AES Poster Provides Safety Insights to Antiseizure Medication Fenfluramine

Joseph Sullivan, MD, FAES

A post-hoc analysis of a phase 3 trial (NCT03355209) and its open-label extension (OLE; NCT03355209) highlighted the long-term safety of fenfluramine (Fintepla; UCB), an FDA-approved antiseizure medication, in patients with Lennox-Gastaut syndrome (LGS). Overall, the most common adverse events (AEs) in the randomized controlled portion included decreases appetite, somnolence, pyrexia, diarrhea, and vomiting, with fatigue having the earliest median time to onset.¹

Presented at the 2024 American Epilepsy Society (AES) Annual Meeting, held October 6-10 in Los Angeles, California, the analysis aimed to describe the time of onset and duration of treatment-emergent AEs (TEAEs) reported in the phase 3 study and its OLE. In the randomized controlled trial (RCT), patients were assigned to fenfluramine 0.2 mg/kg/day (n = 89), fenfluramine 0.7 mg/kg/day (n = 87), or placebo (n = 87), followed by the OLE where they transitioned to fenfluramine 0.2 mg/kg/day for 1 month before flexible titration based on effect and tolerability from month 2 to month 6.

Led by Joseph Sullivan, MD, FAES, professor of neurology and pediatrics, and director of the Pediatric Epilepsy Center of Excellence at the University of California San Francisco, resolution of TEAEs was found in 79.6% of patients on the 0.2 mg/kg/day dose and 64.5% for those on the 0.7 mg/kg/day dose. Between the 0.2 mg/kg/day and 0.7 mg/kg/day groups, the median time to onset for TEAEs was 11 days (1-101) and 7.5 days (1-98), respectively, in the RCT. In the OLE, the median time to TEAE onset was 48.5 days (1-297), with 82.6% of TEAEs occurring in at least 5% of patients resolving.

Across both doses, the most common TEAEs in the RCT were decreased appetite, somnolence, fatigue, pyrexia, diarrhea, vomiting, and fatigue. Fatigue was the earliest TEAE experienced after starting treatment, occurring 4 days after. Additional data from the RCT revealed that first occurrence of pyrexia (n = 16) and vomiting (n = 19) resolved in all treated patients.

READ MORE: Post Hoc Analysis Provides Insights on Low Need for Second Dose of Diazepam Nasal Spray in Pediatric Epilepsy

In the OLE, TEAEs reported by at least 10% of patients included decreased appetite, fatigue, nasopharyngitis, and seizures, with all initial cases of nasopharyngitis (n = 31) resolving in a median of 94 days (range, 13-368). In both the RCT and OLE, the incidence of TEAEs trended down over time, with most occurring in the first few weeks after initiating treatment.

Fenfluramine has been on the market as a treatment for LGS and Dravet syndrome for several years, gaining expanded approval for LGS in 2022. The basis for the approval was data from Study 1601 which showed that treatment with fenfluramine at a dose of 0.7 mg/kg/day was superior to placebo in reducing monthly drop seizure frequency (MDSF). In the trial, fenfluramine-treated patients in the 7 mg/kg/day dose group achieved a –19.9% estimated median difference from placebo in MDSF change from baseline, which was comparable to the magnitude demonstrated in all other LGS randomized controlled trials (range, –14.8% to –21.6%).^2,3

In the publication of the phase 3 study, fenfluramine was considered well-tolerated, with TEAEs that were consistent with what had been previously observed. The most common TEAEs were decreased appetite (22%), somnolence (13%), and fatigue (13%), with decreased appetite occurring more frequently in the fenfluramine groups than placebo. 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. No cases of valvular heart disease or pulmonary arterial hypertension were reported, and one patient with mild aortic regurgitation on an end-of-study echocardiogram was later found to have a normal aortic valve on further testing.

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REFERENCES
1. Sullivan J, Lagae L, Sankar R, et al. Onset and Duration of Adverse Events in Patients Treated with Fenfluramine in the Lennox-gastaut Syndrome Clinical Trials. Presented at: 2024 AES Annual Meeting; December 6-10; Los Angeles, CA. ABSTRACT 2.393
2. FINTEPLA® (fenfluramine) Oral Solution Now FDA Approved for Treatment of Seizures Associated with Lennox-Gastaut Syndrome (LGS). News release. UCB. March 28, 2022. Accessed December 6, 2024. https://finance.yahoo.com/news/fintepla-fenfluramine-oral-solution-now-050000058.html
3. Knupp KG, Scheffer IE, Ceulemans B, et al. Efficacy and safety of fenfluramine for the treatmet of seizures associated with Lennox-Gastaut syndrome: a randomized clinical trial. JAMA Neurol. Published online May 2, 2022. doi:10.1001/jamaneurol.2022.0829