December 29, 2025
2 min read
Key takeaways:
- The treatment group recorded a greater median reduction in countable motor seizure frequency vs. placebo.
- Fenfluramine also led to significantly increased percentages of seizure reduction vs. placebo.
Individuals with a rare form of epilepsy treated with fenfluramine experienced significantly greater seizure reduction as well as clinically meaningful global functioning improvement compared with placebo at 14 weeks, according to a poster.
“CDKL5 deficiency disorder (CDD) is an ultra-rare, X-linked developmental and epileptic encephalopathy characterized by very early-onset, highly drug-resistant seizures and profound global developmental impairment,” Nicola Specchio, MD, PhD, FRCP, chair of the Neurology, Epilepsy and Movement Disorders Unit at Bambino Gesù Children’s Hospital in Rome, told Healio about the research presented at the American Epilepsy Society annual meeting.
Data were derived from Specchio N, et al. Fenfluramine in CDKL5 deficiency disorder: Primary efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study; Presented at American Epilepsy Society annual meeting; Dec. 5-9, 2025; Atlanta.
“Despite intensive polytherapy, seizure freedom is exceptionally rare, and most children continue to have frequent, disabling motor seizures every week or every day,” he said.
Specchio and colleagues sought to examine the safety, efficacy and tolerability of fenfluramine in children, adolescents and adults with frequent motor seizures in CDD.
Their randomized, double-blind, phase 3 clinical trial enrolled 87 patients aged 1 to 35 years with genetically confirmed or likely pathogenic CDKL5 variants and countable motor seizure frequency (CMSF).
Participants were randomly assigned on a 1:1 basis to receive either fenfluramine 0.7 mg/kg per day or matching placebo, added to their existing antiseizure regimen, after a 4-week baseline period. Dosing was subject to a 2-week titration followed by a 12-week maintenance interval.
The primary efficacy endpoint was mean percentage change from baseline in CMSF over 14 weeks compared with placebo, while secondary endpoints included the number of enrollees who achieved at least 25%, 50%, 75% or 100% reduction in CMSF, and percentage of participants with clinically meaningful improvement on the Clinical Global Impression-Improvement (CGI-I) scale score at 14 weeks.
The modified intent-to-treat (mITT) population (n = 86) included all participants who received at least one dose of the drug and completed at least 1 week of post-randomization seizure data in a diary. Safety and tolerability were also measured in the mITT population.
A total of 83 patients completed the trial. Those in the treatment group (n = 42) recorded a significantly greater median reduction in CMSF over the 14-week titration plus maintenance period (-47.6%) vs. those given placebo (n = 44; -2.8%).
Further, those in the fenfluramine group recorded significantly greater improvements in countable motor seizure reductions of at least 25% (73.8% vs. 18.2%), 50% (45.2% vs. 4.5%), 75% (21.4% vs. 2.3%) and 100% (4.8% vs. 0%).
Nicola Specchio
Data additionally showed that 38.1% of those given fenfluramine recorded a CGI-I rating of either “much improved” or “very much improved” vs. 4.5% of the placebo cohort.
The median change from baseline in monthly frequency of CMS-free days over 14 weeks, was 6.4 days in the fenfluramine group vs. 0.1 day in the placebo group.
Regarding safety, Specchio and colleagues reported generally comparable numbers of treatment-emergent adverse events between treatment groups, while no new safety signals emerged. They additionally found no cases of valvular heart disease or pulmonary arterial hypertension with no deaths recorded.
“Clinically, the key message is that adjunctive fenfluramine produced meaningful and clinically significant reductions in motor seizure frequency compared with placebo in patients with CDD, with a safety profile consistent with what we know from Dravet and Lennox–Gastaut syndromes,” Specchio told Healio.
For clinicians, he added, these data mean that fenfluramine can be considered a “promising, evidence-based” adjunctive treatment option for seizures in CDKL5 deficiency disorder.
“For families,” he said, “it offers a realistic possibility of fewer seizures, more seizure-free days, as well as better day-to-day functioning in a condition where therapeutic progress has historically been very slow.”
For more information:
Nicola Specchio, MD, PhD, FRCP, can be reached at neurology@healio.com.
Sources/Disclosures
Source:
Specchio N, et al. Fenfluramine in CDKL5 deficiency disorder: Primary efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study; Presented at American Epilepsy Society annual meeting; Dec. 5-9, 2025; Atlanta.
Disclosures:
Specchio reports serving on scientific advisory boards for Arvelle, BioMarin, GW Pharma (now Jazz Pharmaceuticals), Marinus, Takeda, and UCB; receiving speaker honoraria from Biomarin, Eisai, LivaNova, Sanofi, UCB; serving as an investigator for Biomarin, Marinus, Roche, and UCB.
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