UCB Reports Positive Results from Phase 3 Study in CDKL5 Deficiency Disorder

Rare Daily Staff

UCB reported that a phase 3 study of its seizure medication fenfluramine in children and adults with the ultra-rare developmental and epileptic encephalopathy CDKL5 deficiency disorder met its primary and key secondary endpoints.

The company presented results from its GEMZ study at the American Epilepsy Society meeting in Atlanta, saying the trial demonstrated a statistically significant reduction in countable motor seizure frequency and a clinically meaningful improvement on the Clinical Global Impression–Improvement (CGI-I) scale compared with placebo.

CDKL5 deficiency disorder (CDD) is characterized by multiple types of drug-resistant seizures and severe global neurodevelopmental delays that result in intellectual, motor, cortical visual, gastrointestinal, and sleep impairments as major features. It is caused by pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene located on the X chromosome and affects about four times more females than males.

Fenfluramine, marketed by UCB as Fintepla, is an oral solution originally developed by Zogenix, which UCB acquired in March 2022. Fenfluramine is a serotonin-releasing agent that stimulates multiple 5-HT receptor subtypes through the release of serotonin. It may reduce seizures by acting as an agonist at specific serotonin receptors in the brain, including the 5-HT1D, 5-HT2A, and 5-HT2C receptors, and by acting on the sigma-1 receptor. The precise mechanism of action of fenfluramine in Lennox-Gastaut syndrome (LGS) is not known.

In the European Union, fenfluramine is approved for treating seizures associated with Dravet syndrome and LGS as an add-on therapy to other antiepileptic medicines for patients 2 years of age and older. In the United States, fenfluramine oral solution is indicated for treating seizures associated with Dravet syndrome and LGS in patients 2 years and older. In Japan, it is approved for treating seizures associated with Dravet syndrome and LGS as an add-on therapy for patients 2 years and older. It is not approved for use in CDD by any regulatory authority worldwide.

The GEMZ phase 3 study was a randomized, double-blind, placebo-controlled, fixed-dose, multicenter trial examining the efficacy, safety, and pharmacokinetics of adjunctive fenfluramine treatment in 86 children and adults aged 1 to 35 years with a diagnosis of CDD and uncontrolled seizures.

Patients treated with fenfluramine experienced a median reduction of 47.6 percent in countable motor seizure frequency (CMSF) from baseline, compared with 2.8 percent for placebo. CMSF is a clinical trial measure of observable seizures over a given period. After 14 weeks, 45.2 percent of fenfluramine-treated patients achieved at least a 50 percent reduction in CMSF, compared with 4.5 percent of patients who received placebo.

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.

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. Treatment-emergent adverse events (TEAEs) were consistent with the known safety profile of fenfluramine in Dravet syndrome and LGS, with 14.3 percent of patients who received fenfluramine experiencing serious TEAEs compared with 6.7 percent of patients who received placebo.

UCB 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 adults with CDD.

“Families affected by this ultra-rare condition face immense daily challenges with frequent, treatment-resistant seizures that are profoundly disruptive to daily life,” said Fiona du Monceau, executive vice president, patient evidence at 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.”

Photo: Fiona du Monceau, executive vice president, patient evidence at UCB