Abstracts

Rationale: Cannabidiol (CBD) can reduce seizures in patients with epilepsy. Human work has focused on orally-delivered CBD for children with epilepsy. The current studies evaluated the safety and efficacy of ZYN002 (transdermal CBD gel) as adjunctive therapy for the treatment of adult focal seizures. Methods: STAR 1 was a phase 2A, randomized, double-blind, placebo-controlled, study assessing ZYN002, administered as a transdermal gel BID for 12 weeks to adults with focal seizures. Following an 8-week baseline, patients were randomized 1:1:1 to: CBD 390mg daily in divided doses, CBD 195mg daily in divided doses, or placebo. The primary efficacy endpoint was the change in seizure frequency over the entire treatment period vs baseline.  At the end of week 12, patients could elect to roll into an open label extension (STAR 2) study with the 195 mg BID dose.  Results: 188 patients were enrolled. Their mean age was 39 (18-71) years. At baseline, patients were taking an average of 2.5 AEDs with a median 10.6 (3-330) seizures monthly. After 12 weeks, the median reduction in focal seizures was 18.4% with ZYN002 195 mg/day (n=63), 14.0% with ZYN002 390 mg/day (n=62), and 8.7% with placebo (n=63). There were no statistically significant differences in efficacy between ZYN002 and placebo. 171 patients rolled into STAR 2.   Post-hoc analysis showed by month 3 of STAR 2, patients who received ZYN002 in STAR 1 and STAR 2 (6 months total of ZYN002) had greater reductions in seizure frequency relative to those who only received ZYN002 for the 3 months in STAR 2 (received placebo in STAR 1).  See Table 1.In STAR1 adverse event rates were ZYN002 195 mg/day, 49.2% 51.6% on 390 mg/day and 41.3% on placebo. Two treatment-emergent adverse events occurred in >5% of ZYN002 patients and greater than placebo: fatigue (5.6%, placebo, 1.6%) and headache (5.6%, placebo, 3.2%). The plasma levels of CBD were dose-proportional, but there was no correlation between plasma levels and efficacy. Conclusions: After 12 weeks of blinded treatment, the change in seizure frequency did not differ between placebo and both doses of ZYN002, although there was a trend for seizure reduction in the actively treated patients. Secondary analysis suggested that greater seizure reduction occurred with continued use of ZYN002 in the STAR 2 study. Additional data out to 6 months from the STAR 2 will be presented. ZYN002 was well tolerated. Funding: This study was supported by Zynerba Pharmaceuticals, Inc.