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COWEN COLLABORATIVE INSIGHTS February 25, 2019 Additional Applications / Implications (Nadeau & Osborne) 2 Epilepsy & Psychiatric Conditions (Nadeau) For companies willing to invest in research and manufacturing, the development of FDA- approved cannabinoid-based drugs provides another path to market. GW’s Epidiolex (highly potent, pure CBD) was approved by the FDA in 2018, and several other companies are dedicating resources to conducting the pre-clinical and clinical research necessary to follow in GW’s footsteps. These companies are developing cannabinoids that differ by route of administration (oral capsule, oromucosal spray, sublingual pill, aerosol, topical cream, etc), formulation (level of purification, bioavailability, concentration), and dosing strategy (single agent or in combination). Below we summarize the clinical trial data from GW’s Epidiolex in epilepsy and psychiatric indications, and Zynerba’s transdermal CBD gel ZYNOO2 in Fragile X syndrome. GW conducted a broad Phase III program for Epidiolex in epilepsy, consisting of two Phase Ill trials in Dravet, two Phase II| trials in Lennox-Gastaut syndrome (LGS), a Phase Ill trial in tuberous sclerosis complex, and a Phase II/III trial in infantile spasms. The first three Phase Ill trials (one in Dravet and two in LGS) supported an NDA submission, leading to FDA approval in June 2018. The Phase III efficacy portion of the first Dravet trial randomized 120 patients to either Epidiolex (20 mg/kg/day, n=61), or placebo (n=59). Epidiolex was added to background anti-epileptic drugs (AEDs). On average, patients were taking ~3 AEDS after previously having failed 4 or more. The average age of trial participants was 10 years and 30% of patients were less than 6 years of age. Patients entered the study with a median baseline convulsive seizure frequency of 13/month. The primary endpoint was the % change in monthly frequency of convulsive seizures during the 14-week treatment period compared with the 4-week baseline between Epidiolex and placebo. On the trial's primary endpoint, Epidiolex achieved a highly statistically significant median reduction in monthly convulsive seizures of 39% compared with a reduction in placebo patients of 13% (p=0.01). The difference between Epidiolex and placebo emerged during the first month of treatment and was maintained through the entirety of the treatment period. Nine pre-specified sensitivity analyses of the primary endpoint confirmed the robustness of the primary endpoint result. These analyses dealt with statistical elements such as the data’s normality, assumptions about discontinuations, and the time period over which the data were analyzed. A number of secondary endpoints were also assessed (responder analysis, seizure types, global impression of change). Full data were presented at AES 2016. This presentation disclosed that during the maintenance period the reduction in seizure frequency was 41% for Epidiolex vs. 16% for placebo, p=0.0052. The median reduction in total seizures was 29% for Epidiolex vs. 9% for placebo during the treatment period, and 37% for Epidiolex vs. 10% for placebo during the maintenance period. There was a clear separation between Epidiolex and placebo in a continuous response analysis of convulsive seizures across all reductions in convulsive seizure frequency. In particular 43% of Epidiolex patients vs. 27% of patients taking placebo had at least a 50% reduction in convulsive seizures. 62% of Epidiolex patients vs. 35% of placebo patients were rated slightly improved, much improved, or very much improved on the Caregiver Global Impression of Change (CGIC). It was noted that three Epidiolex and no placebo patients achieved convulsive and total seizure freedom during the treatment period. While the poster did not discuss the impact of concomitant clobazam on efficacy, it did note that "the effect of concomitant AEDs on efficacy will be explored in future pooled analyses." COWEN.COM 87 HOUSE_OVERSIGHT_024903