Dr Kelly KnuppKelly Knupp, MD
Zogenix has announced that the top-line results of its phase 3 Study 1601 of its investigational fenfluramine oral solution (Fintepla; also known as ZX008) are positive. The trial met its primary end point in the treatment of patients with Lennox-Gastaut syndrome (LGS).

The  0.7 mg/kg per day dose was observed to be superior to placebo in reducing the frequency of drop seizures, based on the change between baseline, and the titration and maintenance treatment period (P = .0012) in a cohort of 263 patients with uncontrolled seizures. Additionally, the lower dose of fenfluramine—0.2 mg/kg per day—was also linked to a reduction, though nonsignificant, in the frequency of drop seizures between the baseline and treatment periods (P = .0915).

“LGS is a rare and severe form of epilepsy where nearly all patients have highly treatment-resistant and lifelong seizures. As a result, the frequent falls and injuries, and also the cognitive impairment, limit the quality of life for patients and caregivers, even with current treatment options,” Kelly Knupp, MD, MSCS, principal investigator, and pediatric neurologist, Children’s Hospital Colorado, said in a statement. “The results observed in this placebo-controlled study are indicative of the potential of fenfluramine to treat patients with refractory LGS. If approved, FINTEPLA could represent an important new treatment option for these patients and their families in need.”
 
READ MORE: Studies Investigate 2 Doses of Fenfluramine in Dravet Syndrome

Ultimately, the 2-part trial included a double-blind, placebo-controlled assessment of safety, tolerability and efficacy when fenfluramine was added to a patient’s current anti-epileptic regimen (Part 1), and an ongoing, year-long, open-label extension study to evaluate the long-term safety, tolerability and effectiveness of the therapy (Part 2).

Patients were randomized to 3 treatment groups: 0.7 mg/kg/day (for a 26 mg maximum daily dose; n = 87), 0.2 mg/kg/day (n = 89), and placebo (n = 87). At baseline, the median number of drop seizures per month was 77. Baseline was established over a 4-week period, after which patients were titrated to their respective doses over a 2-week period, and then remained on that dose for 12 weeks of maintenance.

The 0.7 mg/kg dose of fenfluramine also demonstrated statistically significant improvements compared to placebo in a number of secondary efficacy measurements, including the proportion of patients with a clinically meaningful reduction, defined as ≥50%, in drop seizure frequency, which occurred in 25.3% of patients on that dose of active treatment compared to 10.3% on placebo (P = .0165).

All told, those administered the 0.7 mg/kg/day dose achieved a median reduction of seizures of 26.5% compared to 7.8% in the placebo group (P = .0012), with parametric analysis determining that those on the higher dose of fenfluramine experienced an overall 26.5% greater reduction in mean monthly drop seizure frequency compared to placebo (P = .0034). For the lower dose group, the median percent reduction in monthly drop seizures from baseline was 13.2%, though this did not achieve statistical significance compared to placebo (P = .0915).

Overall, the therapy was deemed well-tolerated, with a similar adverse event (AE) profile to what has been previously observed in its Dravet syndrome development. The incidence of patients experiencing an AE was 89.7% in the 0.7 mg/kg group, 76.4% in the 0.2 mg/kg group, and 79.3% in the placebo group.

The most common AEs, occurring at a rate greater than 10% were decreased appetite, somnolence, fatigue, vomiting, diarrhea, and pyrexia. Serious AEs occurred at a rate of 11/5%, 4.5%, and 4.6% in the high-dose, low-dose, and placebo groups, respectively, with 6 patients in the high-dose and 4 in the low-dose discontinuing treatment, compared to 1 on placebo.  A single death occurred during the trial in the high-dose group, determined to be sudden unexpected death in epilepsy (SUDEP), and unrelated to the study drug.

The aforementioned Dravet syndrome clinical development program revealed that fenfluramine was effective in treating this other rare epilepsy as well. In September 2019, Zogenix resubmitted its new drug application (NDA) to the FDA for the treatment of seizures associated with the rare epilepsy, supported by data from a pair of phase 3 clinical trials and an interim analysis of an ongoing open-label extension study. The NDA was previously rejected by the agency in April after it determined that the NDA was not sufficiently complete to permit a substantive review.2

In December 2019, data were presented at the 2019 American Epilepsy Society Annual Meeting, in Baltimore, Maryland, suggesting an association between treatment with fenfluramine and a significant reduction in convulsive seizure frequency and improvement in everyday executive function in patients with Dravet.3
REFERENCES
1. Zogenix Announces Positive Top-line Results from Global Pivotal Phase 3 Trial of FINTEPLA® for the Treatment of Lennox-Gastaut Syndrome [press release]. Emeryville, CA: Zogenix; Published February 6, 2020. zogenixinc.gcs-web.com/news-releases/news-release-details/zogenix-announces-positive-top-line-results-global-pivotal-phase. Accessed February 6, 2020.
2. Zogenix resubmits New Drug Application for FINTEPLA for the treatment of Dravet syndrome to U.S. Food and Drug Administration [news release]. Emeryville, CA: Zogenix, Inc; September 26, 2019. globenewswire.com/news-release/2019/09/26/1921144/0/en/Zogenix-Resubmits-New- Drug-Application-for-FINTEPLA-for-the-Treatment-of-Dravet-Syndrome-to-U-S-Food-and-Drug- Administration.html. Accessed February 6, 2020.
3. Bishop KI, Isquith PK, Gioia G, et al. Profound reduction in seizure frequency (>75%) leads to improved everyday executive function: analysis from a phase 3 study of ZX008 (fenfluramine HCL) in children/ young adults with Dravet syndrome. Presented at: American Epilepsy Society 2019 Meeting. December 6-10, 2019; Baltimore, Maryland. Abstract 2.438.