New meta-analysis reviews safety and efficacy of Epidiolex® near pure cannabidiol (CBD) in difficult to treat epilepsy

Date of publication: November 3, 2018

Top line takeaways

Study design: Meta-analysis

Databases searched: Medline, the Cochrane Central Register of Controlled Trials, and clinicaltrials.gov

Number of studies included in analysis: Four

Number of patients: 550 subjects (Intention To Treat [ITT] analysis): 323 for Epidiolex and 227 for placebo, presenting with Lennox–Gastaut syndrome (LGS) or Dravet syndrome (DS)

Age range of patients: 2-55 years

Drug composition (Epidiolex®): ≈99% shape-specified CBD; <0.15% ∆9-THC (extracted from a proprietary Cannabis sativa chemovar) in sesame oil, with sucralose and strawberry flavor

Dosing duration:

Three to fourteen (3-14) week double-blind treatment period; ≤ 10 days’ tapering-off; 4-week safety follow-up

Dosing schedule: 5, 10, and 20 mg cannabidiol/kg (2.27, 4.53, and 9.07 mg/lb) body weight, twice daily, varying across the four studies, with three studies (14 week duration) employing a dose adjustment (“titration”) period in the first two weeks

Therapy type: Used in addition to (adjunctive) other anti-epileptic drugs (AEDs); patients averaged three other AEDs (used concurrently)

Adverse events (AEs) profile (CBD vs. placebo):

  • Treatment-related: 55.7% vs. 26.9%
  • Treatment-related Serious AEs: 7.7% vs. 0.4% (e.g. status epilepticus, sharp increases in liver enzymes i.e. more than 3x the upper normal limit)

Note: No AEs were described as intoxicating (“stoned-like) effects

Adverse events (AEs) incidence rates (CBD vs. placebo):

  • Somnolence: 24.5% vs. 8.4%
  • Decreased appetite: 20.1% versus 4.8%
  • Diarrhea 18.2% vs. 8.6%,
  • Increased liver enzymes: 16.1% vs. 0.9%

Note: AEs appeared to be drug dose-dependent

Remissions:

  • 5.5% of all patients with LGS were free from drop seizures during Epidiolex maintenance treatment, only 0.6% in the placebo
  • 5% of DS patients treated with CBD were convulsive seizure-free vs. 0% in placebo

Dose-dependent response: Among patients taking the higher dose (20 mg/kg), a notable reduction in non-convulsive seizures was observed (Note: the caregivers of the pediatric patients that were developmentally delayed were not reliable in their ability to discern these types of seizures). In two of the four studies the number of responders to Epidiolex—in relation to reduced drop seizures—was associated with increasing dose or to higher blood concentrations of Cannabidiol or its bioactive metabolite, 7-hydroxy-CBD

Conflicts/Disclosures: Only one of the seven authors disclosed a relationship to the manufacturer of the drug (GW Pharmaceuticals): receipt of consultancy funds

Comments: Epidiolex offers a potent, new addition to the suite of AEDs that are in use in many parts of the world, for a rare type of seizure syndromes. This is the most thorough and rigorous meta-analysis to date (on CBD and seizures). The strength of the efficacy results, coupled with an AEs profile comparable to other AEDs, undoubtedly inspired the US Food and Drug Administration to approve this drug. The finding of a select minority of patients attaining complete or “effective” remission suggests that pharmacogenomic/genomic/epigenetic and perhaps gut microbiome factors may influence the magnitude of blood CBD content and clinical response. Lastly, despite the not uncommon concern of CBD being converted into ∆9-THC (“THC”) in stomach acid and thus exposing a person/patient to systemic THC, pre-approval pharmacokinetic and Human Abuse Potential (“HAP”) studies on Epidiolex revealed THC and its metabolites had quantities that were below the limit of quantitation even though doses of THC (as residual amount from the Cannabis sativa extract that comprises Epidiolex) ranged from 0.3-0.9 mg of THC (from 750 – 1,500 mg of Cannabidiol from the drug).