NICE Approves Fenfluramine for Lennox-Gastaut Syndrome Seizures

NICE Approves Fenfluramine for Lennox-Gastaut Syndrome Treatment

The National Institute for Health and Care Excellence (NICE) has recently approved fenfluramine (brand name Fintepla) for treating seizures in patients with Lennox-Gastaut syndrome (LGS), a severe and treatment-resistant form of epilepsy. This approval, detailed in the final draft guidance, covers patients aged 2 years and older. Fenfluramine is recommended as an add-on treatment to other antiseizure medications, with the condition that patients must demonstrate at least a 30% reduction in seizure frequency during biannual check-ups. Additionally, for NHS England patients, the drug must be provided at a discounted price through a commercial arrangement with the manufacturer, UCB.

This decision follows an appeal after NICE’s initial rejection of fenfluramine in April 2024. The initial guidance raised concerns about the drug's clinical efficacy compared to existing treatments like cannabidiol (Epidyolex) combined with clobazam, as well as uncertainties about its cost-effectiveness. However, after reassessing the cost data, NICE concluded that fenfluramine and cannabidiol-based therapies have comparable costs, with fenfluramine potentially being the more affordable option.

Stephen Powis, MBA, PhD, national medical director for NHS England, commented on the approval, emphasizing the importance of fenfluramine as a viable alternative for patients who cannot tolerate cannabis-based treatments.

Lennox-Gastaut Syndrome (LGS)

Lennox-Gastaut syndrome is a rare and debilitating form of epilepsy, typically diagnosed in children before the age of 8. It is marked by frequent, severe seizures, including drop seizures (which cause sudden loss of muscle tone) and generalized tonic-clonic seizures (which result in muscle jerking and loss of consciousness). LGS is also associated with developmental delays and cognitive impairment. Around 60,000 children in England suffer from epilepsy, with an estimated 1-2% of these cases being diagnosed as LGS.

Fenfluramine’s Mechanism of Action

Fenfluramine works by increasing serotonin levels in the brain and acts as both a serotonergic 5-hydroxytryptamine 2 receptor agonist and a sigma-1 receptor antagonist. Although the precise mechanism behind its anti-seizure effects remains unclear, it is believed that fenfluramine’s action on serotonin receptors plays a key role in its efficacy.

Clinical Trial Evidence

The primary evidence supporting fenfluramine’s use in LGS comes from Study 1601, a Phase 3, randomized controlled trial involving 247 patients aged 2-35 years with LGS. Participants were initially given 0.2 mg/kg/day of fenfluramine, with doses titrated based on response and tolerability. After a median treatment period of 364 days, the study reported a 28.6% reduction in monthly drop seizures. Furthermore, 31.1% of patients experienced a more than 50% reduction in drop seizures. Other seizure types, including tonic-clonic and non-drop seizures, also saw significant reductions of 45.9% and 48.8%, respectively.

The Clinical Global Impression of Improvement scale, used to assess overall patient improvement, showed that 36% of caregivers and investigators rated patients as “much improved” or “very much improved.”

Side Effects and Safety Profile

Fenfluramine is generally well-tolerated, with the most common side effects being decreased appetite and fatigue. Notably, the study did not report any cases of valvular heart disease or pulmonary arterial hypertension, which have been associated with similar drugs in the past.

Fenfluramine is administered as an oral liquid, and the recommended dosing regimen begins at 0.2 mg/kg/day, gradually increasing to a maintenance dose of 0.7 mg/kg/day by day 14. The maximum dose is 26 mg daily for patients not taking stiripentol, or 17 mg if taking stiripentol concurrently.

Cost and Availability

The list price for fenfluramine is £1802 for a 120-mL bottle and £5408 for a 360-mL bottle. Thanks to a commercial arrangement between UCB and the NHS, fenfluramine will be available at a discounted price, making it more accessible to patients in need.

Improving Quality of Life

In response to NICE’s approval, Dr. Ley Sander, medical director at the Epilepsy Society, highlighted that while patients with LGS may not achieve complete seizure freedom, the availability of fenfluramine will improve their overall quality of life by providing an effective treatment option for those who have not responded to other therapies.