Abstracts

Rationale: DS is a developmental and epileptic encephalopathy that is often treatment-resistant, with onset typically by 15 months of age and a high mortality rate. Efficacy and safety of CBD in the treatment of seizures associated with DS was demonstrated in 2 randomized, placebo-controlled trials, GWPCARE1 (NCT02091206) and GWPCARE2 (NCT02224703). Here, we report long-term safety and efficacy results of the third analysis of the OLE (NCT02224573) of these studies, with safety data over the full duration of follow-up (up to 184 weeks) and efficacy data up to 156 weeks. Methods: Patients who completed GWPCARE1/2 could enroll in GWPCARE5 and receive plant-derived highly purified CBD (Epidiolex®; 100 mg/mL oral solution). Initially, the dose was titrated up to the target of 20 mg/kg/d administered in 2 divided doses, and could be decreased or increased to a maximum of 30 mg/kg/d at the investigator’s discretion. The primary endpoint was safety evaluated over the full duration of follow-up. Secondary efficacy endpoints for this analysis included median percentage change from baseline in convulsive and total seizure frequency, and convulsive seizure responder rates, each assessed at 12-wk visit windows up to 156 wks. Results: Of the 330 patients with DS who completed the randomized controlled trials (RCTs), 315 enrolled in the OLE trial. At the time of the analysis, the median treatment time (range) in the OLE was 61 wks (>2‑184 wks); some patients had not yet reached the later treatment windows and 43% withdrew. Mean age of the patients was 10 yrs, 97% were <18 yrs, and 50% were male. Patients were taking a median of 3 concurrent AEDs at baseline. During the OLE, 68% of patients were taking clobazam, 67% valproate, and 38% stiripentol. At baseline of the RCTs, patients had median 12 convulsive and 36 total seizures per 28 d. The mean (SD) modal dose of CBD during the OLE was 22 (5) mg/kg/d. Adverse events (AEs) occurred in 97% of patients, serious AEs in 41%, and discontinuations due to AEs in 9% (see Table 1 for the most common AEs). AEs for liver-transaminase elevations occurring in ≥5% of patients were increased aspartate aminotransferase (12%), increased alanine aminotransferase (11%), and increased gamma-glutamyltransferase (10%). The 4 deaths that occurred during the OLE were not attributed to CBD treatment by the investigator. Median % reductions from baseline, assessed every 12 wks, ranged from 45%–73% for convulsive and 49%–80% for total seizures through 156 wks; last observation carried forward analysis showed similar results (Table 2). Convulsive seizure responder rates (≥50%, ≥75%, and 100% reduction) were consistent across the 12-wk visit windows through 156 wks, ranging from 46%–70%, 27%–46% and 4%–18% (respectively). Conclusions: Long-term, add-on CBD treatment had a similar safety profile to that observed in the RCTs. Sustained reductions in convulsive and total seizures were observed up to 156 wks. Results of this OLE demonstrate the potential long-term benefits of CBD treatment for patients with DS. Funding: GW Research Ltd