UCB's Fenfluramine Shows Significant Seizure Reduction in Phase 3 Trial for CDKL5 Deficiency Disorder
Key Insights
UCB (search)'s GEMZ phase 3 trial demonstrated that fenfluramine achieved a statistically significant 47.6% median reduction in countable motor seizure frequency compared to 2.8% for placebo in patients with CDKL5 Deficiency Disorder (search).
The study met its primary endpoint with 45.2% of fenfluramine-treated patients achieving at least 50% seizure reduction versus only 4.5% of placebo patients, representing a potential breakthrough for this ultra-rare condition.
Fenfluramine was generally well tolerated with no new safety signals, and UCB (search) plans to submit for regulatory approval as soon as possible, marking the third developmental epileptic encephalopathy indication for the drug.
UCB (search) presented positive results from its GEMZ phase 3 study at the American Epilepsy (search) Society meeting, demonstrating that adjunctive fenfluramine significantly reduced seizure frequency in patients with CDKL5 Deficiency Disorder (search) (CDD (search)). The randomized, double-blind, placebo-controlled trial met its primary endpoint and key secondary endpoints, marking a potential therapeutic breakthrough for this ultra-rare condition.
Trial Design and Patient Population
The GEMZ study enrolled 86 children and adults aged 1-35 years with CDD (search) diagnosis and uncontrolled seizures (search). Participants were randomized to receive either fenfluramine (0.7 mg/kg/day, maximum 26 mg/day) or placebo as adjunctive therapy during a 14-week titration and maintenance period.
Primary Efficacy Results
Patients treated with fenfluramine (n=42) experienced a median reduction of 47.6% in countable motor seizure frequency (CMSF) from baseline, compared with 2.8% for placebo (n=44) (p<0.001). This translated into an estimated median reduction of 52.7% (95% CI: −70.0 to −36.7) between treatment groups.
The responder rate analysis showed that 45.2% (n=19) of fenfluramine-treated patients achieved at least 50% reduction in CMSF after 14 weeks, compared with only 4.5% (n=2) of patients who received placebo (p<0.001). Most fenfluramine-treated patients experienced an increase in countable motor seizure-free days, with a median of more than six additional seizure-free days per month from baseline compared with placebo.
Clinical Global Impression Improvements
Secondary endpoints demonstrated clinically meaningful improvements on the Clinical Global Impression-Improvement (CGI-I) scale. Investigators rated 38.1% (n=16) of patients on fenfluramine as "much improved" or "very much improved" compared with 6.8% (n=3) of those on placebo (p<0.001).
According to caregiver reports, 53.7% (n=22) of fenfluramine patients received a CGI-I rating of "much improved" or "very much improved" versus just 2.3% (n=1) in the placebo group (p<0.001).
Safety Profile
Fenfluramine was generally well tolerated in the trial, with no new safety signals identified and no cases of valvular heart disease or pulmonary arterial hypertension occurring. Treatment-emergent adverse events were consistent with the known safety profile of fenfluramine in Dravet syndrome (search) and Lennox-Gastaut syndrome (search).
Serious treatment-emergent adverse events occurred in 14.3% (n=6) of patients who received fenfluramine compared to 6.7% (n=3) of patients who received placebo. In the fenfluramine group, serious adverse events included urinary tract infection (n=2), metapneumovirus infection (n=1), RSV pneumonia (n=1), decreased appetite (n=1), and dyskinesia (n=1).
About CDKL5 Deficiency Disorder
CDD (search) is an ultra-rare developmental and epileptic encephalopathy (search) characterized by multiple types of drug-resistant seizures (search) and severe global neurodevelopmental delays resulting in intellectual, motor, cortical visual, gastrointestinal and sleep impairments. The condition is caused by pathogenic variants in the Cyclin Dependent Kinase-like 5 (search) (CDKL5 (search)) gene located on the X chromosome and affects four times more females than males.
CDD (search) affects approximately 1 in 40,000 to 60,000 live births, with a median age of onset of six weeks. The condition represents a significant unmet medical need, with families facing immense daily challenges from frequent, treatment-resistant seizures (search) that are profoundly disruptive to daily life.
Regulatory Path Forward
"UCB (search) is proud to share these important results with the medical community at AES, especially given the significant unmet need in CDD (search)," said Fiona du Monceau, Executive Vice President, Patient Evidence, UCB. "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."
UCB (search) plans to submit for regulatory approval of fenfluramine for the treatment of seizures (search) associated with CDD (search) as soon as possible. This would mark fenfluramine's third developmental and epileptic encephalopathy (search) indication to be submitted for regulatory approval.
Currently, fenfluramine is approved in the European Union, United States, and Japan for the treatment of seizures (search) associated with Dravet syndrome (search) and Lennox-Gastaut syndrome (search) as an add-on therapy to other anti-epileptic medicines for patients 2 years of age and older. It is not approved for use in CDD (search) by any regulatory authority worldwide.
Long-term Safety Study
UCB (search) is currently conducting an open-label, flexible-dose, long-term 54-week extension phase of the study to characterize the long-term safety profile and tolerability of fenfluramine in children and adult individuals with CDD (search). This extension includes a 52-week treatment period plus a 2-week taper phase.