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CNS Drug Delivery: Beyond the Spinal Cord Mission: I mprove outcomes for epileptic patients who don’t respond to conventional treatments by administering.

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Presentation on theme: "CNS Drug Delivery: Beyond the Spinal Cord Mission: I mprove outcomes for epileptic patients who don’t respond to conventional treatments by administering."— Presentation transcript:

1 CNS Drug Delivery: Beyond the Spinal Cord Mission: I mprove 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

2 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

3 Significant Unmet Medical Need for Neurological Disorders and Disease Large # of Indications Growing patient populations Few effective therapies  Enormous cost of care ~15M US Patients Epilepsy

4 U.S. Epilepsy Market Total Patients1.0% or 3 million 1 Refractory Patients1,000,000 2 Most Severe Refractory Patients600,000 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 1 2 against-epilepsy-consensus-definition-drug-resista

5 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, small molecule (0.2kD) Prialt, peptide (3kD) siRNA (13kD) protein – antibody (150kD) Drugs keep getting bigger: Factors Frustrating CNS Drug Therapy

6 Peripheral Capillary Brain Capillary permeability restricted to: small molecules (<600D) lipophilic substances Protein Glucose Selectivity of the Blood Brain Barrier

7 Anatomy of the Blood Brain Barrier Electron Micrograph of Tight Junctions

8 Crossing the Blood Brain Barrier 1. between permeabilize tight junctions 3. around direct intracranial drug delivery 2. through enhance transport across the endothelium

9 19801980 19821982 19881988 19901990 19911991 19921992 19961996 20002000 20042004 20102010 20122012 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)

10 Several Infusion Systems Available for Targeted Drug Delivery MEDSTREAM™ Programmable Infusion Pump and Control Unit SynchroMed II Infusion Pump & N’vision Clinical Programmer Prometra Pump and Programmer

11 Common Features of Implantable Drug 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

12 Interior of a Drug Infusion Pump Pumphead Drive Gear Battery Electronics Module Refill Port Pumphead Drive 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

13 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

14 Codman MedStream™ - Spasticity Drug Infusion Pump Programmer Fill Sensor Refill Port Ceramic Drive Valve Filter Propellant Gas Flow Restrictor MEDSTREAM™ Control Unit Fluid Flow  Ceramic actuator (when charged) opens valve and allows fluid flow into catheter.  Valve is closed when actuator is discharged.

15 Deer, Krames et al, Neuromodulation: Technology at the Interface 11: 300-328, 2007 Concentrations & Doses of Intrathecal Agents Polyanalgesic Consensus Panel, 2007

16 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 Treatment of Chronic Pain by the Spinal Route *FDA approved for IT therapy for chronic pain

17 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 thought to be at the anterior horn cell It would be expected that intrathecal infusion would have good access to this site Motor Cortex Spinal Cord Medulla Anterior Horn

18 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

19 Blood BrainCSF Bulk Flow Diffusion Ependyma Blood Brain Barrier Choroid Plexus Arachnoid Villi Schematic Equilibrium of Brain Compartments

20 0 1 2 3 4 5 6 04812162024 Bolus Administration Continuous Pump Infusion Wasted Drug Overdose Toxicity Adverse effects Efficacy Time (hours-days) Drug Concentration Underdose Loss of Effect Advantages of Continuous Infusion over Bolus Drug Delivery No effect

21 Efficacy of Opioids in Cancer Pain – by Route of Administration Therapy Excellent Outcome (%) Studies (Patients) Unsatisfactory Outcome (%) Studies (Patients) Intracerebro- ventricular 73 8 Studies N = 295pts 7 8 Studies N = 295pts Epidural72 14 Studies N = 349 13 25 Studies N =794 Subarachnoid62 10 Studies N = 146pts 11 18 Studies N = 333pts Analgesic Outcome: adapted from Ballantyne, Carwood 2009

22 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 Motor Cortex Spinal Cord Medulla Primary Motor Area

23 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

24 Topotecan ICV Advantage

25 Key Elements for Drug : Device Therapy Development Therapy Success Drug/Biologic Delivery Principles Device

26 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)

27 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

28 Indication:Refractory Epilepsy Drug:ICVrx001 Device: Implanted Drug Infusion Pump and ICV Catheter Duration:Life-Long (chronic-intermittent) Desired Effects: Reduce seizure frequency and severity Reduce adverse events Treatment Effect:Palliative Stage:Early Clinical Intracerebroventricular Drug Therapy Product Concept: ICV Drug Therapy for Epilepsy

29 Significant unmet medical need Large, and growing, patient populations 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-Directed Drug Delivery for Treating CNS Disease

30 Drugs-Biologics small molecule peptide - protein oligonucleotides plasmids Implantable Pumps targeted delivery controlled delivery The Future of Medicine: Drug-Device Therapies

31 Thank You …..

32 Clinical Trials of Intracerebroventricular Morphine Therapy

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