Abstracts

Rationale: Data from a US expanded access program suggest that CBD may offer clinically significant seizure reduction in patients with Dravet syndrome (DS). This randomized, double-blind, placebo-controlled study evaluated dose?'ranging safety, tolerability, and pharmacokinetics (PK) of CBD in children with DS in Part A, prior to assessing efficacy and safety in a larger study population in Part B. Methods: After a 4-week baseline period, patients were randomized 4:1 to 1 of 3 doses of CBD (5, 10, 20 mg/kg/day) or placebo (PBO) as add-on therapy for 3 weeks. A pharmaceutical oral formulation of CBD (25 mg/mL or 100 mg/mL) was administered twice daily starting at 2.5 mg/kg/day and increasing by 2.5 mg/kg QOD to randomized dose. On Day 1 (after first dose) and Day 22, PK exposures were expressed as AUC0–t. Dose proportionality was assessed on Day 22 by simple regression analysis. Adverse events (AEs) were recorded daily throughout the trial. Results: Safety analysis included 34 patients, aged 4–10 years, randomized to CBD 5 mg/kg/day (n=10); 10 mg/kg/day (n=8); 20 mg/kg/day (n=9); or PBO (n=7). Demographics were similar across groups, with patients taking a median 3 antiepileptic drugs (AEDs). Most common AEs (CBD vs PBO) were somnolence (19% vs 14%), pyrexia (22% vs 0%), decreased appetite (19% vs 0%), and sedation (15% vs 0%). Medication was discontinued in 2 patients because of AEs (one on 20 mg/kg/day with abnormal liver enzymes and decreased appetite; one on 10 mg/kg/day with pyrexia and rash).  Increases in ALT or AST (levels >3× upper limit of normal) occurred in 6 patients on CBD, all on valproic acid (VPA); none had elevated bilirubin.  Four of the 6 had concomitant viral/bacterial infections. VPA dose was reduced in 1 patient and LFTs in all 6 returned to baseline upon either study completion (n=5) or withdrawal (n=1). Serious AEs were reported in 5 patients: 5 mg-1 (status epilepticus [treatment-related]), 10 mg-2 (1 pyrexia and maculopapular rash [treatment-related]; 1 pyrexia and convulsion), 20 mg-1 (parvovirus), PBO-1 (viral infection and convulsion). There were no clinically relevant changes in vital signs or ECGs and no reports of suicidal behaviour or ideation. After single or twice daily dosing of CBD, 7?'COOH?'CBD was the major circulating metabolite. On Day 22, exposures to CBD and its major metabolites increased dose-proportionally. Total inter-patient variability (%CV) in AUC0–t for CBD was moderate to high, and higher for the metabolites [Table 1]. By Day 22, plasma concentrations of clobazam’s (CLB) metabolite N?'CLB increased  independent of CBD dose [Table 2], except in patients also on stiripentol (STP), possibly due to prior inhibition of CYP2C19 by STP.  There was no obvious effect on other AEDs tested (VPA, topiramate, STP, levetiracetam). Conclusions: CBD was investigated at 5, 10, and 20 mg/kg/day, with 20 mg/kg/day approved by DSMC for further development. Exposure to CBD and its metabolites increased dose proportionally. A PK interaction of CBD on N-CLB was observed, likely mediated through CYP2C19 inhibition. (NCT02091206) Funding: GW Research, Ltd