Leading Regenerative Medicine World Stem Cells & Regenerative - - PowerPoint PPT Presentation

Leading Regenerative Medicine

World Stem Cells & Regenerative Medicine Congress

May 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

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Multiple Pluripotent Cell Platforms

• Single Blastomere-derived Embryonic Stem Cells
• Generating hESC without Destruction of Embryo
• Utilizes a single cell biopsy
• 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.

• Induced Pluripotency Stem Cells (iPS)
• Early Innovator in Pluripotency (before iPS was even a term!)
• Recipient of National Institutes of Health Director's Opportunity Award
• Seminal paper identifying replicative senescence issue for vector-derived iPS cells
• Leading publication on protein induced iPS lines - avoids genetic manipulation with nucleic acid vectors
• Controlling Filings (earliest priority date) to use of OCT4 for inducing pluripotency

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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

RPE Clinical Program

The RPE layer is critical to the function and health of photoreceptors and the retina as a whole.

– RPE cells recycle photopigments, deliver, metabolize and store vitamin A, transport iron and small molecules between retina and choroid and maintain Bruch’s membrane – RPE loss leads to photoreceptor loss and eventually blindness, such as dry-AMD – Loss of RPE layer and appears to lead to decline of Bruch’s membrane, leading progression from dry-AMD to wet-AMD

• Discrete differentiated cell population as target
• Failure of target cells results in disease progression

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Retinal Pigment Epithelial Cells - Rationale

RPE cell as Target

• Pigmented RPE cells are easy to identify – aids manufacturing
• Small dosage vs. other therapies
• The eye is generally immune-privileged site, thus minimal

immunosuppression required

• Ease of administration, with no separate device approval and

straightforward surgical procedure

RPE cell therapy may impact over 200 retinal diseases

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Retinal Pigment Epithelial Cells - Rationale

Risk: Middle-aged adults have about a 2% risk of developing AMD - the risk increases to almost 30% in adults over age 75. Expense: In 2012, the worldwide financial burden of vision loss due to AMD is estimated at >US$350 billion, with >US$250 attributed to direct health care expenditures. On the Rise: Population demographics (“baby boomers”) combined with increased longevity predicts an increase of 50 percent or more in the incidence rate of AMD.

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The Unmet Medical Need

Early Stage AMD (10-15M) Intermediate AMD (5-8M) Late Stage AMD (1.75M)

Few Drusen Deposits Small in size Geographic Atrophy: 1M CNV Occurrence: 1.2M Large Drusen Deposits Pigment Change

Grade 0 0.5% Grade 1 3% Grade 2 9% Grade 3 27% Grade 4 43% Probability of progression to late stage AMD within 5 yrs

U.S. Patent Population We process 80 percent of all our information through our eyes. AMD represents a huge impact

• n QOL in later life

RPE Engraftment and Function – Pre-clinical

Human RPE cells engraft and align with mouse RPE cells in mouse eye

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treated

RPE cells rescued photoreceptors and slowed decline in acuity in RCS rat

control treated

• Established GMP process for differentiation and purification of RPE

– Virtually unlimited supply – Pathogen-free GMP conditions – Minimal batch-to-batch variation – Characterized to optimize performance – Virtually identical expression of RPE-specific genes to controls

GMP Manufacturing

Ideal Cell Therapy Product

• Centralized Manufacturing
• Small Doses
• Easily Frozen and Shipped
• Simple Handling by Doctor

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Characterizing Clinical RPE Lots

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Normal female (46 XX) karyotype

• f the clinical RPE lot.

Up-regulation of RPE markers and down-regulation of hESC markers

Characterizing Clinical RPE Lots

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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

Effects of Pigmentation

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Melanin content can be measured spectrophotometrically and used to determine the

• ptimal 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 80 100 120 Absorbance at 475nm µg/mL Melanin

Phase I - Clinical Trial Design

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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.
• 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

RPE and photoreceptor activity compared before and after surgery

Phase I – Endpoints

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PRIMARY ENDPOINTS:

Safety Assessment acceptable, in the absence of:  Adverse event related to cell product  Any contamination with an infectious agent  Cells exhibiting tumorigenic potential

SECONDARY ENDPOINTS

Successful engraftment via:  OCT, fundus and other similar imaging evidence  ERG showing enhanced activity Evidence of rejection:  Imaging evidence that cells are no longer in the correct location  ERG showing that activity has returned to pre-transplant conditions

RPE Clinical Program – to date

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World-leading eye surgeons and retinal clinics participate in clinical trials, DSMB and Scientific Advisory Board

• US Clinical Trial Sites
• Jules Stein Eye (UCLA)
• Wills Eye Institute
• Bascom Palmer Eye Institute
• Massachusetts Eye and Ear Infirmary
• Stargardts: 1st cohort complete, cleared to treat next cohort
• Dry AMD: 1st cohort complete, will submit data on patients 2

& 3 to DSMB in late May

• European Clinical Trial Sites
• Moorfields Eye Hospital
• Aberdeen Royal Infirmary
• 1st SMD patient treated, about to treat patients 2 & 3

ClinicalTrials.gov US: NCT01345006, NCT01344993 UK: NCTO1469832

Surgical Overview

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• Drs. Steven Schwartz and Robert Lanza
• Subretinal injection of 50,000 RPE cells in a volume of

150µl delivered into a pre-selected area of the pericentral macula

• Procedure:
• 25 Gauge Pars Plana Vitrectomy
• Posterior Vitreous Separation (PVD Induction)
• Subretinal hESC-derived RPE cells injection
• Bleb Confirmation
• Air Fluid Exchange

Straight-forward surgery that is performed

• n outpatient basis

Preliminary Results

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• Structural evidence confirmed cells had

attached and persisted

• No signs of hyperproliferation,

abnormal growth, or rejection

• Anatomical evidence of hESC-RPE

survival and engraftment.

• Clinically increased pigmentation

within the bed of the transplant

Preliminary Results

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Recorded functional visual improvements in both patients.

• SMD Patient: BCVA improved from hand motions to 20/800 and improved from 0 to 5

letters on the ETDRS visual acuity chart

• Dry AMD Patient: Vision improved in the patient with dry age-related macular

degeneration (21 ETDRS letters to 28)

• Nine Month Follow-up:
• Visual acuity gains remain stable for both patients; SMD Patient continues to

show improvement.

• Similar trends observed for latest AMD and SMD patients
• Update on U.K. SMD01 Patient (3 month follow-up)
• ETDRS: Improved from 5 letters to 10 letters
• Subjective: Reports significantly improved ability to read text on TV

Images of hESC-RPE transplantation site in SMD Patient

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pre-transplant 1wk post-op 6wk post-op

Color fundus photographs Clinically increased pigmentation within the bed of the transplant

Images of hESC-RPE transplantation site in SMD Patient

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SD-OCT image collected at month 3 show survival and engraftment of RPE

 Migration of the transplanted cells to the desired anatomical location 3mo post-op

Phase II/III Design

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• Design of future studies dependent upon information gathered throughout PI/II

study

• Efficacy
• Patient population less VA impact 20/200?
• Multiple Injections
• Sub macular Injections
• Further evaluation of I/E criteria
• Potentially less immunosuppression
• Other considerations of efficacy:
• New or more sensitive technologies
• Possible saline placebo injection (same eye)

Working with our experts/investigators in design of studies

RPE Cells – Additional Indications

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• Myopic Macular Dystrophy (MMD)
• Retinopathy of Prematurity
• Angioid Streaks
• Retinitis Pigmentosa
• Bests Disease (vitelliform macular dystrophy)
• Multifocal Choroidopathy Syndromes

Combination Products

• Combined with other cell types (photoreceptor progenitors)
• Combined with anti-angiogenic agents, neuroprotective agents, etc.

Therapeutic Pipeline - Ocular Programs

24 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

RPE layer Photoreceptors

ACT MSC Program

Ocular Program –

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Proprietary scaled manufacturing for generating “young” MSCs from hESC and iPS lines

• hESC-and IPS-MSCs are expanded to large numbers in vitro
• Avoid senescence problem of “old” MSC’s
• Renewable cell source and “Off-The-Shelf” therapy
• hESC-derived MSCs are HLA I+, HLA II-
• Higher immunosuppressive potency relative to adult MSC
• MSCs can migrate to injury sites in eye, exert local

immunosuppressive effects, and repair damaged tissue Ocular Products in Development

▫ Inflammatory diseases of the eye ▫ Photoreceptor/neuron-protective activity ▫ Tolerance to ocular grafts and devices ▫ Delivering therapeutic proteins to the eye

Mesenchymal SCs – Hemangioblast Derived

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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

Strongly advantageous to derive MSCs from our hESC/HB method vs adult or hESC-direct MSC

ACT Management Team

Highly Experienced and Tightly Integrated Management Team

Gary Rabin – Chairman & CEO

• Dr. Robert Lanza, M.D. – Chief Scientific Officer

Edmund Mickunas – Vice President of Regulatory Affairs Kathy Singh - Controller Rita Parker – Director of Operations

• 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

Bill Douglass – Director of Corporate Communications & Social Media

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Thank you For more information, visit www.advancedcell.com