Regenerative Medicine – Building Replacement Organs

1. Regenerative Medicine – Building Replacement Organs Don Bergmann, PhD Senior Vice President Technical Operations

2. AGENDA • 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

3. Science and TechnologyStem Cells – Identity and Fate

4. Science 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

5. Science and TechnologyStem Cells – Adult and Embryonic • Pluripotent 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

6. Science 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

7. Science 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

8. Science 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

9. Science 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

10. Science 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

11. Tengion’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

12. Tengion’s Neo-bladderA Model of Regenerative Medicine (cont’) A surgeon takes a small, full-thickness biopsy from the patient’s bladder. 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. The biodegradable scaffold dissolves and is eliminated from the body, leaving a functioning bladder made only of the patient’s own newly regenerated tissue. The body uses the neo-bladder construct to regenerate and integrate new tissue, restoring the bladder’s functionality. The neo-bladder construct is implanted by the surgeon using standard surgical techniques. 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.

13. Tengion’s Platform TechnologyRegenerative Medicine Opportunities Trachea Muscle Breast Valve Liver Vessels Nerve Kidney Ureter Bladder Bone Other genitourinary Skin Cartilage

14. Product 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 Pre-Clinical production Clinical Production Research and Development

15. Regulatory 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

16. Regulatory 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

17. Regulatory Considerations TE/RM Products as Combination Products • 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.

18. Market 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

19. Market 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

20. Market 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

21. Career Opportunities in TE/RM • All the same careers as one might expect to find in the biopharmaceutical industry

22. Career Opportunities in TE/RMSelected Technical Job Titles

23. Career 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

24. 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

25. Career 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

26. Questions & Answers • THANKS FOR LISTENING