Investigational Drug Study Leads to FDA Approval for Fenfluramine in Treatment for Dravet Syndrome

Children who experience seizures associated with Dravet syndrome have a new medication option, thanks to research at CHOC Children’s that helped gain the recent approval of the U.S. Food and Drug Administration (FDA).

Dravet syndrome is a sodium channelopathy that causes an intractable, difficult-to-control form of epilepsy beginning in the first year of life, as well as significant developmental and motor impairments. Many patients with this rare and severe type of epilepsy experience prolonged and unrelenting seizures and are at risk for SUDEP (sudden unexpected death in epilepsy).

Dravet syndrome is difficult to treat with the antiepileptic medications currently available in the United States, but the FDA has recently approved FINTEPLA® (fenfluramine) for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older. Dr. Mary Zupanc, pediatric epileptologist and co-medical director of the CHOC Children’s Neuroscience Institute, was a key investigator in one of the two international drug studies that led to U.S. FDA approval.

Dr. Mary Zupanc
Dr. Mary Zupanc, pediatric epileptologist and co-medical director of the CHOC Children’s
Neuroscience Institute

“The drug we recently trialed, fenfluramine, showed a significant reduction in convulsive seizures and overall seizures, which helped improve the quality of life not only for patients with Dravet but for their families as well,” Dr. Zupanc said.

Study 1 trialed 0.2 mg/kg/day or 0.7 mg/kg/day. The patients on the higher dose had a 70% reduction relative to placebo in monthly convulsive seizure frequency. And 70% of the patients on the higher dose had at least a 50% reduction in their monthly convulsive seizures compared to 7.7% of patients on placebo. Patients on the lower dose of fenfluramine had a 31.7% reduction relative to placebo in monthly convulsive seizure frequency, and 34.2% of patients on the lower dose had at least a 50% reduction in their monthly convulsive seizures.

In addition to reducing the monthly convulsive seizure frequency in patients whose seizures were not adequately controlled on one or more antiepileptic drugs, most study patients responded to treatment with fenfluramine within three to four weeks, and the effects remained consistent over the treatment period. Dr. Zupanc remarked that fenfluramine’s effectiveness could be “life-changing” for patients with Dravet.

Fenfluramine — used on its own and also paired with phentermine in the popular weight-loss combination known as “fen-phen” — was withdrawn from the U.S. market in 1997 after reports of heart valve disease and continued findings of pulmonary hypertension. Due to these risks, subjects received frequent EKGs and echocardiograms throughout the investigational trial. No valve disease or hypertension was found, but a decrease in appetite and some observations of a minor increase in irritability were noted.

Dr. Zupanc is optimistic about fenfluramine’s application for Dravet, but advised that it is only part of an overall treatment plan. “If a physician has a patient with Dravet syndrome, I would make sure the patient gets referred to a Level 4 epilepsy program, the highest designation for epilepsy centers,” Dr. Zupanc said. “CHOC is a level 4 epilepsy center, which means we do investigational drug studies, vagus nerve stimulation, epilepsy surgery, ketogenic diet and provide a full-service epilepsy program with six epileptologists with board-certification in epilepsy. Because we have participated in these [investigational] studies, we are on the ground floor and know how to dose these drugs and adjust these medications.”

Our Care and Commitment to Children Has Been Recognized

CHOC Children’s Hospital was named one of the nation’s best children’s hospitals by U.S. News & World Report in its 2020-21 Best Children’s Hospitals rankings and ranked in the neurology/neurosurgery specialty.

Learn how CHOC’s neuroscience expertise, coordinated care, innovative programs and specialized treatments preserve childhood for children in Orange County, Calif., and beyond.

Leading-edge biomarker research aids in infantile spasms management

The CHOC Children’s Neuroscience Institute has partnered with the Pediatric Epilepsy Research Consortium (PERC) to advance treatment for infantile spasms.

PERC is a national consortium inclusive of more than 54 epilepsy programs, with 25 centers collaborating on infantile spasms research.

“PERC’s inception 10 years ago was born out of the American Epilepsy Society and a select team of specialists interested in building a wider network and infrastructure for large-scale clinical trials. Many diseases, like infantile spasms, are rare, and collaboration within PERC offers a wider patient pool for researching such uncommon conditions,” says Dr. Daniel Shrey, pediatric epileptologist at CHOC.

Dr. Daniel Shrey, Pediatric Epileptologist at CHOC Children's
Dr. Daniel Shrey, pediatric epileptologist at CHOC Children’s

Dr. Shrey was recently selected to lead PERC’s infantile spasms sub-group. In his new role, he is coordinating efforts between over a dozen pediatric epilepsy centers to catalyze multi-centered research on infantile spasms, a devastating type of epilepsy that typically begins in the first year of life.

Much of the current research on infantile spasms focuses on the visual analysis of a patient’s EEG, whereas Dr. Shrey’s research uses a computational approach. His research uses various mathematical tools to analyze neural data and identify new biomarkers of disease. Most of this work is done in collaboration with Dr. Beth Lopour, assistant professor of biomedical engineering, who leads the Laboratory of Computation and Translational Neuroscience at the University of California, Irvine.

“A novel biomarker we are studying is functional connectivity — measuring how activity in one part of the brain impacts another. We use characteristics of the brain network to predict how patients are likely to respond to treatment, compared to visual measures alone,” Dr. Lopour says.

She and her students develop computer code and perform data analysis for their research.

“This approach removes human interpretation and natural biases to instead focus on the data to make clinical decisions,” Dr. Shrey says.

Biomarkers also advance research by beginning to tell researchers how a disease responds to treatment and evolves over time. Discovering and validating a biomarker opens the possibility for a future clinical trial for patients with rare diseases.

The PERC infantile spasms group combines specialists in biomarker research, genetics, RNA genetics and brain inflammation, among others. In the future, the epilepsy field will look to quantitative approaches to guide clinical decision-making, ultimately improving the lives of children with epilepsy.

Learn how CHOC’s neuroscience expertise, coordinated care, innovative programs and specialized treatments preserve childhood for children in Orange County, Calif., and beyond.

CHOC recognized as one of nation’s best children’s hospitals

CHOC Children’s is one of a select group of pediatric facilities nationwide to have been ranked today as a best children’s hospital by U.S. News & World Report.

The following CHOC specialties are honored in the 2020-21 Best Children’s Hospitals rankings: neonatology; cancer; diabetes and endocrinology; neurology and neurosurgery; orthopaedics; pulmonology; and urology. Both orthopaedics and diabetes and endocrinology earned a “Top 20” spot.

“At CHOC, we are committed to the highest standards of care, safety and service – and this honor reflects that unwavering dedication,” said Dr. James Cappon, CHOC’s vice president, chief quality and patient safety officer and interim chief medical officer. “Not only does this recognition of our excellence in these subspecialties, including two on the top 20 lists, validate our efforts, but it also offers our patients and families additional assurance of our commitment to their health and safety.”

The Best Children’s Hospitals rankings were introduced by U.S. News in 2007 to help families of children with rare or life-threatening diseases find the best medical care available. Only the nation’s top 50 pediatric facilities are distinguished in 10 pediatric specialties, based on survival rates, nurse staffing, procedure and patient volumes, reputation and additional outcomes data. The availability of clinical resources, infection rates and compliance with best practices are also factored into the rankings.

The U.S. News Best Children’s Hospitals rankings rely on clinical data and on an annual survey of pediatric specialists. The rankings methodology factors in patient outcomes, such as mortality and infection rates, as well as available clinical resources and compliance with best practices.

Learn more about Best Children’s Hospitals rankings.

Seizure-free after a rare epilepsy diagnosis

Thanks to the expertise of a CHOC Children’s epileptologist, a 12-year-old boy diagnosed with a rare type of epilepsy is seizure-free and has a bright future ahead – the significance of which is underscored in November, Epilepsy Awareness Month.

Gabriel Lucak had been a healthy, normally developing child until age 3, when he suddenly began experiencing seizures.

CHOC Children's Neuroscience Institute patient Gabriel Lucak poses by the ocean
CHOC Children’s Neuroscience Institute patient Gabriel Lucak

What began as a tonic-clonic seizure in May 2008 rapidly progressed to include myoclonic, atonic, and atypical absence seizures. On his worst days, Gabriel experienced up to 50 seizures a day.

“It was like living out a surreal nightmare,” said his mother, Nicole.

Gabriel was initially diagnosed with myoclonic-astatic epilepsy, also known as Doose syndrome. His seizures were difficult to control, and doctors attempted many different treatments, including eight months on a ketogenic diet. During this time, Gabriel was hospitalized numerous times to modify his medication and control his seizures.

Searching for answers

A low point for the Lucak family came about nine months after the seizures began. While hospitalized for respiratory syncytial virus, Gabriel’s seizures increased significantly. An electroencephalogram (EEG) recorded seizures occurring about once a minute and a slowing brain wave frequency. Magnetic resonance imaging (MRI) revealed decreased brain volume. Gabriel’s health was rapidly deteriorating.

Joe and Nicole desperately began looking elsewhere for help, and in March 2009 found a beacon nearly 1,400 miles away in Dr. Mary Zupanc, a pediatric neurologist and one of the nation’s leading epileptologists, who was then practicing in Wisconsin.

Under Dr. Zupanc’s care, Gabriel was placed on a new treatment program. He stopped following the ketogenic diet and began taking a new antiepileptic medication. He underwent a two-week long-term video EEG monitoring study, which revealed he was experiencing a fifth type of seizure – tonic – during sleep.

CHOC epileptologist Dr. Mary Zupanc holds a model of a human brain..
CHOC Children’s pediatric epileptologist Dr. Mary Zupanc

A new diagnosis

Dr. Zupanc then knew that Gabriel’s epilepsy had evolved into a more severe form called Lennox-Gastaut syndrome (LGS). This rare type of epilepsy is marked by seizures that are difficult to control, and typically persist through adulthood.

In addition, Dr. Zupanc diagnosed Gabriel with cerebral folate deficiency, a rare metabolic condition, following a spinal tap and extensive testing on his cerebral spinal fluid. He immediately began taking a folinic acid supplement and following a strict dairy-free diet.

Under this new treatment plan, Gabriel was seizure-free within two months. A second spinal tap showed a normal level of folate, and another MRI had normal results. The Lucaks were thrilled.

“Gabriel could have suffered severe brain damage, or he might not have survived at all,” Nicole said. “That’s how critical it was for us to have found Dr. Zupanc when we did.”

A bright future

Today, Gabriel is an intelligent, creative and artistic 12-year-old who dreams of being a paramedic when he grows up.

He remains under Dr. Zupanc’s care, traveling from San Diego to the CHOC Children’s Neuroscience Institute and its level 4 epilepsy center for appointments and annual long-term EEG monitoring.

Gabriel is also under the care of Dr. Jose Abdenur, chief of CHOC’s metabolics disorders division. Gabriel, his younger brother, Nolan, and his parents have all participated in several research studies involving genetic testing for both epilepsy and cerebral folate deficiency.

Recently, Gabriel was weaned off the antiepileptic medication and continues to be seizure-free.

“He has the opportunity to live a full life in good health, thanks to an amazing series of events that led to experienced doctors, correct diagnoses and effective treatment,” Nicole said.

Learn more about the CHOC Children’s Neuroscience Institute.

Dr. Mary Zupanc: Sharing My Story with Patients

Dr. Mary Zupanc

Undergoing brain surgery herself made Dr. Mary Zupanc a better, more sensitive clinician when working with epilepsy patients, the CHOC Children’s neurologist writes in The New York TimesWell Blog.

Following a late-night seizure and months of seemingly unrelated symptoms, Dr. Zupanc was diagnosed with a bifrontal meningioma in early 2014.

The questions and fear surrounding her subsequent surgery, as well as the recovery process, have clarified Dr. Zupanc’s understanding of the patient and family experience, she writes.

In The New York Times column, Dr. Zupanc tells her story and explains how becoming a patient herself has changed her practice and how she works with patients and families. Read the column to learn more.