Leading Regenerative Medicine
Investor Presentation – March 2012
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
Cautionary Statement Concerning Forward-Looking Statements
2
ACT Ocular Programs
4
Retinal Pigment Epithelial Cells
Macular Degeneration - dry AMD, Stargardt’s Disease, MMD
Retinitis Pigmentosa
Photoreceptor protection
Hemangioblast cells
Ischemic retinopathy
– diabetic retinopathy, vascular occlusions
Retinal Neural Progenitor cells
Isolated Protective Factors
Photoreceptor Loss, Modulation of Müller Cells
Protection of Retinal Ganglion cells (Glaucoma)
Corneal Endothelium, Corneal Epithelium,
Descemet’s Membrane
Corneal Disease
Mesenchymal Stromal Cells
Glaucoma, Uveitis
Retinitis Pigmentosa
Management of Ocular Surfaces
light
retina
RP
E la
yer
Pho
tore
cept
ors
The RPE layer is critical to the function and health of photoreceptors and the retina as a whole.
– RPE cells secrete trophic factors and impact on the chemical environment of the subretinal space.
» recycle photopigments
» deliver, metabolize and store vitamin A
» transport iron and small molecules between retina and choroid
» maintain Bruch’s membrane
– RPE loss may lead to photoreceptor loss and eventually blindness, such as dry-AMD
– Loss of RPE layer and Bruch’s membrane is substantial feature underlying development of dry-AMD, and may be involved in progression from dry-AMD to wet-AMD
• Discrete differentiated cell population as target
• Failure of target cells results in disease progression 5
Retinal Pigment Epithelial Cells - Rationale
RPE cell as Target
• Pigmented RPE cells are easy to identify (no need
for further staining) – impacts manufacturing
• Small dosage vs. other therapies
• The eye is generally immune-privileged site, thus
minimal immunosuppression required, which may be
topical.
• Ease of administration – Doesn’t require separate approval by the FDA (universal applicator)
– Procedure is already used by eye surgeons; no new skill set required for doctors
RPE cell therapy may impact over
200 retinal diseases 6
Retinal Pigment Epithelial Cells - Rationale
• Established GMP-compliant process for the Reproducible Differentiation and Purification of RPE cells. – Virtually unlimited supply of cells
– Can be derived under GMP conditions pathogen-free
– Can be produced with minimal batch-to-batch variation
– Can be thoroughly characterized to ensure optimal performance
– Molecular characterization studies reveal similar expression of RPE-specific genes to controls and demonstrates the full transition from the hESC state.
GMP Manufacturing
Ideal Cell Therapy Product • Centralized Manufacturing
• Small Doses that can be Frozen and Shipped
• Relative Ease-of-Handling by Doctor
7
RPE Engraftment – Mouse Model
For each set: Panel (C) is a bright field image and
Panel (D) shows immunofluorescence with anti-
human bestrophin (green) and anti-human
mitochondria (red) merged and overlayed on the
bright field image. Magnification 400x
Human RPE cells engraft
and align with mouse RPE
cells in mouse eye
8
RPE Engraft and Function in Animal Studies
RPE treatment in animal model of retinal dystrophy has slowed the natural progression of the disease by promoting photoreceptor survival.
RPE cells rescued photoreceptors and
slowed decline in visual acuity
treated control
Photoreceptor
layer
9
Phase I - Clinical Trial Design
10
SMD and dry AMD Trials approved in U.S., SMD Trial approved in U.K.
• 12 Patients for each trial, ascending dosages of 50K, 100K, 150K and 200K cells.
– For each cohort, 1st patient treatment followed by 6 week DMSB review before remainder of cohort.
• Patients are monitored - including high definition imaging of retina
High Definition Spectral Domain Optical Coherence Tomography (SD-OCT)
Retinal Autofluorescence
50K Cells 100K Cells 150K Cells 200K Cells
Patient 1 Patients 2/3
DSMB Review DSMB Review
Permit comparison of RPE and
photoreceptor activity before
and after treatment
RPE Clinical Program – to date
11
• Dry AMD • IND approved in December 2010
• European CTA in preparation
• Stargardt’s (SMD) Disease • IND approved in November 2010
• European CTA Approved
• Orphan Drug Designation granted in U.S. and Europe
ClinicalTrials.gov US: NCT01345006, NCT01344993 UK: NCTO1469832
RPE Clinical Program – to date
12
Attracting Top Eye Surgeons and Retinal
Clinics to participate in Clinical Trials,
DSMB and Scientific Advisory Board
Dr. James Bainbridge, Moorfields Eye Hospital
• US Clinical Trial Sites • Jules Stein Eye (UCLA)
• Wills Eye Institute
• Status • 2nd and 3rd SMD patients treated (Jan/Feb 2012)
• Completes Cohort 1 (US)
• Enrolling additional dry AMD patients
• Additional Major Clinical Sites to announce
• European Clinical Trial Sites • Moorfields Eye Hospital
• Aberdeen Royal Infirmary
• Status • 1st SMD (Europe) patient treated (20 January 2012)
Surgical Overview • Prospective clinical studies to determine the safety and tolerability of
sub-retinal transplantation of hESC-derived RPE cells.
• Subretinal injection of 50,000 hESC-derived RPE cells in a volume of
150µl was delivered into a pre-selected area of the pericentral macula
• Vitrectomy including surgical induction of posterior vitreous separation
from the optic nerve was carried out
• 25 Gauge Pars Plana Vitrectomy
• Posterior Vitreous Separation (PVD Induction)
• Subretinal hESC-derived RPE cells injection
• Bleb Confirmation
• Air Fluid Exchange
Drs. Steven Schwartz and Robert Lanza
Straight forward surgical approach Can be performed on outpatient basis
13
Surgical Overview
14
Autofluorescence
images of retinas.
The dark spots in the
side panels show a
large area of atrophy in
the macular region.
First SMD Patient
First dry AMD Patient
Surgical Overview
15
Surgical Overview
16
Remove gel from
inner surface of retina
Injection with bleb
formation
Air Fluid Exchange
Injection bleb formed at interface of
atrophic retina and normal retina
Preliminary Results
17
• Dry AMD • The dry AMD patient is a 77 year old female with baseline
BCVA of 20/500, that corresponded to 21 letters in the ETDRS chart.
• Stargardt’s (SMD) Disease • The SMD patient is a 51 year old female with baseline best corrected visual acuity
of hand motion that corresponded to 0 letters in the ETDRS chart.
July 12, 2011: First Patients in each trial
were treated by Dr. Steven Schwartz, M.D
at Jules Stein Eye Institute (UCLA)
Preliminary Results
18
• After surgery, structural evidence
confirmed cells had attached and
continued to persist during study.
• No signs of hyperproliferation,
abnormal growth, or immune mediated
transplant rejection in either patient.
• Anatomical evidence of hESC-RPE
survival and engraftment.
• Clinically increased pigmentation at the level of the RPE within the bed
of the transplant beginning at postoperative week 1.
23 January 2012
Published results for first SMD and
Dry AMD Patients – 4 month time point
Preliminary Results
19
Recorded functional visual improvements in
both patients.
• SMD Patient: Best corrected visual acuity
improved from hand motions to 20/800 and
improved from 0 to 5 letters on the ETDRS
visual acuity chart in the study eye.
• Dry AMD Patient: Vision improved in the
patient with dry age-related macular
degeneration (21 ETDRS letters to 28).
Six Month Follow-up: Visual acuity gains remain stable for both patients; SMD Patient has slight improvement.
Similar trends observed for latest 3 SMD patients
SMD Patient
Images of hESC-RPE transplantation site in SMD Patient
20
pre-transplant 1wk post-op 6wk post-op
Color fundus photographs
We detected clinically increased pigmentation at the level of the RPE within the
bed of the transplant beginning at postoperative week 1 to month 3
Images of hESC-RPE transplantation site in SMD Patient
21
SD-OCT image collected at month 3 show survival and engraftment of hESC-RPE.
Localization of the transplanted cells to the desired anatomical location.
3mo post-op
Media Coverage
22
First Hints That Stem Cells Can
Help Patients Get Better
Headline: “Stem Cell Treatment for Eye Diseases Shows Promise”
Headline: “Some Promising Findings on Embryonic Stem Cells”
Intellectual Property – RPE Program
Dominant Patent Position for Treating Retinal Degeneration • US Patent 7,794,704 broadly cover methods for treating retinal degeneration using human RPE cells differentiated from
human embryonic stem cells (hESCs).
Broad Coverage for Manufacturing RPE Cells from hESC • U.S. Patents 7,736,896 and 7,795,025 are broadly directed to the production of retinal pigment epithelial (RPE) cells from
human embryonic stem cells.
Coverage for RPE Cells derived from other pluripotent stem cells (including iPS cells) • Earliest priority date relates back to 2004 filings
• Methods of manufacturing, use of RPE cells, and pharmaceutical formulations – e.g., source cell defined as pluripotent stem cell that expresses Oct-4, alkaline phosphatase, SSEA-3, SSEA-4, TRA-1-60 and TRA-1-81.
Vigilant Filing on Improvements • Extends patent life cycle, with significance to commercialization
• Include composition-of-matter claims (cell preparations, pharmaceutical preparations, etc.)
• Examples: degree of pigmentation, cell density of preparation, phagocytic activity • Distinguished from adult RPE cell preparations - telomere length, A2E and lipofuscin content of cells, lack of accumulated UV damage
23
Ocular Program – Corneal Endothelium
• More than 10 million people with corneal blindness
• The cornea is the most transplanted organ (1/3 of all
transplants performed due to endothelial failure)
• Solutions include the transplantation of whole cornea
“Penetrating Keratoplasty” (PKP)
• More popular: Transplantation of just corneal
endothelium & Descemet’s membrane (DSEK/DSAEK).
hESC-derived corneal
endothelium resembles
normal human corneal
endothelium
24
Ocular Program – Hemangioblasts
25
The Hemangioblast cell is a multipotent cell, and a common precursor to hematopoietic and endothelial cells.
Hemangioblast cells can be used to
produce all cell types in the circulatory
and vascular systems
• Hemangioblast cells can self-renew.
• Hemangioblast cells can be used to achieve
vascular repair.
• Hemangioblast activity could potentially be
harnessed to treat diseases such as myocardial
infarction, stroke, cancer, vascular injury and
blindness.
Ocular Program – Hemangioblasts
26
Hemangioblasts induce reparative
intraretinal angiogenesis is various
animal models of ischemic retinopathies
• Revascularization is observed in animals
injected either intravitreally or intravenously
with hESC-derived hemangioblasts
• ischemia-reperfusion injury
• diabetic retinopathy
• GFP-labeling reveals incorporation of injected
cells into the vasculature of the eye during
angiogenesis
• Hemangioblasts prevented BRB breakdown in
diabetic rats.
Repair of ischemic retinal vasculature in a mouse
after injection of hESC-derived hemangioblasts
• Generated various retinal neural progenitor cell types – or RNP cells
• From both embryonic and iPS cell sources.
• Discovered a new photoreceptor progenitor cell type.
• Tested in mouse model for retinal degeneration - ELOVL4-TG2 mice
• Observed both structural and physiological consequences
After 2 months
• ERG - increases in both the a-wave and b-wave
• OCT - increases in central retinal thickness
Ocular Program – Retinal Neural Progenitors
27
hESC-derived RNP cells reversed the progression of photoreceptor
degeneration– and appeared to promote regeneration
• Defined culture conditions
• High yield from hESC and iPS
• Homogeneous and highly pure
preparations
Ocular Program – Mesenchymal Stromal Cells
28
Proprietary Large Scale
Manufacturing Process for
Generating “young” MSCs
from hESC and iPS lines
• hESC-MSCs and iPS-MSCs can be expanded to large
numbers in vitro • Avoid premature senescence problem of “old” MSC’s
• Superior quality controls for a renewable cell source
• “Off-The-Shelf” therapy, available for immediate use
• Projected Higher Immunosuppressive Potency relative to adult
MSC
• MSCs can migrate to injury sites in eye – exert
immunosuppressive effects, and facilitate repair of
damaged tissues
Ocular Products in Development ▫ Treating inflammatory diseases of the eye
▫ Providing photoreceptor/neuron-protective activity
▫ Promoting tolerance to ocular grafts and devices
▫ Delivering therapeutic proteins to the eye.
Ocular Program – Mesenchymal Stem Cells
29
33,000 units MSCs from hESC-MSCs
1 unit MSCs
from adult BM
Compared to Adult MSC
• Less labor-intensive
• Single Bank Regulatory Process No need to derive new banks
Quality controls are easier to manage
• Larger yield of MSCs
Compared to hESC-direct
• Less labor-intensive
• Larger yield of MSCs
• Faster Acquisition of Markers
hESC Direct HB Method
Start 350,000 ESC 200,000 EB’s
Collect 48 days 44 days
Yield 4 Million 85 Million
Manufacturing Considerations Favor
hESC/Hemangioblast-derived MSC’s
over Adult MSC and hESC-direct MSC
Platform Technology for Generating
Robust Human Embryonic Stem Cells
Without the Need to Destroy Embryos
Single Blastomere Technology
Generating hESC without Destruction of Embryo • Enables Derivation of new hESC Lines via non-destructive single cell
biopsy method
• Utilizes single cell biopsy similar to pre-implantation genetic diagnostics
(PGD) Does not change the fate of the embryo from which the
biopsy was taken
• Blastomere-derived hESC lines exhibited all the standard characteristics:
undifferentiated proliferation, genomic stability, expression of pluripotency
markers and the ability to differentiate into the cells of all three germ layers both
in vitro and in vivo.
• Roslin Cells and ACT plan to generate GMP-compliant bank of human ES Cells
for research and commercial uses.
31
Worldwide Patent Filings
Issued Broad Claims to Single Blastomere Methodology - U.S. Patent 7,893,315
CONFIDENTIAL
iPS Platform
32 CONFIDENTIAL
• Recipient of National Institutes of Health Director's Opportunity Award
• Seminal paper identifying replicative senescence issue for vector-derived iPS cells • Feng et al. (2010) Stem Cells. 28(4):704-12.
• Leading publication on protein induced iPS lines • Generated stable iPS cells from human fibroblasts by directly delivering reprogramming proteins
associated with cell penetrating agents.
• Avoids replicative senescence problem in vector-induced iPS.
• Kim et al. (2009) Cell Stem Cell. 4(6):472-476.
• Pending patent filings directed to protein induced iPS.
Early Innovator in Pluripotency (before iPS was even a term!)
• Controlling Filings (earliest priority date) to use of OCT4 for inducing pluripotency Beats Yamanaka priority by several years
Financial Update – Strong Balance Sheet
33
Most Stable Financial Situation In Company History
• The Company ended 2011 with $13.1 million cash on hand
• $15 million more equity available
• Virtually debt-free
• Able to self-fund both U.S. clinical trials and EU clinical trial
• Significantly deepened management team (and on-going)
• Put in place first organizational reporting lines in ACT history
• Robert Langer, Zohar Loshitzer and Greg Perry join ACT board, bringing
remarkable scientific, entrepreneurial and partnering skills
• One additional Board member to announce
• Unqualified audit opinion
Continuing clinical trials with a strong balance sheet
ACT Management Team
World Class Scientific Team
Seasoned Management Team
Dr. Robert Lanza, M.D. – Chief Scientific Officer
Dr. Irina Klimanskaya, Ph.D. – Director of Stem Cell Biology
Dr. Shi-Jiang (John) Lu, Ph.D. – Senior Director of Research
Dr. Roger Gay, Ph.D. - Senior Director of Manufacturing
Dr. Matthew Vincent, Ph.D. – Director of Business Development
Gary Rabin – Chairman and CEO
Edmund Mickunas – Vice President of Regulatory Affairs
Kathy Singh - Controller
Rita Parker – Director of Operations
Bill Douglass – Director of Corporate Communications & Social Media
34
Thank you For more information, visit www.advancedcell.com