Terrapinn's Stem Cells USA & Regenerative Medicine Congress, Boston, Mass., Sept. 2012
Boston, MA20 September 2012Boston, MA20 September 2012LEADINGREGENERATIVEMEDICINEStem Cells USA & RegenerativeMedicine Congress
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
Multiple Pluripotent Cell PlatformsSingle Blastomere-derivedEmbryonic Stem Cell LinesGenerating hESC linesWITHOUT DESTRUCTION OF EMBRYOUtilizes aSINGLE CELL BIOPSYInduced Pluripotency Stem Cells (iPS)• Early Innovator in Pluripotency (before iPS was even a term!)• 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
5retinaLife Support to PhotoreceptorsRod outer segmentsCone outer segmentsRPEBruch’s membraneChoroidal vessels
6Life Support to PhotoreceptorsDetoxifies photoreceptor layerMaintains Bruch’s Membrane• natural antiangiogenic barrier• immune privilege of retinaAbsorbs stray light / protects from UVProvides critical nutrients, growthfactors, ions and water• photoreceptors see no bloodRecycles Vitamin A• maintains photoreceptorexcitabilityFunction ofRPE LayerRod outer segmentsCone outer segmentsRPEBruch’s membraneChoroidal vessels
7Life Support to PhotoreceptorsLoss of RPE cellsBuild up of toxic wasteLoss of photoreceptorsDry AMDBruch’s Mem. dehiscenceChoroidal neovascularizationWet AMD
• Easy to identify – aids manufacturing• Small dosage size – less than 200K cells• Immune-privileged site - minimal/no immunosuppression• Ease of administration - no separate device approvalRPE cell therapy may impactover 200 retinal diseases8RPE Therapy- Rationale
9RPE Therapy- RationaleEarly Stage AMD(10-15M)Intermediate AMD(5-8M)Late Stage AMD(1.75M)U.S. Patient Population ACT’s RPE Cell Therapy should addressthe full range of dry AMD patients.• Halt progression of vision loss in earlystage patients• Restore some visual acuity in laterstage patientsDry AMD represents more than 90percent of all cases of AMDNorth America and Europe alone havemore than 30 Million dry AMD patientswho should be eligible for our RPE celltherapy.
• GMP process for differentiation and purification of RPE– Virtually unlimited supply from stem cell source– Optimized for manufacturingIdeal Cell Therapy Product– Centralized Manufacturing– Small Doses– Easily Frozen and Shipped– Simple Handling by DoctorGMP Manufacturing10Product Cold Chain is Easily Scaled for Global Sales
Characterizing Clinical RPE Lots11• RPE cells are derived from an extensively tested hES MCB.• Entire process is aspetic; no antibiotics used (~110 days).• Cryopreserved bulk product is extensively tested prior to release.• Bulk product is thawed and formulated for therapeutic on the day of use.• Some unique quality tests include:• Screening for the absence of hES cells (IFA)• Assessing the extent of differentiation by:• gene expression (q-RT-PCR)• protein deposition (IFA staining)• morphological evaluation• extent of pigmentation (melanin)• potency by phagocytosis assays (FACS)In-Process Quality Testing• Frequent MorphologicalAssessments (1-2days)• Periodic Sterility Testing• Regular Karyotyping• Immunohistochemical Stainingfor RPE Markers
Characterizing Clinical RPE Lots12Quantitative Potency AssayRPE cell potency of each lot is assessedby phagocytosis4°C 37°C
Effects of Pigmentation13Use melanin content to determine optimaltime to harvest and cryopreserve RPE.y = 0.0141x + 0.00070.000.501.001.502.000 20 40 60 80 100120Absorbanceat475nmµg/mL MelaninQuantitative Pigmentation Assay
Preclinical - Examples14control treatedInjected human RPE cellsrepair monolayer structure ineyePhotoreceptorlayerphotoreceptor layeris only 0 to 1 cellthick withouttreatment
Phase I - Clinical Trial Design15SMD and dry AMD Trials approved in U.S., SMD Trial approved in U.K.12 Patients / trialascending dosages of 50K, 100K, 150K and 200K cells.Regular Monitoring - including high definition imaging of retina50K Cells 100K Cells 150K Cells 200K CellsPatient 1 Patients 2/3DSMB Review DSMB Review
Phase I – SMD endpoints16PRIMARY ENDPOINTS:ASSESSMENT OFSAFETYThe transplantation of hESC-derived RPE cells MA09-hRPE will be considered safe and toleratedin the absence of: Any grade 2 (NCI grading system) or greater adverse event related to the cell product Any evidence that the cells are contaminated with an infectious agent Any evidence that the cells show tumorigenic potentialSECONDARYENDPOINTSEvidence of successful engraftment will consist of: Structural evidence (OCT, fluorescein angiography, autofluorescense photography, slit-lampexamination with fundus photography) that cells have been implanted in the correct location Electroretinographic evidence (mfERG) showing enhanced activity in the implant locationEvidence of rejection will consist of: Structural (imaging) evidence that implanted MA09-hRPE cells are no longer in the correctlocation or the presence of vascular leakage. If enhanced electroretinographic activity is observed after the transplantation, subsequentelectroretinographic evidence that activity has returned to pre-transplant conditions may be anindication of graft rejectionCONFIDENTIAL
Phase I – Dry AMD endpoints17PRIMARY ENDPOINTS:ASSESSMENT OFSAFETYThe transplantation of hESC-derived RPE cells MA09-hRPE will be considered safe and toleratedin the absence of: Any grade 2 (NCI grading system) or greater adverse event related to the cell product Any evidence that the cells are contaminated with an infectious agent Any evidence that the cells show tumorigenic potentialSECONDARYENDPOINTSEvidence of successful engraftment will consist of: Structural evidence (OCT, fluorescein angiography, autofluorescense photography, slit-lampexamination with fundus photography) that cells have been implanted in the correct location Electroretinographic evidence (mfERG) showing enhanced activity in the implant locationEvidence of rejection will consist of: Structural (imaging) evidence that implanted MA09-hRPE cells are no longer in the correctlocation or the presence of vascular leakage. If enhanced electroretinographic activity is observed after the transplantation, subsequentelectroretinographic evidence that activity has returned to pre-transplant conditions may be anindication of graft rejectionAdditional secondaryendpoints will beevaluated as exploratoryevaluations for potentialefficacy endpoints.CONFIDENTIAL
Participating Clinical Sites18World-leading eye surgeons and retinalclinics participate in clinical trials, DSMBand Scientific Advisory Board• US Clinical Trial Sites• Jules Stein Eye (UCLA)• Wills Eye Institute• Bascom Palmer Eye Institute• Massachusetts Eye and Ear Infirmary• European Clinical Trial Sites• Moorfields Eye Hospital• Edinburgh Royal InfirmaryClinicalTrials.govUS: NCT01345006, NCT01344993UK: NCTO1469832
Surgical Overview19Procedure:• 25 Gauge Pars PlanaVitrectomy• Posterior Vitreous Separation(PVD Induction)• Subretinal hESC-derived RPEcells injection• Bleb Confirmation• Air Fluid Exchange
Preliminary Results20No Adverse EventsNo signs of hyperproliferation,abnormal growth, rejection or retinaldetachment.Persistence of cellsAnatomical evidence of hESC-RPEsurvival and engraftment.Increased pigmentation within the bedof the transplant.Impact on AcuityRecorded functional visualimprovements in both patients.
Preliminary Results – Initial Patients21Visual Acuity Measurements• SMD Patient: BCVA improved from hand motions to 20/800 andimproved 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)One Year Follow-up:• Visual acuity gains remain relatively stable for both patients• SMD Patient continues to show improvement.U.K. SMD01 Patient (at 6 month follow-up)• ETDRS: Improved from 5 letters to 10 letters• Subjective: Reports significantly improved ability to read text on TV
Current Safety Profile – Stargardt’s Trial227 SMD Patients Treated (as of 7 September 2012)3 patients (50K cells cohort) treated at UCLA – US Trial3 patients (50K cells cohort) treated at Moorfields Eye – UK Trial1 patient (100K cells cohort) treated at Wills Eye – US TrialNo reports of any adverse events or complications due tocells per se• No evidence of inflammation or infiltration• No evidence of ectopic tissue formation• No evidence of retinal detachment
Current Safety Profile – Dry AMD Trial234 dry AMD Patients Treated (as of 7 September 2012)3 patients (50K cells cohort) treated at UCLA – US Trial1 patient (100K cells cohort) treated at Wills Eye – US TrialNo reports of any adverse events or complications due tocells per se• No evidence of inflammation or infiltration• No evidence of ectopic tissue formation• No evidence of retinal detachment
Intellectual Property – RPE Program• Treatment - Dominant Patent Position for Treating Retinal Degeneration• Manufacturing - Broad Coverage for Manufacturing RPE Cells from hESC• Preparations - Claims directed to pharmaceutical preparations of RPE Cellsfrom hESC, including both cell suspensions and scaffolded RPE layers.• Sources – Issued patents cover RPE Cells derived from other pluripotent stemcells (including iPS cells)• Vigilance – Regularly Filing on Improvements• Extend patent life cycle, with significance to commercialization• Include composition-of-matter claims (cell preparations, pharmaceuticalpreparations, etc.)24
RPE Program - Investment Thesis26• Immense unmet medical need• Small Doses• Immunoprivileged – permits central (allogeneic) source of cells• Noninvasive monitoring of retinaMarket potential: More than 50 million patients in major markets.1% market penetration may represent $5-10B market opportunity.Orphan indications are meaningful: Estimating a 10% market penetrationwith reoccurring treatments every 3-5 years, Stargardt’s disease can be a$100+ million/year product.
Mesenchymal Stem Cells in Therapy28Mesenchymal stem cells (MSCs) regulate immune responsesprovide therapeutic potential for treating autoimmune orinflammatory diseases.• Allogeneic - without HLA matching.• Potential• Autoimmune conditions, such as MS, lupus, and Crohns/IBD.• Inflammatory Diseases• Track Record - Adult-derived MSCs already in 200+ clinical trials.An "off-the-shelf" cellular drug ready for treatment of awide range of inflammatory and autoimmune diseases.
Adult Mesenchymal Stem Cells29Impacts on Cell Banking• Limitation on the number of doses that can be generated fromadult donors• Requires constantly creating and validating MSC banksfrom new donorsImpacts on Potency• Passaging reduces immunomodulatory potency of MSC’s.Replicative Capacity - limits adult sources (bone marrow,fat, etc) for allogeneic MSC therapies.Substantial need forbetter MSC products
hESC- and iPS – derived MSC30ACT Proprietary Process• hESC-derived MSCs can be expanded to largenumbers of cells• Have qualities similar to fetal MSC’s• Avoid replicative capacity problem of “old” adult MSC’sAdvantages for Manufacturing• Use Single Master Cell Bank• Simplifies FDA/regulatory process• No need for finding donors• Less labor-intensive
Preliminary Data31Animal Models testing hESC-derived MSC’sSubstantially decrease and reverse disease conditionsin autoimmune models.• Far more potent than adult (BM) derived MSCs.• Have longer duration of action compared to adult(BM) derived MSCs.Potential implications of increased potency and duration…• Broader utility in range of diseases.• Reduced cells per dose – improved safety profile.• Longer duration between injections.
Hemangioblast Program: Overview34The Hemangioblast cell is a multipotent cell, and a commonprecursor to hematopoietic and endothelial cells.Hemangioblast cells can be usedto produce all cell types in thecirculatory and vascular systems
Generation of megakaryoctyes/platelets35Human ES cells HemangioblastsMegakaryocyte Pro‐plateletsCD41/vWF/DAPI
Characterization of Platelets36hESC- and iPS-derived platelets participatein clot formation and retraction
Next Steps37 Testing hES/hiPSC-platelets in vitro• Morphology• Biochemical status• Physiological responses Testing hES/hiPSC-platelets in vivo• Collaborations underway with several leading groups(including Harvard University, Columbia University,and University of Illinois College of Medicine) in vivo circulation and half-life in vivo function
Financial Update – Strong Balance Sheet38• Company ended 2012 Q2 with $10 million cash on hand• $35 million more available under equity line• Virtually debt-free• Received shareholder approval for reverse split• Filed application for NASDAQ uplisting and have initial commentsOther 2012 Milestones (so far)• IRB approvals from Wills Eye Institute, Bascom Palmer Eye Hospital andMassachusetts Eye & Ear• Initiated Europe’s first human ESC-derived transplant at Moorfields Eye Hospital• Published first report of hESC-derived cells transplanted into humans in topmedical journal, The Lancet.• Completed Dose Cohort 1 of patients in both U.S. trials;• Dosed first SMD and dry AMD patients in 100,000 cell cohorts – no AE’s observed.
ACT Management TeamHighly Experienced and Tightly Integrated Management TeamGary Rabin – Chairman & CEODr. Robert Lanza, M.D. – Chief Scientific OfficerEdmund Mickunas – Vice President of Regulatory AffairsDr. 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 ManufacturingKathy Singh - ControllerRita Parker – Director of OperationsDr. Matthew Vincent, Ph.D. – Director of Business DevelopmentBill Douglass – Dir. of Corporate Communications & Social Media39
Thank youFor more information, visit www.advancedcell.com