SummaryObjectiveSince 2014, cannabidiol (CBD) has been administered to patients with treatment‐resistant epilepsies (TREs) in an ongoing expanded‐access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016.MethodsTwenty‐five US‐based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4‐week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2‐10 mg/kg/d, titrated to a maximum dose of 25‐50 mg/kg/d. Patient visits were every 2‐4 weeks through 16 weeks and every 2‐12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last‐observation‐carried‐forward method to account for missing data. Adverse events (AEs) were documented at each visit.ResultsOf 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4‐62). Median number of concomitant AEDs was 3 (range, 0‐10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add‐on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%).SignificanceResults from this ongoing EAP support previous observational and clinical trial data showing that add‐on CBD may be an efficacious long‐term treatment option for TRE.

BackgroundVesicular monoamine transporter 2 (VMAT2) inhibitors can improve hyperkinetic movements, and are effective treatment options for chorea of Huntington disease (HD). Tetrabenazine was assessed for treating chorea in the TETRA-HD trial, and while efficacious, there are tolerability concerns possibly due to its pharmacokinetic properties. Deutetrabenazine is a novel VMAT2 inhibitor that contains deuterium, which extends active metabolite half-lives and minimizes drug concentration fluctuations. In the First-HD trial, deutetrabenazine was efficacious in treating chorea and was generally well tolerated. In the absence of a head-to-head trial, we performed an indirect treatment comparison (ITC) of the tolerability of deutetrabenazine and tetrabenazine for the treatment of HD-associated chorea, as observed in the First-HD and TETRA-HD trials, using well-established comparison methods.MethodsData from the Phase III, 12-week, parallel-group, clinical trials First-HD (N = 90) and TETRA-HD (N = 84) were used to conduct an ITC of the tolerability of deutetrabenazine versus tetrabenazine using two anchor-based methods: Bucher comparison for unadjusted ITCs, and matching indirect comparison for adjusted ITCs. Overall adverse events (AEs; mild, moderate, and severe), serious AEs, specific AEs occurring in ≥10% of patients, and discontinuations (all-cause and AE-related) were included in the analysis. The risk differences of these outcomes for deutetrabenazine and tetrabenazine were estimated by subtracting the applicable placebo-adjusted risk in First-HD from that of TETRA-HD. Sensitivity analyses were performed to address differences between trials, and p-values were obtained from z-tests.ResultsCompared with tetrabenazine, deutetrabenazine was associated with a significantly lower risk of moderate to severe AEs and neuropsychiatric AEs including agitation, akathisia, depression, depression/agitated depression, drowsiness/somnolence, insomnia, and parkinsonism in both adjusted and unadjusted analyses (p < 0.05 for each). Deutetrabenazine had a significantly lower rate of dose reduction or dose reduction/suspension in the unadjusted and adjusted analyses (p < 0.001 for each). Deutetrabenazine resulted in numerically more mild AEs, such as diarrhea and coughing; however, these results were not statistically significant.ConclusionsThis indirect treatment comparison demonstrates that for the treatment of HD chorea, deutetrabenazine has a favorable tolerability profile compared to tetrabenazine.Trial registrationClinicalTrials.gov NCT01795859 and NCT00219804.