Abstracts

Rationale:
Rett syndrome (RS) is a profoundly disabling rare disease affecting 1 in 10,000 females, characterised by profound psychomotor retardation, loss of purposeful hand activity, and epileptic seizures. Epilepsy affects 60-90% of RS patients and is often intractable. Cannabidivarin (CBDV), a non-psychotropic phytocannabinoid, is a propyl analogue of cannabidiol. The mechanism of action is unclear but Mecp2 deletion in mice upregulates CB1 and CB2 receptor levels in the brain and these changes are restored after CBDV treatment. CBDV improves seizures and completely rescues cognitive deficits in Mecp2  KO mice. This phase I study investigated the efficacy and safety of CBDV treatment in refractory epilepsy in children with Rett Syndrome, with known pathogenic MECP2 mutations.
Method:
Five children with RS and intractable epilepsy were enrolled in this phase one trial. Baseline assessments including monthly seizure burden were undertaken. Children were prescribed CBDV 50mg/mL which was titrated across the study period which spanned 11-14m. Data collected included seizure type and frequency, adverse events, and responses to Rett Syndrome Behaviour Questionnaire and Rett Syndrome Symptom Severity Index, patients’ global impression of change scale (PGIC) and clinical global impression (CGIC) score. Seizures were classified per the International League against Epilepsy (ILAE) classification.  
Results:
The maximum dose of CBDV ranged between 8-10mg/kg/day. All five children had a reduction in average monthly seizure burden with a median reduction of 80% (Range: 14-98%): 4/5 >50% reduction; 3/5 >75% reduction. The reduction was non-linear with fluctuations in seizure frequency noted between visits. The commonest reported seizure semiology were focal with impaired awareness and generalised motor seizure, including tonic-clonic seizures. 91% of adverse events reported were mild-moderate and none required drug withdrawal. 3% were related to CBDV; 2/5 children experienced temporary somnolence. 30% were possibly related, 5% reported as severe but resolved without treatment, and included gastrointestinal, respiratory and infections. Two children developed a trunkal tilt that resolved with dose reduction.  No children withdrew from the study and all families wanted to continue ongoing treatment.
Conclusion:
CBDV, at a dose of 10mg/kg/day, produced an overall significant decrease in monthly seizure burden for 80% of participants with refractory epilepsy and Rett syndrome. This dose was well tolerated by all children, with adverse events managed without drug cessation. Non-epilepsy outcome measures are to be analysed. CBDV shows promise for further development as an anti-seizure medicine. 
Funding:
:This was a fully investigator initiated study. The investigational medicinal product was supplied at no cost from GW Pharma. The study was funded fully by an unrestricted grant from the Ministry of Health, State Government of New South Wales, Australia.