Fenfluramine Shows Consistent Seizure Reduction Across Age Groups in CDKL5 Deficiency Disorder

New data from the phase 3 GEMZ trial (NCT05064878), presented at the 55th Child Neurology Society (CNS) Annual Meeting, held October 14-17, 2026, in Montreal, Canada, showed that adjunctive fenfluramine (Fintepla; UCB) produced similar reductions in seizure frequency and a consistent safety profile across age groups in patients with CDKL5 deficiency disorder (CDD). According to the authors, these findings support the use of fenfluramine in both children and adults with the seizure disorder.¹

In patients aged 2 to 6 years, median countable motor seizure frequency (CMSF) changed by −45.7% with fenfluramine compared with 0.1% with placebo. In those older than 6 years and up to 35 years, median CMSF changed by −48.2% with fenfluramine vs −2.8% with placebo (nominal P <.001 for both comparisons). Presented by lead author Brian Moseley, MD, senior medical director at UCB, the analysis also showed that treatment-emergent adverse events occurred in 74% (n = 14) of fenfluramine-treated patients and 85% (n = 17) of placebo-treated patients aged 2 to 6 years, and in 76% (n = 16) and 70% (n = 16), respectively, of those older than 6 years.

GEMZ was a randomized, double-blind, placebo-controlled trial that enrolled patients aged 1 to 35 years with confirmed or likely pathogenic CDKL5 variants, a clinical diagnosis of CDD, and at least 4 caregiver-reported countable motor seizures per week. Patients were randomly assigned to fenfluramine 0.7 mg/kg/day (maximum, 26 mg/day) or placebo over 14 weeks, which included a 2-week titration period and a 12-week maintenance period. The primary end point was change from baseline in CMSF over the titration and maintenance periods.

The safety and modified intent-to-treat populations included 87 patients (fenfluramine, n = 42; placebo, n = 45) and 86 patients (fenfluramine, n = 42; placebo, n = 44), respectively. Investigators stratified results into 3 age groups: 1 to younger than 2 years (n = 4), 2 to 6 years (n = 39), and older than 6 to 35 years (n = 43). Data for the youngest group were not reported because of the small sample size.

CDD is an ultra-rare, drug-resistant, X-linked developmental and epileptic encephalopathy caused by pathogenic CDKL5 variants, with seizures typically beginning within the first 3 months of life and evolving over time. Because the age-group comparisons were reported with nominal P values and involved relatively small subgroups, the results should be viewed as supportive of, rather than independent from, the trial's primary findings. The 14-week controlled period also limits conclusions about long-term efficacy across age groups.

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Positive results from GEMZ, presented at the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9, in Atlanta, Georgia, showed that fenfluramine reduced median CMSF by 47.6% from baseline compared with 2.8% with placebo (P <.001), corresponding to an estimated median difference of −52.7% (95% CI, −70.0% to −36.7%) over the 14-week titration and maintenance period.² Investigators also rated 38.1% of fenfluramine-treated patients as much improved or very much improved on the Clinical Global Impression–Improvement scale, compared with 6.8% of those on placebo (P <.001). In addition, fenfluramine-treated patients gained a median of 6.4 countable motor seizure–free days per month vs 0.1 days with placebo. No cases of valvular heart disease or pulmonary arterial hypertension were observed during the trial.

Fenfluramine is currently approved for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome. Following the positive GEMZ results, UCB announced plans to seek regulatory approval for fenfluramine in CDD, which would mark its third developmental and epileptic encephalopathy indication. In addition, open-label extension phase of the study, evaluating long-term efficacy, safety, and tolerability with flexible dosing over 52 weeks, is ongoing.²

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REFERENCES
1. Moseley B, Marsh E, Devinsky O, et al. Fenfluramine treatment in CDKL5 deficiency disorder: phase 3 primary efficacy and safety results by age. Presented at: CNS 2026; October 14-17, 2026; Montreal, Canada. Poster EOP-3.
2. UCB presents positive results from GEMZ phase 3 study at AES showing fenfluramine significantly reduced countable motor seizure frequency in CDKL5 deficiency disorder. News release. UCB. December 8, 2025. Accessed October 13, 2026. https://www.prnewswire.com/news-releases/ucb-presents-positive-results-from-gemz-phase-3-study-at-aes-showing-fenfluramine-significantly-reduced-countable-motor-seizure-frequency-in-cdkl5-deficiency-disorder-302633492.html