should be administered at home, including the strategic use of rescue therapies, to keep people out of health care facilities, where they are more likely to encounter COVID-19. Second, to minimize the risk of increased seizure severity or frequency, physicians should ensure that their patients adhere to treatment plans and have a regular supply of medication. Learn More
  • Rare Disease Community and COVID-19, a Survey: A new online survey created by the National Institute of Health aims to find out how the COVID-19 pandemic is impacting individuals with rare diseases, their families, and their caregivers. We encourage you to check it out! Learn More

In case you missed it! Our COVID-19 and Epilepsy Resource Hub is now live with resources to help families understand the potential impacts of COVID-19 on epilepsy care. This resource hub includes a guide to preparing for telehealth visits, recorded Q&A sessions, frequently asked questions, and more. Visit Now

Heart Abnormalities Unlikely behind Sudden Unexpected Deaths in Dravet

Heart abnormalities are unlikely to be the reason behind the high rate of Sudden Unexpected Death in Epilepsy (SUDEP) in people with Dravet syndrome, a new study suggests, though further research is needed. The underlying cause of SUDEP in people with Dravet is unclear, but multiple interconnecting factors are likely at play. Better understanding these factors could aid in the development of strategies to help prevent SUDEP.

Studies in mice have suggested that SUDEP might be related to heart rhythm abnormalities, but it is unclear whether these findings might also translate to human disease.

The new study reports findings from a clinical trial (NCT02415686) in which people with Dravet wore electrocardiogram (ECG or EKG) devices to monitor their heartbeats. The devices were worn daily and continuously recorded data. For each Dravet patient, researchers identified two people who were similar in age and sex to serve as controls.

Researchers looked for seizure-associated heart abnormalities that were more common among the Dravet patients than the controls. Such abnormalities could explain the comparatively high rate of SUDEP in Dravet.

Although some of the findings may warrant further study, the researchers found that none of the seizure-associated heart abnormalities could account for the comparatively high SUDEP rate in Dravet Syndrome.

Study suggests that the dual mechanism of a new antiepileptic drug may explain its effectiveness in Dravet Syndrome

In addition to promoting the release of serotonin, a brain chemical typically associated with feelings of well-being and happiness, fenfluramine also seems to control the activity of sigma-1 receptors found on the surface of nerve cells, a study has found.

This dual mechanism of action is likely responsible for the deep and sustained effectiveness of the medication at reducing the frequency of seizures in children and young adults with Dravet syndrome, researchers noted.

Results of the study, “Fenfluramine acts as a positive modulator of sigma-1 receptors,” were published in the journal Epilepsy & Behavior.