2. This presentation is intended to present a summary of ACTâs (âACTâ, or âAdvanced Cell
Technology Incâ, or âthe Companyâ) salient business characteristics.
The information herein contains âforwardâlooking statementsâ as defined under the federal
securities laws. Actual results could vary materially. Factors that could cause actual results
to vary materially are described in our filings with the Securities and Exchange Commission.
You should pay particular attention to the ârisk factorsâ contained in documents we file from
time to time with the Securities and Exchange Commission. The risks identified therein, as
well as others not identified by the Company, could cause the Companyâs actual results to
differ materially from those expressed in any forwardâlooking statements. Ropes Gray
Cautionary Statement Concerning ForwardâLooking Statements
2
3. Multiple Pluripotent Cell Platforms
âą Single Blastomere-derived Embryonic Stem Cells
âą Generating hESC without Destruction of Embryo
âą Utilizes a single cell biopsy
âą Our hESC lines exhibit all the standard characteristics and the
ability to differentiate into the cells of all three germ layers
both in vitro and in vivo.
âą Induced Pluripotency Stem Cells (iPS)
âą Early Innovator in Pluripotency (before iPS was even a term!)
âą Recipient of National Institutes of Health Director's Opportunity Award
âą Seminal paper identifying replicative senescence issue for vector-derived iPS cells
âą Leading publication on protein induced iPS lines - avoids genetic manipulation with nucleic acid vectors
âą Controlling Filings (earliest priority date) to use of OCT4 for inducing pluripotency
3
Final Product Definition: hESC-derived
products will be manufactured using a cell
line made in 2005 from single cell isolated
without the destruction of any embryos
4. The RPE layer is critical to the function and health of photoreceptors and the
retina as a whole.
â RPE cells provide trophic support and detoxification activities to photoreceptor space.
» Recycle photopigments
» Deliver, metabolize and store vitamin A
» Phagocytize and clear cellular waste
» Maintain Bruchâs membrane
» Absorbs incident light, protects space from UV damage
â RPE loss leads to photoreceptor loss and eventually blindness, such as dry-AMD
â Loss of RPE layer and appears to lead to decline of Bruchâs membrane, leading
progression from dry-AMD to wet-AMD
âą Discrete differentiated cell population as target
âą Failure of target cells results in disease progression
4
Retinal Pigment Epithelial Cells - Rationale
No other cell type can perform
this complete set of functions
5. 5
RPE Cell Therapy
Early Stage AMD
(10-15M)
Intermediate AMD
(5-8M)
Late Stage AMD
(1.75M)
U.S. Patient Population
ACTâs RPE Cell Therapy should effectively
address the full range of dry AMD patients.
âą Halt the progression of disease and vision
loss in early stage patients
âą Restore some visual acuity in later stage
patients
Dry AMD represents more than 90 percent of all
cases of AMD
North America and Europe alone have more than
30 Million dry AMD patients who should be
eligible for our RPE cell therapy
On the Rise: Population demographics
(âbaby boomersâ) combined with increased
longevity predicts an increase of 50 percent
or more in the incidence rate of AMD.
6. RPE Engraftment â Mouse Model
Human RPE cells engraft
and align with mouse RPE
cells in mouse eye
6
Injected human RPE cells recapitulates
correct monolayer structure in eye
Human RPE cells fill in empty spaces
adjacent to mouse RPE cells
400x magnification
100x magnification
7. RPE Engraft and Function in Animal Studies
RPE treatment in RCS rat model of retinal dystrophy slowed the
progression of vision loss by promoting photoreceptor survival.
treated control
Photoreceptor
layer
7
photoreceptor layer is
only 0 to 1 cell thick
without treatment
Treated animal â retain 70% of full visual acuity
Control Animal â blind at 6 months
8. âą Established GMP process for differentiation and purification of RPE
â Virtually unlimited supply
â Pathogen-free GMP conditions
â Minimal batch-to-batch variation
â Characterized to optimize performance
â Virtually identical expression of RPE-specific genes to controls
GMP Manufacturing
Ideal Cell Therapy Product
âą Centralized Manufacturing
âą Small Doses
âą Easily Frozen and Shipped
âą Simple Handling by Doctor
8
9. Characterizing Clinical RPE Lots
9
Normal female (46 XX) karyotype
of the clinical RPE lot.
Up-regulation of RPE markers and
down-regulation of hESC markers
10. Characterizing Clinical RPE Lots
10
Quantitative Potency Assay
Each lot is assessed by phagocytosis (critical
function in vivo) of fluorogenic bioparticles.
Flow cytometry histogram showing
phagocytosis of pHrodo bioparticles
4°C 37°C
11. Effects of Pigmentation
11
Melanin content can be measured spectrophotometrically and used to determine the
optimal time to harvest and cryopreserve RPE.
y = 0.0141x + 0.0007
0.00
0.50
1.00
1.50
2.00
0 20 40 60 80 100120
Absorbanceat475nm
”g/mL Melanin
12. Phase I - Clinical Trial Design
12
SMD and dry AMD Trials approved in U.S., SMD Trial approved in U.K.
âą 12 Patients for each trial, ascending dosages of 50K, 100K, 150K and 200K cells.
âą Patients are monitored - including high definition imaging of retina
High Definition Spectral Domain Optical Coherence Tomography (SD-OCT)
Retinal Autofluorescence
50KÂ Cells 100KÂ Cells 150KÂ Cells 200KÂ Cells
Patient 1 Patients 2/3
DSMB Review DSMB Review
RPE and photoreceptor activity
compared before and after surgery
13. Surgical Overview
13
Procedure:
âą 25 Gauge Pars Plana Vitrectomy
âą Posterior Vitreous Separation
(PVD Induction)
âą Subretinal hESC-derived RPE
cells injection
âą Bleb Confirmation
âą Air Fluid Exchange
14. Preliminary Results
14
âą Structural evidence confirmed cells had
attached and persisted
âą No signs of hyperproliferation,
abnormal growth, or rejection
âą Anatomical evidence of hESC-RPE
survival and engraftment.
âą Clinically increased pigmentation
within the bed of the transplant
âą Recorded functional visual
improvements in both patients
15. Images of hESC-RPE transplantation site in SMD Patient
15
SD-OCT images
Demonstrate survival and engraftment of RPE
The injected RPE cells migrate to the desired anatomical location
3mo post-op
16. Phase II/III Design
16
Design of future studies dependent upon information gathered
throughout PI/II study
âą Efficacy
âą Patient population less VA impact 20/200?
âą Multiple Injections
âą Further evaluation of I/E criteria
âą Potentially less immunosuppression
âą Other considerations of efficacy:
âą New or more sensitive technologies
âą Possible saline placebo injection (same eye)
Working with our
experts/investigators in
design of studies
17. Phase II/III Projected Timeline
17
âą Completion of Phase I/II study 2013-2014
âą Design of Phase II and III studies is an ongoing
process, but will become more concrete during
2013
âą Phase III study commencement 2014-2015
18. RPE Cells â Additional Indications
18
âą Myopic Macular Dystrophy (MMD)
âą Retinopathy of Prematurity
âą Angioid Streaks
âą Retinitis Pigmentosa
âą Bests Disease (vitelliform macular dystrophy)
âą Multifocal Choroidopathy Syndromes
Combination Products
âą Combined with other cell types (photoreceptor progenitors)
âą Combined with anti-angiogenic agents, neuroprotective agents, etc.
21. Ocular Program â Corneal Endothelium
âą More than 10 million people with corneal blindness
âą The cornea is the most transplanted organ (1/3 of all
transplants performed due to endothelial failure)
âą Solutions include the transplantation of whole cornea
âPenetrating Keratoplastyâ (PKP)
âą More popular: Transplantation of just corneal
endothelium & Descemetâs membrane (DSEK/DSAEK).
hESC-derived corneal
endothelium resembles
normal human corneal
endothelium
21
22. Ocular Program â Hemangioblasts
22
Hemangioblasts induce reparative
intraretinal angiogenesis is various
animal models of ischemic retinopathies
âą Revascularization is observed in animals
injected either intravitreally or intravenously with
hESC-derived hemangioblasts
âą ischemia-reperfusion injury
âą diabetic retinopathy
âą GFP-labeling reveals incorporation of injected
cells into the vasculature of the eye during
angiogenesis
âą Hemangioblasts prevented BRB breakdown in
diabetic rats.
Repair of ischemic retinal vasculature in a mouse
after injection of hESC-derived hemangioblasts
23. Ocular Program â Hemangioblasts
23
Oxygen-induced Retinopathy Model
OIR+HBOIR+dPBS
hESC-derived
Hemangioblasts Rebuild
Functional Vasculature on
Retina Obliteration Region
and Suppress Pre-retinal
Neovascular Tufts
24. âą Generated various retinal neural progenitor cell types â or RNP cells
âą From both embryonic and iPS cell sources.
âą Discovered a new photoreceptor progenitor cell type.
âą Tested in mouse model for retinal degeneration - ELOVL4-TG2 mice
âą Observed both structural and physiological consequences
After 2 months
âą ERG - increases in both the a-wave and b-wave
âą OCT - increases in central retinal thickness
Ocular Program â Retinal Neural Progenitors
24
hESC-derived RNP cells reversed the progression of photoreceptor
degenerationâ and appeared to promote regeneration
âą Defined culture conditions
âą High yield from hESC and iPS
âą Homogeneous and highly pure
preparations
25. ACT Management Team
Highly Experienced and Tightly Integrated Management Team
Gary Rabin â Chairman & CEO
Dr. Robert Lanza, M.D. â Chief Scientific Officer
Edmund Mickunas â Vice President of Regulatory Affairs
Kathy Singh - Controller
Rita Parker â Director of Operations
Dr. Irina Klimanskaya, Ph.D. â Director of Stem Cell Biology
Dr. Shi-Jiang (John) Lu, Ph.D. â Senior Director of Research
Dr. Roger Gay, Ph.D. - Senior Director of Manufacturing
Dr. Matthew Vincent, Ph.D. â Director of Business Development
Bill Douglass â Director of Corporate Communications & Social Media
25