Tuesday 3 May 2022, Amsterdam
$ UCB (Euronext: UCB), a global biopharmaceutical company, today announced the publication in JAMA Neurology of its multi-center, double-blind, placebo-controlled, parallel-group, randomized Phase 3 trial demonstrating that fenfluramine 0.7 mg/kg/day, when added to a patient’s current anti-epileptic treatment regimen for seizures associated with LGS, is effective in reducing the frequency of drop seizures.1 Drop seizures cause a person to suddenly lose muscle tone, become limp, and fall to the ground, with a high likelihood of injury.6 Within the study, drop seizures were further defined as generalized tonic-clonic (GTC), secondary GTC [focal to bilateral tonic clonic], tonic, atonic, or tonic and atonic.1
LGS is a severe childhood-onset developmental and epileptic encephalopathy characterized by drug-resistant seizures with high morbidity2 as well as serious impairment of neurodevelopmental, cognitive and motor functions.3 LGS has far-reaching effects beyond seizures, including issues with communication, psychiatric symptoms, sleep, behavioral challenges and mobility.7
The trial met its primary efficacy endpoint. Patients taking fenfluramine 0.7 mg/kg/day experienced an estimated mean difference in the reduction of drop seizure frequency by 19.9% from placebo (P=.001). The median percent reduction in the frequency of drop seizures in the 0.7 mg/kg/day group was 26.5%, compared with 14.2% in the 0.2mg/kg/day group, and 7.6% in patients taking placebo (P=.09). In key secondary outcomes, the trial demonstrated that a greater proportion of patients taking fenfluramine experienced a 50% or greater reduction in drop seizure frequency, compared to patients in the placebo group.1
“Our trial data and the clinical evidence demonstrate the safety and efficacy of fenfluramine for the treatment of seizures associated with LGS and especially for patients where generalized tonic-clonic seizures are the predominant seizure type, where there is a greater risk of mortality,” said Kelly Knupp, M.D., MSCS, FAES, Associate Professor, Children’s Hospital Colorado, Principal Investigator of the study. “LGS is a highly treatment-resistant developmental and epileptic encephalopathy and we need differentiated treatment options, such as fenfluramine, which has a unique mechanism of action different from and complementary to current seizure medications.”
The study also included seizure-type subgroup analyses that demonstrated that fenfluramine 0.7mg/kg/day was highly effective in reducing the frequency of GTCs in nearly 50% of patients. During the maintenance and titration period, patients experienced a decrease in frequency of 45.7% in the fenfluramine 0.7mg/kg/day group, a decrease in frequency of 58.2% in the 0.2 mg/kg/day fenfluramine group, compared with an increase in frequency of 3.7% in the placebo group (P=.001 and P<.001 respectively). The percentage reduction in tonic or atonic seizure frequency was 46.7% in the fenfluramine 0.7mg/kg/day group, compared with 6.8% in the placebo group (P=.046).1
The reason these data are compelling is because GTCs are commonly observed in patients with LGS.9 Moreover, GTCs may result in bodily injury.10,11 Sudden unexpected death in epilepsy (SUDEP) is a major concern for people living with LGS and patients with a history of GTCs have an estimated 10-fold greater risk of SUDEP.4
Fenfluramine was generally well-tolerated in this study. The most common treatment-emergent adverse events included decreased appetite (22%), somnolence (13%), and fatigue (13%).1 The fenfluramine safety database includes long-term cardiovascular safety data for patients treated for up to three years in DS and LGS.5
“This study further validates the importance of fenfluramine as a new treatment option for seizures associated with LGS, including generalized tonic-clonic seizures,” said Mike Davis, Global Head of Epilepsy, UCB. “Through our close connection with the LGS community, we know the challenges they face go beyond treatment resistant seizures to include difficulty with behavior and cognition, and we hope that fenfluramine can provide relief for people living with LGS.”
Site investigators and caregivers also rated patients as significantly much or very much improved on the Clinical Global Impression of Improvement (CGI-I) scale (investigators 26% vs. 20% vs. 6% and caregivers 34% vs. 27% vs. 5% for 0.7 mg/kg vs. 0.2 mg/kg vs. placebo, respectively).1
Fenfluramine was approved by the U.S. Food and Drug Administration (FDA) for the treatment of LGS in patients aged 2 and older in March 2022.5 Fenfluramine was also approved for the treatment of Dravet Syndrome in patients aged 2 and older in June 20205 and by the EU Commission in December 2020 as an add-on treatment for seizures associated with Dravet syndrome in patients aged 2 and older.12 UCB acquired Zogenix, Inc. and FINTEPLA® on March 7, 2022. The acquisition is consistent with UCB’s sustainable patient value strategy and continued commitment to providing world-leading patient value to all people living with epilepsy, with an increasing focus on creating value and new solutions that address the unmet needs of people with certain specialized or rare types of epilepsy, where few or no options exist.
Study Design
The multi-center, double-blind, placebo-controlled, parallel-group, randomized Phase 3 clinical trial was conducted from 27 November 2017 to 25 October 2019, and had a 20-week trial duration. Patients were enrolled at 65 study sites in North America, Europe, and Australia.
A total of 263 patients were randomly assigned to receive either fenfluramine 0.7mg/kg/day (n=87) or fenfluramine 0.2mg/kg/day (n=89) or placebo (n=87). After titration (2-week period), patients were maintained on their randomized dose for 12 additional weeks. The median age was 13 years.
Children and adults, aged 2 to 35 years, with a confirmed LGS diagnosis who were using stable anti-seizure medication (ASM) regimens (≥1 and ≤4 concomitant ASMs) were eligible for enrollment if these criteria were met: onset of seizures at age 11 years or younger; multiple seizure types, including tonic and tonic or atonic seizures; stable 4-week seizure baseline with 2 or more drop seizures per week of GTC, or secondary GTC (i.e., focal to bilateral tonic-clonic seizures), tonic, atonic, or tonic or atonic seizure; abnormal cognitive development; and medical history showing electroencephalogram evidence of abnormal background activity with slow spike-and-wave pattern (<2.5Hz). Key exclusion criteria were degenerative neurological disease, history of hemiclonic seizures in the first year of life, only drop seizure clusters, previous or current exclusionary cardiovascular or cardiopulmonary abnormality or concomitant cannabidiol use (not FDA approved at time of study).
This study was funded by Zogenix, Inc., now part of UCB.
Source: UCB
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