CBD in children with treatment-resistant

epilepsies: initial results and planned trials

Maria Roberta Cilio, MD, PhD Professor Neurology & Pediatrics

Director, Pediatric Epilepsy Research University of California, San Francisco

Disclosure

Nothing to disclose

  US survey of 19 parents using artisanal preparations of CBD-enriched cannabis to treat their children with treatment-resistant epilepsy aged 2-16 years

  12/19 had Dravet syndrome   4 patients had Doose syndrome   1 had Epilepsy in Females with Mental Retardation   1 had Lennox-Gastaut Syndrome   1 had idiopathic epilepsy

  Large variety of seizure types   Seizure frequency ranged between 2/week to 250/day   Estimated doses of cannabidiol between 0.5 mg/kg/day

and 28 mg/kg/day   Duration of treatment ranged between two weeks to > 1

year   16/19 parents reported a reduction in seizure

frequency

  2 patients were reported to be seizure-free (1 Doose, 1 DS)

  8 had a reduction in seizure frequency > 80% (5/12 patients with DS)

  3 had a reduction > 50% (DS)   3 had a reduction > 25%   3 patients experience no change (2 DS, 1 Doose)

  Up to 80% reported positive side-effects (better mood, increased alertness, better sleep)

  Less than 1/3 reported negative side effects (drowsiness, fatigue, appetite decrease)

  Severe side effects were not reported

The case for medical marijuana in epilepsy

  Anecdotal reports   Neither the doses nor the exact composition of the

different artisanal compounds can be determined   The impact of the percentages of THC on effects and

side effects cannot be assessed   Impact of placebo effect in this very selected

population

  Scientific support of efficacy very slim   Absolutely no data on drug-drug interaction   No or little data on long-term safety and tolerability

The Myth   It is natural – and organic! It must be good.

  Not perceived as a drug but a natural remedy – requested as a first drug in children with childhood absences

  CBD works better alone: let’s stop the other antiepileptic drugs

  The use of pharmacological compounds derived from cannabis sativa = free marijuana

The context   This is a very sensitive issue for epileptologists and

child neurologist practicing in Colorado as kids are streaming in from all over the country whose parents bring them here to get “Charlotte’s web”. There are likely more kids who have not responded than the few who have and made CNN.

  Children may being given cannabis-based preparations in an uncontrolled and in my opinion unsafe fashion by people with no knowledge or experience in care of epilepsy patients.

The case and the challenges for assessing cannabidiol in

epilepsy   CBD ≠ Marijuana   DEA Schedule 1 substance – license and safe   Children   FDA approval   Internal approval   Import from the UK   Traveling within the US   Foundations have expressed “legal” concerns – study is unfunded

Open-label observational study

  Pharmaceutical preparation of pure CBD   Children with intractable seizures and well-defined epilepsies   Overall responder rate   Seizure-free patients   Responder rate in specific seizure type   Responder rate in specific syndromes   Age of responders   Adverse events   Pharmacokinetic interactions   Negative associations   Possible synergies tested in a wide range of AEDs   Trigger the design of a trial focused on a specific syndrome

Open-label observational study

  Accuracy of diagnosis in terms of epilepsy type/syndrome and seizure type   i.e. mutation in SCN1A gene ≠ Dravet syndrome

  Prospective and non retrospective

Open-label trial of CBD in add-on for children with intractable

epilepsy   Pediatric age: 1-18 years   Accurate electroclinical diagnosis of epilepsy type/syndrome   Video-EEG confirmed seizure type (s) Drug-resistant epilepsy despite trial with 2 or more gold standard

AEDs at therapeutic doses   At least 2 seizures/week during 4-week baseline

  Generalized tonic-clonic   Myoclonic absences   Clonic   Tonic   Tonic-atonic

§  1-3 AEDs   Stable concomitant AEDs during 4-week baseline – stable settings

of VNS and stable ketogenic diet for 3 months   Informed consent

The importance of seizure characterization

  A majority of patients with idiopathic generalized epilepsy had received inappropriate AEDs treatment (Benbadis et al. 2003)

  Children with generalized spike-wave discharges whose staring spells have been misinterpreted as temporal lobe seizures (Hussain & Sankar, 2011)

  The poor response to initial therapy in such cases is clearly not of prognostic significance

  The precise characterization of seizures provide a basis for accurate diagnosis and therapy

  Some patients with non-epileptic paroxysmal events are treated for epilepsy and clearly do not respond to treatment

  Rely on seizure characterization in deciding the treatment

  Carbamazepine and Lamotrigine – two sodium current inhibitors – were expected to be efficacious in patients with SCN1A mutation but they actually worsen the seizures

Exclusion criteria   Neurodegenerative diseases   Inborn error of metabolism   Tumors   Non- well defined epilepsies   Use of cannabis-derived compound in the preceding two

months   Felbamate initiated within the past 18 months

Acknowledgements   Geoffrey Guy   Stephen Wright   Alice Mead   Michelle Welborn   Terry Woodworth

  Joe Sullivan - UCSF   Orrin Devinsky -NYU   Elisabeth Thiele – MGH/Harvard   Helen Cross – Great Ormond Street, London   Eric Marsh – Children’s Hospital Philadelphia   Linda Laux – Children’s Hospital Chicago

Acknowledgements   UCSF   Yelena Belkin and Diana Wong – Investigational

Pharmacy   Parents   Children

Limitations   Results are preliminary   Numbers are small   No statistical analysis   No conclusions

9 patients   Well-defined epilepsies and video-EEG confirmed

seizure types   Genetic testing   MRI   Extensive metabolic testing   All patients followed at UCSF Pediatric Epilepsy Center   All fulfilled the inclusion criteria   Seizure frequency evaluated by seizure diary during

baseline and during treatment   Concomitant AEDs remained unchanged during the first

three months of treatment

Protocol   Starting dose: 5 mg/kg/day   Increased weekly up to 25 mg/kg/day   Clinical evaluation:

  Baseline   Two weeks of treatment   1 month   Every month for the first 3 months   Every 3 months thereafter

  CBC, liver function tests, BUN, creatinine, electrolytes, and concomitant AEDs plasma levels:   Baseline   Every month for the first 3 months

  Cannabidiol plasma level: 1 month and 2 months

9 patients   Follow-up: 2 months – 1 year   Age range: 3 – 17 years

  3 patients: Dravet syndrome – SCN1A positive   4 patients: Epilepsy with myoclonic absences   1 patient: Generalized epilepsy with generalized tonic-

clonic seizures – MRI, extensive genetic and metabolic testing negative

  1 patient: Epilepsy due to bilateral polymicrogyria and focal seizures evolving into bilateral clonic seizure

Concomitant AEDs   Patients with Dravet:

  Clobazam   Levetiracetam   Topiramate   Stiripentol   Phenobarbital   Clonazepam

  Patients with Epilepsy with myoclonic absences   Clobazam   Clonazepam   Lamotrigine   Levetiracetam   Felbatol   Acetazolamide

Concomitant AEDs   1 patient with Generalized epilepsy

  Clobazam   Prednisolone

  1 patient with Epilepsy due to bilateral polymicrogyria:   Phenobarbital   Carbamazepine

Preliminary results   3 patients with Dravet

  2 patients: seizure-free   1 patient: increased seizure frequency – started weaning

of CBD   4 patients with Epilepsy with myoclonic absences

  2 patients: 75% and 90% reduction in seizure frequency – 1 patient on CBD monotherapy

  2 patients: no changes in seizure frequency – 1 started weaning after > 3 months of treatment

  1 patient with Generalized epilepsy   75% seizure reduction

  1 patient with Epilepsy due to bilateral polymicrogyria:   No changes in seizure frequency – CBD weaned after 6

month of treatment

Preliminary side-effects   No significant changes in CBC, LFTs, BUN, Creatinine,

electrolytes   Increased clobazam level   3 patients: appetite loss, food aversion, nausea and

occasional vomiting   1 patient: weight loss of 20%   Dose was decreased in 2/3 patients from 25 to 20 mg/kg/

day with amelioration of symptoms   3 patients: loose stool/diarrhea   1 patient: fatigue

Next step   All open-label studies are biased. This is particularly

true for CBD.   We lack blinded data on safety and efficacy   Company-sponsored randomized double-blind controlled

trials   Dravet syndrome and Lennox-Gastaut syndrome

Placebo-controlled, syndrome- dedicated trial

  Accurate selection of homogenous populations   Small samples of patients may be sufficient to conclude

superiority of CBD   Accurate definition of gold standard treatment for a

specific syndrome – restricted number of co-medication per syndrome

  Better defined targets based on natural history   Based on the known natural history, CBD may be

associated earlier

Dravet syndrome   Stiripentol is the only compound that proved its efficacy in

DS through the methodology of randomized placebo-controlled trial (combined with Valprate and Clobazam)

  Topiramate, Levetiracetam, Potassium Bromide, Ketogenic diet are useful (based on open studies and daily practice)

  Lamotrigine and Carbamazepine should be avoided

  Complete seizure control is rarely obtained particularly on the long-term

  Can seizure reduction improve long-term cognitive outcome?

Chiron et al. Lancet 2001; Chiron and Dulac Epilepsia 2011

Lennox-Gastaut syndrome   Electroclinical syndrome with childhood onset   Onset between 1 and 4 years of age   Many patients experience more than 90 seizures a

month (Glauser 2008)   60 to 80% of patients are refractory   Normal psychomotor development at onset but mostly

global delay   Etiology: genetic, structural/metabolic, and of unknown

origin   22% had neonatal seizures and 40% had West syndrome

(Trevathan et al. 1997)

Lennox-Gastaut syndrome   First recognized by Lennox and Gastaut, and presented

by Niedermayer in 1969   Core seizure types:

  Tonic (hallmark)   Atonic (drop attacks)   Atypical absences (focal dyscognitive)

  May not be the first seizure type to appear in a patient   EEG

  Slow spike-and-wave pattern at a frequency < 3 Hz   Paroxysmal fast activity during sleep   Sleep EEG can be normal at onset

ILAE, Epilepsia 1989

LGS current treatment   Valproic acid – efficacy on myoclonic, atypical absences

and atonic seizures   Several drugs proven effective on randomized placebo

controlled trials as adjuctive: Felbamate, Lamotrigine, Topiramate, Rufinamide, Clobazam (children and adults)

  Ketogenic Diet   VNS   Corpus callosotomy   Avoid medications known to worsen specific seizure

type i.e. i.v. benzodiazepines – worsening of tonic seizures