1. DIRECT CNS DRUG DELIVERY BEYOND THE SPINAL CANAL MIR IMRAN CHAIRMAN, INCUBE LABS, LLC

2. 2 CNS disorders afflict over 60 million Americans And nearly 1.5B worldwide Costs for treating CNS diseases exceed $600B/year far more than any other group of diseases

3. 3 3M Americans suffer from Epilepsy 50M people worldwide have the disease today

4. 4 5.4M Americans suffer from Alzheimer's By 2050, 16M will suffer from it More than 26M worldwide have the disease today 1 in 85 people globally

5. 5 More than 1M suffer from Parkinson's in the US More than 7M patients worldwide have the disease

6. 6 400,000 Americans suffer from Multiple Sclerosis 2.5M worldwide have the disease

7. 7 20M Americans live with Depression 121M people worldwide suffer from the disease

8. 8 Despite Staggering Numbers, Drug Treatments Remain Limited Toxicity and Serious Adverse Events are the Major Causes of Drug Failure Serious Peripheral Side Effects Limit the Use of Powerful CNS Drugs

9. 9 Oral or injectable delivery of CNS drugs can result in serious adverse side effects The Problem with Systemic Delivery of CNS Drugs Powerful large molecules and biologics cannot be delivered systemically Patient compliance is a huge issue with many CNS disorders

10. 10 Direct CNS delivery could address many of these issues..

11. 11 Reduces or eliminates peripheral side effects of potent CNS drugs Allows for transport of large drug molecules across the BBB Solves the issue of patient compliance Intracranial or Intrathecal Delivery of Therapeutic Agents Using an Implantable Drug Delivery System

12. A FEW EXAMPLES… 12

13. 13 BBB transport limitations with protein/antibody based therapies will likely require direct central delivery Acetylcholine esterase inhibitors: could deliver drugs such as revastigmine intracranially Addresses 2 key issues with this class of drugs: Compliance – major issue with Alzheimer's patients Peripheral effects – muscle weakness, cramps, gastrointestinal effects, etc. associated with this class of drugs Alzheimer’s

14. GDNF: intracranial delivery overcomes inability to penetrate BBB Apomorphine: the most effective known dopamine agonist, yet currently can not be used due to systemic effects Intracranial drug delivery addresses key issues with this class of drugs 14 Parkinson’s Disease

15. Several therapeutic approaches, but efficacy is still limited: Interferons (e.g., beta interferon (Avonex)) Hormonal (e.g., adrenocorticotrophic hormone) Immunological (e.g., monoclonal antibodies such as natalizumab (Tysabri)) Gene Therapy (viral vectors, nucleotide/nucleoside therapeutics) Central delivery allows us to optimize efficacy of existing drugs 15 Multiple Sclerosis

16. 16 Monoamine Oxidase Inhibitors (MAOIs): currently, black-box warnings due to side effects Intracranial delivery of MAOIs eliminates these issues Enhanced efficacy – ability to titrate therapeutic levels of drug without causing peripheral side effects (hypertensive episodes) Addresses compliance – a major issue with Depression patients Depression

17. Doxorubicin, etoposide: offer limited efficacy due to low brain penetration of major chemotherapeutic agents Intracranial delivery enables maintenance of high levels of chemotherapeutic agents, while minimizing systemic toxicity No serious peripheral adverse effects leading to increased therapeutic ratio 17 Oncology – Gliomas

18. THANK YOU 18