1. Development of Cellgram & Clinical Trials
PHARMICELL
PRESENTATION
Development of Cellgram & Clinical Trials

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

3. Company
Introduction

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

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

6. Pipeline

7. GMP Facilities
Manufacturing Facilities
Quality Control Facilities

8. Concept of “SCTP” FDA (1997) KFDA (2002)
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
“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
(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
soluble factors
cell to cell interactions
matrix proteins
MSC
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
(HSC)
(MSC)
Cultured MSC
Cultured MSC
(MSC)
(HSC)
Hematopoiesis
All blood components: 1010/day
(HSC)
Support hematopoiesis
(HSC)
Marrow stromal cell / MSC
106 in bone marrow

13. Anti-Scarring(Fibrolysis)
Potency
Stem Cells homing
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
170 clinical trials
<Source>

18. Global Stem Cell Market
The global market for stem cell products was $3.8 billion in 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 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 ( )

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
Total 26,517 dead in 2010
Current treatments
fundamental treatment impossible
thrombolytic agents used to open blood vessels  treatment effects low and pertains to only 1~2% 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,Jin Soo 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 autologous mesenchymal 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 - Stroke75
Independent
Control
MSC
<50 50
50-70
>90
Barthel index (%) 25
Bed ridden
At admission 1 3 6
months
400 cases ( ), 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:

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 May;70(5):

34. Clinical Study – Spinal Cord Injury
Long-term follow-up
• 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
• Three of 10 patients with SCIs who received direct injections of autologous MSCs 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.
Conclusion
Outline
※ Ref. : Neurosurgery May;70(5):

35. Clinical Study – Spinal Cord Injury
Efficacy of stem cell therapeutics proved by Dr Sangyong 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 6,888 deaths in 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 Autologous Mesenchymal Stem Cell Injection Via Hepatic Artery in Patients with Liver Cirrhosis caused by Alcohol
(A) H&E and Masson’ Trichrome Stain
(A) TGF-b1
Pre-stem cell injection (X100)
Post-stem cell injection (X100)
Pre-
Post-
(B) Picrosirius Red Stain
(B) Collagen
Pre-stem cell injection (X100)
Post-stem cell injection (X100)
Pre-
Post-
(C) Collagen Content
(D) Laennec Scoring System
(C) a-SMA
Pre-
Post-
Pre-
Post-
Pre-
Post-
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).
Gene expression analysis by Real time PCR. Liver Fibrosis Relative gene expression of TGF-b1(A), Collagen(B) and a-SAM(C) in biopsies pre and post mesenchymal stem cell treatment.

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 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)
Single Dose Study
Repeated Dose Study
Tumorigenicity
Test Group
Negative Con. (n=40)
Test Article (n=120)
※ Low, intermediate & high dose
Negative control (n=44),
Test article (n=92, BM-MSC: Low, intermediate and high dose)
Blank (n=20)
Negative control (n=20, MRC- 5: embryonic lung fibroblast)
Test article (n=40, BM-MSC: low & high dose)
Positive control (n=20, HT-1080: fibrosarcoma)
Duration
4 weeks (1 time)
4 weeks (3 weeks/3 times)
6 months (1 time)
Result
No mortality & clinical signs
No treatment-related changes in body weight, food consumption, ophthalmoscopic exam., urinalysis, hematology, blood chemistry and organ weight
No significant macroscopic and histopathological findings
No Observed Adverse Effect Level (NOAEL): ≥ 2.1 x 10^5 cells/head (approximately 7 times of the prospected clinical dose)
There were no test substance- related effects on clinical signs, body weights, food consumption, ophthalmic examination, urinalysis, hematology, blood chemistry, organ weights, necropsy and mitogen- induced lymphocyte proliferation
No Observed Adverse Effect Level (NOAEL): ≥ 6×105 cells/head (approximately 20 times of the prospected clinical dose)
There were no treatment-related clinical signs, body weight changes, and tumorigenicity in males and females treated with the test substance at doses of 10× cells/head.
Therefore, the test substance was considered to be no tumorigenicity at doses of 10×105 cells/head
(about 40 times of the prospected clinical dose).
Source: Pharmicell Co., Ltd

43. Clinical Study - AMI LV ejection fraction 49.0 ± 11.7 55.0 ± 11.8
LVEF SPECT)
Initial
6 M
49.0 ± 11.7
55.0 ± 11.8
52.3 ± 9.3
53.9 ± 10.2
0.247
0.704
LVEF (Echo)
48.1 ± 8.0
50.0 ± 8.4
51.0 ± 9.2
50.4 ± 9.4
0.215
0.862
LVEF (CMR)
N=10
46.1 ± 15.2
51.3 ± 13.6
N=7
54.9 ± 9.6
54.6 ± 10.3
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
MSC Treatment
(N=30)
Control (N=28)
P value
P=0.037
※ Source : ACC Academic Society Reports

44. Subgroup analysis : Symptom to balloon ≤ 6h
Clinical Study - AMI
Subgroup analysis : Symptom to balloon ≤ 6h
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
MSC Treatment
(N=20)
Control (N=21)
P value
P=0.007
Further Studies
Repeat doses to evaluate dose responsiveness
Long term follow up for survival benefit
※ Source: ACC Academic Society Reports

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

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 severe fixed defect in the anterior wall.
※ Source: The Korean Society of Cardiology ‘Intervention of the Month (

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.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.
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%).
※ Source: The Korean Society of Cardiology ‘Intervention of the Month (

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

50. THANK YOU