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(Abst. 1.436), 2017

Cannabidiol (CBD) Treatment Responders Analysis in Patients with Lennox-Gastaut Syndrome (LGS) On and Off Clobazam (CLB)
Authors: Elizabeth A. Thiele, Massachusetts General Hospital; Orrin Devinsky, NYU Langone Medical Center; Daniel Checketts, GW Research Ltd; and Volker Knappertz, Greenwich Biosciences
Content: Rationale: Randomized, multicenter, double-blind, placebo-controlled trials (GWPCARE 3 [NCT02224560]; GWPCARE 4 [NCT02224690]) have demonstrated the safety and efficacy of add-on CBD treatment in patients with treatment-resistant LGS. Due to a bidirectional PK interaction between CBD and CLB, a pooled post-hoc analysis of CBD treatment responders and safety outcomes in patients on- and off-CLB was conducted. Methods: Patients aged 2-55 years were randomized to placebo or CBD (100 mg/mL) in oral solution, dosed at 10 mg/kg/day (CBD10) or 20 mg/kg/day (CBD20), with a 2-week titration period followed by a 12-week maintenance period. Patients had LGS, ≥2 drop seizures/week during a 4-week baseline period, and documented failure on ≥1 AED. Assessments included the proportion of patients achieving ≥25%, ≥50%, and ≥75% reduction in drop seizure frequency during the maintenance period and overall incidence of adverse events (AEs). Results: 396 pts were randomized (73 CBD10; 162 CBD20; 161 placebo). Patients took a median of 3 antiepileptic drugs (AEDs) with ~50% on concomitant CLB (37 CBD10; 78 CBD20; 79 placebo patients on-CLB and 36 CBD10; 84 CBD20; 82 placebo patients off-CLB).  Mean daily CLB dose was 0.92 mg/kg (range: 0.11-2.94). Sixty-seven percent of patients not taking CLB had previously discontinued CLB by medical history.The proportions of patients achieving ≥25%, ≥50%, and ≥75% reductions in drop seizure frequency were greater for both doses of CBD than placebo, regardless of CLB status (Table 1). Patients on CBD reported more adverse events (AEs) than placebo for both the on-CLB (92% vs 73%) and off-CLB (84% vs 69%) subgroups. There was 1 death in the CBD20 group, considered unrelated to treatment. Elevated transaminases (>3x ULN) were reported in 3 CBD10, 31 CBD20, and 1 placebo patient, most of whom were on concomitant valproic acid. Some withdrew from treatment; all elevations resolved either spontaneously or with CBD/AED dose adjustment. Conclusions: Add-on CBD treatment of seizures associated with LGS results in clinically meaningful seizure reductions vs. add-on placebo, regardless of concomitant CLB use. AEs were reported more frequently in patients on CBD than placebo. This was a post-hoc analysis of non-randomized subgroups limiting the generalizability of these results. Funding: Funded by GW Research Ltd
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