ACT Annual Shareholders' Meeting, October 22, 2013


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ACT Annual Shareholders' Meeting, October 22, 2013

  1. 1. Annual Meeting LEADING REGENERATIVE MEDICINE Tuesday, Oct. 22, 2013 Palm Springs, CA
  2. 2. 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 2
  3. 3. Gary Rabin Chief Executive Officer, Chairman CEO UPDATE 3
  4. 4. ACT Overview • We continue to appreciate your support through this period where we are working to finally put the past to rest. We share your frustration with how long it has taken to put the last matters to closure • We concluded highly successful meeting with our OAB • We have worked through a 2014 goal-driven plan with our senior management team to advance both our clinical RPE program and our other ophthalmic activities, as well as moving our MSC activities toward the clinic • We are at the beginnings of seeing a real opportunity in our preclinical animal studies and translating that into a veterinary plan • We are starting to engage fully in our up-listing and institutional capital raising strategy, and are optimistic that we will finally achieve our goals. 4
  5. 5. Robust Development Pipeline Provides Multiple Opportunities to Commercialize and Partner Ophthalmology Programs Pre-clinical/ in vitro Dry AMD SMD MMD Photoreceptors Ganglion Neurons Cornea Platelets Mesenchymal Stem Cells 5 POC – Animal Studies IND Approved Phase I Phase II Phase III Approval
  6. 6. Robust Development Pipeline Provides Multiple Opportunities to Commercialize and Partner Ophthalmology Programs Pre-clinical/ in vitro Dry AMD SMD MMD Photoreceptors Ganglion Neurons Cornea Platelets Mesenchymal Stem Cells 6 POC – Animal Studies IND Approved Phase I Phase II Phase III Approval First Priority Based On Current Funding Advance into Phase I and Partner Potential Gov’t Funding Based on POC results, pursue appropriate funding and collaborations
  7. 7. Several Important clinical milestones Q4 2013, 2014 Phase I 150K Dry AMD & SMD Trials 200K ? Cohort 2a 100K Phase II 4Q 2013 MMD Trial 7 Patient follow-up Patient Treatment PII design 1Q 2014 Phase I 3Q 2014 Patient Treatment Jan 2015
  8. 8. BY PRODUCING THE HIGHEST DEGREE OF QUALITY VETERINARY THERAPEUTICS WE INTEND TO BE A LEADER IN VETERINARY REGENERATIVE MEDICINE 8 September 19, 2013 – “ACT Files Investigational New Animal Drug (INAD) Application with FDA to Treat 10 Different Disease Indications Using Pluripotent Stem Cells”
  9. 9. Ophthalmic Advisory Group Summary • Extremely successful and productive meeting • Complete unanimity among company, investigators, and independent board members • Plan agreed on Phase 2 trial design including endpoints and termination strategy for current trials • Currently developing materials to discuss strategy with FDA • Data review and results showing surprising strong statistical success. All board members impressed by aggregate data showing acuity improvements as well as differential between treated and untreated eyes • Working on beginning to write paper for submission to top peer reviewed medical journals 9
  10. 10. Dr. Robert Lanza Chief Scientific Officer SCIENCE UPDATE 10
  11. 11. Research & Development Programs  Treatment of eye diseases • Retinal pigment epithelium (macular degeneration) • • • • Retinal ganglion progenitors (glaucoma) Photoreceptor progenitors (advanced blindness) Mesenchymal stem cells (uveitis) Corneal endothelium (corneal repair)  Single-blastomere technology • Master Cell Bank (ethically-compliant/xeno-free) for future clinical trials  Induced pluripotent stem (iPS) cell technology • Episomal, mRNA, microRNA vs. other reprogramming methods • Master Cell Bank for Phase I/II clinical trials  Megakaryocytes/platelets • Preclinical studies safety & efficacy studies  Mesenchymal stem cells • Manufacturing under GMP conditions (for pre-clinical/clinical studies) • Rodent studies (multiple sclerosis, lupus, pain, ALS, Alzheimer's) • Large-animal studies (hepatitis, glomerulonephritis, osteoarthritis, Crohn’s disease, IBS, spinal cord/disc disease, meningoencephalitis, hemolytic anemia, pancreatitis, sepsis) 11
  12. 12. Ocular Programs Retinal ganglion progenitors  Glaucoma Retinal pigment epithelium  Macular degeneration (AMD, Stargardt’s)  Myopia Corneal endothelium  Corneal disease light Retina Mesenchymal stem cells  Uveitis, glaucoma 12 Retinal neural progenitors  Photoreceptor replacement  Neuroprotection
  13. 13. RPE Clinical Trials  US Clinical Trials • Jules Stein Eye Institute (UCLA) • Wills Eye Institute • Bascom Palmer Eye Institute • Mass Eye & Ear Dry AMD Twelve patients treated - 3 patients (50K cells) - 6 patients (100K cells) (includes 3 better vision) - 3 patients (150K cells) Stargardt’s Disease Nine patients treated - 3 patients (50K cells) - 4 patients (100K cells) (includes 1 better vision) - 2 patients (150K cells) 13 US: NCT01345006, NCT01344993 UK: NCTO1469832 July 12, 2011: First patient in both US trials were treated at UCLA by Steven Schwartz, M.D.  European Clinical Trial Site • Moorfields Eye Hospital Stargardt’s Disease Nine patients treated - 3 patients (50K cells) - 3 patients (100K cells) - 3 patients (150K cells)
  14. 14. OVERALL RESULTS:  No major safety issues related to stem cell treatment  Clear signs of long-term engraftment & survival DAY 1 2 MONTHS 6 MONTHS  During the one-year follow-up period, patients in both the SMD and dry-AMD clinical trials have shown significant improvement in visual acuity in the RPE-treated eyes • vision in one patient improved from 20/400 to 20/40 in first month  By contrast, the fellow (untreated) eyes remained unchanged or continued to show decline in visual acuity during the same time period 14
  15. 15. Next Steps – RPE Program  Complete and publish results of Phase I/II Clinical Trials  Preparation and design of Phase II Clinical Trials  NED-7 GMP Master Cell Bank (MCB) – hESCs derived using single-blastomere technology (no embryos destroyed) – No mouse feeders (no longer a xeno product) – MCB (~500 vials generated) » Working Cell Bank (~260 vials generated) » ~800 vials of RPE (made from 2 vials of WCB) (enough to treat ~800 patients, although could have generated more) * waiting for manufacturing and regulatory sign-offs  15 Begin Phase I Clinical Trial (UCLA) to treat myopia
  16. 16. Megakaryocytes & Platelets • hES/iPSC-platelets participate in clot formation • Incorporate into mouse thrombus (laser-induced arteriolar injury) Both hES and iPS-MKs produce pure platelets Normal blood platelets 16 iPS-derived platelets
  17. 17. Microtubules Morphology/ultrastructure of iPS-platelets identical to normal blood platelets Glycogen Granules Dense Tubular System iPS-PLT Multivesicular Body Mitochondria Alpha-Granule Glycogen Granules blood-PLT Open Canalicular System Microtubules 17 Alpha-Granule Open Canalicular System Dense Tubular System Mitochondria
  18. 18. NEXT STEPS / PLATELET PROGRAM Achieve 1 Million Dose Scale  Optimize MK progenitor/platelet production & functionality in vitro  Scale-up using microfluidics and bioreactor system  Continue preclinical testing in animals (efficacy, biodistribution, safety/tox tumorigenicity)  Complete transfer of technology to GMP/manufacturing (includes assay development and process validation)  Complete clinical regulatory process/file IND NOTE: Strategic decision made to fast-track MSC program into clinic first (potentially greater financial and medical impact in the near term ) 1yr 18 2yr 3yr 4yr 5yr 10yr
  19. 19. Corneal repair: corneal endothelium derived from hESCs • 10 million people with corneal blindness • Cornea the most transplanted organ (1/3 due to endothelial failure) • Solutions: Tx of whole cornea “Penetrating Keratoplasty” (PKP) – More popular: Tx corneal endothelium & Descemet’s membrane (DSEK) hESC-derived cells resemble normal human corneal endothelium Optimized cryopreservation (CECs can now be sent world-wide) 19 Global gene analysis shows that hESCCECs & adult-CECs are nearly identical
  20. 20. Next Steps  Preclinical Studies CEC Lens Cornea 20 Iris Continue testing hESC-derived corneal endothelium in in vivo rabbit cornea model • Model: In vivo edema injection in rabbit (inject dissociated cells to replace native CECs) • Increase purity of CECs to 99% • Design and test hydrogel sheet in vitro (needs to be transparent, flexible and biodegradable) • Design and test CEC/hydrogel sheet in vivo (test sheet to mimic clinical DSEK in rabbit model)
  21. 21. Other Retinal Cell Types RNP PDE6a/DAPI Pluripotent Stem Cell Eye Field Stem Cell Photoreceptor Opsin (green/red) PDE6a/DAPI Math5/DAPI Ganglion Rhodopsin/Recoverin 21
  22. 22. Retinal Neural Progenitors hESC- RNP cells reversed the progression of photoreceptor degeneration b-wave (post-synaptic retinal cells) (cones & rods) RNP, 2 mo ONL RNP, 2 mo RNP, 1 mo RNP, 1 mo PBS, 1 mo PBS, 2 mo 22 } ONL } PBS, 1 mo PBS, 2 mo Thickness of ONL (µm) a-wave Increase in retinal (ONL) thickness by OCT after 2 mos 60 40 20 0 Control No Injection Cell treatment
  23. 23. Identification of endocrine/neuroprotective factors Genomic DNA Q-PCR analysis of whole retina mouse specific probe human specific probe Proteins screened using antibody arrays 23
  24. 24. Preservation of Outer Segments (OS) of Rod Photoreceptors in RCS rats Tail vein injection PBS Rod OS in cell-treated rat retina shown by rhodopsin staining Missing OS 24 Intravitreal injection
  25. 25. Subretinal transplantation Integration of Photoreceptor PROGENITORS 1 week after transplantation 3 week after transplantation HNA antibody/transplanted human cells Human cells migrating into ONL 25
  26. 26. Next Steps  Continue testing RNPs in in vitro and in animal models  Collaborations underway with several leading groups studying various retinal/ocular disease models  Continue identification of paracrine/neuroprotective factors (proteomics, antibody arrays, 2D gel analysis, and mass spec)  Test ability of cell-free lysates (or specific identified factors) to prevent or delay a range of ocular & non-ocular degenerative diseases  Photoreceptor Progenitors  Complete studies of recovery of host visual function and retinal structure  Continue in vitro neuroprotection studies using conditioned medium  In vitro and in vivo functional tests of secreted factors  Ganglion Progenitors  Continue animal experiments/show long term survival of transplanted cell  Integration of transplanted cells  Protection/replacement of host retinal ganglion cells  Optic nerve regeneration 26
  27. 27. Mesenchymal Stem Cells (MSCs)     27 Found in bone marrow, adipose, umbilical cord, tooth buds Can differentiate into fat, bone, cartilage MSCs are immunoprivileged and can: - migrate to injury site - exert immunosuppressive effects - facilitate tissue repair Over 200 clinical trials ( - wide range of clinical indications being pursued - companies such as Pluristem, Mesoblast, Neostem are developing MSC-based therapies using BM or other primary sources of MSCs
  28. 28. hESC-MSCs versus adult derived MSCs ● ● ● ● ● ● “Off the shelf” therapy available for immediate use Unlimited cell source Easy to derive Can be expanded to large numbers in vitro More youthful and live much longer Potentially greater efficacy (older MSCs often serve as negative controls) ● Hemangioblast-derived hESC-MSCs exponentially greater yields than other reported hESC methods A sampling of their in vivo efficacy will be given in the following slides 28 >30,000 X more units from hESC-MSCs than from adult bone marrow MSCs
  29. 29. Treatment of Multiple Sclerosis in Mice (EAE model)  hESC-MSCs dramatically reduce clinical symptoms of EAE  both prophylactic and therapeutic inhibition  In vitro inhibition of T-cell function  Differential cytokine expression (hESCMSCs vs. BM-MSCs)  Differential ability to migrate into damaged tissues (hESC-MSCs vs. BM-MSCs) Untreated Clinical Score: 2-4 (partial to complete hind/front leg paralysis) hESC-MSC Treated*  Additional follow-up studies being completed for scientific publication (based on reviewer suggestions) Clinical Score: <1 (no leg paralysis)  Multiple sclerosis is a leading candidate for clinical translation *BM-MSCs had minimal impact (animals still showed paralysis) 29
  30. 30. hESC-MSC treatment for Uveitis Untreated EAU mice  An inflammatory/auto-immune condition of the uvea  Accounts for 10% of blindness in US (mostly 20-40 year olds)  Experimental autoimmune uveitis (EAU) in mice resembles that of human uveitis  Disease state can be assessed using funduscope imaging/histology 30 PMN and lymphocytes Preliminary studies show that hESC-MSC treatment is effective in treating EAU uveitis
  31. 31. hESC-MSC treatment for SLE/Lupus Nephritis  Systemic lupus erythematosus (SLE) or lupus is a systemic autoimmune disease that can effect virtually any organ or system in the body  There is no cure for SLE  SLE most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system  50% of SLE patients get lupus nephritis (LN)  Immune complex deposition in kidney glomeruli leads to kidney dysfunction/failure  NZB/NZW mice spontaneously develop lupus nephritis (very similar to human SLE) NZB/NZW lupus model  hESC-MSCs have a dramatic effect on morbidity (including proteinuria/kidney function  Protect from death (show marked improvement in survival)  Lead candidate for clinical translation 31
  32. 32. hESC-MSC treatment for Pain  PAIN behavior can be measured in mice using operant equipment (using a reward/conflict paradigm)  hESC-MSCs significantly reduce chemotherapyinduced neuropathy in response to taxol  Also a candidate for clinical translation 32
  33. 33. Potential therapeutic applications for MSCs                   33 >100 autoimmune diseases Multiple Sclerosis Osteoarthritis Lupus Aplastic Anemia  No need for immunosuppression Crohn’s Disease/IBS Chronic Pain  Persist transiently Limb Ischemia Heart Failure/MI  Can be irradiated Stroke Graft-versus-host Disease Spinal Cord Injury Liver Disease Kidney Disease Emphysema/Pulmonary Diseases Wound healing (ulcers/decubitus/burns) HSC engraftment/irradiated cancer patients Eye diseases (uveitis, retinal degeneration, glaucoma) hES/hiPS-MSCs are Ideal for Clinical Translation
  34. 34. Canine Indications for Human MSC Therapy Intervertebral disk disease Orthopedic Osteoarthritis Sepsis MSC Therapy Inflammatory Acute pancreatitis Granulomatous meningoencephalitis Immune-mediated Inflammatory bowel disease Chronic hepatitis Glomerulonephritis Anal furunculosis Immune-mediated hemolytic anemia 34  Filed Investigational New Animal Drug (INAD) application with the FDA to treat 10 different disease indications  Naturally-occurring diseases in large animals, such as dogs, provide an excellent model of human conditions. May provide a more robust assessment of safety and therapeutic endpoints than what can be obtained from inbred rodent models  Initiated collaboration with Tufts University School of Veterinary Medicine, which has a large population of suitable patients, and world-experts in regenerative medicine  Have already received IACUC approval to begin several of the studies  In additional to the obvious veterinary applications, the results may help inform and optimize human clinical trials
  35. 35. Ted Myles Chief Financial Officer & EVP of Corporate Development CORPORATE UPDATE 35
  36. 36. Improving the Balance Sheet, and therefore the Company to Position a 2014 up-listing ACT - Current ~$4m - $5m cash on hand and funding itself through bi-daily issuances of ~2.5m shares of common stock The Company draws from the market slightly less than it spends, in order to build its cash balance, albeit slowly This funding vehicle puts continuous downward pressure on stock and is not enabling of scale up as we prepare for larger clinical trials ACT – end of 2013/early 2014 Raising a tranche of funds ($10m - $15m) in the near-term will improve the balance sheet, and therefore the stability of the company Will also decrease our reliance on the frequent draws, therefore reducing the constant downward pressure on the stock Having ~12 months of cash in the bank will allow the Company to be more strategic as it pursues clinical expansion, corporate development and Nasdaq listing ACT has never had real balance sheet strength and has therefore been forced to make decisions from a “less than optimal” position 36
  37. 37. Why Up-List to Nasdaq? “Over-the-Counter” OTC companies are sometimes associated as being of “poor quality” Naked shorting can damage shareholder value Trading/liquidity is less efficient Equity research analysts want to cover and support companies on national exchanges Institutional investors who can invest substantial capital are less likely to invest in “penny stocks” no matter how great the company Nasdaq Listed “Class effect”, being a Nasdaq-listed company carries with it a cache of quality, based partly on perception and largely on the strict listing requirements Increased shareholder protection due to stringent listing requirements Institutional investors have expressed interest in investing substantial capital into ACT, after up-listing Building a syndicate of equity research analysts who cover the Company can create additional demand for the shares Management believes that a Nasdaq uplisting is in the best interest of all stakeholders Completing a fully marketed financing deal that includes a broad syndicate of bankers and analysts could capitalize the Company through Phase II, and create global awareness of the ACT story 37
  38. 38. Clinical and Corporate Development Support Up-listing, and Growth in Shareholder Value AMD Trials Phase 1 Pre-clinical Clean up Corporate Development MMD Trial MSC and other R&D Progress SEC, etc. Non-dilutive funding Financial 38 Phase 2 Phase 1 All components of the Company complement one another. A transformative process for ACT Partnering Reverse split Nasdaq “re-IPO”
  39. 39. Thank you For more information, visit