Medical Cannabis and Epilepsy: Talking to your doctor, Safety and Update on Clinical Trials Lubov Romantseva, MD Child Neurology and Epilepsy Rush University Medical Center Nov 12, 2016

Disclosures I have no financial interest in any pharmaceutical company mentioned in this presentation I will discuss non-FDA approved use of medical cannabis in epilepsy I am involved in clinical trials for patients with epilepsy

Background on Cannabis 1 Cannabis plant= 100+ bioactive phytocannabinoids Most understood are: CBD and THC CBD=Cannabidiol: likely responsible for most of anti-seizure and anti-pain(analgesia) effects THC=Tetra-hydro-cannabinol: responsible for psychoactive “high” effect, ?anti-seizure effect Each Strain of Cannabis has a DIFFERENT ratio of CBD:THC Within one strain, each individual Cannabis plant has a unique ratio of CBD:THC depending on climate and growing conditions

Artisanal Cannabis preparations are like growing Tomatoes Variable CBD: THC ratio from batch to batch Truthful labeling? Quality control? Contaminated with pesticides? heavy metals? Unregulated industry WITHOUT a common standard Vulnerable patients and caregivers at risk for misinformation and fraud

Evidence for Efficacy-1 162 patients, 1-30 years old 20% Lennox-Gastaut, 20% Dravet, 60% other epilepsies Open label study, safety and efficacy assessed Epidiolex: purified grown cannabis, high CBD: low THC Doses used: 2 mg/kg/day to 25-50 mg/kg/day Efficacy: mean 36% reduction in monthly motor seizure count, 4% became seizure-free Common side effects: somnolence, diarrhea, low appetite Severe side effects: 1 death(SUDEP), status epilepticus 6% Reference: Orrin Devinsky et al. Lancet Neurology 2016;15: 270–278

Evidence for Efficacy-2 Epidiolex study in Lennox-Gastaut patients Double blind, placebo controlled (gold standard) 2-55 years old, 171 patients Patients: median baseline DROP seizure rate was 74/month Epidiolex dose 20 mg/day, added to current meds Response rate: median drop seizure reduction 44% in CBD group vs 22% in placebo group, p=0.0135 Safety profile similar to open-label study

CBD: Safety and Monitoring Mortality: likely low, most deaths appear due to SUDEP or status epilepticus Behavior effects: variable, most are tolerable Interaction with standard seizure drugs** CBD raises CLOBAZAM(Onfi) level by 60-500%: need to track Clobazam levels and adjust doses or risk toxicity CBD also likely raises Valproic acid(Depakote) level Bottom line: CBD interacts with several liver enzymes used in drug metabolism(CYP3A4, CYP2C19) which may result in unexpected effects Reference: A Geffrey et al. Epilepsia 2015;56:1246–1251

Safety: what is NOT known Longterm cognitive effects: learning, attention, organization, memory Longterm psychiatric effects: impulse control, risk of mood disturbance or psychosis, risk of future addiction to “hard drugs” or alcohol Longterm seizure-control rates CBD-Drug interactions? What seizure types/epilepsies worsen with CBD?

Future Clinical Trials Epidiolex(purified plant CBD) study in refractory Infantile Spasms population (GW pharmaceuticals) Pilot study for Infantile Spasms to start in 2017 Synthetic CBD: toxicity and safety studies complete (Insys pharmaceuticals) Lennox-Gastaut efficacy trial: on hold Infantile Spasms trial out of UCLA Tuberous sclerosis trial

Medical Cannabis and FDA Epidiolex makers met with FDA in summer 2016 Plan to submit New Drug Application(NDA) with clinicial trial data in first half of 2017 Epidiolex makers seek FDA approval for treatment of refractory Dravet syndrome refractory Lennox-Gastaut syndrome Timeline to FDA decision?

Future Clinical Trials Website: www.clinicaltrials.gov Search: “cannabidiol and epilepsy” 31 trials registered now, in 2014 there were 4 Conditions addressed: Lennox-Gastaut, Dravet, Infantile Spasms, Tuberous Sclerosis, other refractory epilepsies This is the BEST time to get involved in a clinical trial and help bring CBD therapy out of the shadows

Legal status of Medical Marijuana Federal level Classified as Schedule I substance (no accepted medical use) In same category as heroine and cocaine State level: extremely variable Legal for recreational and medical use Legal for medical use only(specific conditions) Not legal for any use

Medical Cannabis Law in Illinois IL Medical Cannabis Act of 2013 Legal for medical use in specific medical conditions, including refractory epilepsy in children under 18 yo compassionate use for patients who have FAILED standard medical treatment, last resort option Specific procedures to be followed Patient and caregiver must register with the state, receive a registration card, then can obtain LEGAL medical cannabis from one of IL dispensaries Website: www.illinois.gov, links to Medical Cannabis Pilot Program webpage

Medical Cannabis in Illinois Physician CANNOT prescribe dose/frequency Not licensed by FDA, no standard dose yet Physician CAN certify that the patient has a qualifying medical condition under IL law Certifying Physician needs to have a bona fide(pre-existing) relationship with the patient If patient is a minor, 2 physicians need to certify

Medical Cannabis in Illinois Certification by MD is NOT a guarantee of treatment success Certification states that “benefits from medical cannabis MAY outweigh the risks” for a particular patient

Talking to your doctor about Medical Cannabis Ultimately, physicians want to do what is best for their patients Safety is a huge concern: “first do no harm” is a basis of physician practice philosophy Reasons for Provider hesitation: Lack of knowledge of longterm safety/side effects Inability to prescribe a specific dose Lack of FDA approval Uncertain legal status/risk of litigation, loss of license Lack of hospital policies regarding medical cannabis*

Talking to your doctor about medical cannabis Be honest and direct Find out your doctor’s comfort level and knowledge base Remember: most MD’s have no formal training on the subject and are learning as we go Discuss all other options, share what you know Make a joint plan about other medications Change only one thing at a time Keep communication lines open

CBD in National Epilepsy News: The Latest from Child Neurology Society meeting-October 2016 Senior Child Neurologist Dr Elizabeth Thiele from Mass General hospital in Boston sums up the progress made Video clip on Neurology Advisor website http://www.neurologyadvisor.com/cns-2016-coverage/video-cannabidiol-and-our-progress-towards-a-treatment-for-refractory-epilepsy/article/569490/

Summary Points-1 Medical cannabis has some efficacy in treating refractory epilepsies in children and adults Cannabis is a complex plant and its longterm effects on brain and body are not yet known Medical Cannabis has a sensitive legal status, with Federal and State regulations at odds with each other Medical cannabis is NOT FDA approved at this point, but may become so in next 2 years

Summary points-2 Option of Medical Cannabis should be discussed openly and directly with the treating provider Clobazam and Valproic acid levels need to be monitored if CBD is added to treatment regimen FIRST, DO NO HARM Knowledge is POWER=JOIN a Clinical trial

Thank you! Questions?