Joseph Sullivan, MDJoseph Sullivan, MD
After pushing back its decision day by 3 months to review additional data, the FDA has approved fenfluramine (Fintepla; Zogenix) for the treatment of Dravet syndrome.1

The rare, pediatric epilepsy syndrome characterized by frequent and severe refractory seizures is typically addressed with a cocktail of anticonvulsants, and more recently with GW Pharmaceutical’s cannabidiol therapy, Epidiolex.

Fenfluramine will be available as an oral solution for patients age 2 and older. The medication does include a boxed warning for risk of valvular heart disease and pulmonary arterial hypertension, and will be distributed through the Fintepla Risk Evaluation and Mitigation Strategy (REMS) Program by the end of July 2020.

“There remains a huge unmet need for the many Dravet syndrome patients who continue to experience frequent severe seizures even while taking one or more of the currently available antiseizure medications,” said Joseph Sullivan, MD, director of the Pediatric Epilepsy Center of Excellence at the UCSF Benioff Children’s Hospitals, in a statement.1 “Given the profound reductions in convulsive seizure frequency seen in the Fintepla clinical trials, combined with the ongoing, robust safety monitoring that will be part of its use, I feel Fintepla will offer an extremely important treatment option for Dravet syndrome patients.”

The approval was based on data from 2 randomized, double- blind, placebo-controlled phase 3 clinical trials, as well as safety data from an open-label extension trial. Study 1 (NCT02682927; NCT02826863)2 evaluated the efficacy and safety of 2 doses of fenfluramine (0.2 mg/kg/d and 0.7 mg/kg/d) versus placebo as adjunctive therapy over 14 weeks in 117 pediatric and young adult patients with Dravet syndrome who were on a stable antiepileptic regimen. Median reduction in seizure frequency was 74.9% in the 0.7 mg group compared with 42.3% in the 2 mg group and 19.2% in placebo, culminating in a 62.3% greater reduction in mean monthly convulsive seizure frequency in the 0.7 mg group compared with placebo (95% CI, 47.7-72.8; P <.0001).

Study 2 (NCT02926898)3 randomly assigned 85 patients on stable, stiripentol-inclusive antiepileptic drug regimens to 0.4 mg/kg/d fenfluramine or placebo. Overall, patients treated with add-on fenfluramine showed a 59.5% greater reduction in mean monthly convulsive seizure frequency compared with placebo (P <.001), with the median longest seizure-free interval being 17 days on treatment versus 12 days on placebo.

Additional data recently presented as part of the 2020 Science Highlights from the American Academy of Neurology showed that median monthly convulsive seizure frequency was reduced by 83.3% compared with the pre-fenfluramine period for the core study group’s baseline (<.001).4 Over the entire treatment period, 62% of patients experienced clinically meaningful reductions—defined as ≥50%—and 37% experienced profound reductions—defined as ≥75% —in monthly convulsive seizure frequency. That interim analysis, led by Sullivan and colleagues, followed 330 patients over a 2-year treatment period.

Data from a real-world analysis led by M. Scott Perry, MD, medical director of neurology and co-director of the Jane and John Justin Neurosciences Center at Cook Children’s Hospital, showed that 65% of patients included in an expanded access program reported meaningful global clinical improvement, defined as a rating of “very much improved” or “much improved,” with similar improvements reported in cognition, behavior, and motor abilities by 56% (n = 13), 43% (n = 10), and 48% (n = 11) of the cohort, respectively.5

The most common adverse effects observed in the trial program were decreased appetite, somnolence, sedation, lethargy, diarrhea, constipation, abnormal echocardiogram, fatigue, malaise, asthenia, ataxia, balance disorder, gait disturbance, increased blood pressure, drooling, salivary hypersecretion, pyrexia, upper respiratory tract infection, vomiting, decreased weight, falls, and status epilepticus.

The drug, which is a Schedule IV controlled substance, requires that patients receive regular echocardiogram monitoring prior to treatment initiation, every 6 months during treatment, and once 3 to 6 months after treatment discontinuation. Health care providers should consider the risks and benefits of treatment with fenfluramine if a patient presents with signs of valvular heart disease, pulmonary arterial hypertension, or other cardiac abnormalities. Notably, fenfluramine is contraindicated in patients receiving concomitant monoamine oxidase (MAO) inhibitors or within 14 days of administration of an MAO inhibitor due to risk of serotonin syndrome.1

REFERENCES
1. FDA approves Fintepla (fenfluramine) for the Treatment of Seizures Associated with Dravet Syndrome. News release. Zogenix. June 25, 2020. https://www.globenewswire.com/news-release/2020/06/26/2053803/0/en/FDA-Approves-FINTEPLA-fenfluramine-for-the-Treatment-of-Seizures-Associated-with-Dravet-Syndrome.html
2. Lagae L, Sullivan J, Knupp K, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019;394(10216): 2243-2254. Doi: 10.1016/S0140-6736(19)32500-0
3. Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol. 2020;77(3): 300–308. Doi:10.1001/jamaneurol.2019.4113
4. 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.
5. 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.