DIRECT CNS DRUG DELIVERY

BEYOND THE SPINAL CANAL

MIR IMRANCHAIRMAN, INCUBE LABS, LLC

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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

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3M Americans suffer from Epilepsy50M people worldwide have the disease today

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5.4M Americans suffer from Alzheimer'sBy 2050, 16M will suffer from it

More than 26M worldwide have the disease today1 in 85 people globally

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More than 1M suffer from Parkinson's in the US

More than 7M patients worldwide have the disease

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400,000 Americans suffer from Multiple Sclerosis

2.5M worldwide have the disease

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20M Americans live with Depression

121M people worldwide suffer from the disease

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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

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• 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

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Direct CNS delivery could address many of these issues..

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• 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

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A FEW EXAMPLES…

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• 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

• 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

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Parkinson’s Disease

• 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

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Multiple Sclerosis

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• 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

• 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

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Oncology – Gliomas

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THANK YOU