Update on Marijuana for the Treatment of Epilepsy - PowerPoint Presentation

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Update on Marijuana for the Treatment of Epilepsy

Brenda Porter MD, PhD

Cannabis: A complex mixture of chemicals

Disclosures

Dr. Porter has received compensation for working on an advisory board for Upsher-Smith, a data safety monitoring board for a clinical trial run by Greenwich Biosciences, and has through marriage received stock and compensation from Johnson and Johnson. 

The two most commonly discussed chemicals in marijuana

THC

(delta-9-tetrahydro-cannabinol)

CBD

(

cannabidiol

)

Psychoactive (makes

you high)

√

Anti

Nausea

√

Appetite stimulant

√

Pain

Relief

√

√

Anti-inflammatory

√

Anti-seizure

NOTE NOT

√

√

Anti-spasmodic

√

Neuroprotective

√

Binding Affinities of Endogenous and Exogenous Cannabinoids

Ki @ CB1R

Ki @ CB2R

CBD

4350 - >10,000

nM

2400 - >10,000

nM

Δ

9

-THC

5 - 80

nM3 - 75 nM

Pharm. Rev. (2010) 62(4): 588-631

Higher number means it takes more of the compound to bind.

CBD Mechanism of Action

Classical cannabinoid action UNLIKELYTHC example of leading to more neurotransmitter release

Doesn’t bind with high affinity to CB1R or CB2R

Data on CB1R knockout animals

Other mechanisms of

actionHeteromers

, or modulatory effect

Other receptors (GPR55 antagonism, TRPV, 5HT1A,

Adenosine reuptake inhibition

Anti-inflammatory

Extrasynaptic

GABA receptors.

Increased Serotonin synaptic activity

Poorly Controlled Studies

Small studies, 1940-1990 ~ ½ showed seizure improvement ½ did not.-No notable side effects.Open label trial (GW

pharma

CBD) severe childhood onset epilepsy 12 weeks. 214 children. 36.5% median reduction in weekly convulsive seizures. Somnolence diarrhea , decreased appetite, fatigue, convulsion, status epilepticus were side effects noted.

2016

Devinsky et al.

Placebo Controlled Trial-

Dravet

Trial of

Cannabidiol

for Drug-Resistant Seizures in the

Dravet Syndrome

Orrin

Devinsky

, M.D., J. Helen Cross, Ph.D., F.R.C.P.C.H., Linda

Laux

, M.D., Eric Marsh, M.D., Ian Miller, M.D., Rima

Nabbout

, M.D., Ingrid E.

Scheffer, M.B., B.S., Ph.D., Elizabeth A. Thiele, M.D., Ph.D., and Stephen Wright, M.D., for the Cannabidiol in Dravet Syndrome Study Group

*

CBD in Dravet

, 2017Adverse events that occurred more frequently in the cannabidiol

group than in the placebo group included diarrhea, vomiting, fatigue,

pyrexia (fever), somnolence (sleepy),

and abnormal results on liver-function tests. There were more withdrawals from the trial in the

cannabidiol group.

Epidiolex

in Lennox-Gastaut Syndrome170 patients, 10mg/kg/day and 20mg/kg/day

Drop seizures were reduced 37% or 42% respectively

Rare but present withdrawal for adverse events

Drowsiness and Gastrointestinal issues

Interactions between

cannabidiol and commonly used antiepileptic drugsAuthors Tyler E. Gaston,E. Martina

Bebin,Gary

R. Cutter,Yuliang

Liu,Jerzy P. Szaflarski,

AED level

N

Mean baseline level

Mean first “on CBD” level

Mean second “on CBD” level

Normal AED level range (trough)

AED levels

that changed.

Clobazam

a

27

264.7 ± 136.3

331.1 ± 143.2 (dose unchanged)

310.9 ± 104.2 (dose unchanged)

30–300 ng/ml

430.3 ± 327.6 (dose decreased)

285.0 ± 176.0 (dose decreased)

N

-desmethylclobazam

a

26

2,207.5 ± 1,854.0

3,727.7 ± 1,549.3 (dose unchanged)

3,696.8 ± 1,027.1 (dose unchanged)

300–3,000 ng/ml

6,226.8 ± 4,006.9 (dose decreased)

4,843.8 ± 2,982.6 (dose decreased)

Eslicarbazepine

a

4

14.4 ± 7.4

16.8 ± 7.9

17.8 ± 9.1

2–28 μ

g/ml

Topiramate

20

10.3 ± 5.9

10.8 ± 7.0

11.3 ± 8.3

4.5–20 μ

g/ml

Zonisamide

14

17.2 ± 12.2

19.3 ± 13.0

17.2 ± 9.3 (dose unchanged)

10–40 μ

g/ml

42.0 (dose decreased in 1 adult)

Rufinamide

14

24.8 ± 12.8

25.6 ± 13.6

27.0 ± 14.7 (dose unchanged)

5–5

Is “medical” marijuana effective?

Small NOT well controlled studies suggest parents report improvement in many often more than half of the children.

Side effects are relatively mild Somnolence, fatigue unsteady.

NOTE often on very low doses of CBD.

Porter et.

al. 2013,Press et. al. 2014, Tzardok

2016

Medical Marijuana

10 kg child to be on 50-100mg twice a day of CBD for the study. Label and testing of CBD content is NOT regulated. Most bottles are poorly labeled and you, like I have to guess what you are giving your child.

If bought in bulk the cost would be 15-30 dollars per day. Or 500-1000 dollars a month.

Ongoing Clinical Trials

Trial of CBD are ongoing- At least 19 open trials of CBD in clinicaltrials.gov for epilepsy.

Several are closed and have data but not yet reported.

One trial in ASD in Israelis listed in

c

linicaltrials.gov.

Predictions

There will be a clinical formulation of CBD available in the next few months for epilepsy.Approved for drop seizures in

Dravet

and Lennox-

Gastaut

There will be more studies of CBD in autism, inflammation, pain.It will not be a miracle cure for most patients but a few it might be quite helpful for treating epilepsy.

NIH TSC Clinical Trial –

PREVENTING EPILEPSY USING VIGABATRIN IN INFANTS WITH TUBEROUS SCLEROSIS COMPLEX

(PREVeNT Trial)

NEEDED:

Newborns to 6 months old infants with TSC with NO history of seizures

What:

The objective of this study is to compare the developmental impact of early versus delayed treatment with vigabatrin.

The results will help determine if

treatment with vigabatrin

in TSC infants

can prevent or lower the risk of developing infantile spasms or refractory seizures.

Who:

Infants up to 6 months old with TSC and no history of seizures may be eligible to

participate.

Compensation:Compensation may be available to help with study related travel expenses.

Details:

For more information, contact

: Stanford

Principal Investigator

Sweta Patnaik (Study Coordinator)

Brenda Porter,

MD

Email: sweta@Stanford.edu

650-721-1458

Additional contact

:

prevent@uabmc.edu

Regina Ryan PREVeNT Program Manager

205-975-2890

IRB# F160509001