Clinical Outlooks for Regenerative Medicine, Boston. June 2012


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Clinical Outlooks for Regenerative Medicine, Boston. June 2012

  1. 1. Ocular ProgramsJune 2012
  2. 2. This presentation is intended to present a summary of ACT’s (“ACT”, or “Advanced CellTechnology Inc”, or “the Company”) salient business characteristics.The information herein contains “forward‐looking statements” as defined under the federalsecurities laws. Actual results could vary materially. Factors that could cause actual resultsto 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 fromtime to time with the Securities and Exchange Commission. The risks identified therein, aswell as others not identified by the Company, could cause the Company’s actual results todiffer materially from those expressed in any forward‐looking statements. Ropes GrayCautionary Statement Concerning Forward‐Looking Statements2
  3. 3. 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 theability to differentiate into the cells of all three germ layersboth 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 Directors 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 pluripotency3Final Product Definition: hESC-derivedproducts will be manufactured using a cellline made in 2005 from single cell isolatedwithout the destruction of any embryos
  4. 4. The RPE layer is critical to the function and health of photoreceptors and theretina as a whole.– 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 Bruch’s membrane» Absorbs incident light, protects space from UV damage– 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, leadingprogression from dry-AMD to wet-AMD• Discrete differentiated cell population as target• Failure of target cells results in disease progression4Retinal Pigment Epithelial Cells - RationaleNo other cell type can performthis complete set of functions
  5. 5. 5RPE Cell TherapyEarly Stage AMD(10-15M)Intermediate AMD(5-8M)Late Stage AMD(1.75M)U.S. Patient PopulationACT’s RPE Cell Therapy should effectivelyaddress the full range of dry AMD patients.• Halt the progression of disease and visionloss in early stage patients• Restore some visual acuity in later stagepatientsDry AMD represents more than 90 percent of allcases of AMDNorth America and Europe alone have more than30 Million dry AMD patients who should beeligible for our RPE cell therapyOn the Rise: Population demographics(“baby boomers”) combined with increasedlongevity predicts an increase of 50 percentor more in the incidence rate of AMD.
  6. 6. RPE Engraftment – Mouse ModelHuman RPE cells engraftand align with mouse RPEcells in mouse eye6Injected human RPE cells recapitulatescorrect monolayer structure in eyeHuman RPE cells fill in empty spacesadjacent to mouse RPE cells400x magnification100x magnification
  7. 7. RPE Engraft and Function in Animal StudiesRPE treatment in RCS rat model of retinal dystrophy slowed theprogression of vision loss by promoting photoreceptor survival.treated controlPhotoreceptorlayer7photoreceptor layer isonly 0 to 1 cell thickwithout treatmentTreated animal – retain 70% of full visual acuityControl Animal – blind at 6 months
  8. 8. • 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 controlsGMP ManufacturingIdeal Cell Therapy Product• Centralized Manufacturing• Small Doses• Easily Frozen and Shipped• Simple Handling by Doctor8
  9. 9. Characterizing Clinical RPE Lots9Normal female (46 XX) karyotypeof the clinical RPE lot.Up-regulation of RPE markers anddown-regulation of hESC markers
  10. 10. Characterizing Clinical RPE Lots10Quantitative Potency AssayEach lot is assessed by phagocytosis (criticalfunction in vivo) of fluorogenic bioparticles.Flow cytometry histogram showingphagocytosis of pHrodo bioparticles4°C 37°C
  11. 11. Effects of Pigmentation11Melanin content can be measured spectrophotometrically and used to determine theoptimal time to harvest and cryopreserve RPE.y = 0.0141x + 0.00070.000.501.001.502.000 20 40 60 80 100120Absorbanceat475nmµg/mL Melanin
  12. 12. Phase I - Clinical Trial Design12SMD 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 retinaHigh Definition Spectral Domain Optical Coherence Tomography (SD-OCT)Retinal Autofluorescence50K Cells 100K Cells 150K Cells 200K CellsPatient 1 Patients 2/3DSMB Review DSMB ReviewRPE and photoreceptor activitycompared before and after surgery
  13. 13. Surgical Overview13Procedure:• 25 Gauge Pars Plana Vitrectomy• Posterior Vitreous Separation(PVD Induction)• Subretinal hESC-derived RPEcells injection• Bleb Confirmation• Air Fluid Exchange
  14. 14. Preliminary Results14• Structural evidence confirmed cells hadattached and persisted• No signs of hyperproliferation,abnormal growth, or rejection• Anatomical evidence of hESC-RPEsurvival and engraftment.• Clinically increased pigmentationwithin the bed of the transplant• Recorded functional visualimprovements in both patients
  15. 15. Images of hESC-RPE transplantation site in SMD Patient15SD-OCT imagesDemonstrate survival and engraftment of RPEThe injected RPE cells migrate to the desired anatomical location3mo post-op
  16. 16. Phase II/III Design16Design of future studies dependent upon information gatheredthroughout PI/II study• Efficacy• Patient population less VA impact 20/200?• Multiple 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 ourexperts/investigators indesign of studies
  17. 17. Phase II/III Projected Timeline17• Completion of Phase I/II study 2013-2014• Design of Phase II and III studies is an ongoingprocess, but will become more concrete during2013• Phase III study commencement 2014-2015
  18. 18. RPE Cells – Additional Indications18• Myopic Macular Dystrophy (MMD)• Retinopathy of Prematurity• Angioid Streaks• Retinitis Pigmentosa• Bests Disease (vitelliform macular dystrophy)• Multifocal Choroidopathy SyndromesCombination Products• Combined with other cell types (photoreceptor progenitors)• Combined with anti-angiogenic agents, neuroprotective agents, etc.
  19. 19. Therapeutic Pipeline -Ocular Programs
  20. 20. 20Retinal Pigment Epithelial Cells Macular Degeneration - dry AMD, Stargardt’s Disease, MMD Retinitis Pigmentosa Photoreceptor protectionHemangioblast cells Ischemic retinopathy– diabetic retinopathy, vascular occlusionsRetinal Neural Progenitor cellsIsolated Protective Factors Photoreceptor Loss, Modulation of Müller Cells Protection of Retinal Ganglion cells (Glaucoma)Corneal Endothelium, Corneal Epithelium,Descemet’s Membrane Corneal DiseaseMesenchymal Stromal Cells Glaucoma, Uveitis Retinitis Pigmentosa Management of Ocular SurfaceslightretinaRPElayerPhotoreceptors
  21. 21. Ocular Program – Corneal Endothelium• More than 10 million people with corneal blindness• The cornea is the most transplanted organ (1/3 of alltransplants performed due to endothelial failure)• Solutions include the transplantation of whole cornea“Penetrating Keratoplasty” (PKP)• More popular: Transplantation of just cornealendothelium & Descemet’s membrane (DSEK/DSAEK).hESC-derived cornealendothelium resemblesnormal human cornealendothelium21
  22. 22. Ocular Program – Hemangioblasts22Hemangioblasts induce reparativeintraretinal angiogenesis is variousanimal models of ischemic retinopathies• Revascularization is observed in animalsinjected either intravitreally or intravenously withhESC-derived hemangioblasts• ischemia-reperfusion injury• diabetic retinopathy• GFP-labeling reveals incorporation of injectedcells into the vasculature of the eye duringangiogenesis• Hemangioblasts prevented BRB breakdown indiabetic rats.Repair of ischemic retinal vasculature in a mouseafter injection of hESC-derived hemangioblasts
  23. 23. Ocular Program – Hemangioblasts23Oxygen-induced Retinopathy ModelOIR+HBOIR+dPBShESC-derivedHemangioblasts RebuildFunctional Vasculature onRetina Obliteration Regionand Suppress Pre-retinalNeovascular Tufts
  24. 24. • 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 consequencesAfter 2 months• ERG - increases in both the a-wave and b-wave• OCT - increases in central retinal thicknessOcular Program – Retinal Neural Progenitors24hESC-derived RNP cells reversed the progression of photoreceptordegeneration– and appeared to promote regeneration• Defined culture conditions• High yield from hESC and iPS• Homogeneous and highly purepreparations
  25. 25. ACT Management TeamHighly Experienced and Tightly Integrated Management TeamGary Rabin – Chairman & CEODr. Robert Lanza, M.D. – Chief Scientific OfficerEdmund Mickunas – Vice President of Regulatory AffairsKathy Singh - ControllerRita Parker – Director of OperationsDr. Irina Klimanskaya, Ph.D. – Director of Stem Cell BiologyDr. Shi-Jiang (John) Lu, Ph.D. – Senior Director of ResearchDr. Roger Gay, Ph.D. - Senior Director of ManufacturingDr. Matthew Vincent, Ph.D. – Director of Business DevelopmentBill Douglass – Director of Corporate Communications & Social Media25
  26. 26. Thank youFor more information, visit