Fenfluramine Shows Pronounced Effect on Tonic-Clonic Seizures Across Range of Developmental and Epileptic Encephalopathies

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Clinically meaningful reductions in seizures through fenfluramine is likely to contribute to nonseizure benefits such as improvement in comorbidities, decreased use of other antiseizure medications, and reduction in premature death.

Kelly Knupp, MD, pediatric neurologist and associate professor of pediatrics and neurology at the University of Colorado,

Kelly Knupp, MD

Findings from a meta-analysis published in Epilepsia showed that treatment with fenfluramine (Fintepla; UCB) resulted in improvements in generalized tonic-clonic (GTCS) or tonic-clonic seizure (TCS) frequency regardless of the developmental and epileptic encephalopathy (DEE) evaluated. Future studies may evaluate fenfluramine’s impact on behavior, sleep, cognition, and reduced risk of death.1,2

Using the Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Review Guidelines (PRISMA-ScR), the literature search, conducted through February 2023, identified 422 records, of which 14 were included in the review. Of these, 9 included patients with Dravet syndrome (DS), 1 with CDKL5 deficiency disorder, 1 SCN8A-related disorder, 1 Lennox-Gastaut syndrome (LGS), 1 SCN1B-related disorder, and 1 with other DEEs.

The median percent reduction in GTCS or TCS from baseline was available in 10 studies (n = 328) and ranged from 47.2% to 100%. In the 4 non-DS publications specifically, the median percent reduction in GTCS or TCS from baseline ranged from 48.8% to 100% in 115 patients. In the three DS randomized controlled trials, median percent reductions in GTCS ranged from 47.2% to 90.8%. In the other DS publications, which consisted of case reports or open-label studies, the median reductions reported were 75.0%, 74.5%, and 100%.

"Improving seizure control, especially of the most severe seizures, could mitigate neurodevelopmental delay, improve quality of life, minimize polypharmacy, and reduce injury and premature death, namely sudden unexpected death in epilepsy (SUDEP)," Kelly Knupp, MD, pediatric neurologist and associate professor of pediatrics and neurology at the University of Colorado, said in a statement.1 "This analysis, coupled with established data from the FINTEPLA clinical trial program, positions FINTEPLA to be a promising future option for the management of various DEEs."

Clinical Takeaways

  1. Fenfluramine Reduces Seizure Frequency: Treatment with fenfluramine significantly reduces generalized tonic-clonic seizure frequency in patients with developmental and epileptic encephalopathies.
  2. Broad Efficacy Across Disorders: The meta-analysis shows consistent seizure reduction in patients with various DEEs, including Dravet syndrome and Lennox-Gastaut syndrome.
  3. Potential Beyond Seizure Control: Future studies will evaluate fenfluramine's impact on behavior, sleep, cognition, and reduced risk of death, enhancing overall patient quality of life.

Across 10 studies with available data on seizure reduction thresholds, 72% of patients achieved at least 50% reduction in GTCS or TCS from baseline. Among 9 studies that reported thresholds of at least 75% or 100%, 54% and 29% of patients achieved at least 75% and 100% reduction in GTCS or TCS from baseline, respectively. For the non-DS studies, 100%, 93%, and 36% of patients achieved at least 50%, 75%, and 100% reductions in GTCS or TCS from baseline, respectively.

"For people and caregivers impacted by DEEs such as DS and LGS, the ability to effectively manage seizures is critical. These findings reinforce the potential of Fintepla in reducing seizure frequency among patients with DEEs," Rebecca Burns, PhD, PharmD, medical strategy lead of Epilepsy and Rare Syndromes at UCB, said in a statement. “The publication of these results underscores our commitment to bringing improvements to the lives of those impacted by rare epilepsies as we leverage today’s expertise for a better tomorrow."

The study had a few noted limitations, mainly arising from the heterogeneity of the source data. Due to the fact that most of the analysis focused on subpopulations of patients, demographics or disposition data for the patients with the specific seizure types of interest (GTCS or TCS) could not be discerned for all the studies presented, especially the larger studies. In addition, there were 3 studies that evaluated total seizure reduction, and therefore, the frequency of other seizure types may have impacted the results in a positive or negative manner.

REFERENCES
1. FINTEPLA® (fenfluramine) Results Examining its Impact in Managing Generalized Tonic-Clonic Seizures in Developmental and Epileptic Encephalopathies Published in Epilepsia. News release. June 24, 2024. Accessed June 25, 2024. https://www.ucb-usa.com/stories-media/UCB-U-S-News/detail/article/FINTEPLA-fenfluramine-results-examining-its-impact-in-managing-generalized-tonic-clonic-seizures-in-developmental-and-epileptic-encephalopathies-published-in-epilepsia
2. Nagel AG, Cross HJ, Devinsky O, et al. Comprehensive scoping review of fenfluramine’s role in managing generalize tonic-clonic seizures in developmental and epileptic encephalopathies. Epilepsia. Published online June 21, 2024. doi:10.1111/epi.18020
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