WASHINGTON – The oral experimental agent fenfluramine, also known as ZX008, has been associated with a high degree of efficacy and good tolerability for the adjunctive treatment of Dravet syndrome, according to combined results of the first patients enrolled in two phase III trials.
“For me, a highlight of this study is the finding that 45% of patients on the higher dose achieved at least a 75% reduction from baseline in monthly convulsive seizures. This is a life-changing improvement,” reported Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco. He presented the results at the annual meeting of the American Epilepsy Society.
Ted Bosworth/Frontline Medical News
Dr. Joseph Sullivan
“If fenfluramine is approved as an adjunctive agent, it is likely to be introduced as the second or third medication in an effort to gain adequate symptom control,” Dr. Sullivan speculated.
Three phase 3 trials with fenfluramine are underway. The data presented at the American Epilepsy Society meeting were based on the first 119 patients who had participated in either of the two identical trials conducted in Europe and North America. The data from these two trials has now been combined, and the outcomes in the remaining patients in these two trials will be presented at a later time along with results from a third phase 3 study.
Patients between the ages of 2 and 18 years with a clinical diagnosis of Dravet syndrome were eligible for the European and North American trials if they were not controlled on current therapy, which could include multiple agents. However, patients had to be on stable therapies prior to enrollment for at least 4 weeks. Once enrolled, they were observed for 6 weeks prior to randomization.
After randomization to placebo, 0.2 mg/kg fenfluramine, or 0.8 mg/kg fenfluramine, patients completed a 2-week titration before they reached their maintenance dose. They were then evaluated over an additional 12-week treatment period. There were three withdrawals over the course of treatment in the placebo group, none in the lower-dose fenfluramine group, and six in the higher-dose fenfluramine group.
The primary endpoint was change in mean monthly convulsive seizure frequency from the observation period. When compared with placebo, these reductions were 63.9% (P less than .001) in the 0.8-mg/kg group and 33.7% (P = .019) in the 0.2-mg/kg group. When expressed as the median percent reduction in convulsive seizures from the observation period per 28 days, the reductions were 72.4% for the 0.8-mg/kg dose (P less than .001 vs. placebo), 37.6% for the 0.2-mg/kg group (P = .185 vs. placebo), and 17.4% for placebo.
Other efficacy measures supported the relative advantage of fenfluramine. For example, 70% and 41% of the patients in the 0.8-mg/kg and 0.2-mg/kg groups, respectively, versus 8% of placebo patients, had at least a 50% reduction in seizure frequency. Median seizure-free intervals for the three groups were 20.5, 14, and 9 days, respectively. Seizure activity was reduced to one or no seizures over the treatment period in 25% of the 0.8-mg/kg group, 12.8% of the 0.2-mg/kg group, and 0% of the placebo group.
The most common adverse events on the 0.8-mg/kg dose of fenfluramine, compared with placebo, were decreased appetite (37.5% vs. 5%) and lethargy (17.5% vs. 5%). The proportion of patients with weight loss was also greater on 0.8 mg/kg (5%) and 0.2 mg/kg (12.8%) versus placebo (0%). Diarrhea was more common in the 0.2-mg/kg group (30.8%) than in the 0.8-mg/kg group (17.5%) or in the placebo group (7.5%).
Although monitored closely, cardiotoxicity was not observed in this study. Concern about potential cardiotoxic effects was generated by the increased risk of valvular disease observed in patients taking fenfluramine with phentermine (fen-phen) for weight loss in the 1990s. This combination was withdrawn from the market in 1997.
“The potential for cardiotoxicity will continue to be monitored closely, but these initial results were reassuring,” reported Dr. Sullivan, who noted that a history of cardiovascular or cerebrovascular disease were exclusion criteria from this study.
Application for regulatory approval is not anticipated until all the phase 3 trial data are available, but Dr. Sullivan said that the results so far suggest that fenfluramine as an adjunctive agent “may represent a significant advance over existing treatment options for Dravet syndrome.”
The studies are funded by Zogenix. Dr. Sullivan reported financial relationships with Epygenix and Zogenix.