Authors :
Presenting Author: James Wheless, MD – Le Bonheur Children's Hospital
An-Sofie Schoonjans, MD, PhD – Antwerp University Hospital; Shawna Evans, PharmD – UCB Biosciences, Inc.; Diego Morita, MD – UCB Biosciences, Inc.; Yamina Merazga, PhD – UCB Biosciences, Inc.; Elena Cleary, PhD – UCB Biosciences, Inc.
Rationale:
Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by pharmacoresistant seizures that begin early in life (< one year old) and neurodevelopmental comorbidities that follow. While seizure-freedom may not be attainable, early diagnosis and treatment may improve long-term outcomes. In the phase 3 randomized-controlled trials, fenfluramine (FFA) demonstrated safety and efficacy in patients two to eighteen years with DS and is currently approved for the treatment of seizures associated with DS in patients ≥ two years old in the US, EU, UK, and Japan. Here we describe the open-label, phase 3 study to evaluate FFA use in infants one to < two years old with DS.
Methods:
Participants are eligible if they have a documented or likely diagnosis of DS (according to International League Against Epilepsy criteria and confirmed by Epilepsy Study Consortium), are one to < two years old, and weigh ≥ 8 kg. They must be receiving one to four concomitant anti-seizure medications (ASMs) and be experiencing ≥ four countable motor seizures (CMS) per month (28 days). Exclusion criteria include: pulmonary arterial hypertension (PAH), history of cardiovascular or cerebrovascular diseases, moderate to severe renal or hepatic impairment, or any clinically significant medical condition. This study will consist of a four week baseline period, a dose-finding treatment period (eight weeks), and subsequent maintenance period (Weeks 9-52, maximum of 44 weeks). (See Figure) FFA will be administered in equal doses twice daily. Caregivers will record number, type, duration of seizures, incidence of status epilepticus, and use of rescue medication(s) daily; cardiac safety will be evaluated by electrocardiogram (ECG) and echocardiogram. The primary objective is to evaluate safety and tolerability of FFA; secondary objectives include efficacy and the pharmacokinetic profile.
Results:
Up to 20 participants are expected to enroll. Participants will initiate FFA at 0.2 mg/kg/day and investigators may up-titrate during the dose-finding period to a maximum of 0.7 mg/kg/day (0.4 mg/kg/day, if on concomitant stiripentol) based on response and tolerability. Doses can be flexibly titrated during the maintenance period. At Visit 13 (Week 52), change from baseline in QTcF interval on ECG or occurrence of valvulopathy or PAH will be evaluated. Additionally, at each visit, change from baseline in body weight and incidence of treatment-emergent adverse events will be recorded. Effectiveness will be measured by change from baseline in CMS frequency (CMSF) during Weeks nine through twenty. At Week 12, pharmacokinetic (PK) parameters of FFA and norfenfluramine will be evaluated (Cmin, Cmax, and AUC
0-24). Achievement of “much improved” or “very much improved” on the Clinical Global Impression-Improvement (CGI-I) rating scale reported by caregivers and investigators will also be described.
Conclusions:
This study will evaluate safety, effectiveness, and PK of FFA in infant patients with DS, providing an opportunity to expand ASM options that may be initiated soon after diagnosis.
Funding: Funded by UCB Pharma.