Authors :
Presenting Author: Wesley Kerr, MD, PhD – UPMC Presbyterian Hospital
Author: Samden Lhatoo, MD, FRCP – University of Texas Health Science Center at Houston
Elaine Wirrell, MD – Mayo Clinic
Elizabeth Donner, MD, FRCPC – Hospital for Sick Children
Joseph Sullivan, MD – University of California San Francisco Weill Institute for Neurosciences
Renzo Guerrini, MD, FRCP, FAES – Meyer Children’s Hospital IRCCS, and University of Florence
Ingrid Scheffer, MBBS, PhD, FRACP, FRS – University of Melbourne, Austin Hospital and Royal Children's Hospital, Florey and Murdoch Children’s Research Institutes
Sylvain Rheims, MD, PhD – Hospices Civils de Lyon and Lyon 1 University
J. Helen Cross, MBChB, PhD – UCL-Great Ormond Street Institute of Child Health; Great Ormond Street Hospital
Lieven Lagae, MD, PhD, FRCP – Member of the European Reference Network EpiCARE, University of Leuven
Philipe Ryvlin, MD, PhD – University of Lausanne
Antonio Gil-Nagel, MD, PhD – Hospital Ruber Internacional
Jeffrey Noebels, MD. PhD – Baylor College of Medicine
Jenna Roberts, PhD – UCB Pharma
Amélie Lothe, PhD – UCB Pharma S.A.
Milena Tryfon, MSc – UCB Pharma
Michael Rañopa, PhD – UCB Pharma
Orrin Devinsky, MD – NYU Grossman School of Medicine
Rationale:
In the United States (US), fenfluramine (FFA) is approved for management of seizures in patients ≥2 years old with Dravet syndrome (DS), with a single specialty pharmacy distribution model.
A high premature mortality risk has been observed in patients with DS; previous all-cause mortality rates per 1000 person-years have been reported as 15.8 (98% CI, 9.0-27.9) and 8.6 (95% CI, 5.4-13.0). (Cooper MS, et al.
Epilepsy Res. 2016; Donnan AM, et al.
Neurology. 2023).
A post-hoc analysis of the FFA clinical trials, early access programs, and open label studies has shown a lower all-cause mortality rate in treated patients with DS compared to the expected rate (Cross JH, et al.
Seizure. 2021).
While valuable, clinical trial experiences may not reflect real-world outcomes, thus in this study we describe mortality rates and real-world use of FFA in US patients with DS who were new FFA users.
Methods:
This retrospective cohort study evaluated US patients with DS who were new users of FFA obtained from the single specialty pharmacy; patients must have received their first shipment of FFA (defined as index date) ≥6 months prior to data cut. Outcomes reported include demographics, initial and maintenance FFA doses, FFA persistence (by index year), and mortality rate. Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) for 2021-2023 were also reported. Descriptive statistics were used to summarize data.
Results: From commercial launch (July 1, 2020), through the most recent data cut (March 15, 2024), data are available for 1043 new users of FFA for DS. Demographic data are noted in
Table 1; 49.2% of patients were 6-17 years old at time of prescribing, 56.6% prescribed by a pediatric epileptologist, and 56.0% of patients had been previously treated with cannabidiol. Initial median FFA dose was 0.3 mg/kg/day (range: 0.1-1.1 mg/kg/day) and median maintenance dose was 0.5 mg/kg/day (range: 0.02-1.4 mg/kg/day).
Persistence by index year at 6 months and 12 months: in 2020, 90.9% and 78.5%, respectively; in 2021: 85.8% and 76.9%, respectively. Persistence in 2022 at 6 months and 12 months: 83.5% and 74.8%, respectively.
Median treatment duration was 21.3 months and 729 patients were still on FFA at data cut.
During this analysis period, there were 16 deaths per 1865 patient-years, which corresponds to an estimated mortality rate of 8.6 per 1000 person-years (95% CI, 5.6-11.6) and overall SMR from 2021-2023 of 2.0 (95% CI, 1.1-3.3).
Conclusions: This first real-world analysis of patients in the US with DS revealed that patients taking FFA had a similar mortality rate to the most recent analysis of patients with DS (Donnan AM, et al.
Neurology. 2023) and demonstrated an encouraging SMR over 2021-2023. Future studies will evaluate patient characteristics and causes of death, including rates of sudden unexpected death in epilepsy (SUDEP), and real-world use of FFA in other indications.
Funding: UCB Pharma