番茄社区

NEW ORLEANS -- Low-dose fenfluramine (Fintepla; ZX008) continued to show efficacy and safety in children with Dravet syndrome, according to late-breaking findings presented at the meeting here.

A second pivotal phase III study showed that fenfluramine -- the serotonergic agent once used in combination with phentermine ("fen-phen") for weight loss -- again bested placebo in reducing convulsive seizure frequency among Dravet syndrome patients, this time in children taking a background regimen that included stiripentol (Diacomit), reported Kelly Knupp, MD, of Children's Hospital Colorado in Aurora, and co-authors.

This trial, of children and young adults randomized to placebo (n=44) or fenfluramine 0.5 mg/kg/day (n=43), showed a 54% greater reduction in mean monthly convulsive seizures with the active drug than with placebo (P<0.001) over 12 weeks.

Median reduction in monthly convulsive seizure frequency was 63.1% in the fenfluramine group, compared with 1.1% in placebo patients. "No matter how you look at it, there is a significant improvement in seizures," Knupp said in an interview with 番茄社区.

These Dravet syndrome patients, who averaged about age 9, had been on a stable anti-epileptic drug regimen for ≥4 weeks that included stiripentol as well as clobazam and/or valproic acid before starting the trial; some were also on ketogenic diets or used vagus nerve stimulation. earlier this year for Dravet syndrome patients taking clobazam; it was in 2014 as adjunctive therapy for patients using valproate and clobazam.

Like patients in the first phase III trial, these children showed no signs of valvulopathy, an adverse effect linked to fen-phen before it was pulled off the market in 1997.

"The concern given the prior history of the drug was cardiac valvular toxicity," said Jack Parent, MD, of the University of Michigan in Ann Arbor, who was not involved with the study.

"But, the subjects in the recent fenfluramine trials underwent extensive cardiac monitoring with repeated echocardiograms. The researchers found no evidence of significant cardiac valvular abnormalities, specifically valvular regurgitation, during the trials," Parent told 番茄社区.

An interim analysis of an open-label extension of the first phase III trial -- which studied patients on standard anti-seizure medications, but not stiripentol -- also showed no evidence of valvulopathy or pulmonary hypertension in 232 children over a median of 256 days. "These kids are being monitored super-carefully to be sure we are not missing anything," Knupp explained.

The most common side effect of the drug were decreased appetite -- not surprising given its history as a diet drug. "There was some weight loss seen, but overall, the kids have maintained their weight," Knupp noted. A total of 13.4% of children lost >7% body weight at some point during the open-label extension; 42% of those children regained some weight during the period covered by the interim analysis.

The open-label extension analysis also showed that the median percent reduction in monthly convulsive seizures over the entire extension period was 66.8% over baseline, on doses that could be titrated up to 0.8 mg/kg/day. Families also reported seeing meaningful improvements in children's behavior and cognition as their seizure frequency decreased, Knupp added. A total of 9.5% of patients discontinued treatment during the open-label extension period, mainly because the drug stopped working.

Fenfluramine hydrochloride manufacturer Zogenix plans to file a new drug application with the FDA in the first quarter of 2019, a company spokesperson said.