Transcript epilepsie ppt

CNS Drug Delivery:
Beyond the Spinal Cord
Mission: Improve outcomes for epileptic patients who don’t respond
to conventional treatments by administering reformulated, microdoses of anti-epileptic drugs directly to the brain.
Daniel J. Abrams, MD December 2012
Disclaimer on Product Use
• This presentation includes the description of drugs,
devices and their therapeutic uses that are in early stages
of development, are not commercially available and have
not been approved by regulatory institutions.
• Before commercialization is possible the drugs, devices
and their therapeutic uses need to undergo additional
preclinical and clinical evaluation and obtain regulatory
approval.
Significant Unmet Medical Need for
Neurological Disorders and Disease
Spinal Muscular
Atrophy
• Large # of Indications
• Growing patient
populations
Glioma
Neurometabolic
Syndrome
Spinal Cord Injury
ALS
Huntington's Disease
Cerebral Palsy
Multiple Sclerosis
Parkinson's Disease
Alzheimer's
Disease
Chronic Pain
• Few effective therapies
 Enormous cost of care
Epilepsy
Epilepsy
Traumatic Brain
Injury
Stroke
~15M US Patients
U.S. Epilepsy Market
Total Patients
1.0% or 3 million1
Refractory Patients
1,000,0002
Most Severe Refractory Patients
600,000
Refractory Epilepsy Treatment Market
$2.5 billion
Antiepileptic Drug Market (World, 2008)
$11.34 billion
Implantable Pump Market
- Pain & spasticity applications
10,000 units,
$600 million
1http://www.epilepsyfoundation.org/aboutepilepsy/whatisepilepsy/statistics.cfm
2http://www.touchneurology.com/articles/update-and-overview-international-league-
against-epilepsy-consensus-definition-drug-resista
Factors Frustrating CNS Drug Therapy
The Blood Brain Barrier excludes most
drugs from Brain and Spinal Cord . . .
. . . despite most dense
vascular bed of any organ.
*
radioactively labeled tracer drug given intravenously
Drugs keep getting bigger:
Gabapentin, small
molecule (0.2kD)
Prialt, peptide
(3kD)
siRNA
(13kD)
protein – antibody
(150kD)
Selectivity of the Blood Brain Barrier
Peripheral Capillary
Protein
Glucose
Brain Capillary
permeability restricted to:
• small molecules (<600D)
• lipophilic substances
Anatomy
of
the
Blood
Brain
Barrier
Blood Brain Barrier
Blood Brain Barrier
Electron Micrograph of
Physical
Barriers
Tight
Junctions
apposed endothelium
(no fenestrations - holes)
tight junctions
glial endfeet
Functional Barriers
limited vesicular uptake
multi-drug resistance (MDR) gene
Crossing the Blood Brain Barrier
1. between
permeabilize tight junctions
2. through
enhance transport across
the endothelium
3. around
direct intracranial drug delivery
IT Therapy Development History
(Selected Highlights)
First human implant of SynchroMed pump (Medtronic)
SynchroMed pump receives FDA approval (Medtronic)
Infumorph (IT morphine) approved (Medtronic)
Lioresal (IT baclofen) approved for spasticity
(Medtronic)
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MedStream (constant flow) pump
approved (Codman – JnJ)
SynchroMed II pump receives FDA approval (Medtronic)
Prialt (IT Ziconitide) approved for chronic pain (Azur)
Gablofen (IT baclofen) approved for spasticity (CNS Therapeutics)
Prometra Programmable Pump approved for IT pain (Flowonix)
MedStream Programmable Pump System approved for IT spasticity (Codman – JnJ)
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Several Infusion Systems Available
for Targeted Drug Delivery
MEDSTREAM™ Programmable
Infusion Pump and Control Unit
Prometra Pump and
Programmer
SynchroMed II Infusion Pump &
N’vision Clinical Programmer
Common Features of Implantable
Drug Infusion Systems
Catheter Access Port – bypasses
drug reservoir, used to check for
catheter patency
Reservoir Refill Port – septum
through which drug enters the
pump upon refill
Titanium Housing – typically rigid
outer housing that protects pump
from mechanical damage
Programmer – used
with ‘smart’ pumps,
Drug Catheter – flexible tubing
controls drug infusion
that runs from the pump with
rate, records drug
special tip for drug delivery
history
Medtronic SynchroMed® II pump and N’Vision® Programmer shown above
Interior of a Drug Infusion Pump
Electronics
Module
Refill Port
Catheter
Access Port
Pumphead
Drive Gear
Battery
Rotor
Assembly
(x-Ray)
Images taken from a Medtronic SynchroMed® II Pump
Example of a battery-driven
electro-mechanical pump,
other pump models use a
variety of drive and valve
mechanisms to deliver drugs
Flowonix Prometra - Pain
Infusion System Features:
• Dose Accuracy
– 98%
• Longevity
– >10 years
• Weight
– 10% lighter
• Easy refill
• Designed to deliver any compound
• Can deliver micro-doses
• Can be programmed off
Codman MedStream™ - Spasticity
Drug Infusion Pump
Programmer
Ceramic Drive Refill Port
Valve
Fill Sensor
MEDSTREAM™ Control Unit
 Ceramic actuator (when charged)
Fluid
Flow
Flow
Restrictor
Filter
Propellant Gas
opens valve and allows fluid flow into
catheter.
 Valve is closed when actuator is
discharged.
Concentrations & Doses of Intrathecal
Agents Polyanalgesic Consensus Panel, 2007
Deer, Krames et al, Neuromodulation: Technology at the Interface 11: 300-328, 2007
Non-Opioid Drugs used for Treatment
of Chronic Pain by the Spinal Route
Local Anesthetics
• Bupivicaine
• Ropivicaine
• Tetracaine
Adrenergic Agonists
• Clonidine
• Tizanidine
NMDA Antagonists
• Ketamine
Other
• Adenosine
• Aspirin
• Baclofen
• Droperidol
• Gabapentin
• Ketorolac
• Midazolam
• Octreotide
• Neostigmine
• Ziconitide (Prialt)*
*FDA approved for IT therapy for chronic pain
IT Baclofen for Spasticity
• Large % of refractory spasticity patients
Motor
Cortex
• Intrathecal baclofen (ITB) has been used to
treat spasticity since 1988, particularly dystonia
secondary to cerebral palsy or traumatic brain
injury
• ITB is an approved use of the Medtronic
Infusion System
• The site of action is thought
to be at the anterior horn cell
Anterior
• It would be expected that
intrathecal infusion would have Horn
good access to this site
Medulla
Spinal
Cord
Compartments of the Brain
• The brain can be modeled as
having three compartments
Blood ↔ CSF ↔ Brain
• CSF is held within a defined
set of compartments
> yellow – ventricles
> light blue – subarachnoid &
intrathecal
• Volume of CSF: 140ml
• Rate of CSF production: 35ml/hr
• CSF turnover: 4-6x/day
• Blood flows through the brain at a
rate of 60 l/hr
Schematic Equilibrium of
Brain Compartments
Blood
Arachnoid Villi
Blood Brain Barrier
Choroid Plexus
Diffusion
Ependyma
Brain
Bulk Flow
CSF
Advantages of Continuous Infusion
over Bolus Drug Delivery
Efficacy
No
effect
6
Drug Concentration
Adverse
effects
Wasted Drug
Overdose
Toxicity
5
4
3
2
Bolus Administration
Continuous Pump Infusion
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Time (hours-days)
16
20
Underdose
Loss of Effect
24
Efficacy of Opioids in Cancer Pain
– by Route of Administration
Analgesic Outcome:
Excellent
Outcome (%)
Studies
(Patients)
Unsatisfactory
Outcome (%)
Studies
(Patients)
Intracerebroventricular
73
8 Studies
N = 295pts
7
8 Studies
N = 295pts
Epidural
72
14 Studies
N = 349
13
25 Studies
N =794
Subarachnoid
62
10 Studies
N = 146pts
11
18 Studies
N = 333pts
Therapy
adapted from Ballantyne, Carwood 2009
ICV Baclofen for Dystonia (Albright)
Results:
• 8 of 10 patients responded to the treatment
• 2 non-responding patients also did not
respond to previous IT treatment
• 3 pump-related adverse effects
Motor
Cortex
Primary
Motor Area
Medulla
Spinal
Cord
Albright et al, Neurosurg Pediatrics 3:000–000, 2009
Comparison IT and ICV
Chemotherapy
• CSF Chemotherapy used for 30
years by IT and ICV routes
• Useful for overcoming the BBB
limitation on distribution of
drugs and metabolites
• PK studies demonstrate high
CSF drug concentrations can
be achieved
• Effective for treatment of
meningeal leukemia in humans
• Not as effective treatment for
deep parenchymal distribution
into the brain
Blasberg et al, Cancer Treat Rep 61:1977
Topotecan ICV Advantage
Key Elements for Drug : Device
Therapy Development
Device
Drug/Biologic
Therapy
Success
c
   cv  Dc   Rc
t
Delivery
Principles
Around the BBB: Intracerebroventricular
(ICV) Drug Delivery
Lateral view of brain with the
cerebral ventricles shown in blue
Cross section of the brain shown
with a catheter placed in the
lateral ventricle (blue)
Technology: Combining
Drugs & Pumps for Brain Delivery
Several benefits of delivering drugs
directly to the brain fluid:
• Significantly Lower dose
 Less risk of side effects and organ toxicity
 Improved Tolerability
• Target effectiveness
 Consistent drug levels lessens difficulty
finding therapeutic ratio for an each patient
 “Last pass metabolism”: Drugs do not go first
through GI tract, then liver, etc…
• Adherence - Overcome patients inability to take
medication
• Additional drug options for refractory disease targeted nature of the delivery platform allows
additional drug candidates
Intracerebroventricular Drug Therapy
Product Concept: ICV Drug Therapy for Epilepsy
Indication: Refractory Epilepsy
Drug: ICVrx001
Implanted Drug Infusion Pump
Device:
and ICV Catheter
Duration: Life-Long (chronic-intermittent)
Reduce seizure frequency and severity
Desired Effects:
Reduce adverse events
Treatment Effect: Palliative
Stage: Early Clinical
Factors Driving Site-Directed
Drug Delivery for Treating CNS Disease
• Significant unmet medical need
• Large, and growing, patient
populations
36.6M Patients/20 disorder
$95.5B Market across 7MM
>21% share of Pharma
• Substantial revenue potential
• Blood Brain Barrier (BBB) stops
most drugs from entering CNS
• Combined with other therapeutic advantages, BBB creates
need for targeted drug delivery
The Future of Medicine:
Drug-Device Therapies
Drugs-Biologics
• small molecule
• peptide - protein
• oligonucleotides
• plasmids
Implantable Pumps
• targeted delivery
• controlled delivery
Thank You …..
Clinical Trials of Intracerebroventricular
Morphine Therapy