The positive top-line data from Study 3 revealed that children with Dravet syndrome experienced more than a 60% greater reduction in mean monthly convulsive seizures compared to placebo.
Zogenix has announced that the top-line results of its third phase 3 study—aptly named Study 3—of fenfluramine (Fintepla) in patients with Dravet syndrome are positive, corroborating the findings of the 2 prior phase 3 trials, Study 1 and Study 2.
Ultimately, the international, randomized, double-blind trial included 143 children and young adults and revealed that those treated with 0.7 mg/kg per day fenfluramine experienced a 64.8% greater reduction in mean monthly convulsive seizures compared to the placebo group (P <.0001). The median reduction in the monthly frequency of convulsive seizures was 73.7% for the fenfluramine group. Comparatively, the placebo group experienced a 7.6% monthly reduction.
The study also expanded the evaluation of fenfluramine to more locales, this time including patients from Japan, in line with the company’s plans to submit a new drug application (J-NDA) there for the oral agent in 2021. The agent was approved in the US for the treatment of Dravet syndrome in June 2020.
“There remains a substantial unmet need in the Dravet treatment landscape globally and these compelling results corroborate the substantial levels of seizure control provided by Fintepla in Dravet syndrome that was also demonstrated in Studies 1 and 2,” said Stephen J. Farr, PhD, president and CEO, Zogenix, in a statement. “Importantly, Study 3 included subjects from Japan and, based on our prior discussions with Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), should meet the requirements to serve as the pivotal study for a J-NDA submission. We are excited to work with our commercialization partner in Japan, Nippon Shinyaku, to leverage their expertise and commitment to rare diseases to provide Fintepla, if approved, as a potential new treatment option for patients and their families.”
The median age of patients in Study 3 was 9 years (range, 2–18) and the average baseline convulsive seizure frequency across the study groups was approximately 63 seizures per month. After a 6-week baseline observation period, patients were randomized to 1 of 3 treatment groups: 0.7 mg/kg per day (n = 49), 0.2 mg/kg per day (n = 46), or placebo (n = 48). Patients were titrated to their target dose of FINTEPLA over 2 weeks and then remained at that fixed dose for 12 weeks (26-mg maximum daily dose).
The lower dose group, in comparison with placebo, achieved a 49.9% greater reduction in mean monthly convulsive seizures (P <.0001), measured as a key secondary objective. Collectively, these top-line data are highly consistent with the results of Study 1 in demonstrating a dose-response relationship for the agent in the treatment of convulsive seizures in Dravet syndrome.
Additional key secondary objectives of the study were to compare the 0.7 mg/kg per day dose and the 0.2 mg/kg per day dose (independently) with placebo in terms of the proportion of patients who achieved ≥50% reductions in monthly convulsive seizures and who achieved ≥75% seizure reductions, as well as the median of the longest convulsive seizure-free interval.
All told, 72.9% of those in the high-dose group (P <.0001) and 45.7% of the low-dose group (P <.0010) achieved a ≥50% reduction of monthly convulsive seizures, compared to 6.3% of placebo patients. The high- and low-dose groups achieved ≥75% reduction at rates of 47.9% (P = .0001) and 28.3% (P = .0047), respectively, compared to 4.2% in the placebo group.
The longest seizure-free interval in the 0.7 mg/kg per day group was 43 days (P <.0001), in the 0.2 mg/kg per day group was 24 days (P <.0010), compared to the placebo group’s 13.3 days.
“Dravet syndrome is a rare, highly refractory form of childhood-onset epilepsy marked by frequent and often prolonged seizures that are difficult to control with existing medications,” said principal investigator Joseph Sullivan, MD, professor of neurology and pediatrics, and director, Pediatric Epilepsy Center of Excellence, UCSF Benioff Children's Hospitals, in a statement. “Given the profound reductions in convulsive seizure frequency seen across clinical studies, combined with the ongoing, robust safety monitoring that will be part of this medicine’s use, I continue to believe that it will offer an extremely important treatment option for Dravet syndrome patients, and bring new hope to families around the world living with the severe effects of this disease.”
As for safety, the agent was generally well-tolerated in Study 3, with adverse events (AEs)consistent with those observed in the prior studies. The incidence of treatment-emergent AEs was higher in the treatment groups as compared to the placebo group, with 91.7% (n = 44) of patients in the high-dose group and 91.3% (n = 42) of patients in the low-dose group experiencing ≥1 compared to 83.3% (n = 40) of patients in the placebo group.
The incidence of serious AEs was similar in every group, with 6.3% (n = 3) and 6.5% (n=3) of patients in the high- and low-dose groups, respectively, experiencing ≥1 treatment-emergent serious AE compared to 4.2% (n = 2) of patients in the placebo group. One placebo patient died due to sudden unexpected death in epilepsy (SUDEP). Prospective cardiac safety monitoring throughout the study showed that no study patients developed valvular heart disease or pulmonary arterial hypertension.
“On behalf of everyone at Zogenix, I would like to extend sincere gratitude to the patients, families and investigators involved in this study. With Fintepla now commercially available in the US and under regulatory review in Europe, we are excited to continue our work to bring Fintepla to patients in additional countries over time,” Farr said.