A recent post-hoc analysis presented at the 2024 American Epilepsy Society (AES) Annual Meeting provides further insights into the long-term safety of fenfluramine (Fintepla; UCB) in treating Lennox-Gastaut syndrome (LGS). The analysis, led by Joseph Sullivan, MD, FAES, from the University of California San Francisco, examined data from a phase 3 trial (NCT03355209) and its open-label extension (OLE; NCT03355209).
The study aimed to characterize the onset and duration of treatment-emergent adverse events (TEAEs) reported during the trial and its OLE. In the randomized controlled trial (RCT), patients were administered fenfluramine at doses of 0.2 mg/kg/day (n = 89) or 0.7 mg/kg/day (n = 87), or placebo (n = 87), followed by the OLE where all patients transitioned to fenfluramine 0.2 mg/kg/day for one month, with subsequent flexible titration based on effect and tolerability from months 2 to 6.
TEAE Onset and Resolution
The analysis revealed that TEAEs resolved in 79.6% of patients on the 0.2 mg/kg/day dose and 64.5% on the 0.7 mg/kg/day dose. The median time to TEAE onset in the RCT was 11 days (range: 1-101) for the 0.2 mg/kg/day group and 7.5 days (range: 1-98) for the 0.7 mg/kg/day group. In the OLE, the median time to TEAE onset was 48.5 days (range: 1-297), with 82.6% of TEAEs occurring in at least 5% of patients resolving.
Common Adverse Events
Across both doses in the RCT, the most common TEAEs included decreased appetite, somnolence, fatigue, pyrexia, diarrhea, and vomiting. Notably, fatigue was the earliest TEAE experienced, occurring a median of 4 days after treatment initiation. All initial cases of pyrexia (n = 16) and vomiting (n = 19) resolved during the RCT.
In the OLE, TEAEs reported by at least 10% of patients included decreased appetite, fatigue, nasopharyngitis, and seizures. All initial cases of nasopharyngitis (n = 31) resolved within a median of 94 days (range: 13-368). The incidence of TEAEs generally decreased over time in both the RCT and OLE, with most events occurring in the initial weeks of treatment.
Fenfluramine's Role in LGS Treatment
Fenfluramine has been approved for treating LGS and Dravet syndrome, with expanded approval for LGS in 2022. The approval was based on data from Study 1601, demonstrating that fenfluramine at 0.7 mg/kg/day significantly reduced monthly drop seizure frequency (MDSF) compared to placebo. Patients treated with fenfluramine in the 0.7 mg/kg/day group achieved a -19.9% estimated median difference from placebo in MDSF change from baseline.
Tolerability Profile
The initial phase 3 study publication indicated that fenfluramine was generally well-tolerated, with TEAEs consistent with previous observations. The most common TEAEs were decreased appetite (22%), somnolence (13%), and fatigue (13%). Weight loss of 7% or more from baseline was observed in 8% and 2% of patients in the fenfluramine 0.7 and 0.2 mg/kg/day groups, respectively, compared to 2% in the placebo group. Importantly, no cases of valvular heart disease or pulmonary arterial hypertension were reported during the study.
