Fenfluramine Meets End Points in Phase 3 GEMZ Study of CDKL5 Deficiency Disorder

Fiona du Monceau

In a new announcement from UCB, fenfluramine (Fintepla), an FDA-approved antiseizure medication, met its primary and secondary end points in the phase 3 GEMZ trial of patients with CDKL5 deficiency disorder (CDD). Based on these data, the company plans to submit an application for fenfluramine to become a potential treatment option for patients living with CDD.

Between baseline and the titration plus maintenance phase, fenfluramine demonstrated statistically significant changes relative to placebo on the primary end point of percent change in countable motor seizure frequency. In this phase 3, double-blind, placebo-controlled, fixed-dose study, fenfluramine continued to show a safety profile that was consistent with its previous indications in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

In the trial, which included 87 children and adults aged 1-35, with a CDD diagnosis and uncontrolled seizures, fenfluramine met its secondary end points as well. Full results are expected to be presented at an upcoming scientific meeting but for now, UCB remains committed to an open-label, flexible-dose, long-term 52-week extension phase of the study to further test the therapy’s long-term safety and tolerability in CDD.

"These results pave the way for creating significant therapeutic progress and represent an important milestone in UCB’s mission to bring meaningful innovation to individuals and families affected by developmental and epileptic encephalopathies (DEEs),” Fiona du Monceau, executive vice president, Patient Evidence at UCB, said in a statement.¹ "We are grateful to the patients, families, and researchers who made this progress possible, and we look forward to working with the health authorities to make treatment available as soon as possible."

READ MORE: The Changing Landscape of Dravet Syndrome

Fenfluramine, first approved in 2020, has a dual mechanism of action. Firstly, it enhances serotonin release and inhibits reuptake, impacting neurotransmission involved in seizure activity. Secondly, the medication modulates sigma-1 receptors, which are thought to contribute to antiseizure effects, particularly in patients with pharmacoresistant epilepsy. Unlike traditional antiseizure medications that primarily target ion channels or GABA/glutamate balance, fenfluramine's serotonergic and sigma-1 activity provides a unique multimodal approach to seizure control.

The therapy demonstrated preliminary efficacy in CDD in a small-scale study presented at the 2020 American Epilepsy Society (AES) Annual Meeting. The study enrolled 6 patients with CDD with uncontrolled epilepsy whose seizures failed to be controlled with 5 to 12 antiseizure medications as well as with dietary and other therapies. Four of the 6 patients received the maximum dose of fenfluramine 0.7 mg/kg/day while the other 2 patients were maintained on 0.4 mg/kg/day.²

Overall, treatment with fenfluramine was associated with a median 90% reduction in 5 patients with tonic-clonic seizures. In addition, there was a 50% to 60% reduction in the frequency of seizures in 2 patients with tonic seizures. In terms of safety, 2 patients experienced adverse events, with decreased appetite and flatus the main causes. Lethargy was documented when valproate was started in the only patient who had a new medication added on to fenfluramine therapy.

REFERENCES
1. UCB announces positive results from GEMZ phase 3 study of fenfluramine in CDKL5 Deficiency Disorder. News release. UCB. June 27, 2025. Accessed June 27, 2025. https://www.ucb.com/newsroom/press-releases/article/ucb-announces-positive-results-from-gemz-phase-3-study-of-fenfluramine-in-cdkl5-deficiency-disorder
2. Devinsky O, King L, Price D. Fenfluramine to treat convulsive seizures in patients with CDKL5 Deficiency Disorder. Presented at AES 2020 Annual Meeting; December 4–8, 2020; Abstract 1060.