The submission includes findings from Study 1601, along with long-term safety and efficacy data from Zogenix’s ongoing open-label extension trials.
Zogenix has announced that it submitted a supplemental new drug application (sNDA) for fenfluramine (Fintepla), an already FDA-approved treatment for Dravet syndrome (DS), to treat seizures associated with Lennox-Gastaut syndrome (LGS).1
The application was backed by data from the phase 3 Study 1601 (NCT03355209), which met its primary end point, with the treatment demonstrating significant improvement in monthly drop in seizure frequency (MDSF) among a cohort of 263 patients with LGS. Long-term safety and efficacy of fenfluramine in ongoing open-label extension trials were also included in the submission.
"As LGS is a severe, rare form of epilepsy that is not well-controlled by currently available anti-seizure medications, we believe that Fintepla, if approved, would become an important new treatment option that addresses a significant unmet need for this patient population," Gail Farfel, PhD, executive vice president and chief development officer, Zogenix, said in a statement.1 "We would like to thank the LGS patients, families, and healthcare providers who worked tirelessly alongside us to achieve this milestone in Fintepla’s development. We appreciate the FDA’s guidance through the submission process and look forward to continuing to work closely with the Agency during their review of our application."
At the 2020 American Epilepsy Society (AES) Annual Meeting, results from Study 1601 showed that fenfluramine 0.7 mg/kg/day (n = 87) achieved a –19.9% estimated median difference (ESM) from placebo (n = 87) in MDSF from baseline (P = .001).2 The data, presented by Kelly Knupp, MD, pediatric neurologist and epilepsy specialist, Children’s Hospital Colorado, were comparable to the magnitude demonstrated in all other recently completed LGS randomized controlled trials (range, –14.8% to –21.6%).
The ESM in MDSF from baseline for those in the fenfluramine 0.2 mg/kg/day group (n = 89) did not reach statistical significance (–10.5%; P = .09); however, more investigators and caregivers rated patients “much improved” or “very much improved” on clinical global impression of improvement (CGI-I) for both doses compared with placebo. Tonic-clonic seizures, which were documented in 43% of the patient population, were reduced by 45.7% (P = .007) and 58.2% (P <.0001) with treatment of fenfluramine 0.7 mg/kg and 0.2 mg/kg per day, respectively.
Original topline data announced in February 2020 showed statistically significant improvements compared to placebo for those in the 0.7 mg/kg/day group on several secondary efficacy measurements, including the proportion of patients with a clinically meaningful reduction, defined as at least 50% in drop seizure frequency, which occurred in 25.3% of patients compared to 10.3% on placebo (P = .0165).3
Overall, the therapy’s safety profile was well-tolerated and similar to what had been previously observed in studies of DS. The incidence of patients experiencing an adverse event was 89.7% in the 0.7 mg/kg/day group, 76.4% in the 0.2 mg/kg/day group, and 79.3% in the placebo group.
Additional data from Study 1601 was presented at the 2021 American Academy of Neurology Annual Meeting, April 17-22, which demonstrated fenfluramine’s positive impact on everyday function. Using the Behavior Rating Inventory of Executive Function (BRIEF) scale, patients with LGS between 6 to 18 years old showed improvements in each of the 4 BRIEF 2 indexes compared to those on placebo.4 More specifically, there was a 24% improvement in Behavior (placebo, 13%; P = .118), 19% improvement in Emotions (placebo, 16%; P = .665), 27% improvement in Cognition (placebo, 13%; P = .665), and 25% improvement in Global Executive Composite (GEC) overarching summary score (placebo, 11%; P = .034).
NeurologyLive caught up with Knupp at AES 2020 to discuss the findings of the study, including the most notable end points and the importance of the data in patients with LGS. Watch her commentary below, as she explains more about fenfluramine’s robust efficacy.