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Results of a phase 3, randomized, placebo-controlled trial show fenfluramine “produced a profound reduction in convulsive seizures in many patients, has a fairly quick onset of action, and is durable,” study investigator Bradley S. Galer, MD, chief medical officer of Zogenix, Inc, the manufacturer of the drug, told Medscape Medical News.
The study also showed no cardiovascular side effects, which is important given the history of fenfluramine with respect to the risk of valvular heart disease and pulmonary arterial hypertension (PAH), Galer added.
The study was published online today in JAMA Neurology.
Dravet syndrome (DS) is a rare but severe developmental epileptic encephalopathy that typically presents in the first year of life. It is characterized by frequent, drug-resistant convulsive seizures that may contribute to intellectual disability and impairments in motor control, behavior, and cognition.
In an estimated 70% to 85% of cases, DS is caused by a mutation in the sodium channel, voltage-gated, type I alpha subunit (SCN1A) gene.
It’s not unusual for children with DS to be on three or four antiepileptic drugs (AEDs), said Galer. But even with polypharmacy, seizures remain poorly controlled in most patients.
The antiepileptic drug (AED) stiripentol was approved by the US Food and Drug Administration (FDA) in 2018 for DS but must be coprescribed with clobazam.
Research shows that combination stiripentol therapy reduces seizure frequency, but that most patients continue to experience seizures.
Fenfluramine is as an anorectic agent that was used to treat obesity until it was removed from the market in 1997 because of reports of increased risk of valvular heart disease when prescribed in higher doses (60-120 mg/day) and most often when prescribed with phentermine. The combination of the two drugs was known as “fen-phen.” Cases of PAH were also reported.
Fenfluramine reduces seizures by binding to specific serotonergic receptors. Another potential mechanism is through type 1 sigma receptors.
The multicenter study included 87 patients (57% male, mean age 9.1 years). Participants had to be free of cardiovascular disease and have poorly controlled seizures on their current drug regimen.
At baseline, participants were experiencing high numbers of seizures. Some had previously tried cannabidiol, either Epidiolex (GW Pharmaceuticals) or an artisanal product, said Galer.
Safe, Well Tolerated
Children were randomly assigned to receive fenfluramine twice daily or matching placebo. The fenfluramine starting dose was 0.2 mg/kg/day, with a gradual titration to 0.4 mg/kg/day (maximum 17 mg/day) over 3 weeks.
After the initial titration period, patients received fenfluramine or placebo for an additional 12 weeks and then continued treatment in an open-label extension study or discontinued treatment with a blinded, downward dose-tapering protocol.
A total of 77 participants completed the study. Three in the placebo group and seven in the fenfluramine group withdrew early.
The primary efficacy endpoint was change in mean monthly convulsive seizure frequency (MCSF).
Results showed that patients randomly assigned to fenfluramine achieved an estimated 54% greater reduction in mean MCSF than those who received placebo (95% confidence interval [CI], 35.6% – 67.2%; P < .001).
Significantly more patients in the fenfluramine than the placebo group experienced reductions in MCSF that were clinically meaningful (≥50%; 54% vs 5%, P < .001) and profound (≥75%; 35% vs 2%; P = .003).
This type of response “is quite unheard of for this refractory population,” said Galer.
The fenfluramine group also had significantly longer seizure-free intervals compared with placebo (median 22 days vs 13 days; P = .004). In addition, a significantly greater proportion in this group experienced no more than one convulsive seizure (12% vs 0%; P = .03).
With respect to nonseizure outcomes, significantly more patients in the fenfluramine group were rated by investigators as being “very much” improved or “much” improved.
Caregivers/parents as well as investigators reported statistically significant differences between treatment groups for “any improvement.” The results were similar “regardless of age or gender” of study subjects, said Galer.
Fenfluramine was generally well tolerated. The most common treatment-related adverse events included decreased appetite, pyrexia (fever), fatigue, and diarrhea.
Two patients receiving placebo and nine receiving fenfluramine had weight decreases of 7% or more from baseline. Of these patients, five were also receiving topiramate, another agent with anorectic properties.
Although there was a higher incidence of weight loss in those taking fenfluramine, “we did not have any discontinuations due to weight loss,” said Galer. “Weight has not been a major concern.”
While weight loss may have led to unblinding, the authors noted that a post hoc analysis showed no evidence of this.
Importantly, none of the participants developed valvular heart disease or PAH, and all echocardiograms in all patients demonstrated normal valve function with no abnormal valve morphology.
This supports previous reports of cardiovascular safety in patients with DS at the relatively low doses used for seizure management, said the authors.
The investigators are now looking at the effect of adjunctive fenfluramine on executive function and other cognitive and behavioral benefits in patients with DS, said Galer.
Results of the open label extension trial suggest the drug’s effects are long lasting.
“We are seeing the same consistent effect and it seems to be durable and patients don’t develop tolerance, which seems to happen with other anticonvulsants,” he said.
Top line results of this open label extension trial should be available early next year, said Galer.
Researchers in Belgium, who have 30-year data on fenfluramine in DS, have also observed similar positive results, he added.
Zogenix also has an ongoing phase 3 global trial of fenfluramine in Lennox-Gastaut Syndrome (LGS).
Commenting on the study for Medscape Medical News, Jacqueline French, MD, a professor at NYU Langone Health’s Comprehensive Epilepsy Center in New York City, said the data are “very impressive.”
She noted that the FDA is giving the therapy a priority review and that this is “good sign” for doctors and DS patients. “Clearly, the FDA feels that it’s an important drug to get to the clinic as quickly as is safe and appropriate,” said French, who was not involved with the study.
French pointed out that fenfluramine “is not especially sedating,” which is good news for children with an epileptic encephalopathy. “You don’t want them to be overly sleepy or lethargic.”
On the other hand, children taking this drug need to have regular echocardiograms “in order to make sure that their heart valves are not thickening,” a follow-up protocol that may be difficult for families, said French.
Some people with the SCN1A mutation don’t have DS. “Nobody has tried fenfluramine on those people with the genetic mutation who don’t have DS, but it would be interesting to do that,” said French.
Also commenting for Medscape Medical News, Amy Brooks-Kayal, MD, codirector of the Translational Epilepsy Research Program and chief of pediatric neurology at Children’s Hospital Colorado in Aurora, said these new results “are definitely exciting.”
“Despite several new medications being approved for this condition, a significant proportion of Dravet patients remain medically refractory,” said Brooks-Kayal, who was not associated with the current research. “Having another medication in our armamentarium that can be helpful in the treatment of these patients is most welcome.”
The study was funded by Zogenix. Galer is an employee of and owner of stock from Zogenix. French’s NYU center was one of the study sites, but she reports she was not the investigator. She is the president of the nonprofit Epilepsy Study Consortium that reviewed every case in this study. However, she reports she was not involved in this process. She also reports she has consulted for Zogenix and that the company paid her travel expenses for a trip to Greece to lecture on epileptic encephalopathy trial designs. Brooks-Kayal has disclosed no relevant financial relationships.
JAMA Neurology. Published online December 2, 2019. Full text