番茄社区

WASHINGTON -- Fenfluramine, the serotonergic agent that was part of the sacked weight-loss combination drug Fen-Phen, has anti-seizure effects in Dravet syndrome, researchers reported here.

In a phase III trial, two doses of ZX008 were better at reducing convulsive seizures than placebo over 14 weeks, Joseph Sullivan, MD, of the University of California San Francisco, reported during a

There was no evidence of valvulopathy during the trial -- a concern given that it was the serotonergic effects of fenfluramine, not the noradrenergic effects of phentermine, that were thought to cause the valvulopathy seen with Fen-Phen. Fenfluramine targets serotonin 5-HT2B receptors, which are abundant in the heart.

Sullivan said the case for using fenfluramine in Dravet was first hinted at by a French neurologist who started using the drug to treat seizures in the 1980s. In 2012, an of patients who'd been on the drug for Dravet for a decade suggested a benefit, spurring the interest of pharmaceutical companies.

Zogenix acquired the current low-dose fenfluramine formulation when it purchased Brabant Pharma in 2014, subsequently conducting open-label trials initially and moving right into phase III, as toxicology and early studies have already been done for the drug's initial FDA approval. Additional juvenile toxicity studies were done in parallel to the phase III, Sullivan said.

The phase III study was a prospective merged analysis of two identical phase III trials totaling 119 pediatric and young adult patients ages 2 to 18 with convulsive seizures who weren't controlled on their current anti-epileptic drug (AED) regimens. They were randomized to placebo or one of two daily doses of fenfluramine (0.2 or 0.8 mg/kg) on top of their current AEDs. Patients first had 2 weeks of titration followed by 12 weeks of maintenance therapy. (The typical fenfluramine dose in adult Fen-Phen regimens was 60-120 mg/day.)

Cardiac valve structure and function and pulmonary hypertension were assessed by echocardiography at baseline, 6 weeks, and 12 weeks. Kids could not have any trace regurgitation to be enrolled in the study.

Monthly mean convulsive seizure frequency at baseline was 46 in the placebo group, 47 in the 0.2 mg/kg group, but only 33 in the 0.8 mg/kg group.

Sullivan reported a significantly greater reduction in the primary endpoint of monthly mean seizures compared for both the 0.8 mg dose compared with placebo (a 64% relative reduction, P<0.001) and the 0.2 mg/kg dose over placebo (34% relative reduction, P=0.019).

Median seizure reduction from baseline was greater with both drugs, but was only significant for the 0.8-mg/kg dose group (72.4% versus 17.4%, P<0.001). The lack of significance with the 0.2-mg/kg dose (37.6% reduction from baseline) was driven by some outliers, Sullivan said.

They also found that significantly more patients treated with both doses the drug achieved at least a 25%, 50%, or 75% reduction in convulsive seizure frequency over baseline, with significantly greater odds of achieving a clinically meaningful (≥50%) or substantial (75%) reduction in convulsive seizure frequency compared with placebo (70% versus 7.5%, OR 29.1, P<0.001 and 45% versus 2.5%, OR 49.5, P=0.001, respectively).

Also, the proportion of patients having no seizures or only one seizure during the study period was significantly greater in both drug groups: 25% with 0.8 mg/kg and 12.8% with 0.2 mg/kg compared with none in the placebo group.

Investigators and parents were far more likely to rate the patients as "very much improved" or "much improved" as measured by Clinical Global Impression of Change if they were on the drug, Sullivan added.

One of the most common side effects was decreased appetite (37.5% for 0.8 mg/kg and 20.5% for 0.2 mg/kg vs 5% for placebo), which "doesn't come as a surprise given that it was used as a weight-loss drug," Sullivan said. "Interestingly, the proportion of patients with weight loss was lower than that for decreased appetite, suggesting that appetite reduction dose improve as they acclimate to the drug." Weight decrease was seen in 5% of those on the 0.8 mg/kg dose, 12.8% of those on the 0.2 mg/kg dose, and none of those in the placebo group.

There were no cases of FDA-defined cardiac valvulopathy during the trial, but rates of trace mitral or aortic regurgitation were 12.5% in the placebo group, 17.9% with 0.2 mg/kg fenfluramine, and 22.5% with 0.8 mg/kg, which "supports what all our cardiology colleagues tell us, that this is a normal physiologic change over time," Sullivan said. "If you do an echocardiogram on a child every 6 weeks, you're going to see these little squeaks."

Also, there was no evidence of pulmonary hypertension, he added.

An open-label extension phase is ongoing, and a second pivotal phase III trial is planned to be fully enrolled by the end of the month, with top-line results expected in June, Sullivan said. Both doses are expected to be evaluated, because the lower dose does have evidence of efficacy, and there "seems to be a dose-response with some adverse effects, so if we can get away with the low dose, we should do so," he said.

Gregory Krauss, MD, of Johns Hopkins University in Baltimore, who wasn't involved in the study, applauded the "careful echo monitoring for valve thickening," which was not reported in the phase III poster.

"Mild valve changes are common with chronic fenfluramine treatment," Krauss told 番茄社区. "This is similar to vigabatrin orphan therapy for infantile spasms, where the severity of the disorder justifies possible therapy with careful safety monitoring."

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