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ASX: LCT - OTCQX: LVCLY Bioscience Enterprise Forum 7 August 2009 1 Replacing Lost Cells LCT products in Development and Clinical Trial DIABECELL® • Porcine islet cells within micro-capsules injected into abdomen to form artificial insulin producing tissue • In Phase I/IIa Clinical Trial NeurotrophinCell® • Porcine choroid plexus cells producing neurotrophins implanted to repair endogenous brain and nerve tissue • Pre-Clinical Development and Research 2 DIABECELL® • Protective Encapsulation Aim: Delivery of insulin in a regulated manner Reliable source of live insulin producing cells Simple laparoscopic procedure Islet Cells No immunosuppressive drugs • Composition Porcine pancreatic islets Purified Sodium Alginate Polyornithine Saline Product: Encapsulated Neonatal Porcine Islets • Indication: Insulin deficiency, Type 1 diabetes 3 DIABECELL® • Cells excised from piglets and coated in patented alginate-based gel to form microspheres • Microspheres injected into patient using a laparoscope incorporating endoscopic placement • Engineered structure of microspheres enables nutrients to reach cells but prevents immunological rejection of cells • Immunosuppressants not required • Cells function naturally in body 4 NanoBioCapsule Attributes Strong, Elastic Physical Barrier Unrestricted Cell Viability Nutrients Allow Inward Nutrient Diffusion Outward Protein and Metabolite Release Immunoisolation Control Internal Cell Attachment Biocompatible 5 Program for a Safe and Effective Product Regulatory Guidelines US FDA Guidance for Industry on the Source Animal, Product, Preclinical and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans 2003 US Department of Health & Human Services Secretary’s Advisory Committee on Xenotransplantation (SACX) Recommendations, 2004 US Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation 2001 WHO Guidance on Xenogeneic Infection/Disease Surveillance and Response: A Strategy for International Cooperation The European Agency for the Evaluation of Medicinal Products, Points to Consider on Xenogeneic Cell Therapy Medicinal Products New Zealand Government Gene Technology Advisory Committee Xenotransplantation Checklist – Addendum to Guidelines for Application to GTAC Draft Guidelines for Preparation of Applicants Involving Clinical Trials of Xenotransplantation in New Zealand 6 Regulatory Approvals NEW ZEALAND Medsafe Good Manufacturing Practice (GMP) certification for manufacture of DIABECELL® for use in humans: Approval updated for current product in December 2006 , then annually IANZ, International Accreditation New Zealand: accreditation for Molecular Diagnostic Laboratory to carry out diagnostics tests relevant to xenotransplantation: Approval 2007, then annually GTAC, Gene Technology Advisory Committee through Medsafe: Submitted August 2006 Approval 2007 • Ethics and cultural consideration • Safety: pig herd, porcine endogenous retrovirus and diagnostic assays • Public Health, long term monitoring • Pre-clinical Data/Efficacy Regional Ethics Committee including Maori Review Research Committee Approval 2007 Minister for Health • National Health Committee • Ministers Peer Review of Monitoring Protocol • Approval Jun 2009 RUSSIA • • Scientific Committee Sklifosovsky Research Institute of Intensive Care Medicine 2006 Ethical Committee Sklifosovsky Research Institute of Intensive Care Medicine 2006 7 Critical Capabilities for Clinical Trial High Health Status Pigs: • US FDA Guidelines 2003 Molecular Diagnostic Laboratory • International Accreditation New Zealand certified Manufacturing Plant: • GMP certification annual recertification and audit • Cell Processing • Encapsulation Technology • Toxicity data • Quality Certified Encapsulated Product Preclinical/Clinical Data • Safety and efficacy studies in animals: • Data from two patients implanted with prototype Monitoring • Safety monitoring for donors and recipients 8 High Health Status Closed Pig Herd High health status pigs: US FDA Guidelines 2003 • Source Herd: Absence of xeno-relevant viruses, bacteria and parasites. Does not secrete pig endogenous retroviruses. A closed herd bred in isolation (across 2 facilities): 3 yr health records and regular monitoring . Three generations without mammalian content in feed. NULL pigs • Pig Breeding Facilities and Operations: Two herds in North & Southland, Concession to remaining pigs on Auckland Island • Health Monitoring of pig herd. Panel of tests by accredited laboratory. Donor database. • Xenotransplantation Risk Assessment and Risk Management Strategy Report by Morris, Jackson, Stevenson, Pearce: Professor Roger Morris, Massey University Auckland Islands - NZ 9 Cell Processing of Encapsulated Cell Product Process Flow Diagram Transport of donor transportation times conditions Preparation of donors Equipment Materials Reagents medications Surgical anaesthetics exsanguination surgical procedure warm/cold ischaemia time TMRE Cell processing enzyme digestion QC of cells pre-encapsulation 10 Manufacturing Consistency 2004-2007 A Islet Yield B Islet MIR ANOVA p<0.0001 d3 vs d4's p=NS for d4's *** 800 uU/100 IEQ/h IEQ/g pancreas 100000 80000 60000 40000 20000 0 ANOVA p = 0.007 d3 d4 96-102 d4 . 53-94, 2004-5 2006 BR Number and Day 103-109 d4 2007 * * d3 d4 600 400 200 0 96-102 d4 . 53-94, 2004-5 2006 BR Number and Day 103-109 d4 2007 Data are mean + 95% 11 Shelf Life Stability (BR103-109) Islet Viability % Viability 105 100 95 90 85 DB 4 5-7 18 25 26 29 32 40 BR Day Data are mean + SD 12 Shelf Life Functional Stability (BR103-109) Islet MIR ** ** ** 29 32 40 uU/100 IEQ/h 800 * 600 400 200 0 DB 4 5-7 12 15 16-7 18 21-2 25 26 BR Day 13 Islet Maturation Insulin Glucagon CK7 day 1 (free islets) day 4 (free islets) day 35 (encapsulated islets) BR109 Clinical Batch 4μm, 40x 14 Islet Maturation BR109 Clinical Batch Glucagon % Positive Staining per islet 50 40 30 20 10 0 d1f d4f d5e Time Point d15e d35e % Positive staining per islet % Positive Staining per islet Insulin CK7 55 50 45 40 35 30 25 20 15 10 5 0 d1f d4f d5e d15e d35e Time Point 100 75 50 25 0 d1f d4f d5e d15e d35e Time Point 15 Cell Encapsulation Cells Alginate Suspension Coating Agents Alginate 16 Capsulation Wall Integrity Wall thickness 14-18 um Immune Cells Nutrients Insulin Unacceptable capsule with compromised wall Alginate Coating PLO Alginate Islet of Langerhans 17 3-D Structure of APA Capsule Membranes Atomic Force Microscopy Pores around undulating surfaces Scans performed at the top position of the APA capsules. The undulating surface is quite homogenous and smooth with pores (Arrows) 18 APA Capsules In Vivo Stability Scanning Electron Microscopy (SEM) APA capsules retrieved from the peritoneum of model animals Capsules remain intact and without pitting defects after 215 days with ultrapure alginate (enhanced formulation) 19 Stability of APA capsules: In vivo APA capsules remained stable for more than nine months • • Enhanced Formulation: Shoulder at 1550 cm-1 associated with the amide bond of PLO layer detected as a small amplitude peak, and the carboxyl peak of the alginate component at 1590 cm-1 maintain uniformity. Baseline Formulation: Transition from day 28 to day 60, where the amount of surface pitting reaches the level to completely shift the spectrum to that of PLO. Fournier Transformed Infra Red Spectroscopy 20 Capsule Strength 21 Biocompatibility studies: APA capsules In vivo studies: Cluster of APA capsules in peritoneal cavity with high vascularization. Capsules remain clear. Viability of cells: >90% 22 STZ Diabetic Rat Study Dose Response 23 STZ Diabetic Rat Clusters of encapsulated islets showing capillary vessels on the surface 12 weeks after transplantation. 24 MH Laparoscopy 9.5 years after Transplantation 25 MH Retrieved Capsules 9 years after Transplantation H&E H&E x 10 H&E x 20 Islets inside capsules showing well structured endocrine cells. Insulin Glucagon 26 DIABECELL® Prototype Functional after 10 years 70.0 Porcine 60.0 Standards OGTT 0 Insulin uU/mL 50.0 Human OGTT 60 40.0 OGTT 120 30.0 20.0 10.0 0.0 14 14.5 15 15.5 16 16.5 Elution Time (min) In Vivo Porcine Insulin 27 DIABECELL® Phase I/IIa In Moscow 2008 This patient has had type 1 diabetes for 15 years. She has had implants of DIABECELL® and is presently off insulin injections A world first independence from injected insulin following encapsulated porcine islet implant without immunesuppression 28 DIABECELL® Phase I/IIa Clinical Trial: clinical effect at lowest dose Russia preliminary data: Open label study protocol LCT/DIA-07R Site: Sklifosovsky Institute, Moscow, Russia CRO: Geny Research, Boston, USA Principal Investigator: Prof N Skaletsky Patient # Implants Follow Up weeks Insulin Pre-enroll Insulin Change % HbA1c % Pre-enroll HbA1c % Current 1 2X 96 113 -33 7.1 6.1 2 3X 84 22 -100 8.2 7.1 3 2X 72 60 -12 10 7.4 4 2X 60 30 -10 7.6 6.5 5 2X 30 68 -29 9.8 7.2 6* 1X 20* 41 - 8.5 8.5 7 1X 18 37 -100 8.3 4.8 *Patient lost to follow-up after 20 weeks. Insulin Pre = Daily insulin dose before implant . Insulin % change = Current daily dose change from pre implant baseline HbA1c =glycated hemoglobin , an indicator of blood glucose control. 29 DIABECELL® Phase I/IIa Clinical Trials Patient R001 preliminary data: Implant Jun 2007 Retrieved Capsule Dec 2007 30 Porcine Insulin In Vivo Insulin Detection in Post HPLC Eluates Patient# 1 before and after glucagon stimulation Porcine Insulin 120 100 Insulin (Relative) 80 60 40 20 Human Insulin 0 12min 20sec 30 40 50 13 min 10 20 30 40 50 14 min 10 20 Elution Time 31 DIABECELL® : Preliminary Phase I/Ila Data Safety: • No significant adverse events. No evidence of zoonotic (animal to human) infections. Multiple implants are safe. Benefit: • Clinical benefit up to 96 weeks to date indicating no immune rejection without use of immunosuppressive drugs • Reduction in daily insulin dose . Two of seven patients off insulin • Normalized HbA1c reflecting good blood glucose control • No clinical hypoglycaemia • Micro-capsules retrieved during second implant were intact and contained live cells showing no evidence of immune injury • Detection of porcine insulin in blood indicating a functional implant Implications: • Implanted cells produce insulin in patients and provide benefit • Expect to benefit more patients with higher doses 32 NZ Government Authorization A milestone in the expansion of LCT’s clinical trial programme • The Minister of Health has authorized LCT’s clinical trial in NZ • This trial will include 8 patients to be treated with DIABECELL 4 patients - 10,000 IEQ/kg (medium dose) 4 patients - 15,000 IEQ/kg (high dose) • Aim of trial is to determine the optimum dose and confirm safety • Trial to be conducted by Dr John Baker, Clinical Director of Diabetes Program at Middlemore Hospital 33 Integrating Operations Towards Commercialization with Strategic Alliances CLINICAL DEVELOPMENT Phase I/IIa Trials 18 Patients COMMERCIAL Pivotal Data Patients N = 50 Approval of Non-Human Islet Cell Implant 2012 PIG BREEDING IN NZ 20 Sows for supply to Phase I/IIa Trials 50 Sows for supply to Pivotal Trial New Site for 500 Sows and Replicate optimum units GMP MANUFACTURING IN NZ Pilot GMP Facility 2008-2009 Scale-Up for supply to Pivotal trial 2010-11 Scale-Up & Set-Up of New Site for Product Manufacturing 2012-13 34 LCT to Scale Up to Meet Market Demand All LCT Cell Products Use Porcine Cells • • • • Scale-up is straight forward Modular facilities for stepped expansion ~Fifteen (12 – 18) piglets required for each patient Breeding program will provide sufficient cells for commercial volume within 3 yrs • 1,200 patients could be treated within 3 yrs of expansion from 100 sows Females (for breeding) Males (used for cells) Number of Patients Treatable* Year Sows Piglets 1 100 1,000 500 500 33 2 600 6,000 3,000 3,000 200 3 3,600 36,000 18,000 18,000 1,200 *The number of piglets required to treat one patient depends on the weight of the patient and the dose. 35 DIABECELL® Commercial Model LCT Manufacturer & Supplier Clinical Service Provider Diabetes Patient Breed pigs Establish Clinical Center of Excellence Consults Diabetes Physician Manufacture DIABECELL® Supply DIABECELL® Diabetes Physician refers Patients and conducts pre-implant tests Train Clinical Teams Test for potential infections and maintains implant register Negotiates re-imbursement with public or private funders Surgeon implants to LCTapproved procedure Provides Informed Consent For surgery and post Implant follow-up Blood tests at intervals as advised by Physician Surgical facilities and DIABECELL® handling and short-term storage Diabetes Physician Follow-up of recipient 36 NeurotrophinCell®: New Treatment Paradigm NTCELL Alginate encapsulated porcine choroid plexus cells • Choroid plexus cells secrete brain reparative hormones • NTCELL secretes BDNF, GDNF, NT-3 and many other neurotrophins • Neurotrophins protect brain and nerve cells from degeneration or injury • Neurotrophins recruit natural progenitor cells (stem cell like) to the site of disease and injury and enhance repair • NTCELL has been implanted in the brain of study animals and shown to be tolerated with cells surviving beyond 6 months 37 NeurotrophinCell for Neurologic Disorders • Potential treatment for Stroke, Huntington’s disease, Parkinson’s disease, brain injury, hearing loss from auditory nerve degeneration • NTCELL has shown benefit in restoring function and decreasing the size of the lesion in the Parkinson’s Disease and Stroke models in rats Huntington’s disease models in the rat and monkey Untreated Treated Rat brain sections from stroke model White areas indicate damaged brain tissue 19 38 Porcine Bio Products Cell Products Choroid Plexus Pancreatic islets Liver cells Biologics Amylases, Lipases Factor VIII, Heparin Tissues Heart valves Dermal, Collagen Small Intestine Submucosa 39 Company Structure • • • • Formed in 2003 Acquired NZ operation, IP & 17+ years of R&D Listed on ASX September 2004 Listed on OTCQX June 2008 % Shareholding • Shareholding : As at 25 May 2009 Shares held No of Holders Australia New Zealand USA Elsewhere 86,733,357 66,050,325 82,100,140 3,414,930 238,298,752 1,319 404 42 41 1,806 USA 35% Elsewhere 1% Australia 36% New Zealand 28% 40 A new bioindustry for New Zealand 41