AES Poster Shines Light on Positive Phase 3 GEMZ Study of Fenfluramine in CDKL5

Investigators have presented more detailed results from the positive phase 3 GEMZ trial assessing fenfluramine (Fintepla; UCB), an FDA-approved antiseizure medication (ASM), in patients with CDKL5 Deficiency Disorder (CDD). As previously reported, the trial met its primary end point and key secondary end points, with treated patients showing statistically significant reductions in countable motor seizure frequency (CMSF) relative to placebo.^1,2

In this double-blind, placebo-controlled, fixed-dose study, 86 children and adults aged 1-35 with CDD were randomly assigned 1:1 to fenfluramine 0.7 mg/kg/d or placebo for a 2-week titration period, followed by a 12-week maintenance treatment period. Presented at the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9 in Atlanta, Georgia, those on fenfluramine demonstrated a 47.6% median reduction in CMSF, the primary end point, relative to baseline, compared with 2.8% of those on placebo (P <.001).

On the primary end point, the between-group differences translated into a median CMSF reduction of 52.7% (95% CI, –70.0 to –36.7) over the 14-week period. Notably, at the end of the maintenance phase, 45.2% (n = 19) of fenfluramine-treated patients achieved at least a 50% reduction in CMSF, compared with only 4.5% (n = 2) of patients on placebo (P <.001).

"UCB is proud to share these important results with the medical community at AES, especially given the significant unmet need in CDD. Families affected by this ultra-rare condition face immense daily challenges with frequent, treatment-resistant seizures that are profoundly disruptive to daily life," Fiona du Monceau, executive vice president of Patient Evidence at UCB, said in a statement. "These trial results emphasize the impact that seizure control can have on the lives of patients and their families, and we look forward to working with health authorities to make this treatment available as soon as possible."

Coming into the study, the baseline characteristics between both cohorts were balanced, with most patients (fenfluramine: 64%; placebo: 62%) receiving at least 3 concomitant ASMs. There was a similar rate of female patients in the study (fenfluramine: 86%; placebo: 89%), and the mean age at baseline was 8.6 (±6.8) in the fenfluramine group and 9.1 (±7.6) in the placebo group. Coming into the study, the baseline median CMSF for patents in the fenfluramine and placebo groups, respectively, were 44 (range, 16-290) and 49 (0-1382).

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GEMZ was considered the first trial testing fenfluramine, which had been approved for other rare epilepsies like Dravet syndrome and Lennox-Gastaut syndrome, for CDD. In addition to the primary end point, treatment with fenfluramine led to statistically significant effects on secondary end points, which included at least 50% reduction in CMSF, ratings of clinically meaningful improvement on Clinical Global Impression-Improvement (CGI-I) by investigators, and change in monthly generalized tonic-clonic seizure (GTCS) frequency.

In the study, most patients treated with fenfluramine experienced a meaningful increase in CMSF days, with a median gain of more than 6 additional seizure-free days per month from baseline compared with placebo. Investigators rated 38.1% of fenfluramine-treated patients as much improved or very much improved on the CGI-I, compared with 6.8% of those receiving placebo. Caregivers reported an even greater perceived benefit, with 53.7% rating patients on fenfluramine as much improved or very much improved, versus only 2.3% in the placebo group.

Using a subset of patients who had GTCS at baseline, the percentage change in GTCS over the 14-week period was –61.5% (n = 14) for fenfluramine-treated patients vs –13.5% (n = 18) for those on placebo (P = .099). Achievement of at least a 75% reduction or 100% reduction in CMSF was found in 21.4% and 4.8% of patients, respectively, on fenfluramine, vs 1.3% and 0.0% of those on placebo.

In terms of safety, there was no new signals observed, as well as no cases of valvular heart disease or pulmonary arterial hypertension. Treatment emergent adverse events (TEAEs) occurred in 76.2% of fenfluramine-treated patients, with pyrexia (19.0%; n = 8), diarrhea (19.0%), and somnolence (19.0%) the most commonly observed. Other notable TEAEs included nasopharyngitis (9.5%), decreased appetite (16.7%), upper respiratory tract infection (9.5%), seizure (7.1%), and insomnia (7.1%).

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REFERENCES
1. UCB presents positive results from GEMZ phase 3 study at AES showing fenfluramine significantly reduces countable motor seizure frequency in CDKL5 Deficiency Disorder. News release. UCB. December 8, 2025. Accessed December 11, 2025. https://www.ucb.com/newsroom/press-releases/article/ucb-presents-positive-results-from-gemz-phase-3-study-at-aes-showing-fenfluramine-significantly-reduces-countable-motor-seizure-frequency-in-cdkl5-deficiency-disorder
2. Specchio N, March E, Devinsky O, et al. Fenfluramine in CDKL5 Deficiency Disorder: Primary Efficacy and Safety Results From a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study. Presented at: 2025 AES Annual Meeting; December 5-9; Atlanta, Georgia. Abstract 2.429