Cannabidiol (4) – Epidyolex®

Patients aged 2 years and over with Lennox-Gastaut syndrome

• Overall, there is a hint of considerable additional benefit.
• mortality
  • No deaths occurred in the studies.
• Morbidity – frequency of convulsive and non-convulsive seizures
  • At the end of treatment, there was a statistically significant percentage reduction in the median change in the frequency of convulsive seizures (all classified as tonic-clonic, tonic, clonic or atonic) compared with baseline.
  • Here, for responders with a reduction of ≥ 50% in the frequency of convulsive seizures, there was a statistically significant advantage for cannabidiol 10 mg/kg/day.
  • At doses below 20 mg/kg/d, statistically significant advantages for cannabidiol were observed in reductions of 25%, 50% and 75%, as well as in the analysis of increases in the frequency of convulsive seizures (each analysed in the meta-analysis).
  • No patient achieved seizure freedom (a 100% reduction).
  • In the analysis of the endpoint ‘change in non-convulsive seizures’ (all myoclonic, countable partial and other partial seizures, or absence seizures), only those patients who had already reported non-convulsive seizures at baseline were included.
  • Here too, statistically significant differences were observed for both dosages.
• Morbidity – status epilepticus
  • Status epilepticus, defined as any seizure lasting 30 minutes or longer, was also recorded via the telephone diary and occurred in isolated cases in the studies in both convulsive and non-convulsive forms.
  • No statistically significant differences were observed.
• quality of life
  • Health-related quality of life was assessed using the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire, which is generally considered suitable for patients up to the age of 18.
  • In the present studies, however, the questionnaire was used for some patients over the age of 18, although the exact number is unclear.
  • As it is therefore not possible to determine the response rate, the QOLCE analysis cannot be used for the benefit assessment.
  • Due to its unclear validity, the questionnaire for adult patients, the Quality of Life in Epilepsy version 2 (QOLIE-31-P), is also not used to derive the additional benefit.
• Side effects
  • For the population under assessment, the meta-analysis of 20 mg/kg/day cannabidiol revealed a statistically significant difference between the treatment arms, to the detriment of cannabidiol, in the assessment of serious adverse events and therapy discontinuations due to AEs.
  • No suitable data were available for the endpoint of severe AEs, as the studies did not use a standardised definition based on severity.
  • When considering AEs with an incidence of ≥ 10%, statistically significant differences to the detriment of cannabidiol were observed at doses below 10 mg/kg/day for the PT subgroup (fatigue, pneumonia, somnolence) and for the SOC subgroup (nervous system disorders), and in the PT ‘nasopharyngitis’, a statistically significant difference in favour of cannabidiol was observed; at doses below 20 mg/kg/day, for AEs from the system organ classes ‘General disorders and administration site conditions’, ‘Investigations’, ‘Nervous system disorders’ and ‘Psychiatric disorders’, disorders of the kidney and urinary tract, disorders of the respiratory tract, thoracic cavity and mediastinum, and disorders of the skin and subcutaneous tissue in the individual studies.
  • Furthermore, at doses below 20 mg/kg/day, a statistically significant disadvantage was observed for the serious AEs ‘Respiratory, thoracic and mediastinal disorders’ and ‘Acute respiratory failure’.
• Overall assessment
  • For the benefit assessment of cannabidiol in the treatment of Lennox-Gastaut syndrome in patients aged 2 years and over, the patient population defined in accordance with the summary of product characteristics (SmPC) – i.e. those patients receiving additional clobazam treatment – is considered.
  • Findings relate to mortality, morbidity and side effects.
  • No deaths occurred in the patient population under consideration.
  • In the category of morbidity, a reduction in seizure frequency in this therapeutic indication is an important therapeutic goal and is of high clinical relevance.
  • For the clinically relevant endpoints in this therapeutic indication—the frequency of convulsive and non-convulsive seizures and a 50% reduction in convulsive seizures—a statistically significant advantage of cannabidiol over placebo was observed in each case, and, for the 20 mg/kg/d dose, also for reductions of 25% and 75%, and for an increase of > 0%.
  • The results regarding health status, assessed by the carer using the CGI-C, support this finding: an improvement in health status was noted significantly more frequently in the cannabidiol arm.
  • Although there is a statistically significant difference in favour of cannabidiol for the endpoint of frequency of non-convulsive seizures, the results are biased as they do not relate to the entire patient population.
  • No relevant effects were observed for the additional morbidity endpoint of status epilepticus, which is relevant to the assessment.
  • The advantages in the morbidity endpoint category are assessed as considerable overall.
  • No suitable data were available for the quality of life category.
  • In the ‘side effects’ category, there are statistically significant differences to the detriment of cannabidiol in the overall rates of serious adverse events and therapy discontinuations due to adverse events at doses below 20 mg/kg/day of cannabidiol.
  • These disadvantages, which were observed exclusively at the 20 mg/kg/d dose, are not considered sufficient to downgrade the advantages in the morbidity category, which are assessed as considerable.
  • In particular, it is assumed that the risk of such adverse effects occurring in the everyday healthcare situation can be reduced through individual dose titration as envisaged in the marketing authorisation, which was not reflected in the studies.

Courtesy translation only, please refer to the German original.