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Leading Regenerative Medicine

Regenerative Medicine Insight Track

~ Biotech Showcase - January 2012 ~


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


Hemangioblast cells

  • Ischemic retinopathy
  • – diabetic retinopathy, vascular occlusions
  • Retinal Pigment Epithelial Cells
  • Macular Degeneration - dry AMD, Stargardt’s Disease, MMD
  • Retinitis Pigmentosa
  • Photoreceptor protection
  • Corneal Endothelium, Corneal Epithelium, Descemet’s Membrane
  • Corneal Disease



RPE layer


  • Retinal Neural Progenitor cells
  • Isolated Protective Factors
  • Photoreceptor Loss, Modulation of Müller Cells
  • Protection of Retinal Ganglion cells (Glaucoma)
  • Mesenchymal Stromal Cells
  • Glaucoma, Uveitis
  • Retinitis Pigmentosa
  • Management of Ocular Surfaces

Cold Spring Harbor Laboratories


Retinal Pigment Epithelial Cells - Rationale

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

RPE cell as Target

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

Retinal Pigment Epithelial Cells - Rationale

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

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

RPE Engraftment – Mouse Model

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

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


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

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

Phase I - Clinical Trial Design

Permit comparison of RPE and photoreceptor activity before and after treatment

Patient 1

Patients 2/3

150K Cells

200K Cells

50K Cells

100K Cells

DSMB Review

DSMB Review

  • Engraftment and photoreceptor activity data available early in Phase I study.

RPE Program Summary

  • Stargardt’s (SMD) Disease
    • IND approved inNovember 2010
    • European CTA Approved – enrolling patients
    • Orphan Drug Designation granted in U.S. and Europe
    • The SMD patient is a 26 year old female with baseline best corrected visual acuity of hand motion that corresponded to 0 letters in the ETDRS chart.
  • Dry AMD
    • IND approved inDecember 2010
    • European CTA in preparation
    • 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.
  • July 12, 2011: First Patients in each trial were treated by Dr. Steven Schwartz, M.D at Jules Stein Eye Institute (UCLA)

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


Surgical Overview

First dry AMD Patient

Autofluorescence images of retinas.

The dark spots in the side panels show a large area of atrophy in the macular region.

First SMD Patient


Surgical Overview

Remove gel from inner surface of retina

Injection with bleb formation

Injection bleb formed at interface of atrophic retina and normal retina

Air fluid exchange


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


Ocular Program – Hemangioblasts

The Hemangioblast cell is a multipotent cell, and a common precursor to hematopoietic and endothelial cells.

  • 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.

Hemangioblast cells can be used to produce all cell types in the circulatory and vascular systems


Ocular Program – Hemangioblasts

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

Repair of ischemic retinal vasculature in a mouse after injection of hESC-derived hemangioblasts


Ocular Program – Retinal Neural Progenitors

  • Generated various retinal neural progenitor cell types – or RNP cells
    • From both embryonic and iPS cell sources.
    • Discovered a new RNP 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
  • Defined culture conditions
  • High yield from hESC and iPS
  • Homogeneous and highly pure preparations

hESC-derived RNP cells reversed the progression of photoreceptor degeneration– and appeared to promote regeneration


Ocular Program – Mesenchymal Stromal Cells

  • 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
    • hESC-derived MSCs are HLA I+, HLA II-
  • 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.

Proprietary Large Scale Manufacturing Process for Generating “young” MSCs from hESC and iPS lines


Single Blastomere Technology

Platform Technology for Generating Robust Human Embryonic Stem Cells

Without the Need to Destroy Embryos


First Proven Alternative hESC Method

Single Blastomere Technology

Enables Derivation of new hESC Lines via single cell biopsy method  Does not change the fate of the embryo from which the biopsy was taken

Utilizes single cell biopsy similar to pre-implantation genetic diagnostics (PGD).

Roslin Cells and ACT plan to generate GMP-compliant bank of human ES Cells for research and commercial uses.

Head-to-head comparison with 24 NIH lines: Average 5X more efficient than best NIH lines for producing cells from all three germ layers.


Intellectual Property Overview

  • Retinal Pigment Epithelial Cells
  • Worldwide Patent Portfolio
  • 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.
  • Single Blastomere Technology
  • Worldwide Patent Filings
  • Broad Claims to use of Single Blastomeres
    • U.S. Patent 7,893,315 broadly covers ACT’s proprietary single-blastomere technology that provides a non-destructive alternative for deriving human embryonic stem cell (hESC) lines.
  • Hemangioblast Technology
  • Worldwide Patent Filings
  • U.S. Patent 8,017,393 - Dominant Patent Position for deriving hemangioblast cells from embryonic stem cells.
  • Other Notables
  • Controlling Filings (earliest priority date) to use of OCT4 relating to induced pluripotency (iPS).
  • Pending and issued patent filings directed to significant protocols for transdifferentiation.

Financial Update – Strong Balance Sheet

  • Most Stable Financial Situation In Company History
  • The Company ended 2011 Q3 with $13.9 million cash on hand
  • $17 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

  • 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

World Class Scientific Team

Seasoned Management Team

  • Gary Rabin – Chairman and CEO
  • Edmund Mickunas – Vice President of Regulatory Affairs
  • Stephen Price – Interim SVP – Corporate Development
  • Kathy Singh - Controller
  • Rita Parker – Director of Operations
  • Bill Douglass – Director of Corporate Communications & Social Media