Authors :
Presenting Author: Rebecca Zhang-Roper, MD, PhD – UCB Pharma
Najla Dickson, MD – UCB Biosciences, Inc.
Madhur Goyal, MPharm – UCB Biosciences, Inc.
Geraldine Prager, MS – UCB Pharma
Diego Morita, MD – UCB Biosciences, Inc.
Jenna Roberts, PhD – UCB Pharma
Mélanie Langlois, PhD – UCB Pharma S.A.
Amélie Lothe, PhD – UCB Pharma S.A.
Laura Maile, PhD, RAC – UCB Biosciences, Inc.
Rationale:
Fenfluramine (FFA) is approved for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in the United States (US), European Union, United Kingdom, Japan, and Israel in patients ≥ 2y of age. Safety and efficacy of FFA in patients with DS and with LGS has been evaluated in phase 3 randomized clinical trials and their open-label extensions.
FFA distribution is regulated via the Risk Evaluation and Mitigation Strategy program in the US and controlled-access programs in other regions. These programs require cardiac monitoring due to association with valvular heart disease (VHD; ≥ mild aortic or ≥ moderate mitral regurgitation with additional characteristics of VHD) and pulmonary arterial hypertension (PAH; PASP ≥ 35mmHg) at previously administered high FFA doses in the treatment of adult obesity.
Methods:
The UCB Global Safety Database includes spontaneous and solicited reports, post-marketing surveillance reports, and serious events from clinical studies, irrespective of attribution to FFA. The database was searched using MedDRA v27.0 terms (reporting interval: 06-25-2023 to 06-24-2024). Assessment of new information received for the recognized safety concerns was performed to further characterize the safety profile (Table).
Potential VHD and PAH cases were adjudicated by a panel of 3 external cardiologists with FFA expertise.
Results:
Marketing authorization was not withdrawn in any country during the reporting interval. Exposure to FFA was 4550 worldwide (excluding the US) and 4242 patient-years in the US.
One event of PAH (serious) was adjudicated as probable PAH. This event was likely related to FFA treatment. PAH, previously an important potential risk, has been updated as an important identified risk.
Based on post-marketing cases, serotonin syndrome was categorized as an important identified risk. Characterization of the important potential risks of VHD, suicidal ideation/behavior, and growth retardation were unchanged following assessment of reported cases. Of 10 adjudicated cases of VHD, one case was probable VHD. This case was considered unlikely related to FFA.
Of 55 cases (111 events) where exposure reported was >3 years (longest exposure: 5.25y), 38 were serious. The most frequent reported events were seizure (n=11) and decreased appetite (n=5). The events reported following long‑term exposure do not present a different safety profile compared to the overall safety profile of fenfluramine.
No cases of off-label use relating to obesity were received.
Conclusions:
PAH and serotonin syndrome were reclassified as important identified risks in this FFA safety profile update and should be considered when treating patients with DS or LGS with FFA. FFA continues to be well tolerated and does not present a different safety profile based on the ongoing review of long-term safety data. The benefit-risk balance of FFA continues to remain favorable for patients with DS or LGS. These findings highlight the importance of UCB’s continued monitoring of adverse events for trends and possible signals.Funding: UCB Pharma.