Post on 15-Apr-2017
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
Road Map
Clinical trials process
Road to new LGS therapies
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
19
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
Lennox Gastaut 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?
26
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
Road map
West syndrome
Dravet syndrome
Lennox Gastaut syndrome
Seizures in tuberous sclerosis
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.
Ng et al. Neurology 2011;77:1473-1481
Drop vs non-drop seizures – CLB
Ng et al. Neurology 2011;77:1473-1481
Road map
West syndrome
Dravet syndrome
Lennox Gastaut syndrome
Seizures in tuberous sclerosis
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
Lennox Gastaut syndrome
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
Ambassador Program
Committee Members
Newsletter Contributors
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.
advocacy
Advocacy can mean many things
Empowering Advocates
BUT WAIT?
AREN’T WE EMPOWERED ALREADY?
Walk for LGS
Events
Team LGSF @ National
Walk
National Walk for
LGS
Organize your own
Walk
Team LGS Foundation
LGSF Programs and Tools
100+ family members | Meet & Greet | Organized Tours | Walk Team | T-Shirts Hotel Discounts | Other Activities| No cost to LGS Families
National Walk for LGS
LGSF Programs and Tools
Walks for LGS
Organize a Walk
Research Program
Research & Participation
Future Conferences:
Future Conferences:
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Take the Poll
• Central / Southern FL
• Central Texas
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Thank You
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
Copyright 2016 Realm of Caring
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
Copyright 2016 Realm of Caring
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
Copyright 2016 Realm of Caring
www.theroc.us Copyright 2016 Realm of Caring
www.theroc.us
RoC Research focused: Observational Research
Registry NOW ENROLLING for Any symptom whether you are using cannabis or not
Copyright 2016 Realm of Caring
• 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
Copyright 2016 Realm of Caring
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
Copyright 2016 Realm of Caring
www.theroc.us
CBD, THC, THCA – oh my
What is the difference?
Copyright 2016 Realm of Caring
www.theroc.us
Research & Literature Review
Neuroprotectant
immunosuppressant antidepressant Anti-convulsant
Anti-degenerative
Anti-inflammatory anti-anxiety antipsychotic
Antioxidant anti-tumoral
Anti-emetic
Copyright 2016 Realm of Caring
www.theroc.us
FDA List of Approved Drugs for Children
Copyright 2016 Realm of Caring
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
Copyright 2016 Realm of Caring
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
Copyright 2016 Realm of Caring
www.theroc.us
ENDOCANNABINOID SYSTEM
Copyright 2016 Realm of Caring
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
Copyright 2016 Realm of Caring
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
Copyright 2016 Realm of Caring
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
Copyright 2016 Realm of Caring
www.theroc.us
Potential Interactions
Copyright 2016 Realm of Caring
www.theroc.us
Administration
• Sublingual
• In capsules
• GT/GJ
• Rectal
• Transdermal
• Topical
• Vapor
Copyright 2016 Realm of Caring
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
Copyright 2016 Realm of Caring
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.”
Copyright 2016 Realm of Caring
www.theroc.us
www.theroc.us
719-347-5400
info@theroc.us
“We care, we care a lot. It’s kind of our thing…”
Copyright 2016 Realm of Caring
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