Abstract Details

Title Safety, Tolerability, Pharmacokinetics, and Efficacy of Fenfluramine in Combination With Cannabidiol: Results From a Phase 1 Study

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) P9 - Poster Session 9 (11:45 AM-12:45 PM)

Poster/Presentation
Number 9-010

Objective To assess the safety, tolerability, pharmacokinetics, and efficacy of fenfluramine and cannabidiol in a small cohort of patients with Dravet syndrome (DS) or Lennox-Gastaut syndrome (LGS).

Background DS and LGS are lifelong developmental and epileptic encephalopathies. Fenfluramine and cannabidiol are approved for the treatment of seizures in DS and LGS in the US and Europe. Cannabidiol’s CYP450 inhibitory activity overlaps substantially with fenfluramine-metabolizing CYP450 enzymes.

Design/Methods A phase 1, open-label study (NCT03467113) enrolled patients 2-18 years old with DS or LGS and a stable cannabidiol dose (cannabidiol source was not controlled). Patients had a 4-week baseline phase, ≤4-week titration phase, ≤104-week maintenance phase, and ≤6-month follow-up. In the titration phase, fenfluramine was titrated from 0.2 mg/kg/day to a target dose of 0.7 mg/kg/day (maximum 26 mg/day) and continued throughout maintenance. Safety and tolerability (primary objective), pharmacokinetics, and change in seizure frequency were assessed for fenfluramine and cannabidiol combination.

Results Nine patients (DS, n=4; LGS, n=5) were enrolled and received ≥1 dose of fenfluramine. Mean treatment duration was 552.0 days. All patients reported ≥1 TEAE; of 62 TEAEs reported, nasopharyngitis (55.6%) and somnolence (44.4%) were most common; no valvular heart disease or pulmonary arterial hypertension were observed during echocardiographic monitoring. No deaths and no discontinuations due to TEAEs were reported. Median pre-dose plasma concentrations for fenfluramine and cannabidiol were 49.7 and 26.6 ng/mL respectively, and the highest concentrations were 72.6 (4-hours post-dose) and 81.3 ng/mL (2-hours post-dose), respectively. In the titration and maintenance periods, median change from baseline in DS convulsive seizure frequency and LGS drop seizure frequency was -65.6% and -23.2%, respectively. During the maintenance period, ≥50% of patients were “improved”, and no patients worsened according to investigator-rated CGI-I scores.

Conclusions Fenfluramine 0.2-0.7 mg/kg/day was well tolerated when administered with cannabidiol. These data further support the safe use of fenfluramine and cannabidiol combination.

Authors/Disclosures
Brooks Boyd, PhD PRESENTER	Dr. Boyd has received personal compensation for serving as an employee of UCB Biosciences. Dr. Boyd has stock in UCB Biosciences. Dr. Boyd has received intellectual property interests from a discovery or technology relating to health care.
Rebecca Zhang-Roper, MD, PhD	Dr. Zhang-Roper has received personal compensation for serving as an employee of UCB. Dr. Zhang-Roper has stock in UCB.
Aravind Mittur, PhD	Dr. Mittur has received personal compensation for serving as an employee of UCB. Dr. Mittur has stock in UCB. Dr. Mittur has received intellectual property interests from a discovery or technology relating to health care.
Melanie LANGLOIS (UCB Pharma)	Melanie LANGLOIS has received personal compensation for serving as an employee of UCB Pharma. Melanie LANGLOIS has stock in UCB Pharma.
Shawna Evans, PharmD	Dr. Evans has received personal compensation for serving as an employee of UCB Biosciences. Dr. Evans has stock in UCB Biosciences.
Diego Morita, MD (UCB Biosciences, Inc)	Dr. Morita has received personal compensation for serving as an employee of UCB Biosciences, Inc. Dr. Morita has stock in UCB, Inc.
Steven A. Phillips, MD (Mary Bridge Children's Hospital)	No disclosure on file

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