Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: interim analysis of an open-label extension study.

2023

Knupp, Kelly G

Scheffer, Ingrid E

Ceulemans, Berten

Sullivan, Joseph

Nickels, Katherine C

Lagae, Lieven

Guerrini, Renzo

Zuberi, Sameer M

Nabbout, Rima

Riney, Kate

Agarwal, Anupam

Lock, Michael

Dai, David

Farfel, Gail M

Galer, Bradley S

Gammaitoni, Arnold R

Polega, Shikha

Davis, Ronald

Gil-Nagel, Antonio

Lennox-Gastaut syndrome

developmental and epileptic encephalopathies

fenfluramine

long-term open-label extension

Journal Article

https://orcid.org/0000-0002-1967-0827

https://orcid.org/0000-0002-2311-2174

https://orcid.org/0000-0002-6579-3035

https://orcid.org/0000-0002-7118-0139

https://orcid.org/0000-0002-7272-7079

https://orcid.org/0000-0001-5877-4074

https://orcid.org/0000-0002-1122-3555

https://orcid.org/0000-0002-4735-3327

https://orcid.org/0000-0002-4775-2862

10.1111/epi.17431

To evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome (LGS). Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE; NCT03355209). All patients were initially started on 0.2 mg/kg/day fenfluramine and, after 1 month, were titrated to effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months. As of 10/19/2020, 247 patients were enrolled in the OLE. Mean age was 14.3±7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2-4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was -28.6% over the entire OLE (n=241) and -50.5% at Month 15 (n=142) (P<0.0001); 75/241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in non-drop seizure frequency was -45.9% (n=192; P=0.0038). Generalized tonic-clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (P<0.0001; n=106) and 35.8% (P<0.0001; n=186), respectively. A total of 37.6% (95% CI: 31.4%, 44.1%; n=237) of investigators and 35.2% of caregivers (95% CI: 29.1%, 41.8%; n=230) rated patients as "Much Improved"/"Very Much Improved" on the Clinical Global Impression of Improvement (CGI-I) scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for SUDEP. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS.

link

Epilepsia 2023; 64(1)

Epilepsia