Safety and Tolerability of GWP42006 (Cannabidivarin) in Subjects with Drug Resistant Epilepsy and Autism Spectrum Disorder

Background: Epilepsy and autism have been estimated to coexist in 20-30% of patients with either disorder. The wide prevalence and association of these two disorders suggest common genetic factors and pathway correlations along with an increased predisposition for other pathologies. Lack of evidence-based recommendations for people afflicted by both these disorders suggest that insights into the common signaling systems of both disorders is needed. Phytocannabinoids may be a good class of compounds to search for modulators of both excitability and behavioral/cognitive phenotypes.

Objectives: To determine the safety and tolerability of GWP42005 (Cannabidivarin: CBDV) in autism and epilepsy subjects.

Methods: An expanded access protocol was developed via collaboration between the University of Louisville Autism Center and GW Pharmaceuticals. Although planned for 30-50 subjects, an initial pilot cohort of 5 subjects (ages 6-18 years) with documented autism and epilepsy was recruited. Autism spectrum disorder (ASD) was verified via Autism Diagnostic Observation Schedule (ADOS) testing and treatment resistant epilepsy (defined as 2 or more countable seizures per month) was verified via clinical history, initial 28-day seizure diary, and sleep eeg/polysomnogram. Clinical phenotyping by a senior psychologist and research team included seizure diary, actigraphy, Children’s Sleep Habit Questionnaire, Children Behavioral Checklist, Vineland scales, Mean Length Utterance, Differential Ability Scales, Social Communication Questionnaire, ADOS Severity Score, Pervasive Developmental Disorder Behavioral Inventory (PDD-BI), and motor battery. Subjects were titrated from 1 mg/kg/day to 10mg/kg/day cannabidivarin (CBDV) (GWP42006; GW Pharmaceuticals) divided BID. Safety profiles for side effects, antiepileptic drug levels, liver function, basic metabolic panel, amylase/lipase, CBCs, ECG, and Columbia Suicide Scale were monitored.

Results: ADOS severity score was an average of 7 (range 4-10) and the baseline 2 week seizure frequency was 15 (range 2-50). Safety profiles of all 5 subjects suggest that CBDV is well tolerated at 10 mg/kg/day dosing through 44 weeks. No major laboratory abnormalities were noted. Gastroesophageal reflux, aggression, and sedation were the most common adverse events upon CBDV initiation and were likely related to elevated AED levels.We report seizure and cognitive/behavioral data at the 44 week time point when all 5 subjects were treated with 10 mg/kg/d CBDV. Three subjects with generalized epilepsy are seizure free. Caretakers of all subjects report consistent gains in social engagement and communication regardless of seizure frequency. Initial testing at 8 (6 mg/kg/d) and 24 weeks (10 mg/kg/day) suggest statistically significant reductions in the generalized seizure frequency (from 22 to 6 per 2 week epoch) at p<0.0001. Suggestions of impact on communication and core autism symptoms were documented by the increased Mean Length Utterance score, increased DAS nonverbal IQ, and a decreased ADOS-CSS (p=0.09-0.18).

Conclusions: The initial data suggest that CBDV 10 mg/kg is well tolerated and certainly has potential as an AED in the autism/epilepsy population. Interestingly, the initial cohort suggest CBDV may impact communication, social interactions, and core autism symptoms. Our current plan is to expand our cohort to all autism subpopulations and increase CBDV dosing up to 20 mg/kg/day in children 6 years of age and older.