Abstracts

Rationale: LGS is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of CBD in the treatment of seizures associated with LGS was demonstrated in two Phase 3 controlled trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690). Here we report a third analysis of the OLE (NCT02224573) of these trials, designed to assess long-term safety and efficacy of CBD added to existing antiepileptic drug (AED) treatment in children and adults with LGS. This analysis reports safety data over the full duration of follow-up (up to 179 weeks) and efficacy data up to 156 weeks. Methods: Patients who completed either 14-wk double-blind, randomized controlled trial could enter this OLE trial, in which they received plant-derived highly purified CBD (Epidiolex®; 100 mg/mL oral solution). Initially, patients were titrated to 20 mg/kg/d administered in two divided doses; the dose could then be decreased or increased up to 30 mg/kg/d at the investigator’s discretion. The primary endpoint was safety evaluated for the entire duration of follow-up.  Secondary efficacy endpoints for this analysis included median percentage change from baseline in drop seizure and total seizure frequency, and drop seizure responder rates, each assessed at 12-wk visit windows up to 156 wks. Results: Of 368 patients with LGS who completed the core studies, 366 (99%) enrolled in the OLE and median follow-up was 150 wks (range: 3 d to 179 wks). At the time of this analysis 119 (33%) patients had withdrawn from the OLE; the most common reasons for withdrawal were patient or parent/guardian decision (45 patients) and adverse event (AE) (37 patients). Mean age was 16 yrs, with 33% ≥18 yrs, and 54% male. Patients were taking a median of 3 concomitant AEDs at baseline. During the OLE, 54% of patients were taking clobazam and 39% valproic acid. At pre‑randomization baseline, patients had a median of 80 drop seizures and a median of 168 total seizures per 28 d. Mean modal dose of CBD during the OLE treatment phase was 24 mg/kg/d (range: 2.5–30 mg/kg/d across the 12‑wk visit windows). During the extended follow-up, AEs occurred in 96% of patients, serious AEs in 42%, and discontinuations due to AEs in 12% (see Table 1 for the most common AEs). AEs for liver transaminase elevations occuring in ≥5% of patients were alanine aminotransferase increased (8%), gamma‑glutamyltransferase increased (6%), and aspartate aminotransferase increased (5%). There were 11 deaths (3%), none deemed related to CBD treatment by the investigator(s). Median % reductions in drop and total seizures, assessed at 12-wk visit windows, were maintained up to 156 wks, ranging from 48%‑71% for drop seizures and 48%–68% for total seizures; last observation carried forward (LOCF) analyses showed similar findings. Drop seizure responder rates (≥50%, ≥75%, and 100% reduction) were maintained up to 156 wks, ranging from 49%–68%, 29%–46% and 3%–11% across the 12‑wk visit windows (Table 2). Conclusions: Long-term, add-on CBD treatment had a similar safety profile to that observed in the core studies. Sustained reductions in drop and total seizure frequency were observed up to 156 wks of follow-up. Overall, these results demonstrate the potential long-term benefits of CBD treatment for patients with LGS. Funding: GW Research Ltd