MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY

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MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY
MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE
              SYMPTOMATIC TREATMENT OF EPILEPSY

                                                     MISTY D. SMITH, PH.D.1,2
                          1DEPARTMENT        OF PHARMACOLOGY & TOXICOLOGY, COLLEGE OF PHARMACY
                            2ORAL    BIOLOGY, MEDICINE & PATHOLOGY SECTION, SCHOOL OF DENTISTRY,
                                                       UNIVERSITY OF UTAH

10 Aug 2021 Utah Cannabinoid Product Board Meeting                                   ©UNIVERSITY OF UTAH HEALTH, 2017
MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY
THE UNMET NEED FOR EPILEPSY THERAPEUTICS

•    Epilepsy affects ~2.9 million people in USA & over 65 million people worldwide.

                                                              https://quotesgram.com/img/epilepsy-awareness-quotes/738382/

•    Characterized by recurrent seizures, epilepsy encompasses a spectrum of
     different disorders caused by a variety of etiologies.
•    Adversely impacts the patient’s quality of life.
•    Prevalence of medically refractory epilepsy in the US is >730,000 people and
     21.7 million people worldwide
                                                        SOURCE: www. cdc.gov/epilepsy; Fisher RS, et al. (2005); Kwan and Brody (2000); IOM report on epilepsy (2012)

               10 Aug 2021 Utah Cannabinoid Product Board Meeting                                                  ©UNIVERSITY OF UTAH HEALTH, 2017
MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY
THE UNMET NEED FOR EPILEPSY THERAPEUTICS
•   None of currently available antiseizure drugs (ASDs) prevent the underlying
    cause of epilepsy or the epileptogenic process.
•   1/3rd of patients with epilepsy fail to achieve seizure freedom after two or more
    appropriately selected & dosed ASDs
•   Patients resistant to multiple ASDs have an increased risk of sudden
    unexpected death in epilepsy (SUDEP) and other forms of epilepsy-related
    mortality.

                                                             SOURCES: Nilsson L et al. ((1999); Kwan and Brody (2000); Walczack TS et al. (2001); Kwan P. et al. (2011)

              10 Aug 2021 Utah Cannabinoid Product Board Meeting                                                ©UNIVERSITY OF UTAH HEALTH, 2017
MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY
RARE PEDIATRIC EPILEPTIC ENCEPHALOPATHIES
•   Dravet syndrome: rare form of intractable epilepsy           •     Lennox-Gastaut syndrome (LGS): rare form of
    that begins in infancy and accumulates morbidity                   intractable epilepsy involving with multiple
    throughout lifetime.                                               different seizure phenotypes,
•   Incidence of 1:15,700 individuals, 80% have a                      particularly tonic (stiffening) and atonic (drop)
    mutation in their SCN1A gene.                                      seizures.
•   Behavioral & developmental delays, movement &                •     Intellectual development is usually delayed and
    balance issues and disruptions of autonomic nervous                often worsens over time. Behavioral problems,
    system (difficulty regulating body temperature, heart              including hyperactivity, agitation, aggression and
    rate, blood pressure) require lifetime care.                       autism, are common.
•   Severely impacts both the patient’s and the family’s         •     Although LGS may be caused by early brain injury
    quality of life.                                                   from infection or trauma, genetic causes, or brain
                                                                       malformations, in 1 out of 4 children the cause of
•   15-20% mortality rate due to SUDEP (Sudden
    Unexpected Death in Epilepsy), prolonged seizures or               LGS is unknown.
    seizure-related accidents (i.e., drowning & infections).     •     Severely impacts both the patient’s and the
•   Current treatment options are limited                              family’s quality of life.
                                                                 •     Current treatment options are limited
                                                 SOURCE: Wu, E., et. al. (2015); Cooper, M.S., et. al. (2016); Skluzacek, et. al. (2011).
                                                                                              ©UNIVERSITY OF UTAH HEALTH, 2017
MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY
LONG HISTORY OF MEDICINAL CANNABIS:
                                                                                 Early-Mid 20th Century
2900 B.C.                       1000 B.C.                      1841              1850-1942- Cannabis listed in US
                                                                                 Pharmacopiea
                                                                                 1906 – Pure Food & Drug Act (labels
                                                                                 patent medicines).
                                                                                 1937 – Marijuana Tax Act regulated
                                                                                 import, cultivation, possession &
                                                                                 distribution of cannabis (officially
                                                                                 illegal)
                                                                                 1938 – Food, Drug & Cosmetics Act
                                                                                 gave federal oversight
                                                                                 1970 – Controlled Substance Act

Present Day
                Epidiolex™ FDA approvals for                                     2013 - Weed© CNN docuseries hosted
                seizures in rare pediatric epilepsy                              by Sanjay Gupta on Charlotte Figi, 6 y.o.
                syndromes:                                                       patient w/ Dravet Syndrome on CBD oil
                • June 2018 – Dravet & Lennox
                    Gestaut Syndrome
                • July 2020 – Tuberous Sclerosis
                    Syndrome
                                                                      SOURCES: Time’s Documentary “A Journey for Oil”; Spicer 2002

              10 Aug 2021 Utah Cannabinoid Product Board Meeting                   ©UNIVERSITY OF UTAH HEALTH, 2017
MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY
PHYTOCANNABINOIDS:
– The cannabis plant produces between 80-100 cannabinoids plus > 300 non-cannabinoid chemicals.
– Subdivided based on chemical structure and extent of psychological activity:
       •   Cannabigerols (CBG)
       •   Cannabichromenes (CBC)
       •   Cannabidiols (CBD)
       •   Cannabidivarin (CBDV)
       •   Tetrahydrocannabinols (THC)
       •   Cannabinol (CBN) & cannabinodiol (CBDL)
       •   Other cannabinoids:
            – cannabicyclol (CBL), cannabielsoin (CBE), cannabitriol (CBT) and others

–   Two most prevalent phytocannabinoids in the marijuana plant: D9-THC and CBD.
–   Most exogenous cannabinoids target endogenous cannabinoid receptors (CB1 & CB2) and have either
    orthosteric or allosteric effects.
                                                                  SOURCE: http://LearnAboutMarijuanaWA.org/factsheets/cannabinoids.htm

             10 Aug 2021 Utah Cannabinoid Product Board Meeting                       ©UNIVERSITY OF UTAH HEALTH, 2017
MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY
TAKE HOME (PRIOR TO 2015)
• Despite anecdotal reports & widespread interest from
  parents, patients, and the scientific community regarding
  the potential of medical cannabis to treat seizures, a
  systematic analysis of clinical trial data (1978-2014) by the
  Academy of Neurology and a Cochrane Database
  review both concluded that “medical cannabis is of
  “unknown efficacy” to treat epilepsy.”

                                                             SOURCES: Koppel BS, et al. (2014); Gloss D and Vickrey B ( 2014)

        10 Aug 2021 Utah Cannabinoid Product Board Meeting                  ©UNIVERSITY OF UTAH HEALTH, 2017
MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY
INADEQUATE CLINICAL TRIAL DATA (1978-2014)
 •   Double blinded clinical trial in 9 patients with treatment resistant epilepsy. Of the 4 patients receiving
     200 mg CBD daily for 3 months. 2 patients were seizure free during treatment, one patient had partial
     improvement, the other had no improvement. No significant toxicity was reported. (Mechoulam R,
     Carlini EA (1978))
 •   Double blinded clinical trial in 15 patients (ages 14-49 yrs) with secondarily generalized epilepsy with
     temporal focus. Of the 8 patients were randomly assigned to the treatment group (200-300 mg CBD
     daily for 8-18 weeks) in addition to their standard ASD regiment, 4 patients were reported as “almost
     free of convulsive crisis”, 3 had partial improvement and one had no change. No toxicity was reported.
     (Cunha JM, Carlini EA, Pereira AE, et al. (1980))
 •   Double blinded clinical trial by Ames et al. (1986) in 12 patients institutionalized due to “mental
     retardations with uncontrolled seizures.” In the 6 patients receiving CBD treatment (300 mg of CBD daily
     for one week and then 200 mg daily for three weeks) or the control groups, no difference in seizure
     frequency was reported. Mild drowsiness was only reported adverse affect. (Ames FR, Cridland S
     (1986))
 •   Cross-over clinical trial by Trembly et al. conducted in 12 patients in which all were treated with
     placebo for 6 months followed by 300 mg of CBD or placebo in a crossover design over the next 12
     months, No change in seizure frequency or adverse effects were reported. (See Gloss D, Vickrey B.
     (2014))

                                       SOURCES: In addition to the articles cited above, Zaheer et al. (2018); Gloss & Vickrey (2014), Minnesota Dept. of Health
                                       Office of Medical Cannabis report on “Review of Medical cannabis Studies for Qualifying Medical Conditions” July 2016
                                                                                                            ©UNIVERSITY OF UTAH HEALTH, 2017
MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY
CANNABIDIOL (EPIDIOLEX™)

•   First FDA approved Cannabis-derived treatment for seizures associated with rare,
    treatment-resistant pediatric epilepsy syndromes
•   Proprietary oral solution of purified plant-derived cannabidiol, or CBD, in oil.
•   Indications:
     –   Treatment of seizures associated with Dravet’s & Lennox-Gestaut Syndromes in patients 2 years and
         older. (FDA approved in June 2018)
     –   Treatment of seizures associated with Tuberous Sclerosis Complex (TSC) in patients one year of age and
         older. (FDA approval in 2020)
     –   Well-tolerated in doses up to 25mg/kg/d
•   Rescheduled to Schedule V since Oct 2018
•   Most Common Side Effects: sleepiness, decreased appetite, diarrhea, transaminase
    elevation

                                                                   SOURCE: https://www.gwpharm.com/healthcare-professionals/research-trials/epilepsy

            2019 Addictions Update Conference: Science, Policy and Treatment                             ©UNIVERSITY OF UTAH HEALTH, 2017
MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY
EPIDIOLEX™ CLINICAL TRIALS (GW PHARMACEUTICALS)
Randomised, double-blind, placebo-controlled trials (since June 2015): patients
reported significant improvement (% symptom reduction).

                                                            SOURCE: GW Biosciences (2018); Thiele et al. (2018); Guy et al (2014); Devinsky et al. (2015)

            10 Aug 2021 Utah Cannabinoid Product Board Meeting                                                ©UNIVERSITY OF UTAH HEALTH, 2017
EPIDIOLEX™ TRIALS (GW PHARMACEUTICALS)

                    SOURCE: https://www.epidiolexhcp.com/efficacy-and-safety/LGS; https://www.epidiolexhcp.com/efficacy-and-safety/dravet-syndrome

       10 Aug 2021 Utah Cannabinoid Product Board Meeting                                             ©UNIVERSITY OF UTAH HEALTH, 2017
TUBEROSCLEROSIS COMPLEX (TSC)-ASSOCIATED SEIZURES
 a new indication for Epidiolex™ (GW Pharmaceuticals) for the treatment of seizures
 associated with TSC was FDA approved in 2020.

                                                             SOURCE: https://www.epidiolexhcp.com/efficacy-and-safety/tsc

             10 Aug 2021 Utah Cannabinoid Product Board Meeting                                          ©UNIVERSITY OF UTAH HEALTH, 2017
INSYS THERAPEUTICS INC. (PHOENIX, AZ)
• Synthetic CBD oral solution (up to 40
  mg/kg/day)
• Orphan drug designation granted in June
  2014 for the treatment of Lennox-Gestaut
  syndrome and for the treatment of infantile
  spasms in August 2015.

                                                           SOURCE: INSYS Therapeutics, 2016; Parikk, 2018

      10 Aug 2021 Utah Cannabinoid Product Board Meeting           ©UNIVERSITY OF UTAH HEALTH, 2017
POTENTIAL CONTRIBUTING MECHANISMS (CB-RECEPTOR INDEPENDENT)
  •   Anticonvulsant effects
       - inhibition of GPR55 mediated presynaptic calcium release,
       - modulation of adenosine signaling (also anti-inflammatory)
  •   Anti-inflammatory, antioxidant, & neuroprotective effects:
       - reduction in serum cytokine levels
             -    (i.e., IL-4, IL-5, IL-13, IL-6, and TNF-α).

  •   Other biological effects:
       - Serotonin (5HT1A) agonist (antidepressant)
       - CBD acts as a potent FAAH enzyme inhibitor, which increases endogenous anandamide levels
       - Antiemetic,
       - Anxiolytic effects

  TAKE HOME: More research is needed!
       –   Mechanisms underlying CBD’s therapeutic effects remain unclear
       –   Much More to Learn: Drug interactions, Long Term QOL Outcomes, Special Populations

                 SOURCE: Consroe et al., 1986; During & Spencer, 1992; Mechoulam et al., 2002; Grotenhermen, 2004; Vaccani et al., 2005; Sylantyev et al., 2013; Rimmerman et
                 al., 2013; Ianotti et a., 2014; Devinsky et al., 2014.

                 2019 Addictions Update Conference: Science, Policy and Treatment                                       ©UNIVERSITY OF UTAH HEALTH, 2017
WHAT ABOUT THC?
• No clinical trial data available for THC,
  THC:CBD combinations, other cannabinoids or
  medical cannabis in patients with epilepsy

                                                                     SOURCE: www.clinicaltrials.gov

       10 Aug 2021 Utah Cannabinoid Product Board Meeting   ©UNIVERSITY OF UTAH HEALTH, 2017
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