LGS Foundation 2016 Conference - Sunday

Emerging Therapies for LGS
and the Clinical Trials
Process
Dennis J. Dlugos, MD
The Children’s Hospital of Philadelphia
Departments of Neurology and Pediatrics
Perelman School of Medicine at the University of
Pennsylvania
The Epilepsy Study Consortium
April 2016

Starting point
 Current FDA approved treatments for LGS
 Felbamate
 Lamotrigine
 Topiramate
 Rufinamide
 Clobazam
 These medications have helped reduce
seizures with acceptable side effects
 There are still many un-met needs

For the next LGS treatment…
 A product
 Probably a medication
 Maybe a device
 A sponsor
 Probably a pharmaceutical company
 Maybe an academic center or a non-profit
 Proof that the product is safe and effective in
humans in short-term use
 Successful navigation of the FDA regulatory process

Road Map
 Clinical trials process
 Road to new LGS therapies

Counting, counting, counting…
 “Science begins with counting.”
 Siddhartha Mukherjee
 “If you can’t measure it, you can’t improve it.”
 Atul Gawande
 “Everything that can be counted does not
necessarily count; everything that counts
cannot necessarily be counted.”
 Albert Einstein

USA versus Europe
 FDA
 New treatment must show it’s better than
something (superiority)
 Europe
 New treatment must show it’s not worse than an
existing treatment (non-inferiority)
Marson A, Williamson P. Curr Opin Neurol 2009;22:167-173

8
Patient selection for trials
Marson A, Williamson P. Curr Opin Neurol 2009;22:167-173

Typical road to FDA approval
 Phase 1 studies
 20-100 healthy volunteers
 Safety and dosage
 Phase 2 studies (70% of drugs make it here)
 A few hundred patients
 Efficacy and side effects
 Phase 3 studies (33% make it here)
 300-3,000 patients
 Efficacy and side effects
 Control group

Orphan Diseases
• US Orphan Drug Act (ODA) - 1983
– Disease affecting less than 200,000 persons in the US
– About 6,000 orphan diseases
– 25 million US residents affected
• EU Orphan Medicinal Product Regulation (OMP) -
2000
– Life-threatening or chronically debilitating conditions
affecting not more than 5 persons per 10,000 citizens in the
European Community
– 30 million European residents affected

Provisions of US ODA - 1983
• Federal tax credits for research done (up to 50% of
costs) to develop a drug
• 7-year monopoly on drug sales
– Applies only to approved use
• Waiver of drug approval application fees
– About $1.5 million
• Waiver of annual FDA product fees

Orphan Drugs by Disease Categories
Haffner ME. NEJM. 2006;354:445-447.

Orphan Drugs for Epilepsy
• Since 1993
– LGS: Felbamate, Rufinamide, Clobazam
– Infantile spasms: ACTH, Vigabatrin
– Acute repetitive seizures (ARS): Rectal Diazepam
– Short-term PHT replacement, Status: Fosphenytoin
– Dravet syndrome: Stiripentol (EU only)
• More than 350 orphan drugs approved in US
– About 1/3 of all FDA approvals

ODA - Limitations
• No approvals for very rare epilepsies
• None of the approved drugs for epilepsy are good
enough
• Decreasing incentives to develop new treatments
for common epilepsies
• Cost of approved products

Patient selection for an LGS study
 Is the LGS diagnosis accurate?
 Does EEG support the diagnosis?
 Are the episodes seizures?
 Can the seizures be reliably counted?
 Do the seizures occur at regular intervals?
 How many errors and mistakes can the study
tolerate?
 Some types of epilepsy are “easier” to study than
others

Four examples
 West syndrome
 Dravet syndrome
 Lennox Gastaut syndrome
 Seizures in tuberous sclerosis

ACTH vs Prednisone
 Counted
 Infantile spasms (yes or no)
 Primary outcome
 Cessation of spasms and elimination of
hypsarrhythmia by the end of 2-week treatment period
 ACTH 87% vs Prednisone 29%
 Challenges for future treatments
 Demonstrating short-term superiority over existing
therapies
 Long duration studies needed to assess relapse rates,
developmental outcome
Baram et al. Pediatrics 1996;97:375-379

Road map
 West syndrome
 Dravet syndrome
 Seizures in tuberous sclerosis

Dravet syndrome – diagnosis
 Seizure onset 3-15 months of age
 Initial seizures
 Hemi-clonic or GTC
 Often triggered by fever
 Often prolonged
 Other seizures emerge between 1-5 years
 Myoclonic
 Focal
 Absence
 Status
 Development
 Normal in 1st year, then slows
 Genetics
 SCN1A mutation in 70-80%

Dravet syndrome – red flags
 Development never normal
 Seizure onset outside of 3-15 months of age
 Single seizure type, other than hemi-clonic or
GTC
 Atypical seizures before 12 months of age
 Infantile spasms
 Abnormal neuro-imaging

Akman et al. Seizure 2009;18:524-529
Accuracy by Seizure Type

Dravet syndrome – challenges
 Infrequent prolonged seizures
 Variable seizure flurries
 Difficult-to-count seizures
 Length of pre-treatment baseline phase
 4, 6 or 8 weeks?
 Clinical or genetic diagnosis?

Dravet syndrome – CBD
 CBD versus placebo as add-on therapy
 120 patients
 Mean age = 10 years
 Median convulsive seizures/month = 13
 Mean of 3 current AEDs, 4 past AEDs
 4 week baseline, 14 week treatment period
 Central review of patient diagnosis and seizure types
 Results
 CBD – 39% convulsive seizure reduction
 Placebo – 13% convulsive seizure reduction (p = 0.01)
GW Pharma, press release 2016

Without impairment of awareness
With impairment of awareness
Evolving to a bilateral convulsive
seizure
Focal

Seizure counting – Clobazam
 Clobazam (CLB)
 Randomized, double-blind, placebo-controlled
 LGS ages 2-60 years
 “… seizures were recorded by patients’
patients/caregivers in daily seizure diaries.”
Ng et al. Neurology 2011;77:1473-1481

Reliable seizure types – CLB
 Primary efficacy endpoint
 Percentage decrease in mean weekly drop
seizure rates
 CLB 41%, 49%, 68% vs Placebo 12%
 Significant difference
 Drop seizure - a drop attack or spell involving the entire body,
trunk, or head that led to a fall, injury, slumping in a chair, or the
patient’s head hitting a surface or that could have led to a fall or
injury, depending on the patient’s position at the time of the
attack or spell.

Drop vs non-drop seizures – CLB

Tuberous sclerosis – Everolimus
 Everolimus versus placebo as add-on therapy
 Central review of seizure types
 Effective in reducing seizures compared to
placebo
AAN annual meeting, 2016

Counting, counting, counting…
 West syndrome
 Clinical infantile spasms and hypsarrhythmia
 Dravet syndrome
 Countable convulsive seizures
 Drop seizures
 Tuberous sclerosis
 Definite, countable seizures

Errors, mistakes, other troubles
 Non-seizure events called seizures
 Seizure events not identified
 Inconsistent counting between baseline and
treatment phase
 Length of baseline phase
 Placebo response
 Drug unsafe, ineffective

Placebo response
 Meta-analysis of pediatric focal epilepsy trials
 20% of pediatric patients in placebo arm were
50% responders
Rheims S et al. PLoS Medicine 2008;5:e166

Placebo response – why?
 Meta-analysis of pediatric (6-18 years)
antidepressant trials
 Number of study sites, less severe disease
Bridge J al. Am J Psych 2009;166:42

French et al, AAN 2011
Effect size by region

Conclusions
 Some epilepsy types are easier to study than others
 Careful diagnosis and seizure counting are always
important
 LGS has a long history of successful drug approvals
 The bar for the next LGS treatment is higher
 Optimism given recent positive studies of Dravet
syndrome and Tuberous Sclerosis
 Valuable lessons for future studies
 Placebo response has many facets and is poorly
understood
 How many errors and mistakes can a study tolerate?
 Central review of study subjects is now commonly used
and is helpful

LGS FOUNDATION CONFERENCE
MAY 1, 2016

Involvement in LGS
Advocacy
Overview
Research &
Participation
LGSF
Programs
& Tools
Facebook
Clinical Trials
Surveys and Studies
Ambassador Program
Planning Committee Members
Newsletter Contributors
LGS Awareness Day
Advocacy Opportunities
Research

Clinical Trials
Advocacy
Overview
Research &
Participation
LGSF
Programs
& Tools

What’s the Point?
Surveys & Studies
• Measure’s health status and risk
factors
• Evaluates quality of health care
received
• Identifies health disparities
• Helps stakeholders understand
needs and issues better
• Helps companies and organizations
develop tools to help you

International LGS Awareness Day
Awareness Day
November 1 annually, the LGS Foundation organizes
events across the United States to raise awareness of
Lennox-Gastaut Syndrome.
Press kits are available at
www.lgsfoundation.org/lgsaware.

BUT WAIT?
AREN’T WE EMPOWERED
ALREADY?

Walk for LGS
Events
Team LGSF
@ National
Walk
National
Walk for
LGS
Organize
your own
Walk

National Walk for LGS
LGSF Programs and Tools

Take the Poll
• Central / Southern FL
• Central Texas
• Minneapolis area
• Pacific Northwest
• Atlanta

www.theroc.us
Presented by: Heather Jackson, CEO

www.theroc.us
“ ”
Quality of
Life
Matters
- Realm of Caring
Before CW
● Seizure onset 4 months
● Almost Daily seizures for 9+ years
● MAE - Doose Syndrome
● 17 Pharmaceuticals failed
● Receiving Hospice Palliative
● 6 seizure types/Status
● Developmentally delayed
● Autistic tendencies
Started CW 7/12
● 3+ Years seizure free
● Pharmaceutical free
● Learning and social
● significantly reduced autistic
tendencies
● Positive side effects: better
sleep, better appetite, less
negative behavior
Our Journey
An ‘anecdotal’ story and why we started the RoC
Copyright 2016 Realm of Caring

www.theroc.us
Because quality of life matters
The Realm of Caring Foundation (RoC) is a non-profit organization that provides support services
and resources for those using cannabinoid products.
Research ∙ Education ∙ Advocacy ∙ improving Lives ∙ Measureable
results

www.theroc.us
MEMBERS/CLIENTS
• Providers guide
• How to talk with your doctor
• Guide to using cannabinoid oils
• Research library
• ORR (research) IRB approved
• Dosing resources and calculators
• AED interaction information
• Videos
• Orientation (both live and google hangout)
• Online Forums
• Support groups
• dx2dx – connect with others with your diagnosis
• Steep discounts on approved CBD products
• Realm Cares™ - Family assistance grants
• Joy Fund – Relocation grants
• More
Services
For members, physicians, community
PHYSICIANS
• Provider resources
• Referrals
• Use of ORR for approved
physicians
• Provider education
• Dash board for helping their
clients
• Research assistance
• Funding for research
COMMUNITY
• School education
• Hospital education
• Nursing agency education
• Grassroots political effort
• Public hearing speaking
• Family support
• Public speaking
• Continuing Education Units

www.theroc.us
From prohibition in 1937 to 2013 (76
years)
20 states passed cannabis legislation.
20 states have passed cannabis
legislation
since 3/2014 – 24 months
5 did not limit the THC%
15 did limit the THC%
State legislative efforts continue
• H.R. 1635 Federal Bill to
DEschedule hemp (<.3% THC,) and
CBD
• CARERS Act Federal Bill to
reschedule cannabis, allow for
banking, allow veterans to have
recommendations
Legislative Efforts
State & Federal

www.theroc.us

www.theroc.us
RoC Research focused: Observational Research
RegistryNOW ENROLLING for Any symptom whether you are using cannabis or not
• IRB approved, Johns Hopkins University
• Assessment items for the Baseline and Monthly Follow-
up forms were derived from the Common Data
Elements (CDEs) for epilepsy research developed by
the National Institute of Neurological Disorders and
Stroke (NINDS),
• As it relates to epilepsy: Baseline over 200 self/caregiver
reported questions: Demographics (14), Family History (13),
Medical History (17), Seizure History (48), syndromes by age
of onset (18), Etiology (13), Previous medications/treatments
(20) Provider (18), Prior CBD/Cannabis use (41), Prior
months seizure activity (17).
• Monthly follow up’s include: CBD dosing, other cannabis,
medications, seizure activity and other measureables, ER
and outpatient visits, hospitalizations, changes in sleep,
function, cognition and quality of life.

www.theroc.us
• Close to 25,000 members
• About 6,000 using cannabis
• About 50% have epilepsy
Realm Demographics

www.theroc.us
Quality Matters
Because Quality of Product Matters
• The only way to prove efficacy is to measure, and repeat with consistent products
• FACT: Cannabis is safe. Very safe
• Not ensuring consistency, proper labeling and testing can cause in inadvertent event

www.theroc.us
CBD, THC, THCA – oh my
What is the difference?

www.theroc.us
Research & Literature Review
Neuroprotectan
t
immunosuppressant antidepressantAnti-convulsant
Anti-
degenerative
Anti-inflammatory anti-anxiety antipsychotic
Antioxidant anti-tumoral
Anti-emetic

www.theroc.us
FDA List of Approved Drugs for Children

www.theroc.us
Neuron Death Triad
Cannabinoids and Neuronal Health
Reactive Oxidative Stress
Excitotoxicity
Neuronal Inflammation
Antioxidant
Neuro-protectant /
Neurogenesis
Neuro-modulation
CB1
glutamate, Ca
channels
Anti-inflammatory
Immune-modulation
CB2

www.theroc.us
ENDOCANNABINOID SYSTEM
• ECS isolated and described in 1992 team of scientist at
Hebrew University: William Anthony Devane, Lumir
Ondrey Hanus Endogenous
• Anandamide (Cannabinoid Neurotransmitter)
• 2-Arachidonoylglycerol (agonist)
• CB1 Receptors located in the brain (not in the brain
stem where heart and respiration are regulated)
•CB2 Receptors located in areas of body related to:
• Immune system (spleen, leukocytes)
• Gastrointestinal system
• Peripheral nervous system
• Heart
• Liver
• Bone
• Reproductive organs
“The endocannabinoid system is essential to life
and it relates messages that affect how we relax,
eat, sleep, forget and protect”
-Italian researcher Vincenzo Di Marzo

www.theroc.us
ENDOCANNABINOID SYSTEM

www.theroc.us
MECHANISM OF ACTION
• Neuro and Immune modulation
• Evidence that CBD works on the following brain receptors
• CB1 neuro-modulation
• CB2 neuro/immune modulation
• 5-HT1A receptors, antidepressant, anxiolytic,
• opioid receptors, a mechanism for pain (analgesic) effects
• GABA
• Decrease glutamate
• Regulate Ca2 Channels
• Modulate ion channels
• Enhancing adenosine, endogenous anti-inflammatory
• Apoptosis, programed cell death
• Anti-angiogenesis
• It also acts upon other receptors, with neuroprotective effects, .
• Possible increase in blood flow.
High CBD Oil

www.theroc.us
Reasonable Expectations
What will I measure, how will I measure success
How long will this take anyway?
Measure - consistent,
daily, objective
What are you going to
track
This is not an overnight
process, this can take
several months, tweaking,
labs etc.
Notebook
Online resources
• Seizure tracker
• Other
Seizures
Cancer scans
Pain rating
Quality of Life

www.theroc.us
Side Effects of CBD
No known serious adverse side effects
“Chronic use and high doses up to 1,500 mg/day of CBD are
reportedly well tolerated in humans”
Potential Drug-Drug Interaction: CBD is metabolized in the liver
by the Cytochrome P450 (CYP) system and can interfere with
metabolism of other medications that use the same system for
metabolism, which can result in altered levels
LD-50 Rating: Cananbis1:20,000-1:40,000, Aspirin 1:20
No documented deaths from cannabis overdose. Yet every 19
min there is a pharma death in the US.
Monitor: monitor patient closely for any negative side effects, get
AED levels checked, be followed by a physician
Source: Beramaschi, et al. Safety and Side Effects of
Cannabidiol, a Cannabis sativa Constituent. Current
Drug Safety, 2011 6:4;237-249

www.theroc.us
Potential Interactions

www.theroc.us
Administration
•Sublingual
•In capsules
•GT/GJ
•Rectal
•Transdermal
•Topical
•Vapor

www.theroc.us
DOSING
• Starting dose is 0.25 or 0.5 mg/lb/day
RESOURCES
• Dosing calculator online
• Recommend 2-3 x a day
• space 2 hours from pharmaceuticals
• Potential interactions (doctor/pharmacist)
• Frequent monitoring
• Baseline treatment and medication levels, including desmethyl levels
• Transition to a new bottle
Charlotte’s Web Hemp Oil

www.theroc.us
Physician Statement
Dr. Orrin Devinsky, Director of Comprehensive
Epilepsy Center, NYU Langone Medical Center
“For patients who have had little success in treating
their seizures with other medications, CBD could be a
last resort.”

www.theroc.us
www.theroc.us
719-347-5400
info@theroc.us
“We care, we care a lot. It’s kind of our thing…”

Cannabis and
Epilepsy:
A Clinician’s Experience
JEREMY TOLER, MD
ASSISTANT PROFESSOR OF PEDIATRICS AND NEUROLOGY
UNIVERSITY OF COLORADO, ANSCHUTZ MEDICAL CAMPUS
CHILDREN’S HOSPITAL COLORADO

Disclosures
 Grant funding:
 American Academy of Pediatrics
 Maternal and Child Health Bureau
 No pertinent disclosures to this topic

Case 1:
 8 year old Female
 Developmental delay noted
around 16 months
 MRI: Subcortical band
heterotopia and frontally
oriented pachygyria
 Seizures began at 18 months
Multiple daily GTC, absence,
atonic seizures

Case 1:
 Previous treatments:
Levetiracetam Lamotrigine
Oxcarbazepine Pregabalin
Felbamate Clobazam
Rufinamide Valproic Acid
Methosuximide Modified Adkins Diet
VNS
 Current Medicaions: Zonisamide, Vigabatrin
 Moved to Colorado for access to Cannabidiol

Case 2:
 7 year old Male.
 Diagnosed with Dravet Syndrome
 Seizures consist of Myoclonic, Absence, GTCs
 Multiple myoclonic seizures/day
 GTCs 6-7 times/month
 Medications tried: Levetiracetam, Clonazepam,
Topiramate, Verapamil, Ketogenic Diet
 Current Medications: Divalproex, Clobazam,
Ethosuximide
 Family relocated to Colorado to access
Cannabidiol

Case 3:
 5 year old Female
 Episodes of staring and unresponsiveness lasting
seconds.
 History of 2 febrile seizures in 2011 (before age of 2),
one with febrile status epilepticus
 Staring episodes are daily according to teachers.
Family notices sporadically.
 Had maternal uncle with epilepsy (unknown cause)
 EEG: 3 Absence seizures, generalized discharges
 Ethosuximide recommended.
 Family requested time to “think about it”
 Asked about “natural therapies” like medical
marijuana

Treatments for Epilepsy
 Medications
 Diets
 Neurostimulation (VNS, DBS, RNS)
 Cortical resection
 Corpus Callosotomy
 Hemispherectomy
But despite best efforts…

…Some Patients Remain
Intractable
 2000 study of epilepsy prognosis
 525 individuals aged 9-93
 13 year observational period
 63% were treatment responsive
Seizure free for at least 1 year
 37% were poorly controlled
Kwan and Brodie, N Engl J
Med, 2000

Patient (and Provider)
Frustrations
 Easy for patients to become
disillusioned with available treatments.
 “Medication roulette”
 Potential and experienced side
effects.
 Finances
 Frequent testing—EEG, EMU, MRI, PET,
SPECT, MEG, WADA, fMRI
 Connotations regarding surgery.

The “Natural” Treatments
 Benign/Safe
 Non-pharmacologic
 Non-invasive
 Risk-free
 “Nontoxic”

Complementary and
Alternative Therapies
 Herbal remedies
 Vitamins/Minerals
 Melatonin
 Massage
 Aromatherapy
 Acupuncture
 Homeopathy
 Naturopathy
 Biofeedback
And of course…
Medical Marijuana

Medical Marijuana in
Colorado
 Regulations for Minors:
Must have approval from 2
independent physicians
Parents must consent to medical
use
Registered on Med. Marijuana
registry
Caregivers must oversee
administration

Recent Research
 Survey of parents of children with epilepsy
 Presented to multiple online parent forums
 117 responses
 53 responses from patients with infantile spasms or
Lennox-Gastaut Syndrome
 85% of all responders reported seizure reduction
 14% reported seizure freedom
 Median latency from seizure onset to CBD: 5 years
 Median number of previous medications: 8
Hussain, et al. Epilepsy &
Behavior. 2015

Recent Research
Hussain, et al. Epilepsy &
Behavior. 2015

Retrospective Chart
Review
 N = 75 (average age 7y)
 1/3 report a 50% reduction in seizures
 Response rate similar with all products
 Families that moved from out of state 2x more
likely to report an improvement
 Response rate varied by syndrome LGS>Dravet
 11 patients (15%) discontinued treatment,
largely due to inefficacy
 2 patients seizure free
Press, C Epilepsy & Behavior 2015

Retrospective Chart
Review
 Adverse events in 44%
 Increased or new seizures in 13%
 Fatigue 12%
 GI symptoms 11%
 Rare events: developmental regression, new
movement disorder, transient hemiparesis, cholecystitis,
opisthotonus, status epilepticus requiring intubation,
and death
 Benefits outside seizure reduction
 Improved behavior/alertness in 25 (33%)
 Improved language (i.e., now using three words) in 8
(11%)
 Improved motor skills in 8 (11%)

Back to Case 1:
 No effect with CBD, family switched to high THC-A
strain.
 Seizures initially controlled and family initiated self-
guided taper of Zonegran and reluctant provider
initiated taper of Vigabatrin.
 Seizures returned early in 2015 after 3-6 months of
seizure freedom on THC-A
 Carbamazepine initiated and family reports
improved seizure frequency
 Continues to have 2-3 tonic/clonic seizures per
week.

Back to Case 2:
 Family continues to slowly increase CBD,
notes increased seizures control
 Has not switched to other strains or
artisanal products
 Consistently requires AED reduction
because of elevated levels
 Continues to have weekly GTCs—
continues to have improved overall
seizure frequency on CBD
 Recently agreed to start Modified Adkins
Diet

Back to Case 3:
 Family refused to accept
prescription for Ethosuximide.
 Family called for seizure action plan
to be drafted for the school
 Family reports they are “going the
medical marijuana route”
 Lost to Follow-up.

Pitfalls of Medical
Marijuana Therapy
 Lack of standardization
 Lack of FDA oversight
 Disillusionment with medical system
leads to distrust of
providers/unauthorized changes to
medications
 Changes in metabolism for other
medications
 Unknown long-term consequences

Moving Forward…
 There has been a huge amount of interested and
research into the human endocannabinoid
system over the last several decades.
 It is complex
 There is more to understand
 May be a good target for new pharmaceuticals
 Clinical studies of pharmaceutical products are
occurring now
 There is lot more work to be done!
 Randomized, double blind, placebo controlled
trials

LGS Foundation 2016 Conference - Sunday

LGS Foundation 2016 Conference - Sunday

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LGS Foundation 2016 Conference - Sunday