Fenfluramine Safe and Effective in Lennox-Gastaut Syndrome Regardless of Concomitant Vagus Nerve Stimulation

A post-hoc analysis of the phase 3 1601 study (NCT03355209) and its open-label extension (OLE) revealed that fenfluramine (Fintepla; UCB) was effective and safe in patients with Lennox-Gastaut syndrome (LGS) irresponsive of concomitant use of vagus nerve stimulation (VNS). In fact, at times, patients on a combination of both fenfluramine and VNS performed worse on responder analyses and experienced fatigue more frequently, raising the need to further investigate the settings and duration of VNS therapy.¹

In the original 14-week randomized controlled trial (RCT), patients were randomized to fenfluramine 0.2 mg/kg/day, fenfluramine 0.7 mg/kg/day (max 26 mg/day) or placebo. In the OLE, patients transitioned to fenfluramine 0.2 mg/kg/day for 1 month, followed by flexible titration, with no changes to VNS settings or concomitant antiseizure medications (ASMs) allowed during the RCT and first 6 months of the OLE.

Led by Lieven Lagae, MD, PhD, a professor of pediatric neurology at the University of Leuven, in Belgium, results showed that a combination of fenfluramine and VNS led to greater reductions in generalized tonic-clonic seizures (GTCS) than without VNS during the RCT; however, in the OLE, data showed a higher median reduction in GTCS when fenfluramine was given alone. In the RCT, investigators reported median reductions of –69.6% (0.2 mg/kg/day) and –50.1% (0.7 mg/kg/day) in GTCS in the combination group vs reductions of –57.0% and –41.2% for those without, respectively. In comparison, those on fenfluramine without VNS experienced median reductions of –56.3% in the OLE vs reductions of –37.9% for those with VNS.

Presented at the 2024 American Epilepsy Society (AES) Annual Meeting, held December 6-10 in Los Angeles, California, the RCT featured 82 patients with concomitant VNS (fenfluramine: n = 50; placebo: n = 32) and 181 who were not on concomitant VNS. In the OLE, 80 of the 241 patients who entered were on a combination of both at RCT baseline. All told, results revealed that when combining the fenfluramine groups in the RCT, a larger proportion of patients achieved both at least a 50% and 75% reduction in seizures associated with a fall when treated without VNS compared with patients on concomitant treatment (27.8% and 11.1% vs 24.0% and 4.0%).

In the OLE, where patients were flexibly titrated treatment to effect and tolerability, 32.9% and 13.7% of fenfluramine-treated patients without VNS achieved at least 50% and 75% reduction in seizures associated with a fall, respectively, versus 27.5% and 7.5% of patients on concomitant treatment. In terms of safety, among the commonly reported treatment-emergent adverse events (TEAEs) observed in the RCT and OLE, fatigue was more prevalent among patients on both fenfluramine and VNS vs those without VNS (RCT: 17.1% vs 11.6%; OLE: 18.8% vs 11.2%).

Study 1601, the study that led to fenfluramine’s 2022 approval in LGS, was published in JAMA Neurology shortly after the drug’s approval. All told, the study’s primary end point was met, with a 19.9% estimated mean difference (95% CI, –31.0 to –8.7) in monthly drop seizure frequency (MDSF) between the fenfluramine 0.7-mg/kg/day group and placebo (P = .001). The lower dose cohort produced lesser effects, with an estimated mean difference of 10.5% (95% CI, –25.0 to 4.0) in MDSF reduction compared with placebo (P = .09).

The percentage reduction in GTC frequency during the titration and maintenance period was 45.7% in the fenfluramine 0.7-mg/kg/day group (P <.001) and 58.2% in the 0.2-mg/kg/day group (P <.001) compared with an increase of 3.7% in the placebo group. In the fenfluramine 0.7- and 0.2-mg/kg/day groups, the estimated median difference in GTC seizure frequency was –50.3% (95% CI, –76.7 to –23.8; P = .001) and –60.4% (95% CI, –84.9 to –36.0; P <.001), respectively, compared with placebo.

Originally marked as a Schedule IV controlled substance, fenfluramine was removed from this list in April 2023 after the DEA conducted a review. With the ruling, it allowed prescribers the ability to write a prescription for a full year’s supply versus the previous limitation of 6 months. The therapy also has boxed labeling about potential decreased appetite and weight, as well as increased sleepiness, sedation, and lack of energy.³