PDF: Fenfluramine LGS
(2022)Objective
Fenfluramine 0.7 mg/kg/d and 0.2 mg/kg/d — to evaluate efficacy and safety of fenfluramine, a serotonergic/sigma-1 modulator, for drop seizures in Lennox-Gastaut syndrome.
Study Summary
• 25% of patients on the 0.7 mg/kg/d dose achieved ≥50% drop-seizure response vs 10% on placebo (p=0.02), and clinician/caregiver global impression ratings favored fenfluramine (26% vs 6% much/very much improved; p=0.001).
• Critically, no cases of valvular heart disease or pulmonary arterial hypertension were observed — allowing fenfluramine to be re-positioned as a treatment for pediatric developmental and epileptic encephalopathies despite its historic withdrawal for weight-loss indications.
Intervention
Fenfluramine 0.7 mg/kg/d or 0.2 mg/kg/d (maximum 26 mg/d) vs matching placebo; 2-week titration followed by 12-week maintenance (14 weeks total).
Inclusion Criteria
Patients 2-35 years with confirmed diagnosis of Lennox-Gastaut syndrome and ≥2 drop seizures per week during a 4-week baseline.
Study Design
Arms: Fenfluramine 0.7 mg/kg/d vs 0.2 mg/kg/d vs Placebo
Patients per Arm: 0.7 mg/kg/d: 87; 0.2 mg/kg/d: 89; Placebo: 87
Outcome
• ≥50% responder rate: 25% (0.7 mg/kg/d) vs 10% (placebo); p=0.02
• Clinical Global Impression of Improvement (much/very much improved): 26% (0.7 mg/kg/d) vs 6% (placebo); p=0.001
• Generalized tonic-clonic seizure subtype showed greatest response (−45.7% in 0.7 mg/kg/d, −58.2% in 0.2 mg/kg/d, +3.7% in placebo)
• Most common AEs: decreased appetite 22%, somnolence 13%, fatigue 13%
• No valvular heart disease or pulmonary arterial hypertension observed
Clinical Question
Does fenfluramine reduce drop seizures in Lennox-Gastaut syndrome, and is it safe regarding cardiac valvular and pulmonary hypertension risks that led to its original withdrawal?
Bottom Line
Fenfluramine 0.7 mg/kg/d reduced drop seizure frequency by an estimated median 19.9 percentage points more than placebo (p=0.001) over 14 weeks in Lennox-Gastaut syndrome, with 25% achieving ≥50% response vs 10% on placebo (p=0.02). Clinical global impression favored the active drug, and crucially no valvular heart disease or pulmonary hypertension was observed — supporting fenfluramine as a new treatment option for this refractory encephalopathy.
Major Points
- Phase 3, multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial
- Conducted November 2017 to October 2019 at 65 sites in North America, Europe, and Australia
- 263 patients aged 2-35 years with confirmed LGS and ≥2 drop seizures/week during 4-week baseline
- Randomized 1:1:1 to fenfluramine 0.7 mg/kg/d, 0.2 mg/kg/d, or placebo
- 2-week titration + 12-week maintenance (14 weeks total)
- Maximum dose cap 26 mg/d to limit risk of cardiac AEs
- Primary endpoint: % reduction in drop seizure frequency (0.7 mg/kg vs placebo)
- Median reduction: 26.5% (0.7 mg/kg) vs 14.2% (0.2 mg/kg) vs 7.6% (placebo)
- Estimated median difference for 0.7 mg/kg vs placebo: -19.9 percentage points (95% CI -31.0 to -8.7); p=0.001
- ≥50% responder rate: 25% (0.7 mg/kg) vs 10% (placebo); p=0.02
- CGI-I much/very much improved: 26% (0.7 mg/kg) vs 6% (placebo); p=0.001
- Generalized tonic-clonic seizure subtype most responsive (-45.7%/-58.2% vs +3.7%)
- Key safety result: NO cases of cardiac valvulopathy or pulmonary arterial hypertension during trial — supports safe repurposing at epilepsy doses
- Most common AEs: decreased appetite (22%), somnolence (13%), fatigue (13%)
- Supported FDA approval of fenfluramine (Fintepla) for LGS in 2022, extending its 2020 Dravet approval
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 263
- Follow-up
- 14 weeks (2-wk titration + 12-wk maintenance)
- Centers
- 65
- Countries
- USA, Canada, Australia, Europe
Primary Outcome
Definition: Percentage change from baseline in drop seizure frequency (0.7 mg/kg/d vs placebo)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 7.6% median reduction (placebo) | 26.5% median reduction (0.7 mg/kg/d fenfluramine) | - (-31.0 to -8.7) | p=0.001 |
Limitations & Criticisms
- Short 14-week follow-up does not assess durability, tachyphylaxis, or long-term cardiac safety
- Placebo response was low (7.6%); real-world utility depends on comparable response
- Maximum dose capped at 26 mg/d to minimize cardiac risk — lower than historical weight-loss doses but long-term monitoring warranted
- Long-term echocardiographic and cardiac Doppler monitoring still required per FDA REMS
- No head-to-head comparison with rufinamide, clobazam, or cannabidiol (other LGS drugs)
- Cost and access concerns
Citation
JAMA Neurology 2022;79(6):554-564