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PHARMICELL PRESENTATION

PHARMICELL PRESENTATION. Development of Cellgram & Clinical Trials. CONTENTS. Ⅰ. COMPANY INTRODUCTION. Ⅱ. MESENCHYMAL STEM CELLS. Ⅲ. CLINICAL TRIALS. Ⅳ. CELLGRAM. Ⅴ. CASE STUDY. Company Introduction. Company Overview. Name. Foundation. Pharmicell Co.,Ltd . May 3 rd , 2002.

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PHARMICELL PRESENTATION

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  1. PHARMICELL PRESENTATION • Development of Cellgram & Clinical Trials

  2. CONTENTS Ⅰ COMPANY INTRODUCTION Ⅱ MESENCHYMAL STEM CELLS Ⅲ CLINICAL TRIALS Ⅳ CELLGRAM Ⅴ CASE STUDY

  3. Company Introduction

  4. Company Overview Name Foundation PharmicellCo.,Ltd. May 3rd, 2002 CEO Hyun-Soo Kim Capital Website www.pharmicell.com 20,843B (KRW) Employees Address 103 ppl 12F~15F, Chungho B/D, 3-2 Nonhyun-dong, Gangnam-gu, Seoul

  5. Business Area SCTP • SCTP development • Sales of HeartiCellgram-AMI • Cerebropathy therapy product • Liver disease therapy product • Spinal cord injury therapy product • Lung disease, anti-cancer therapy • product SC Cosmetics • hSC conditioned media material development and sales • hSC conditioned media cosmetics By Pharmicell Lab Business Area SC Banking • Adult SC banking (Twelve-adult) • Cord blood banking (Twelve-baby) CMO Business • CMO • Provision of SC culture media • Sales of medicine and medical • devices

  6. Pipeline

  7. GMP Facilities Manufacturing Facilities Quality Control Facilities

  8. Concept of “SCTP” KFDA (2002) FDA (1997) The FDA proposed a new approach to the regulation of human cellular and tissue-based products. Docket Number 97N-0068 (Feb. 28, 1997) The KFDA set up ‘the concept of cell therapy’ by revising “The regulation of safety & efficacy test of drug”. KFDA Notification No. 2001-35 “Cell therapy product” means a medicinal product manufactured through physical, chemical, and/or biological manipulation, such as in vitro culture of autologous, allogeneic, or xenogeneic cells. KFDA Notification No. 2010-50 (Amended on June 29, 2010) The FDA proposed the management of human-derived cells or tissues to be approached step-by-step based on the degree of given-risk to patients.

  9. Stem Cell Manufacturing Know-How • step1 • Initial Checkup(blood test) & Bone Marrow aspiration • Hospital • step2 • Mononuclear cell(MNC) separation • Grade 1A/1B • step3 Mesenchymal stem cell(MSC) separation • Grade 1A/1B • step 4 • MSC culture (P0 – P1) • Grade 1A/1B • step5 MSC culture (P2-P4 or P2-P5) • Grade 1A/1B • step6 • MSC harvest • Grade 1A/1B • step7 • Filling • Grade 1A • step8 • Packaging • Grade 2

  10. About MSCs

  11. Bone Marrow Stromal Cell (MSC) and Hematopoiesis HSC HSC MSC soluble factors cell to cell interactions matrix proteins HSC HSC MSC HSC HSC • Hematopoiesis requires an intact and fully functioning bone marrow stroma. • Cellular components of bone marrow stroma • : macrophages, endothelial cells, fibroblasts, adipocytes and osteogenic precursor cells

  12. Bone Marrow Stromal Cell (MSC) and Hematopoiesis Cultured MSC (HSC) (MSC) Cultured MSC (MSC) (HSC) Hematopoiesis All blood components: 1010/day (HSC) Support hematopoiesis (HSC) Marrow stromal cell / MSC 106 in bone marrow

  13. Potency Stem Cellshoming Angiogenesis VEGF-A ANGPT-1 TGF- β1 IL-6 PDGF-A ANG SDF-1 VEGF-A FGF-2 CCL2 SCF Stem cell Anti-apoptosis Anti-Scarring(Fibrolysis) SFRP-2 SFRP-1 Tβ4 HGF IGF-1 LIF Tβ4 FGF-2 MMP-1 MMP-2 MMP-9 TIMP-1 TIMP-2 CTGF Anti-inflammation IL-6 IL-11

  14. Minimal Criteria of MSC / Key Properties • Adherent to tissue culture flask • Positive for CD105, CD73, CD90 and negative for CD45, CD34, CD14, CD11b, CD 79a or CD19 • Ability to differentiate into osteoblasts, adipocytes and chondroblasts • Capacity of differentiation • Ability to secrete soluble factors that are crucial for cell survival and proliferation • Ability to modulate immune response • Ability to migrate to the exact site of injury

  15. MSC and Skin Regeneration

  16. MSC and Aging Process

  17. MSC Clinical Trials (worldwide) <Clinical phase> Source: Trounson et al., BMC Medicine, 2011 (As of Jan 2012, a search of www.clinicaltrials.gov) 170 clinical trials <Source>

  18. Global Stem Cell Market • The global market for stem cell products was $3.8 billion in 2011. This market is expected to reach nearly $4.3 billion in 2012 and $6.6 billion by 2016, increasing at a compound annual growth rate (CAGR) of 11.7% from 2011 to 2016. • The American market for stem cell products was $1.3 billion in 2011. This sector is expected to rise at a CAGR of 11.5% and reach nearly $2.3 billion by 2016. • The European market for stem cell products was $872 million in 2011 and is expected to reach nearly $1.5 billion by 2016, a CAGR of 10.9%. ※ Ref.: 「 Global Markets for Stem Cells 」 by BCC Research (2012. 07)

  19. Clinical Trials

  20. Clinical Study - Stroke Indication • Occurs when blood vessel to the brain is blocked and there is damage to • brain cells leading to loss of brain functions • Accompanied by speech impairment, cognitive impairment, and dyspraxia Market status • 2nd leading cause of Korean deaths, 1st in mortality rate among diseases • Total26,517 dead in 2010 Current treatments • fundamental treatment impossible • thrombolytic agents used to open blood vessels treatment effects low and pertains to only1~2%stroke patients Pharmicell research • MRI showed clear decrease in brain damage and contraction • Clear increase of ability for daily life conduct /decrease in disability • Independent walking possible after 6 months of transplant • (increase in physical ability) Commercialization • Phase III clinical trial currently under progress • Clinical results secured

  21. Clinical Study - Stroke Oh Young Bang,JinSoo Lee Department of Neurology, School of Medicine, Ajou University Background & Objective : Mesenchymal stem cell transplantation has been shown to improve functional recovery after ischaemic stroke in animal studies. We examined the feasibility, efficacy and safety of cell replacement therapy using culture-expanded autologousmesenchymal stem cells (MSCs) in patients with ischaemic stroke. Methods : After standard therapy of acute cerebral infarction, we prospectively randomised 30 patients with ischaemic stroke who had had cerebral infarcts within the middle cerebral arterial territory and shown severe neurological deficits; the MSC group, i.e. autologous 1x10(8) MSCs (the dose that was effective in animal studies) intravenous infusion (n=5), and control group (n=25). Changes in neurological deficits and functional improvement were compared between the groups, for up to one year after symptom onset. Neuroimaging was per! formed serially in 5 patients of both groups. Result : All outcomes measurements were significantly improved in patients of the MSC group compared with those of the control group; the Barthel index (P=0.01 at 3months, P=0.05 at 6months, and P=0.04 at 12months) and modified Rankin score group (P=0.04 at 3months, P=0.03 at 6months, and P=0.02 at 12months) of the MSC group were consistent in identifying a trend toward improved scores during follow-up period. Serial evaluations showed no adverse cell-related serologic or imaging-defined effects. Magnetic resonance imaging showed no evidence of mass formation, and atrophic changes around infracted area was less prominent at the follow-up imaging. Conclusions : In patients with severe cerebral infarcts, intravenous infusion of autologous MSCs appears to be feasible and safe and may beneficially affect functional recovery.

  22. Clinical Study - Stroke

  23. Clinical Study - Stroke 75 Control MSC Independent <50 50 50-70 >90 Barthel index (%) 25 Bed ridden 0 months 1 3 6 At admission 400 cases(2001-2002), Ajou University Hospital, Dept. of Neurology

  24. Clinical Study - Stroke

  25. Clinical Study - Stroke A. MRI at admission and after 1year B. CT scan at admission and after 8 months C. Size of ischemic lesion(left) and size of atrophy(right) between at admission and after follow up

  26. Clinical Study - Stroke

  27. Clinical Study - Stroke

  28. Clinical Study - Stroke ※ Ref.Stem Cells 2010;28:1099-1106

  29. Clinical Study – Multiple System Atrophy

  30. Clinical Study – Multiple System Atrophy

  31. Clinical Study – Multiple System Atrophy

  32. Clinical Study – Spinal Cord Injury Indication • The spine which connects the brain with the body becomes damaged by • trauma and causes trouble in nervous system • Partial or total loss of motor and sensory functions Market status • Due to unexpected accidents • Approximately 170,000 spinal damage patients in Korea Current treatments • Due to unexpected accidents • Approximately 170,000 spinal damage patients in Korea Pharmicell research • Observing for neurological restoration and functional • restoration (sensory functions, motor skills) Commercialization • Phase II and III human clinical trials under progress

  33. Clinical Study – Spinal Cord Injury ※ Ref. : Neurosurgery. 2012 May;70(5):1238-47

  34. Clinical Study – Spinal Cord Injury ※ Ref. : Neurosurgery. 2012 May;70(5):1238-47 Long-term follow-up Outline • • Subjects : 10 • • Inclusion Criteria : ASIA A or B • • F/U : max. 55 months • • Administration (total 9.8 X107 cells) 8X106 cells –spinal cord (intramedullary) 4X107 cells – intradural space 5X107 cells – lumbar tapping • • Assessments : motor power grade MRI electorphysiological recording Patient 1 Conclusion • • Three of 10 patients with SCIs who received direct injections of autologousMSCs showed continuous and gradual motor improvements in the upper extremities and significant MRI and electrophysiological changes during long-term F/U. • • Direct intramedullary injection of MSCs into SCI patients did not results in permanent complications.

  35. Clinical Study – Spinal Cord Injury Efficacy of stem cell therapeutics proved by DrSangyong Chun, from Seoul Asan Hospital, from a quadriplegic Dr Chun is checking the muscle of the patient, Park, who got better after an autologous stem cell treatment

  36. Clinical Study – Alcoholic Liver Cirrhosis Indication • Liver hardens due to excessive drinking and chronic hepatitis • leading High mortality because of complications to liver failure Market status • Ranked as 8th cause of death among Koreans • No. 1 cause of death for men in their 40-50s • Total 6,888deathsin 2010 Current treatments • Damaged liver cannot be repaired • Liver transplant is the only viable option but • lack of donated livers for transplant / immunorejection / high costs Pharmicell research • Hardness of liver clearly decreased • Index showing improvement of liver function clearly increased • Confirmed liver tissue regeneration to improve • liver function and decrease complications Commercialization • IIT complete • Preparing IND approval data necessary for commercialization • Expect to supply products at ¼ the cost of liver transplants

  37. Clinical Study – Alcoholic Liver Cirrhosis Efficacy of Bone Marrow derived AutologousMesenchymal Stem Cell Injection Via Hepatic Artery in Patients with Liver Cirrhosis caused by Alcohol (A) TGF-b1 (A) H&E and Masson’ Trichrome Stain Pre-stem cell injection (X100) Post-stem cell injection (X100) Post- Pre- (B) Picrosirius Red Stain (B) Collagen Pre-stem cell injection (X100) Post-stem cell injection (X100) Post- Pre- (C) Collagen Content (D) Laennec Scoring System (C) a-SMA Post- Pre- Pre- Post- Pre- Post- Gene expression analysis by Real time PCR. Liver Fibrosis Relative gene expression of TGF-b1(A), Collagen(B) and a-SAM(C) inbiopsies pre and post mesenchymal stem cell treatment. Liver biopsy and histomorphological analysis at pre treatment and post treatment. Mild. The biopsies evaluated the degree of fibrosis(A,B and C) and Cirrhotic change according to the Laennec System(D).

  38. Global Market Size for Liver Disease • In 2009, the global market for drugs used to treat liver disease was worth approximately $12.4 billion. Sales in 2010 decreased and the market did not see much progress, causing overall global sales to remain stagnant at $12.4 billion. Estimated sales in 2011 a projected $12 billion (excluding protease inhibitors).  The market is expected to rise at a CAGR of 3.3% and reach nearly $14.2 billion by 2016. • The U.S. region constituted approximately 36% of the total market for drugs used to treat liver disease in 2010 and was valued at $4.5 billion. In 2011, the market continued to decrease and will hit nearly $4.2 billion. BCC expects this market to increase in the future rising at a CAGR of 3% to reach nearly $4.9 billion by 2016. • The European market constituted approximately 31% of the total market and was $3.8 billion in 2010. This market is expected to see a decrease in 2011 totaling nearly $3.6 billion. This market is forecast to grow at a CAGR of 1% and should be worth $3.7 billion by 2016.

  39. About Cellgram

  40. The World’s First Stem Cell Therapy Product

  41. Basic Understanding of SCTP Actual Procedure Stem cells in the body Extract stem cells Cultivate (stem cell itself, Cellgram) Inject into body regeneration in body at injured organs Improved Damaged Part The Infusion Route (percutaneous coronary intervention)

  42. Toxicology Study (injection route: iv) Source: Pharmicell Co., Ltd

  43. Clinical Study - AMI LV ejection fraction MSC Treatment (N=30) Control(N=28) P value P=0.037 49.0 ± 11.7 55.0 ± 11.8 52.3 ± 9.3 53.9 ± 10.2 LVEF SPECT) Initial 6 M 0.247 0.704 48.1 ± 8.0 50.0 ± 8.4 51.0 ± 9.2 50.4 ± 9.4 LVEF (Echo) Initial 6 M 0.215 0.862 N=10 46.1 ± 15.2 51.3 ± 13.6 N=7 54.9 ± 9.6 54.6 ± 10.3 LVEF (CMR) Initial 6 M 0.197 0.591 Change of LVEF % SPECT Echo Cardiac MR 5.9 ± 8.5 1.9 ± 2.7 5.2 ± 7.6 1.6 ± 7.0 -0.5 ± 1.8 -0.3 ± 0.9 0.037 <0.001 0.049 ※ Source : 2011 ACC Academic Society Reports

  44. Clinical Study - AMI Subgroup analysis : Symptom to balloon ≤ 6h MSC Treatment (N=20) Control(N=21) P value P=0.007 LVEF SPECT) Initial 6 M 46.7 ± 10.5 55.0 ± 11.5 51.0 ± 8.7 52.3 ± 8.9 0.165 0.398 Change of LVEF % SPECT 8.3 ± 8.3 1.3 ± 7.5 0.007 Further Studies Repeat doses to evaluate dose responsiveness Long term follow up for survival benefit ※ Source: 2011 ACC Academic Society Reports

  45. Clinical Ref. Overview - AMI • A LVEF of 40% was an important predictor of 3-year mortality (hazard ratio [HR] 6.02, 95% confidence interval [CI] 3.68 to 9.85, p 0.001). ※ Source: Am J Cardiol. 2010 Jun 1;105(11):1528-34. Epub 2010 Apr 14.

  46. Case Study (June 2012) • The initial electrocardiogram showed ST segment elevation in the anterior leads. • Transthoracic Echocardiography demonstrated akinesia in the anterior wall with a decreased left ventricular systolic function (EF=38.4%). • Baseline coronary angiography (CAG) revealed a total occlusion in proximal left anterior descending artery(LAD) and no critical stenosis in other coronary arteries (Fig. 2). Fig.1 The electrocardiogram showed ST-segment elevation in leads of V1-V5. Fig.2 Baseline coronary angiogram showed total occlusion in the proximal left anterior descending artery. ※ Source: The Korean Society of Cardiology ‘Intervention of the Month 2012. 06 (http://www.circulation.or.kr)

  47. Case Study (June 2012) • Baseline M-SPECT showed moderate LV dysfunction (EF=33%) with large severe fixed defect in the anterior wall (Fig. 4). • One month after percutaneous coronary intervention, his stem cell therapy was done. • Follow up CAG showed a patent stent in p-LAD. Fig.3 Percutaneous coronary intervention was performed in left anterior descending artery using 3.0x34 mm Resolute Integrity®. Fig.4 Baseline M-SPECT showed moderate left ventricular dysfunction(Ejection fraction=33%) with large severefixed defect in the anterior wall. ※ Source: The Korean Society of Cardiology ‘Intervention of the Month 2012. 06 (http://www.circulation.or.kr)

  48. Case Study (June 2012) • Subsequently, we performed ballooning twice every 30 seconds to temporarily induce occlusion of coronary blood flow (Fig. 5). • At this important point, stem cells should not be exposed with contrast because of its toxicity. • Three months later, follow up M-SPECT showed markedly reduced size of infarcted myocardium and improvement in a left ventricular systolic function (EF=44%, almost 11%↑) (Fig. 6). Fig.6 Three months later, follow-up M-SPECT showed markedly reduced size of infarcted myocardium and improved left ventricular systolic function (Ejection fraction=44%). Fig.5 A Helios balloon catheter (OSCAR Inc.) was located in proximal site of stent, and then stem cell culture medium was infused via intracoronary. Subsequently, we performed ballooning every 30 seconds twice for temporarily induced occlusion of coronary blood flow. ※ Source: The Korean Society of Cardiology ‘Intervention of the Month 2012. 06 (http://www.circulation.or.kr)

  49. Expanding Indications Myocardial Infarction Liver Disease Burn Injury Cerebropathy Anti-aging 탈모방지 및 모발재생 hBM-MSCs Anti-aging 심근경색 화상치료 유방재건 Click to add text Breast reconstruction Spinal Cord Injury 퇴행성뇌질환 시각장애 척수손상 자가면역질환 Diabetes Hair loss By Dendritic Cell 당뇨병 Auto Immune Disease Visual Impairment 간질환 암질환 Cancer

  50. THANKYOU

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