Clinical Outlooks for Regenerative Medicine …Clinical Outlooks for Regenerative Medicine!...
Transcript of Clinical Outlooks for Regenerative Medicine …Clinical Outlooks for Regenerative Medicine!...
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Clinical Outlooks for Regenerative Medicine 6/19/2012
Allan Robins Ph.D. Acting CEO, VP & CTO
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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.
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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™
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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
4 Confidential © 2012 ViaCyte, Inc.
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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
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Cell Manufacturing and Overview of QC Testing
Confidential © 2012 ViaCyte, Inc.
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
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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
Confidential © 2012 ViaCyte, Inc. 7
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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
Confidential © 2012 ViaCyte, Inc.
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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
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Does Encapsulated Pro-Islet Make Functional Endocrine Cells In Vivo?
Pro-Islet
+
10 Confidential © 2011 ViaCyte, Inc
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Encapsulated Pro-Islet Grafts Function Long-term in Encaptra
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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
Confidential © 2011 ViaCyte, Inc. 12
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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
13 Confidential © 2012 ViaCyte, Inc.
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CGM in Nude Rats
Confidential © 2011 ViaCyte, Inc. 14
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BLOOD GLUCO
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E2248 NUDE RAT A1015; 2X EN20-‐30uL; 16 WEEKS POST-‐TX CGM
BG CAL ON FAST 6H FAST IP GLUCOSE REFEED IVGTT
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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.
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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.
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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.
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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.