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Regenerative Medicine – Building Replacement OrgansRegenerative Medicine – Building Replacement Organs

Don Bergmann, PhDSenior Vice PresidentTechnical Operations

Don Bergmann, PhDSenior Vice PresidentTechnical Operations

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AGENDAAGENDA

Science and Technology of Tissue Engineering and Regenerative Medicine

Tengion’s Neo-bladder – A Model of Regenerative Medicine

Product Development & Regulatory Considerations

Market Opportunities for Regenerative Medicine

Career Opportunities in Tissue Engineering and Regenerative Medicine

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Science and TechnologyStem Cells – Identity and FateScience and TechnologyStem Cells – Identity and Fate

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Science and TechnologySource of Cellular Starting MaterialScience and TechnologySource of Cellular Starting Material

Two main sources of cells that can serve as biological tissue engineering and regenerative templates Embryonic stem cells Adult stem cells

– Committed progenitor cells from mature tissue– Non-progenitor adult stem cells from other tissues

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Science and TechnologyStem Cells – Adult and EmbryonicScience and TechnologyStem Cells – Adult and EmbryonicPluripotent or multi-potent depending upon source Embryonic stem cells that are completely non-differentiated have capability of

becoming any cell type in the body; as they differentiate, become increasingly limited Adult stem cells have already progressed partway along the differentiation pathway

and are limited to the cell types they can mature into

Relies on migration to appropriate location of action in the body and the receiving of appropriate stimuli to differentiate to desired tissue type

Able to be grown in large numbers in-vitro under specific media conditions

Seemingly infinite life span as long as no differentiation occurs Applies primarily to embryonic stem cells and less so with adult stem cells

Immunogenicity Stem cells derived from same patient are non-immunogenic Some cell types can be used allogeneically without immune response

– Tend to be tissue specific

Tumorgenicity

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Science and TechnologyProgenitor CellsScience and TechnologyProgenitor Cells

Cells isolated from mature tissue that are not fully matured along the differentiation pathway, but are committed to becoming a specific cell type Originate from a tissue specific stem cell lineage Process of normal tissue repair

Are able to grow in large numbers under special conditions in-vitro for a limited number of passages as long as they do not fully differentiate

Once appropriately stimulated will mature to its final pre-programmed cellular type Generally non-tumorigenic If placed back into same person then non-immunogenic

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Science and TechnologyAutologous vs Allogeneic Cell SourcesScience and TechnologyAutologous vs Allogeneic Cell Sources

Autologous Cells From self No immune reaction when implanted

– Recognized as self

Allogeneic Cells From different person May create immune reaction when implanted

– Search for allogeneic cell types that have histotypes that do not cross-react or are masked (immuno-transparent) and thus: no immune response

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Science and TechnologyStem Cells vs Progenitor Cells Role in RegenerationScience and TechnologyStem Cells vs Progenitor Cells Role in Regeneration

Stem cells require external signaling (e.g., cytokines from differentiated cells, micro-environmental signals, etc.) to differentiate into specific cell types Stem cells need to be directed to become a cell lineage and then differentiate to a

selected progenitor state in order to mature to final cell type Once differentiating can now also become source of cellular messaging to recruit

other non-differentiated cells to location and to differentiate

Progenitor cells are already committed to become a specific cell type, and once initiated to differentiate, can act as cellular messengers to recruit other progenitor cells to location to reform tissue

Progenitor and stem cells that are recruited to site reform (regenerate) appropriate tissue provide proper signaling

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Science and TechnologyRegenerative Template for Organ RegenerationScience and TechnologyRegenerative Template for Organ Regeneration

Need cells of appropriate type(s) to serve as the biological part of the template

Need a structure to serve as a physical template for various cell types to grow on and organize to form neo-organ Several biological and artificial matrices have been used

– Natural de-cellularized collagen– Biodegradable templates made of materials such as PGA

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Science and TechnologyOrgan Augmentation vs ReplacementScience and TechnologyOrgan Augmentation vs Replacement

Organ augmentation enhances an existing organ that is not providing proper physiological function for patient E.g., Enhancing volume of undersized bladder by adding a larger

bladder dome to existing bladder using a construct made of a patient’s own cells

Organ replacement fully replaces existing organ that is not providing proper physiological function for the patient E.g., Fully replacing a diseased or cancerous bladder with new

regenerative bladder construct made of healthy cells from patient

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Tengion’s Neo-bladderA Model of Regenerative MedicineTengion’s Neo-bladderA Model of Regenerative Medicine

Integrated technology platform combining autologous progenitor cells derived from patient’s own tissue and the use of biodegradable scaffolds to form a regenerative template from which new organs (neo-organs) can be developed within the patient’s body Based on 15 years of seminal work by Dr. Anthony Atala at Harvard

University (currently Director of the Institute of Regenerative Medicine at Wake Forest University)

Potential to improve upon current medical therapies that may not re-capitulate organ function, and/or have potential serious side effects

Avoids the potential complications of organ rejection as neo-organs are derived from patient’s own cells

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Tengion’s Neo-bladderA Model of Regenerative Medicine (cont’)Tengion’s Neo-bladderA Model of Regenerative Medicine (cont’)

Tengion scientists isolate urothelial and smooth muscle cells that are capable of regeneration.

The isolated cells are cultured separately until there are a sufficient quantity.

The cultured cells are properly seeded onto a biodegradable scaffold shaped like a bladder.

Tengion scientists ensure that the cells attach and grow properly throughout the scaffold. After about 8 weeks, the neo-bladder construct is returned to the surgeon for implantation.

The neo-bladder construct is implanted by the surgeon using standard surgical techniques.

The body uses the neo-bladder construct to regenerate and integrate new tissue, restoring the bladder’s functionality.

The biodegradable scaffold dissolves and is eliminated from the body, leaving a functioning bladder made only of the patient’s own newly regenerated tissue.

A surgeon takes a small, full-thickness biopsy from the patient’s bladder.

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Other genitourinary

Ureter

Valve

Cartilage

Muscle

Trachea

Nerve

Bone

Kidney

Bladder

Vessels

Skin

Liver

Breast

Tengion’s Platform TechnologyRegenerative Medicine OpportunitiesTengion’s Platform TechnologyRegenerative Medicine Opportunities

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Product Development ConsiderationsSteps to New Product ApprovalProduct Development ConsiderationsSteps to New Product Approval

•Discovery research and process development•Pre-clinical research and development•Clinical development and human trials under an IND•Market application to the FDA•Product and facility approval

Research and Development

Pre-Clinical production

Clinical Production

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Regulatory Considerations for Regenerative MedicineRegulatory Considerations for Regenerative Medicine

Traditional pathway for new biologicals, devices, and medicinals follow a predefined route from research to market approval Product discovery and early development Pre-clinical development and trials Human clinical development and trials over 3 or 4 Phases

– Phase 1 – Safety studies in healthy volunteers– Phase 2 – Dose ranging and indicator of efficacy in patients– Phase 3 – Large scale clinical trials that prove safety and efficacy of product– Phase 4 – Post approval market surveillance (on case by case basis)

Market application– Biological License Application (BLA) – for biologicals– New Drug Application (NDA) – for new chemical entities (medicinals)– Pre-market Authorization (PMA) – for devices

Process from discovery to approval may span from 6 to over 10 years

There are some aspects of Regenerative Medicine that may pose a paradigm shift from the traditional approaches to product development

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Regulatory ConsiderationsRegenerative Medicine Paradigm ShiftRegulatory ConsiderationsRegenerative Medicine Paradigm Shift

Safety studies in healthy volunteers may not apply E.g., Replacing a healthy organ with an experimental product is not

practical

Traditional clinical studies are blinded with placebo controls Not practical to blind studies that are augmenting or replacing

organs How does one select a placebo?

Regenerative products may have characteristics of more than one type of product – e.g., combination product

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Regulatory ConsiderationsTE/RM Products as Combination Products

Biological MedicalProducts Devices

CombinationProducts

Biological MedicalProducts Devices

CombinationProducts

• TE/RM products may have both biological and device like characteristics which may drive oversight by more than one branch of the FDA. Typically one branch takes the lead while other agencies support. Decision of who is the lead agency is driven by the primary mode of action of the product.

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Market Opportunities for Regenerative MedicineBuilding an IndustryMarket Opportunities for Regenerative MedicineBuilding an Industry

> 350 Private or Public corporations in EU, Asia, and US developing tissue engineering / regenerative medical products Small/large molecule, scaffold, cell, combination

6 major therapeutic categories Cardiology, Dermal, Dental, Neurology, Orthopedic, Urology

Industrial Pipeline – worldwide >100 companies currently with active R&D product program ~50-75 different product programs within each therapeutic category

– 60% Research/Preclinical Development, 40% Clinical

Financials >$5B Market Capitalization (US) ~33% of VC’s

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Market Opportunities for Regenerative MedicineSelected Examples of Building an IndustryMarket Opportunities for Regenerative MedicineSelected Examples of Building an Industry

1996: Integra's Artificial Skin approved by the FDA Cell based/natural scaffold product

1997: Genzyme’s Carticel approved by FDA. Cell based/scaffold free product

1998: Organogenesis’ Apligraf Skin Equivalent approved by FDA Claim: "first manufactured living human organ"

1998: DePuy’s Restore Orthobiologic Soft Tissue Implant approved by FDA Scaffold based/cell free product

2006: Osiris’s PROCHYMAL™ Fast-Track by FDA/Orphan status by EMEA Cell based/scaffold free product

2006: Tengion’s neo-bladder Phase II IND accepted by FDA. Cell based/synthetic scaffold product

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Market Opportunities for Regenerative MedicineAnticipated Industry Revenue GrowthMarket Opportunities for Regenerative MedicineAnticipated Industry Revenue Growth

U.S. TE/RM Markets in 2005 was $145MM Bone regeneration products (15 percent of revenues) Skin-engineering products (50 percent of revenues) Cartilage-repair products (35 percent of revenues)

The U.S. TE/RM markets for products considered Exponential growth in the next decade Revenues forecast by 2015 to reach >$2B

Compounded annual growth rate of 28 percent from 2005 to 2015 for products considered

Other market forecasts not considered: Organ replacements, restoration, and reconstruction Spinal repair therapies Vascular replacements Market opportunities may far exceed those considered

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Career Opportunities in TE/RMCareer Opportunities in TE/RM

All the same careers as one might expect to find in the biopharmaceutical industry

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Career Opportunities in TE/RMSelected Technical Job TitlesCareer Opportunities in TE/RMSelected Technical Job Titles

Discovery Research

Lab Assistant

Research Associate

Senior RA

Scientist

Senior Scientist

Research Director

Regulatory Affairs

Document Specialist

Regulatory Associate

Labeling Associate

Dossier Management Associate

Director Regulatory Affairs

Quality Control

QC Lab Assistant

QC Microbiologist

QC Cell Biologist

QC Biochemist

QC Chemist

QC Director

Manufacturing

Materials Handler

Manufacturing Asst

Manufacturing Assoc

Sr. Manuf Associate

Lead Manuf Assoc

Manuf Supervisor

Manuf Mgr or Dir

Clinical Development

Document Assistant

Data Associate

Biostatistician

Research Associate

Medical Writer

Medical Expert

Medical Director

Quality Assurance

Document Specialist

QA Associate

QA Specialist

QA Auditor

QA Engineer

Validation Associate

Validation Specialist

QA Director

Process Development

PD Assistant

PD Associate

PD Scientist

PD Engineer

PD Director

Facilities

Mechanic

Electrician

Instrument Tech

Facilities Engineer

Project Engineer

Health and Safety Eng

Maintenance Mgr

Facilities Director

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Career Opportunities in TE/RMSelected Technical Degree LevelsCareer Opportunities in TE/RMSelected Technical Degree Levels

Technical HS; AS; BS, MS, Ph.D., DVM, MD

Education required for increasingly complex roles are driven by knowledge, capability, and experience required to be proficient at the role

Increasing technical degree level increases the opportunities for greater roles in the field and opportunities for career growth

Nothing substitutes for experience, but the degree is always the entry card

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Career Opportunities in TE/RMWhat about Manufacturing Jobs?Career Opportunities in TE/RMWhat about Manufacturing Jobs?

Finding staff with the right mix of technical education and career interest has always been a challenge Traditionally new complex technologies will gravitate towards the 4

year degree with experience As technologies mature and become more routine, keeping the

interest of 4 year degreed staff becomes challenging– Staff who have progressed through 4 years to technical degree usually have

higher aspirations than day-to-day production with limited growth potential– Supervisory/Management roles are usually limited to 4 year degreed staff but

those opportunities are obviously limited in number

As the technology matures finding technically qualified staff who will have a long-term interest in operating in a routine production environment is essential in-order to maintain a sufficient workforce and also to contain manufacturing costs

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Career Opportunities in TE/RMTengion’s Experience at the W-S, NC CenterCareer Opportunities in TE/RMTengion’s Experience at the W-S, NC Center

Tengion Labs in Winston-Salem, NC has partnered with ForsythTech Community College in W-S to provide educational programs that provide future non-four year degreed workforce to our Pilot Plant operations located there Associates in Applied Science Internships/Co-ops at Tengion

Essential technical grounding with lab courses in: Biology

– General/cell culture/microbiology/immunology/biotech lab experience Chemistry

– General/organic/biochemistry/analytical Math

– General/graphic analysis/statistics Writing Computers

Tengion is looking to replicate our experience in NC at our Manufacturing Center in Pennsylvania through local community colleges

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Questions & AnswersQuestions & Answers

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