Old drug offers new hope for children with devastating disorder

December 17, 2019

A drug that once helped obese adults lose weight, but was withdrawn from the market due to heart risks, may be safe and effective for children with a life-threatening seizure disorder called Dravet syndrome, say researchers from UCSF Benioff Children's Hospitals and other major treatment centers.

The drug fenfluramine -- one half of the discontinued prescription weight-loss cocktail fen-phen -- was developed for pediatric use and found to decrease the number of seizures by more than half for many Dravet syndrome patients, according to their study, which publishes in The Lancet on Dec. 17, 2019.

The 119 study participants were between 2 and 18 years old, with an average age of 9 years, and were diagnosed with Dravet syndrome, a treatment-resistant form of epilepsy that develops in infancy and affects one in 15,700 babies born each year. The syndrome is characterized by prolonged and frequent seizures, developmental delays, speech impairments, sleep disturbances, and behavioral and health issues. Tragically, some 10 to 15 percent of Dravet patients die by age 25 from so-called sudden unexpected death, which may be due to seizure-triggered irregular heart rhythm or suffocation.

"If children with Dravet syndrome can be diagnosed and effectively treated when they are young, they may be spared further neurodevelopmental delays caused by repeated seizures," said co-first author Joseph Sullivan, MD, professor of neurology and pediatrics at UCSF Benioff Children's Hospitals, and director of the Pediatric Epilepsy Center of Exellence. "The results of this study may have significant quality-of-life implications for patients with Dravet syndrome and their families."

The participants, who had an average of 40 convulsive seizures in the month before the trial, despite their current medication regimen, were enrolled at hospitals in the United States, Canada, Australia and Europe. They were assigned to one of three groups in this phase 3 trial: 0.7mg/kg/day of fenfluramine, with a maximum daily dose of 26 mg per day; a lower dose of 0.2 mg/kg/day; or placebo, along with their current medications.

Higher Study Dose Means Fewer Seizures

The researchers found that patients who received the higher of the two study doses had 62 percent fewer convulsive seizures per month than those on placebo, and that those on the lower dose had 32 percent fewer convulsive seizures per month than the placebo participants. The average longest seizure-free interval was 25 days for the higher-dose group, 15 for the lower-dose group and nine days for those on placebo.

For parental assessment of improvements, 22 of 40 parents (55 percent) whose children participated in the higher-dose cohort said that their children were "much improved" or "very much improved," versus 16 of 39 parents (41 percent) in the lower-dose group and four of 40 parents (10 percent) whose children had taken placebo.

The researchers acknowledged that fenfluramine had been withdrawn from the market by the U.S. Food and Drug Administration in 1997, due to reports in some patients of damage to heart valves.

"This was a concern, but we knew the drug used in this study had undergone tests to enable pediatric use and that patients would be followed closely as part of the study," said Sullivan, who was the principal investigator in the North American study sites. "At the start of the study, when I asked parents what they would do if their child developed heart valve abnormalities, yet had significantly fewer seizures, they said they were willing to accept some risk. They knew that every seizures comes with the risk of sudden unexpected death."

To minimize risk, the children were exempted from the trial if heart valve irregularities were spotted via electrocardiogram at the screening visit, even though these findings are considered by most cardiologists to be normal. Additionally, the maximum daily dose in the study was capped at 26 mg, versus doses of 52-to-104 mg or more for the adults who took fenfluramine as part of the weight loss combination prescription fen-phen.

No cases of heart valve damage or pulmonary hypertension were identified during the 14-week trial, nor in the ongoing open-label extension trial with many patients taking the study drug for more than one year.

Weight Loss, Lethargy, Sleepiness are Side Effects

Most side effects were mild-to-moderate and were evenly distributed among the higher-dose, lower-dose and placebo groups. However, weight loss was evident in the fenfluramine groups: eight of 40 patients (20 percent) in the higher-dose group lost weight, ranging from 7.2 percent to 11.4 percent of their body weight, compared with five of 39 patients (13 percent) in the lower-dose group. Those children's weight loss ranged from 8.4 percent to 21.9 percent of their body weight. The authors note that in this latter case, the patient had been "actively managed for obesity by a nutritionist."

Cases of diarrhea, lethargy and sleepiness were also higher in the two fenfluramine groups than in the placebo patients.

Sullivan said a reduction in the number of seizures was "tremendously encouraging for patients and families." This was reinforced by the experience of Dravet patients in Belgium, where fenfluramine was approved for compassionate use in 2002. "Some of these patients have been taking fenfluramine for up to 30 years, with sustained, clinically meaningful reductions in seizure activity without evidence of cardiopulmonary disease," he said.
Authors: Co-first author is Lieven Lagae, MD, of the department of pediatric neurology, University of Leuven, Belgium. Senior author is Berten Ceulemans, MD, of the department of pediatric neurology, University of Antwerp, Belgium. A complete list of the 17 U.S. and Belgian co-authors can be found in the paper.

Funding and Disclosures: The trial was sponsored by Zogenix, Inc., a global pharmaceutical company that develops therapies for rare diseases. Zogenix designed the study with input from investigators. Sullivan serves on the Dravet Syndrome Foundation Medical Advisory Board, but does not receive payments or consulting fees.

About UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF's primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. Learn more at https://www.ucsf.edu, or see our Fact Sheet.

University of California - San Francisco

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