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.