CNS Drug Delivery: Beyond the Spinal Cord

Mission: Improve outcomes for epileptic patients who don’t respond to conventional treatments by administering reformulated, micro-doses of anti-epileptic drugs directly to the brain.

Daniel J. Abrams, MD December 2012

• 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.

Disclaimer on Product Use

Significant Unmet Medical Need for Neurological Disorders and Disease

• Large # of Indications

• Growing patient

populations

• Few effective therapies

Enormous cost of care

Parkinson's Disease

Glioma

Neurometabolic Syndrome

Spinal Muscular Atrophy

Cerebral Palsy

ALSHuntington's Disease

Alzheimer'sDisease

Traumatic Brain Injury Stroke

Epilepsy

Chronic Pain

Spinal Cord Injury

Multiple Sclerosis

~15M US Patients

Epilepsy

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.cfm2http://www.touchneurology.com/articles/update-and-overview-international-league-against-epilepsy-consensus-definition-drug-resista

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

Gabapentin, smallmolecule (0.2kD)

Prialt, peptide(3kD)

siRNA(13kD)

protein – antibody(150kD)

Drugs keep getting bigger:

Factors Frustrating CNS Drug Therapy

Peripheral Capillary Brain Capillary

permeability restricted to:• small molecules (<600D)• lipophilic substances

Protein

Glucose

Selectivity of the Blood Brain Barrier

Blood Brain BarrierBlood Brain Barrier

apposed endothelium(no fenestrations - holes)

tight junctions

glial endfeet

Physical Barriers

Functional Barrierslimited vesicular uptakemulti-drug resistance (MDR) gene

Blood Brain BarrierBlood Brain Barrier

apposed endothelium(no fenestrations - holes)

tight junctions

glial endfeet

Physical Barriers

Functional Barrierslimited vesicular uptakemulti-drug resistance (MDR) gene

Anatomy of the Blood Brain Barrier

Electron Micrograph ofTight Junctions

Crossing the Blood Brain Barrier

1. betweenpermeabilize tight junctions

3. arounddirect intracranial drug delivery

2. throughenhance transport acrossthe endothelium

1980

1982

1988

1990

1991

1992

1996

2000

2004

2010

2012

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)

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)

IT Therapy Development History(Selected Highlights)

Several Infusion Systems Available

for Targeted Drug DeliveryMEDSTREAM™ Programmable Infusion Pump and Control Unit

SynchroMed II Infusion Pump & N’vision Clinical Programmer

Prometra Pump and Programmer

Common Features of ImplantableDrug Infusion Systems

Medtronic SynchroMed® II pump and N’Vision® Programmer shown above

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

Drug Catheter – flexible tubing that runs from the pump with special tip for drug delivery

Programmer – used with ‘smart’ pumps, controls drug infusion rate, records drug history

Interior of a Drug Infusion Pump

Pumph

ead

Drive G

ear

Battery

ElectronicsModule Refill Port

PumpheadDrive Gear

Rotor Assembly

(x-Ray)

Catheter Access Port

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

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

Flowonix Prometra - Pain

Codman MedStream™ - SpasticityDrug Infusion Pump Programmer

Fill SensorRefill PortCeramic Drive

Valve

Filter Propellant GasFlowRestrictor

MEDSTREAM™ Control Unit

FluidFlow

Ceramic actuator (when charged) opens valve and allows fluid flow into catheter. Valve is closed when actuator is discharged.

Deer, Krames et al, Neuromodulation: Technology at the Interface 11: 300-328, 2007

Concentrations & Doses of IntrathecalAgents Polyanalgesic Consensus Panel, 2007

Local Anesthetics• Bupivicaine• Ropivicaine• Tetracaine

Adrenergic Agonists• Clonidine• Tizanidine

NMDA Antagonists• Ketamine

Other• Adenosine• Aspirin• Baclofen• Droperidol• Gabapentin• Ketorolac• Midazolam• Octreotide• Neostigmine• Ziconitide (Prialt)*

Non-Opioid Drugs used for Treatmentof Chronic Pain by the Spinal Route

*FDA approved for IT therapy for chronic pain

IT Baclofen for Spasticity• Large % of refractory spasticity patients

• 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 thoughtto be at the anterior horn cell

• It would be expected that intrathecal infusion would havegood access to this site

MotorCortex

SpinalCord

Medulla

AnteriorHorn

Compartments of the Brain• The brain can be modeled as having

three compartments Blood ↔ CSF ↔ Brain

• CSF is held within a definedset 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

Blood

Brain CSF

Bulk Flow

DiffusionEpendym

a

Blood Brain Barrier Choroid Plexus

Arachnoid Villi

Schematic Equilibrium of Brain Compartments

0

1

2

3

4

5

6

0 4 8 12 16 20 24

Bolus AdministrationContinuous Pump Infusion

Wasted DrugOverdoseToxicityAdverse

effects

Efficacy

Time (hours-days)

Dru

g C

once

ntra

tion

UnderdoseLoss of Effect

Advantages of Continuous Infusion over Bolus Drug

Delivery

Noeffect

Efficacy of Opioids in Cancer Pain – by Route of Administration

TherapyExcellent

Outcome (%)Studies

(Patients)UnsatisfactoryOutcome (%)

Studies (Patients)

Intracerebro-ventricular 73 8 Studies

N = 295pts 7 8 StudiesN = 295pts

Epidural 72 14 StudiesN = 349 13 25 Studies

N =794

Subarachnoid 62 10 StudiesN = 146pts 11 18 Studies

N = 333pts

Analgesic Outcome:

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

Albright et al, Neurosurg Pediatrics 3:000–000, 2009

MotorCortex

SpinalCord

Medulla

PrimaryMotor Area

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 : DeviceTherapy Development

TherapySuccess

Drug/Biologic

DeliveryPrinciples

cRcDctc

v

Device

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: CombiningDrugs & 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

Indication: Refractory Epilepsy

Drug: ICVrx001

Device: Implanted Drug Infusion Pumpand ICV Catheter

Duration: Life-Long (chronic-intermittent)

Desired Effects: Reduce seizure frequency and severityReduce adverse events

Treatment Effect: Palliative

Stage: Early Clinical

Intracerebroventricular Drug TherapyProduct Concept: ICV Drug Therapy for Epilepsy

• Significant unmet medical need

• Large, and growing, patientpopulations

• 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

36.6M Patients/20 disorder$95.5B Market across 7MM

>21% share of Pharma

Factors Driving Site-DirectedDrug Delivery for Treating CNS Disease

Drugs-Biologics• small molecule• peptide - protein• oligonucleotides• plasmids

Implantable Pumps• targeted delivery• controlled delivery

The Future of Medicine:Drug-Device Therapies

Thank You …..

Clinical Trials of IntracerebroventricularMorphine Therapy