Clinical Outlooks for Regenerative Medicine 6/19/2012

Allan Robins Ph.D. Acting CEO, VP & CTO

Cell Therapy Approach for IDDM Islet Transplantation: Clinical Proof of Principle

•  >750 patients successfully transplanted since 2000

•  Transplant site complications

•  Chronic immunosuppression necessary

•  Limited supply

2 Confidential © 2012 ViaCyte, Inc.

Core Elements of ViaCyte’s Diabetes Product

•  Renewable cell source: human embryonic stem cells –  CyT49

•  Cell product: pancreatic progenitor with β-cell potential –  Pro-Islet

•  Durable immunoisolation delivery device –  Encaptra™

Human Embryonic Stem Cells Represent an Indefinitely Renewable Cell Source

•  Virtually unlimited proliferative potential •  Rapid expansion (billions in 2-3 weeks) •  Genetically stable •  Pluripotent •  Biology is well characterized •  ViaCyte’s clinical hESC line: CyT49

–  Derived under GMP-compliant conditions –  Ethically derived –  Single-cell passaged GMP banks (MCB and WCB) –  Passed adventitious agent testing –  Xeno-free culture conditions

>1010 hESC

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Manufacturing Overview

Confidential © 2012 ViaCyte, Inc.

hESC Bank

Freeze Pro-Islet

Thaw, Formulate, Load, Pkg

Ship to

clinic

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Cell Process 1) ESC expansion

2) ESC aggregation 3) Differentiation

4) Cryopreservation

Combination Product 1)  Thaw cells 2)  Recovery 3)  Formulate 4)  Load device 5)  Package Device manufacturing

1)  Cut parts 2)  Weld sandwich together 3)  QC devices 4)  Assemble into packaging 5)  ETO sterilization

Expand hESC (15 days) Differentiate (13 days) 12 mo+ stability 3 days 2+ days

Cell Manufacturing and Overview of QC Testing

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hESC Bank

Cell Product Bank

Thaw, Formulate, Load, Pkg

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Flow cytometry -  98% pancreatic -  2% residual

OCT4+ screening - No ESCs

up to 1x1010

RNA profiling -  >30 genes -  Target (identity) -  Non-target (purity)

Sterility Viability

Ship to

clinic

PTC tested (MCB) Sterility Endotoxin Mycoplasma Viability Karyotype Gene expression

Cell yields

Expand hESC (15 days) Differentiate (13 days) 12 mo+ stability 3 days 2+ days

Efficient Directed Differentiation: Recapitulating Developmental Biology by Empirical Optimization

D’Amour et al. Nature Biotechnology 23, 1534-1541 2005 D’Amour et al. Nature Biotechnology 24, 1392-1401 2006 Kroon et al. Nature Biotechnology 26, 443 - 452 2008 Kelly et al. Nature Biotechnology, 29, 750-756, 2011 Schulz et al. PLoS ONE, 7(5):e37004, 2012

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(OCT4) RCB MCB4

In Process Assessment of Cell Product Manufacture Ave. +/- SD for biological triplicates; 12 manufacturing runs; 2 cell banks

IDENTITY IDENTITY PURITY PURITY

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Pancreatic progenitors become islets In Vivo

Human Islet Graft Implanted 360 days

Pro-Islet Graft Implanted 377 days

Glucagon Somatostatin Insulin

Schematic from Ricordi & Edlund, Nature Biotech News & Views, 2008

(ViaCyte implants)

Grafts show hallmarks of bona fide human islets

Does Encapsulated Pro-Islet Make Functional Endocrine Cells In Vivo?

Pro-Islet

+

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Encapsulated Pro-Islet Grafts Function Long-term in Encaptra

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1 2 3 4 1 2 3 4 1 2 3 4 5 6

EFP - 3M Cells Encaptra™ - 3M Cells Control Device - 3M Cells

Seru

m C

-Pep

tide

(pM

)

Fasting Maximum (30min)

Glucose Stimulated Insulin Secretion at 21 Wk Post-Implant in SCID/Bg Mice

2843 ± 700

3849 ± 744

3995 ± 872

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Tissue Capsule & Vasculature at 18wks

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Highly Enriched Endocrine Cell Composition Within the Device

GCG SST INS 100 µm 19 weeks

•  Primarily Endocrine: Insulin, Glucagon, Somatostatin, Ghrelin, PP •  Minimal Exocrine: IHC and RNA •  Device lumens are not expanded

CHGA

GCG SST INS DAPI

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CGM in Nude Rats

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BLOOD  GLUCO

SE  (mg/dL)

E2248  NUDE  RAT  A1015;  2X  EN20-­‐30uL;  16  WEEKS  POST-­‐TX  CGM

BG CAL ON  FAST 6H  FAST IP  GLUCOSE REFEED IVGTT

GLP Safety and Efficacy Study

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•  Male and female mice in GLP study of combo product show excellent in vivo function

•  Food consumption, body weight and blood glucose measurements also look good

•  End point safety: blood chemistry, opthamology, organ panel histopathology, device

and adjacent tissue histopathology, urinalysis

Female SCID-Bg Male SCID-Bg

STZ @ 33wk STZ @ 33wk

Robust glycemic control

Confidential © 2012 ViaCyte, Inc.

Transplant under the skin allows use of ultrasound to monitor the device implant

1.89  mm  

In vivo imaging of teratoma formation

Mapping of device vascularization in vivo

Image Processing and Volume Analysis in vivo

16 Confidential © 2012 ViaCyte, Inc.

Product Safety: Multi-tiered Risk Reduction

1)  Cell manufacturing: Ø  Highly enriched for product cells Ø  No ES cells detected in product

2)  Product cells cryopreserved: allows time for lot release assays

3)  Product encapsulated: in a bio-stable device and device integrity thoroughly assured Ø  Prevents cell biodistribution Ø  Contains a teratoma (should one form, we haven’t seen any) Ø  Retrievable

4)  Device loading system: Ø  Ensures viability of cells is maintained during device loading Ø  Eliminates risk of damage to device Ø  Eliminates introduction of cells on outside of device

5)  Subcutaneous implantation: Ø  Administration and retrieval with minimal surgical risk Ø  Minimizes potential for localized toxicity effects Ø  Permits monitoring of inflammation

6)  In vivo imaging: to monitor device for teratoma formation

17 Confidential © 2012 ViaCyte, Inc.

ViaCyte,  Inc.  Evert  Kroon  Olivia  Kelly  Laura  MarEnson  Alan  Agulnick    Chad  Green  Kuniko  Kadoya  Mark  Moorman  Eugene  Brandon  Holly  Young  Susan  McClatchey    Tom  Schulz  Allan  Robins  Mike  ScoS  Tony  Gringeri  

Key ViaCyte Staff and Collaborators

LIAI  Mathias  von  Herrath  

UCSF  Jeff  Bluestone  Peter  Stock  Mathias  Hebrok  Mike  German  

Brussels  Free  Univ.  Danny  Pipeleers  

Univ.  Alberta,  Edmonton  James  Shapiro  

Funding  Support  

Sanford-­‐Burnham  Pam  Itkin-­‐Ansari  

Univ.  Georgia  Steve  Dalton  Univ.  Chicago  Chris  Rhodes  

UCSD  Maike  Sander  Monash  Univ.  Andrew  Elefanty  Ed  Stanley  

Confidential © 2012 ViaCyte, Inc.