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

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

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



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

Road map

West syndrome

Dravet syndrome



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


Road map

West syndrome

Dravet syndrome



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


LGSF Programs & Tools

https://youtu.be/Z-E6f4f3FbA

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.

http://www.lgsfoundation.org/lgsaware

advocacy

Advocacy can mean many things

Empowering Advocates

BUT WAIT?

AREN’T WE EMPOWERED ALREADY?

https://www.youtube.com/watch?v=IZ17ohZROk8

Walk for LGS

Events

Team LGSF @ National

Walk

National Walk for

LGS

Organize your own

Walk

National Walk for LGS

LGSF Programs and Tools

Walks for LGS

Organize a Walk

Research Program

Future Conferences:

Future Conferences:

? ?

? ?

?

Take the Poll

• Central / Southern FL

• Central Texas

• Minneapolis area

• Pacific Northwest

• Atlanta

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


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

RoC Research focused: Observational Research

Registry NOW 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

Neuroprotectant

immunosuppressant antidepressant Anti-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

[email protected]

“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

Healthcare

Transcript of LGS Foundation 2016 Conference - Sunday