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Regenerative Medicine:

Impact of Convergence on Drug, Device and Biologics Development

Annemarie Moseley, PhD, MD

Acting CEO, Aggregate Therapeutics, Inc.

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It’s a new age….

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1. Human cell, tissue, or cellular and tissue-based product (HCT/P)

2. Drug

3. Device

4. Biological product

5. Combination product

Five Product Categories

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• Articles containing or consisting of human cells or tissues

• Intended for implantation, transplantation, infusion, or transfer into a human recipient

• Examples: bone, ligament, skin, dura mater, heart valve, cornea

What is an HCT/P?

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•Product intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease;

What is a Drug?

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•An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or similar article

•Intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease; or

•Which does not achieve its intended purposes through chemical action in man and which is not dependent upon being metabolized to achieve its primary purposes.

What is a Device?

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1. Virus (or gene therapeutic)

2. Therapeutic Serum

3. Toxin or Antitoxin

4. Vaccine

5. Blood, Blood Component, or Blood Derivative

6. Allergenic Product

7. Cellular Therapy

What is a Biological Product?

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What is a Combination Product?

A combination product is a product composed of any

combination of :

–drug and a device

–biological product and a device

–drug and a biological product;

–drug, device, and a biological product

(DES)

(Dermagraft)

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Two or more separate products packaged

together in a single package or as a unit

comprising:

•drug and device products,

•device and biological products,

•biological and drug products

Combination Products Include

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Any investigational drug, device, or

biological product packaged separately that

according to its proposed labeling is for use

only with another individually specified

investigational drug, device, or biological

product where both are required to achieve

the intended use, indication, or effect.

Combination Products Include

(MiniMed Pump)

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To determine the agency with primary

jurisdiction for the premarket review and

regulation of a combination product, will be

based on the primary mode of action of the

product.

Designated Agency

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The Regenerative Medicine Triad

•Growth Factors

•Cells

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•BioMaterials

•Matrices

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The Regenerative Medicine Duo

•Cells

•Growth Factors

•Delivery Devices

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• New and/or improved angiogenesis

• Proteins

• Gene Therapy

• Cell Therapy

• Improved outcome for tissue function

• Cell Therapy

Case Study: Cardiac Regeneration / Repair

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Bone marrow stem cells

…within 3 months researchers found that the pumping activity had increased…this work, although preliminary, has the potential to revolutionize the treatment of heart failure….

AHA advertisement in Time Magazine, 2004

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Bone Marrow

Adult Stem Cells

Myoblasts

Will one delivery approach fit them all?

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1. Direct needle injection during open surgical procedure

2. Intracoronary delivery

3. Endomyocardial injection

4. Retrograde coronary venous

5. Tangential transvenous intramyocardial

6. Minimally invasive thoracoscopic epicardial injection

Delivery Approaches for Biologicals

Almost 10 years in development—none approved

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• Does balloon occlusion increase adhesion and migration of cells into myocardium?

• By stretching the artery wall does the balloon cause potential arterial damage and stenosis?

• Suitable for all indications and cell suspensions? Potential for “clogging” lumen and impact of flow rate?

• Is cell viability / functionality adversely affected by lumen materials or by shear force?

• Potential for catheter materials to adversely affect viability / functionality of cells?

FDA Responses:

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• Cell and gene products characterized according to somatic cell and gene therapy guidelines

• Biologic products will need to be studied for safety and efficacy

• Both large and small animal models may be used depending on whether the studies are evaluating mechanism of action or device delivery

• Preclinical studies must address role of local deposition, dose response, timing of delivery, differentiation and retention of biologic products

Convergence: Impact on Biologics Development

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• Bench tested with biologic for compatibility

• Tested in large animal preclinical models for safety of delivery

• No devices are marketed today for delivery of therapeutics to the heart; no clear “predicate” devices

• Will be approved as combination product with biologic for specific indication (BLA)

• Partnerships between biologic and device manufacturers for product development strategies.

Convergence: Impact on Device Development

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Changing Trends

Previously, biologics development focused on :

–Oncology

–Immunodeficiencies

–Inherited Diseases

Increasing development in :

–Neurology

–Cardiovascular

–Orthopedics

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Why?

–Increased focus on aging population

–New means of delivery are being developed

–New biomaterials

–Shift by interventional physicians to the use of biological products (cardiologists, neurosurgeons, radiologists)

Why?

–Increased focus on aging population

–New means of delivery are being developed

–New biomaterials

–Shift by interventional physicians to the use of biological products (cardiologists, neurosurgeons, radiologists)

Changing Development Trends

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Investing in Convergence

•Intellectual Property

•Partnering / Licensing

•Development Timelines

•Manufacturing and Quality

•Regulatory Strategy

•End-user / customer

•Distribution channels

•Reimbursement

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Investing in Convergence

Device which has been combined with drug?

- Is the drug approved? Human safety?

- Is the drug delivered via a polymer or other drug delivery vehicle?

- Manufacturing GMP vs. existing quality systems and impact on cost and timing

- Value proposition?

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Investing in Convergence

Delivery device?

- Drug or biologic delivered?

- Is there a predicate?

- Is there an existing market?

- Have you covered delivery of all drugs, biologics etc in IP claims

- Value proposition?

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Investing in Convergence

Biologic?

- Does the biologic require or have improved efficacy with local delivery?

- Is local delivery more cost efficient?

- Do distribution channels exist?

- Does it need a newly designed delivery system or can it be delivered with existing device?

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Risk Profile for Convergence Products

RISK

1. Approved drugs Phase 3 Phase 1-2 NCE

2. Approved polymer Polymer formul. Polymer IDE Novel

3. Approved device clinical trials Predicate IDE

4. Approved indicat. Other indication Clinical trialsPre-clin

5. Existing customer New customer Market Adoption

6. Co-development Licensing—transfer Contract manuf In-house

7. Standard assay New assay No assay immeasurable

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Commercialization

Target Product Profile

-Indication

-Patient Benefit

-Asking price/cost of goods

-Delivery

-Reimbursement Potential

It’s never too early!!

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RIS

K

TIER 1 TIER 2 TIER 3 Pipeline

REDUCED RISK THROUGH LEVERAGED PRODUCT APPROACH

Synovo-Derm ATX-Derm ATX-CNS DiabetesSynovo-Joint ATX-Ortho Cancer DX

Marketed material; Novel ATX cells + New Indication forimproved formulation Synovo ATX cells

30 Sg2 Healthcare intelligence 2006

Looking to the future—learning from the past!