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LEADING REGENERATIVE MEDICINE
Annual Meeting
Tuesday, Oct. 22, 2013
Palm Springs, CA
2
Cautionary Statement Concerning Forward-Looking Statements
This presentation is intended to present a summary of ACT’s (“ACT”, or “Advanced
Cell Technology Inc”, or “the Company”) salient business characteristics.
The information herein contains “forward-looking statements” 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 “risk factors” 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 Company’s
actual results to differ materially from those expressed in any forward-looking
statements. Ropes Gray
CEO UPDATE
Gary Rabin Chief Executive Officer, Chairman
3
4
• We continue to appreciate your support through this period where we
are working to finally put the past to rest. We share your frustration with
how long it has taken to put the last matters to closure
• We concluded highly successful meeting with our OAB
• We have worked through a 2014 goal-driven plan with our senior
management team to advance both our clinical RPE program and our
other ophthalmic activities, as well as moving our MSC activities
toward the clinic
• We are at the beginnings of seeing a real opportunity in our pre-
clinical animal studies and translating that into a veterinary plan
• We are starting to engage fully in our up-listing and institutional capital
raising strategy, and are optimistic that we will finally achieve our
goals.
ACT Overview
5
Pre-clinical/ in vitro
POC – Animal Studies IND Approved Phase I Phase II Phase III Approval
Dry AMD
SMD
MMD
Photo-receptors
Ganglion
Neurons
Cornea
Platelets
Mesenchymal Stem Cells
Robust Development Pipeline Provides Multiple Opportunities to
Commercialize and Partner O
ph
tha
lmo
log
y P
rog
ram
s
6
Pre-clinical/ in vitro
POC – Animal Studies IND Approved Phase I Phase II Phase III Approval
Dry AMD
SMD
MMD
Photo-receptors
Ganglion
Neurons
Cornea
Platelets
Mesenchymal Stem Cells
Robust Development Pipeline Provides Multiple Opportunities to
Commercialize and Partner
Potential Gov’t Funding
First Priority Based On Current Funding
Advance into Phase I and Partner
Based on POC results,
pursue appropriate
funding and collaborations
Op
hth
alm
olo
gy
Pro
gra
ms
Several Important clinical milestones Q4 2013, 2014
150K 200K ?
Cohort 2a
100K
1Q 2014 Jan 2015
Dry AMD
& SMD Trials
Patient follow-up
PII design Patient Treatment Phase II
Patient Treatment MMD Trial
7
4Q 2013 3Q 2014
Phase I
Phase I
8
BY PRODUCING THE
HIGHEST DEGREE OF QUALITY
VETERINARY THERAPEUTICS
WE INTEND TO BE
A LEADER IN
VETERINARY
REGENERATIVE MEDICINE
September 19, 2013 –
“ACT Files Investigational New Animal
Drug (INAD) Application with FDA to Treat
10 Different Disease Indications Using
Pluripotent Stem Cells”
9
• Extremely successful and productive meeting
• Complete unanimity among company, investigators, and
independent board members
• Plan agreed on Phase 2 trial design including endpoints and
termination strategy for current trials
• Currently developing materials to discuss strategy with FDA
• Data review and results showing surprising strong statistical success.
All board members impressed by aggregate data showing acuity
improvements as well as differential between treated and untreated
eyes
• Working on beginning to write paper for submission to top peer
reviewed medical journals
Ophthalmic Advisory Group Summary
SCIENCE UPDATE
Dr. Robert Lanza Chief Scientific Officer
10
Treatment of eye diseases
• Retinal pigment epithelium (macular degeneration)
• Retinal ganglion progenitors (glaucoma)
• Photoreceptor progenitors (advanced blindness)
• Mesenchymal stem cells (uveitis)
• Corneal endothelium (corneal repair)
Single-blastomere technology
• Master Cell Bank (ethically-compliant/xeno-free) for future clinical trials
Induced pluripotent stem (iPS) cell technology
• Episomal, mRNA, microRNA vs. other reprogramming methods
• Master Cell Bank for Phase I/II clinical trials
Megakaryocytes/platelets
• Preclinical studies safety & efficacy studies
Mesenchymal stem cells
• Manufacturing under GMP conditions (for pre-clinical/clinical studies)
• Rodent studies (multiple sclerosis, lupus, pain, ALS, Alzheimer's)
• Large-animal studies (hepatitis, glomerulonephritis, osteoarthritis, Crohn’s disease, IBS,
spinal cord/disc disease, meningoencephalitis, hemolytic anemia, pancreatitis, sepsis)
Research & Development Programs
11
Ocular Programs
Retinal pigment epithelium
Macular degeneration (AMD, Stargardt’s)
Myopia
Retinal ganglion progenitors
Glaucoma
Retinal neural progenitors
Photoreceptor replacement
Neuroprotection
Corneal endothelium
Corneal disease
Mesenchymal stem cells
Uveitis, glaucoma
light
Retina
12
RPE Clinical Trials
US Clinical Trials
• Jules Stein Eye Institute (UCLA)
• Wills Eye Institute
• Bascom Palmer Eye Institute
• Mass Eye & Ear
Dry AMD
Twelve patients treated
- 3 patients (50K cells)
- 6 patients (100K cells)
(includes 3 better vision)
- 3 patients (150K cells)
Stargardt’s Disease
Nine patients treated
- 3 patients (50K cells)
- 4 patients (100K cells)
(includes 1 better vision)
- 2 patients (150K cells)
July 12, 2011: First patient in both US trials were treated
at UCLA by Steven Schwartz, M.D.
Stargardt’s Disease
Nine patients treated
- 3 patients (50K cells)
- 3 patients (100K cells)
- 3 patients (150K cells)
European Clinical Trial Site
• Moorfields Eye Hospital
ClinicalTrials.gov US: NCT01345006, NCT01344993 UK: NCTO1469832
13
OVERALL RESULTS:
No major safety issues related to stem cell treatment
Clear signs of long-term engraftment & survival
During the one-year follow-up period, patients in both the
SMD and dry-AMD clinical trials have shown significant
improvement in visual acuity in the RPE-treated eyes
• vision in one patient improved from
20/400 to 20/40 in first month
By contrast, the fellow (untreated) eyes remained
unchanged or continued to show decline in visual acuity
during the same time period
DAY 1 2 MONTHS 6 MONTHS
14
Next Steps – RPE Program
Complete and publish results of Phase I/II Clinical Trials
Preparation and design of Phase II Clinical Trials
NED-7 GMP Master Cell Bank (MCB) – hESCs derived using single-blastomere technology (no embryos destroyed)
– No mouse feeders (no longer a xeno product)
– MCB (~500 vials generated) » Working Cell Bank (~260 vials generated)
» ~800 vials of RPE (made from 2 vials of WCB)
(enough to treat ~800 patients, although could have generated more)
* waiting for manufacturing and regulatory sign-offs
Begin Phase I Clinical Trial (UCLA) to treat myopia
15
Megakaryocytes & Platelets
• hES/iPSC-platelets participate in clot formation
• Incorporate into mouse thrombus
(laser-induced arteriolar injury)
Both hES and iPS-MKs produce pure platelets
Normal blood platelets iPS-derived platelets
16
Glycogen
Granules Dense Tubular
System
Open
Canalicular
System
Alpha-Granule Mitochondria
Micro-
tubules
Multivesicular
Body
Glycogen
Granules
Alpha-Granule
Mitochondria
Open
Canalicular
System
Dense Tubular
System Microtubules
Morphology/ultrastructure of iPS-platelets
identical to normal blood platelets
iPS-PLT
blood-PLT
17
Achieve
1 Million Dose Scale
1yr 2yr 3yr 4yr 5yr 10yr
NEXT STEPS / PLATELET PROGRAM
Optimize MK progenitor/platelet production &
functionality in vitro
Scale-up using microfluidics and bioreactor system
Continue preclinical testing in animals (efficacy,
biodistribution, safety/tox tumorigenicity)
Complete transfer of technology to
GMP/manufacturing (includes assay development and
process validation)
Complete clinical regulatory process/file IND
NOTE: Strategic decision made to fast-track MSC program into clinic
first (potentially greater financial and medical impact in the near term )
18
Corneal repair: corneal endothelium derived from hESCs
• 10 million people with corneal blindness
• Cornea the most transplanted organ (1/3 due to endothelial failure)
• Solutions: Tx of whole cornea “Penetrating Keratoplasty” (PKP)
– More popular: Tx corneal endothelium & Descemet’s membrane (DSEK)
Global gene analysis shows that hESC-
CECs & adult-CECs are nearly identical
Optimized
cryopreservation
(CECs can now be
sent world-wide)
19
hESC-derived cells resemble normal human corneal endothelium
Next Steps
Preclinical Studies
Continue testing hESC-derived corneal endothelium
in in vivo rabbit cornea model
• Model: In vivo edema injection in rabbit
(inject dissociated cells to replace native
CECs)
• Increase purity of CECs to 99%
• Design and test hydrogel sheet in vitro (needs
to be transparent, flexible and biodegradable)
• Design and test CEC/hydrogel sheet in vivo
(test sheet to mimic clinical DSEK in rabbit
model)
Cornea Iris
Lens
CEC
20
Other Retinal Cell Types
Pluripotent
Stem Cell
Eye Field
Stem Cell
RNP
Photoreceptor
Ganglion
PDE6a/DAPI
Opsin (green/red)
PDE6a/DAPI
Rhodopsin/Recoverin
Math5/DAPI
21
Retinal Neural Progenitors
a-wave (cones & rods)
b-wave (post-synaptic retinal cells)
RNP, 2 mo RNP, 2 mo
RNP, 1 mo
PBS, 1 mo
PBS, 2 mo
RNP, 1 mo
PBS, 1 mo
PBS, 2 mo
Increase in retinal (ONL)
thickness by OCT after 2 mos
hESC- RNP cells reversed the progression of
photoreceptor degeneration
0
20
40
60
Control No Injection Cell treatment Th
ick
nes
s of
ON
L (
µm
)
} ONL ONL }
22
Identification of endocrine/neuroprotective factors
mouse specific probe
human specific probe
Genomic DNA Q-PCR analysis
of whole retina
Proteins screened using antibody arrays
23
Preservation of Outer Segments (OS) of Rod Photoreceptors in RCS rats
PBS
Tail vein injection
Intravitreal injection
Missing OS
Rod OS in cell-treated
rat retina shown by
rhodopsin staining
24
Subretinal transplantation Integration of Photoreceptor PROGENITORS
1 week after transplantation 3 week after transplantation
HNA antibody/transplanted human cells Human cells migrating into ONL
25
Next Steps Continue testing RNPs in in vitro and in animal models
Collaborations underway with several leading groups studying various retinal/ocular disease
models
Continue identification of paracrine/neuroprotective factors (proteomics, antibody arrays, 2D
gel analysis, and mass spec)
Test ability of cell-free lysates (or specific identified factors) to prevent or delay a range of
ocular & non-ocular degenerative diseases
Photoreceptor Progenitors
Complete studies of recovery of host visual function and retinal structure
Continue in vitro neuroprotection studies using conditioned medium
In vitro and in vivo functional tests of secreted factors
Ganglion Progenitors
Continue animal experiments/show long term survival of transplanted cell
Integration of transplanted cells
Protection/replacement of host retinal ganglion cells
Optic nerve regeneration
26
Mesenchymal Stem Cells (MSCs)
Found in bone marrow, adipose, umbilical
cord, tooth buds
Can differentiate into fat, bone, cartilage
MSCs are immunoprivileged and can:
- migrate to injury site
- exert immunosuppressive effects
- facilitate tissue repair
Over 200 clinical trials
(www.clinicaltrials.gov)
- wide range of clinical indications being
pursued
- companies such as Pluristem,
Mesoblast, Neostem are developing
MSC-based therapies using BM or
other primary sources of MSCs
27
hESC-MSCs versus adult derived MSCs
● “Off the shelf” therapy available for immediate use
● Unlimited cell source
● Easy to derive
● Can be expanded to large numbers in vitro
● More youthful and live much longer
● Potentially greater efficacy
(older MSCs often serve as negative controls)
● Hemangioblast-derived hESC-MSCs exponentially
greater yields than other reported hESC methods
>30,000 X more units from hESC-MSCs
than from adult bone marrow MSCs
A sampling of their in vivo efficacy
will be given in the following slides
28
Treatment of Multiple Sclerosis in Mice (EAE model)
Clinical Score: 2-4
(partial to complete
hind/front leg paralysis)
Untreated hESC-MSC Treated* Clinical Score: <1
(no leg paralysis)
*BM-MSCs had minimal impact (animals still showed paralysis)
hESC-MSCs dramatically reduce clinical
symptoms of EAE
both prophylactic and therapeutic
inhibition
In vitro inhibition of T-cell function
Differential cytokine expression (hESC-
MSCs vs. BM-MSCs)
Differential ability to migrate into damaged
tissues (hESC-MSCs vs.
BM-MSCs)
Additional follow-up studies being
completed for scientific publication (based
on reviewer suggestions)
Multiple sclerosis is a leading candidate for
clinical translation
29
hESC-MSC treatment for Uveitis
An inflammatory/auto-immune condition of the uvea
Accounts for 10% of blindness in US (mostly 20-40
year olds)
Experimental autoimmune uveitis (EAU) in mice
resembles
that of human uveitis
Disease state can be assessed using funduscope
imaging/histology
PMN and lymphocytes
Untreated EAU mice
Preliminary studies show
that hESC-MSC treatment
is effective in treating EAU
uveitis
30
hESC-MSC treatment for SLE/Lupus Nephritis Systemic lupus erythematosus (SLE) or lupus is a systemic autoimmune disease that can
effect virtually any organ or system in the body
There is no cure for SLE
SLE most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous
system
50% of SLE patients get lupus nephritis (LN)
Immune complex deposition in kidney glomeruli leads to kidney dysfunction/failure
NZB/NZW mice spontaneously develop lupus nephritis (very similar to human SLE)
NZB/NZW lupus model
hESC-MSCs have a dramatic effect on
morbidity (including proteinuria/kidney
function
Protect from death (show marked
improvement in survival)
Lead candidate for clinical translation
31
hESC-MSC treatment for Pain
PAIN behavior can be
measured in mice using
operant equipment (using a
reward/conflict paradigm)
hESC-MSCs significantly
reduce chemotherapy-
induced neuropathy in
response to taxol
Also a candidate for clinical
translation
32
Potential therapeutic applications for MSCs
>100 autoimmune diseases
Multiple Sclerosis
Osteoarthritis
Lupus
Aplastic Anemia
Crohn’s Disease/IBS
Chronic Pain
Limb Ischemia
Heart Failure/MI
Stroke
Graft-versus-host Disease
Spinal Cord Injury
Liver Disease
Kidney Disease
Emphysema/Pulmonary Diseases
Wound healing (ulcers/decubitus/burns)
HSC engraftment/irradiated cancer patients
Eye diseases (uveitis, retinal degeneration, glaucoma)
hES/hiPS-MSCs are
Ideal for Clinical Translation
No need for immunosuppression
Persist transiently
Can be irradiated
33
Canine Indications for Human MSC Therapy
MSC Therapy
Orthopedic
Intervertebral disk disease
Osteoarthritis
Inflammatory
Sepsis
Acute pancreatitis
Immune-mediated
Granulomatous meningoencephalitis
Inflammatory bowel disease
Chronic hepatitis
Glomerulonephritis
Anal furunculosis
Immune-mediated hemolytic anemia
Filed Investigational New Animal Drug (INAD)
application with the FDA to treat 10 different
disease indications
Naturally-occurring diseases in large animals,
such as dogs, provide an excellent model of
human conditions. May provide a more robust
assessment of safety and therapeutic endpoints
than what can be obtained from inbred rodent
models
Initiated collaboration with Tufts University
School of Veterinary Medicine, which has a large
population of suitable patients, and world-experts
in regenerative medicine
Have already received IACUC approval to begin
several of the studies
In additional to the obvious veterinary
applications, the results may help inform and
optimize human clinical trials
34
CORPORATE UPDATE
Ted Myles Chief Financial Officer & EVP of Corporate Development
35
Improving the Balance Sheet, and therefore the Company to Position a 2014 up-listing
36
ACT - Current
~$4m - $5m cash on hand and funding
itself through bi-daily issuances of
~2.5m shares of common stock
The Company draws from the market
slightly less than it spends, in order to
build its cash balance, albeit slowly
This funding vehicle puts continuous
downward pressure on stock and is not
enabling of scale up as we prepare for
larger clinical trials
ACT – end of 2013/early 2014
Raising a tranche of funds ($10m - $15m) in
the near-term will improve the balance
sheet, and therefore the stability of the
company
Will also decrease our reliance on the
frequent draws, therefore reducing the
constant downward pressure on the stock
Having ~12 months of cash in the bank will
allow the Company to be more strategic as
it pursues clinical expansion, corporate
development and Nasdaq listing
ACT has never had real balance sheet strength and has therefore
been forced to make decisions from a “less than optimal” position
Why Up-List to Nasdaq?
37
“Over-the-Counter”
OTC companies are sometimes
associated as being of “poor quality”
Naked shorting can damage
shareholder value
Trading/liquidity is less efficient
Equity research analysts want to cover
and support companies on national
exchanges
Institutional investors who can invest
substantial capital are less likely to
invest in “penny stocks” no matter how
great the company
Nasdaq Listed
“Class effect”, being a Nasdaq-listed
company carries with it a cache of quality,
based partly on perception and largely on the
strict listing requirements
Increased shareholder protection due to
stringent listing requirements
Institutional investors have expressed
interest in investing substantial capital into
ACT, after up-listing
Building a syndicate of equity research
analysts who cover the Company can create
additional demand for the shares
Completing a fully marketed financing deal that includes a broad syndicate of
bankers and analysts could capitalize the Company through Phase II, and create
global awareness of the ACT story
Management
believes that
a Nasdaq up-
listing is in
the best
interest of all
stakeholders
Clinical and Corporate Development Support Up-listing,
and Growth in Shareholder Value
38
All components
of the
Company
complement
one another. A
transformative
process for
ACT
R&D
Progress
Phase 1 Phase 2 AMD Trials
MMD Trial Phase 1
Corporate
Development
MSC and
other Pre-clinical
SEC, etc. Clean up
Partnering Non-dilutive
funding
Reverse split Financial Nasdaq “re-IPO”
Thank you
For more information, visit www.advancedcell.com
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