Real-world data that were accepted for presentation at the American Academy of Neurology (AAN) 2020 Annual Meeting suggest that those with Dravet syndrome who are treated with fenfluramine (Fintepla; Zogenix) have clinically meaningful responses to the therapy, similar to that observed in clinical trials.1
Conducted by M. Scott Perry, MD, medical director of neurology, and co-director, Jane and John Justin Neurosciences Center, Cook Children’s Hospital, and colleagues, this initial report of the US Expanded Access Program for fenfluramine included 23 patients with Dravet syndrome with a mean age of 6.8 years (range, 2–22), who had been treated for a median of 90 days (range, 30–180). Overall, 65% (n = 15) of the cohort reported meaningful global clinical improvement, defined as a rating of “very much improved” or “much improved.”
Perry and colleagues noted that similar improvements were reported in cognition, behavior, and motor abilities by 56% (n = 13), 43% (n = 10), and 48% (n = 11) of the cohort, respectively.
As for safety measures, the most commonly reported adverse events (AEs) occurring in ≥10% of patients were fever (30%), decreased appetite (17%), and emesis (13%). Most AEs were mild-to-moderate in intensity, and no patients developed valvular heart disease or pulmonary arterial hypertension. There were no discontinuations due to an AE.
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The most common concomitant antiepileptic drugs (AEDs) were clobazam, valproate, stiripentol, and cannabidiol (CBD). Every patient began treatment with fenfluramine at 0.2 mg/kg/day for 14 days, after which doses could be adjusted based on effectiveness and tolerability to a maximum of 0.7 mg/kg/day—not exceeding 26 mg/day. Those treated with stiripentol had a maximum threshold of 0.4 mg/kg/day—not exceeding 17 mg/day. A 7-point Likert scale was used by the treating clinician to assess improvement in global clinical status, cognition, behavior, and motor abilities.
Additionally, Zogenix was set to present data on its ongoing open-label extension study in Dravet syndrome, conducted by Joseph Sullivan, MD, director, Pediatric Epilepsy Center, UCSF Benioff Children’s Hospital, and colleagues, which suggest that over a 2-year period, fenfluramine provided durable and meaningful reductions in monthly convulsive seizure frequency, and was generally well-tolerated.2
On February 15, 2019—the time of the analysis—330 patients with a mean age of 9 years (standard deviation [SD], ±4.6) were enrolled, with a median treatment duration of 445 days (range, 7–899). After 2 years on therapy, the median monthly convulsive seizure frequency was reduced by 83.3% compared with the pre-fenfluramine period for the core-study group’s baseline (P <.001). Over the entire period of therapy, 62% of patients experienced clinically meaningful—defined as ≥50% reduction—and 37% experienced profound—defined as ≥75% reduction—reductions in monthly convulsive seizure frequency.
The most common non-cardiovascular AEs, occurring in ≥15% of patients, were nasopharyngitis (23%), pyrexia (23%), decreased appetite (21%), and diarrhea (15%). Notably, by the most recent visit, 8% of the patients experienced a ≥7% weight loss while 39% gained ≥7% weight, compared to the baseline in the core studies. As was the case in the real-world data, were no echocardiographic or clinical observations of valvular heart disease or pulmonary hypertension at any time during the extension.
At the end of February, the FDA extended the review period for fenfluramine, citing the need for additional time to assess additional data it requested from Zogenix, according to a recent announcement from the company. Its Prescription Drug User Fee Act (PDUFA) action date has been moved to June 25, 2020, a 3-month extension from its original date of March 25. The FDA informed Zogenix that additional data submission has constituted a major amendment to the NDA.3
At the time, Stephen J. Farr, PhD, president and CEO, Zogenix, said in a statement that Zogenix “remain[s] very confident in the data supporting our NDA submission, and look[s] forward to continuing discussions with the FDA during the review process,” noting that they are “committed to bringing this investigational therapy forward to help meet the needs of patients and families with Dravet syndrome.”
Fenfluramine, which was previously known as ZX008, has had an eventful ride on its track to FDA review. Zogenix originally filed its NDA in April 2019, only to receive a refusal to file letter from the agency due to some missing and incorrect datasets. It was resubmitted in September 2019 after the company worked with the agency to clarify the issues identified.
1. Perry MS, Wirrell E, Burkholder D, Galer BS, Gammaitoni A. Real-world Experience with ZX008 (Fenfluramine HCl) for the Treatment of Seizures in Dravet Syndrome: Initial Report from United States Expanded Access Program. Neurology. 2020;94(15 Suppl): 1985.
2. Sullivan J, Suvin S, Pringsheim M, et al. Long-Term (2-Year) Safety and Efficacy of Adjunctive ZX008 (Fenfluramine Hydrochloride Oral Solution) for Dravet Syndrome: Interim Results of an Ongoing Open-Label Extension Study. Neurology. 2020;94(15 Suppl): 4684.
3. Zogenix Announces FDA Extension of Review Period for FINTEPLA® in Dravet Syndrome [press release]. Emeryville, CA: Zogenix; Published February 27, 2020. Accessed April 23, 2020. globenewswire.com/news-release/2020/02/27/1991846/0/en/Zogenix-Announces-FDA-Extension-of-Review-Period-for-FINTEPLA-in-Dravet-Syndrome.html.